Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Mepolizumab in a population with severe eosinophilic asthma and corticosteroid dependence: results from a French early access programme.

BACKGROUND: Mepolizumab was available in France as part of an early access programme for patients with severe eosinophilic asthma (nominative autorisation temporaire d'utilisation [temporary use authorisation] (nATU)) before its commercialisation. This study aimed to characterise patients who received mepolizumab in the nATU. METHODS: This retrospective, observational study analysed data from the hospital medical records of patients up to 24 months after treatment initiation. Study objectives were to describe patient baseline characteristics, the evolution of disease severity and treatment modifications during follow-up; safety was also investigated. FINDINGS: Overall, 146 patients who received ≥1 dose of mepolizumab were included. At inclusion, patients had a mean age of 58.2 years with a mean severe asthma duration of 13.4 years, and 37.0% had respiratory allergies. Patients experienced, on average, 5.8 exacerbations per patient per year at baseline, 0.6 and 0.5 of which required hospitalisation and emergency department visits, respectively. These values improved to 0.6, 0.1 and 0.1 exacerbations per patient per year, respectively, at 24 months of follow-up. Most patients (92.8%) were using oral corticosteroids at baseline, compared with 34.7% by 24 months of follow-up. Moreover, mean blood eosinophil counts improved from 722 cells·µL-1 at baseline to 92 cells·µL-1 at 24 months of follow-up; lung function and asthma control followed a similar trend. INTERPRETATION: Results confirm findings from clinical trials, demonstrating that mepolizumab is associated with important improvements in several clinically meaningful outcomes and has a favourable safety profile in a population with severe eosinophilic asthma, outside of the controlled environment of a clinical trial.

Intensity and quality of exertional dyspnoea in patients with stable pulmonary hypertension.

Dynamic hyperinflation is observed during exercise in 60% of patients with clinically stable pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), intensifying exertional dyspnoea. The impact of dynamic changes in respiratory mechanics during exercise on qualitative dimensions of dyspnoea in these patients has not been evaluated.26 patients (PAH n=17; CTEPH n=9) performed an incremental symptom-limited cycle exercise test. Minute ventilation (V'E), breathing pattern, operating lung volumes and dyspnoea intensity were assessed throughout exercise. Dyspnoea quality was serially assessed during exercise using a three-item questionnaire (dyspnoea descriptors). The inflection point of tidal volume (V T) relative to V'E was determined for each incremental test. Changes in inspiratory capacity during exercise defined two groups of patients: hyperinflators (65%) and non-hyperinflators (35%). Multidimensional characterisation of dyspnoea was performed after exercise using the Multidimensional Dyspnea Profile.In hyperinflators, inspiratory capacity decreased progressively throughout exercise by 0.36 L, while remaining stable in non-hyperinflators. The "work/effort" descriptor was most frequently selected throughout exercise in both types of patients (65% of all responses). At the V T/V'E inflection, work/effort plateaued while "unsatisfied inspiration" descriptors became selected predominantly only in hyperinflators (77% of all responses). In the affective domain, the emotion most frequently associated with dyspnoea was anxiety.In pulmonary hypertension patients who develop hyperinflation during exercise, dyspnoea descriptors referring to unsatisfied inspiration become predominant following the V T/V'E inflection. As these descriptors are generally associated with more negative emotional experiences, delaying or preventing the V T/V'E inflection may have important implications for symptom management in patients with pulmonary hypertension.

Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort.

BACKGROUND: Dupilumab is a monoclonal anti-IL-4Rα antibody developed for the treatment of severe asthma (SA). An early access programme for dupilumab was opened in France in SA patients experiencing unacceptable steroids side-effects and/or life-threatening exacerbations. OBJECTIVE: To assess changes in asthma control between baseline and 12 months of treatment. METHODS: Multi-centre (n = 13) retrospective real-life cohort study. This study is registered on ClinicalTrials.gov (NCT04022447). RESULTS: Overall, 64 patients with SA (median age 51, interquartile range [44-61]; 53% females) received dupilumab as add-on therapy to maximal standard of care; and 76% were on oral daily steroids at baseline. After 12 months, median asthma control test score improved from 14 [7-16] to 22 [17-24] (P < .001); median forced expiratory volume in 1 seconds increased from 58% [47-75] to 68% [58-88] (P = .001); and daily prednisone dose was reduced from 20 [10-30] to 5 [0-7] mg/d (P < .001). Annual exacerbations decreased from 4 [2-7] to 1 [0-2] (P < .001). Hypereosinophilia ≥1500/mm3 was observed at least once during follow-up in 16 patients (25%), persisting after 6 months in 8 (14%) of them. Increase in blood eosinophil count did not modify the clinical response during the study period. Injection-site reaction was the most common side effect (14%). Three deaths were observed, none related to treatment by investigators. CONCLUSION & CLINICAL RELEVANCE: In this first real-life cohort study of predominantly steroid-dependent SA, dupilumab significantly improved asthma control and lung function and reduced oral steroids use and exacerbations rate. Despite limitations due to the retrospective study, these results are consistent with controlled trials efficacy data. Further studies are required to assess the clinical significance and long-term prognosis of sustained dupilumab-induced hypereosinophilia.

Outpatient pulmonary rehabilitation for severe asthma with fixed airway obstruction: Comparison with COPD.

Background: The benefit of exercise has been demonstrated in asthma, but the role of pulmonary rehabilitation (PR) in people with severe asthma, especially with airway obstruction, has been less investigated. The activity limitation mechanisms differ in asthma and COPD, so the effect of a PR program not specific to asthma is unclear. Methods: We retrospectively compared the effect of an ambulatory PR program in nonsmoking patients with severe asthma and airway obstruction (FEV1/FVC ratio <70% and FEV1 < 80% measured twice, not under an exacerbation) and sex-, age-, FEV1-, and BMI-matched COPD controls. Results: We included 29 patients, each with asthma and COPD. Airway obstruction was moderate (median FEV1 57% [44-64]). VO2 at peak was higher for asthma than COPD patients (19.0 [15.7-22.2] vs 16.1 [15.3-19.6] ml.min-1.kg-1, p = 0.05). After PR, asthma and COPD groups showed a significant and similar increase in constant work cycling test of 378 [114-831] s and 377 [246-702] s. Changes in Hospital Anxiety and Depression Scale (HAD) total score were similar (-2.5 [-7.0 to 0.0] vs -2.0 [-5.0 to 2.0], p > 0.05). Quality of life on the St. George's Respiratory Questionnaire (SGRQ) was significantly improved in both groups (-14.0 [-17.7 to -2.0], p < 0.005 and -8.3 [-13.0 to -3.6], p < 0.0001). Conclusion: Outpatient PR is feasible and well tolerated in patients with severe asthma with fixed airway obstruction. A nondedicated program strongly improves HAD and SGRQ scores and constant work-rate sub-maximal cycling, with similar amplitude as with COPD.

Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space.

The lungs and heart are irrevocably linked in their oxygen (O2) and carbon dioxide (CO2) transport functions. Functional impairment of the lungs often affects heart function and vice versa The steepness with which ventilation (V'E) rises with respect to CO2 production (V'CO2 ) (i.e. the V'E/V'CO2 slope) is a measure of ventilatory efficiency and can be used to identify an abnormal ventilatory response to exercise. The V'E/V'CO2 slope is a prognostic marker