Disease trajectories in interstitial lung diseases - data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression. RESULTS: Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001). CONCLUSION: Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.

Hospitalisation patterns in interstitial lung diseases: data from the EXCITING-ILD registry.

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection. RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005). CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.

[Patient safety 4.0: "Failure of the Week" It's all about role modelling!] / Patient*innen-Sicherheit 4.0: "Fehler der Woche" ­ Um die Vorbildfunktion geht's!

BACKGROUND: The rate of mistakes and near misses in clinical medicine remains staggering. The tendency to cover up mistakes is rampant in "name-blame-shame" cultures. The need for safe forums where mistakes can be openly discussed in the interest of patient safety is evident. Following a comprehensive review of the literature, a semi-structured weekly conference, named "mistake of the week" (MOTW), was introduced, enabling physicians to voluntarily discuss their mistakes and near-misses. The MOTW is intended to encourage cultural change in how physicians approach, process, accept and learn from their own and their peers' mistakes. This study seeks to assess if physicians appreciate, benefit from and are motivated to participate in MOTW. METHODS: Physicians and medical students of the I. and II. Medizinische Klinik at the Academic Teaching Hospital Klinikum Konstanz (Germany) were eligible to participate voluntarily. Four groups of physicians (n=3-6) and one group of medical students (n=5) volunteered to participate in focus group interviews, which were videotaped, transcribed and analyzed. RESULTS: The following success factors are crucial for dealing with and voluntarily disclosing mistakes and near-misses: 1. Exemplification ("follow the boss's lead"), 2. Fixed time slots and a clear forum, 3. Reporting mistakes without fear of penalty or punishment, 4. A trusting working atmosphere. The key effects of the MOTW approach are: 1. People report their mistakes more, 2. Relief, 3. Psychological safety, 4. Lessons learned/errors (potentially) reduced. DISCUSSION: The MOTW conference models an ideal forum to mitigate hierarchy and promote a sustainable organizational dynamic in which mistakes and near misses can be discussed in an environment free from "name-blame-shame", with the ultimate goal of potentially improving patient care and safety.

Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.

BACKGROUND: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients. METHODS: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension). FINDINGS: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). INTERPRETATION: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration. FUNDING: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Heart Failure Results in Inspiratory Muscle Dysfunction Irrespective of Left Ventricular Ejection Fraction.

BACKGROUND: Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) results from both cardiac dysfunction and skeletal muscle weakness. Respiratory muscle dysfunction with restrictive ventilation disorder may be present irrespective of left ventricular ejection fraction and might be mediated by circulating pro-inflammatory cytokines. OBJECTIVE: To determine lung and respiratory muscle function in patients with HFrEF/HFpEF and to determine its associations with exercise intolerance and markers of systemic inflammation. METHODS: Adult patients with HFrEF (n = 22, 19 male, 61 ± 14 years) and HFpEF (n = 8, 7 male, 68 ± 8 years) and 19 matched healthy control subjects underwent spirometry, measurement of maximum mouth occlusion pressures, diaphragm ultrasound, and recording of transdiaphragmatic and gastric pressures following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. New York Heart Association (NYHA) class and 6-min walking distance (6MWD) were used to quantify exercise intolerance. Levels of circulating interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using ELISAs. RESULTS: Compared with controls, both patient groups showed lower forced vital capacity (FVC) (p < 0.05), maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) (p < 0.05), diaphragm thickening ratio (p = 0.01), and diaphragm strength (twitch transdiaphragmatic pressure in response to supramaximal cervical magnetic phrenic nerve stimulation) (p = 0.01). In patients with HFrEF, NYHA class and 6MWD were both inversely correlated with FVC, PImax, and PEmax. In those with HFpEF, there was an inverse correlation between amino terminal pro B-type natriuretic peptide levels and FVC (r = -0.77, p = 0.04). In all HF patients, IL-6 and TNF-α were statistically related to FVC. CONCLUSIONS: Irrespective of left ventricular ejection fraction, HF is associated with respiratory muscle dysfunction, which is associated with increased levels of circulating IL-6 and TNF-α.

Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy.

INTRODUCTION: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp). METHODS: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS). RESULTS: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147). CONCLUSIONS: METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.

Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry.

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.

Inspiratory muscle dysfunction and restrictive lung function impairment in congenital heart disease: Association with immune inflammatory response and exercise intolerance.

BACKGROUND: In adult patients with congenital heart disease (ACHD), both underlying disease and lung restriction contribute to exercise intolerance. In ACHD the yet incompletely understood mechanism underlying restricted ventilation may be inspiratory muscle weakness. Therefore, this study comprehensively evaluated inspiratory muscle function in ACHD and associations with systemic inflammation and the clinical severity of exercise intolerance. METHODS: 30 ACHD patients (21 men, 35 ± 12 years) and 30 healthy controls matched for age, gender and body mass index underwent spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound. Six-minute walking distance (6MWD) and New York Heart Association functional class were used to quantify exercise intolerance. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assays. RESULTS: ACHD patients showed lower forced vital capacity (FVC), and maximum inspiratory (PImax) and expiratory (PEmax) pressures compared with controls (all p < 0.05). On ultrasound, ACHD patients showed a lower diaphragm thickening ratio (2.3 ± 0.5 vs. 2.8 ± 0.9, p < 0.01) and lower diaphragm excursion velocity during a voluntary sniff maneuver (5.7 ± 2.2 vs. 7.6 ± 2.0 cm/s, p < 0.01). Respiratory parameters, such as FVC (r = 0.53; p < 0.01) and PImax (r = 0.43; p = 0.02), correlated with 6MWD. Furthermore, amino terminal pro B-type natriuretic peptide levels were inversely correlated with FVC (r = -0.54; p < 0.01). Circulating pro-inflammatory cytokines were markedly increased, and IL-6 was correlated with 6MWD, dyspnea, and biomarkers of heart, lung and inspiratory muscle function (all p < 0.05). CONCLUSIONS: Our findings show that diaphragm dysfunction is present in ACHD and relates to restrictive ventilation disorder and exercise intolerance, possibly mediated by increased IL-6 levels.

Respiratory Muscle and Lung Function in Lung Allograft Recipients: Association with Exercise Intolerance.

BACKGROUND: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). OBJECTIVE: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs. METHODS: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays. RESULTS: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H2O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H2O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02). CONCLUSION: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.

General measures and supportive therapy for pulmonary arterial hypertension: Updated recommendations from the Cologne Consensus Conference 2018.

In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines aiming at their practical implementation, considering country-specific issues, and including new evidence, where available. To this end, a number of working groups was initiated, one of which was specifically dedicated to general measures (i.e. physical activity/supervised rehabilitation, pregnancy/contraception, elective surgery, infection prevention, psychological support, travel) and supportive therapy (i.e. anticoagulants, diuretics, oxygen, cardiovascular medications, anaemia/iron deficiency, arrhythmias) for PAH. While the European guidelines provide detailed recommendations for the use of targeted PAH therapies as well as supportive care, detailed treatment decisions in routine clinical care may be challenging, and the relevance of supportive care is often not sufficiently considered. In addition, new evidence became available, thus requiring a thorough reevaluation of specific recommendations. The detailed results and recommendations of the working group on general measures and supportive therapy for PAH, which were last updated in the spring of 2018, are summarized in this article.

Sedation during flexible bronchoscopy in patients with pre-existing respiratory failure: Midazolam versus Midazolam plus Alfentanil.

BACKGROUND: The use of sedation during flexible bronchoscopy (FB) is undisputed; however, the combination of benzodiazepines and opiates, although reasonable, is suggested to cause hypoventilation, particularly in patients with pre-existing respiratory failure. OBJECTIVES: To assess respiratory function during FB. METHODS: Transcutaneous PCO(2 )(PtcCO(2)), oxygen saturation, patients' tolerance, time after FB until recovery and application of drug dosage were assessed in patients receiving either midazolam with alfentanil (n = 15) or midazolam alone (n = 15) for sedation for FB. RESULTS: There were no differences in PtcCO(2) values during FB between the two groups (all p > 0.05). However, PtcCO(2 )significantly increased over time in both groups (both p < 0.001; RM-ANOVA on ranks). Minimum oxygen saturation (SaO(2)) [89 (interquartile range 79.8/92.8) vs. 86 (interquartile range 82.3/87.8)%; p = 0.46] and the duration until recovery, i.e., achieving an ALDRETE score of > or =9 [30 (interquartile range 10/90) vs. 10 (interquartile range 10/105) min; p = 0.68] were comparable for monosedation and combined sedation, respectively. The total amount of midazolam [4.0 (interquartile range 4.0/4.0) vs. 2.0 (interquartile range 2.0/2.0) mg; p < 0.001] was lower in patients receiving combined sedation. Significantly lower scores for pain and asphyxia, and a clear tendency to less nausea and cough were reported by patients receiving combined sedation. CONCLUSIONS: Combined sedation during FB produced a comparable degree of desaturation and hypoventilation, and is associated with a comparable time to full recovery compared to monosedation in patients with pre-existing respiratory failure. Importantly, FB using combined sedation is better tolerated by patients despite only 50% midazolam consumption.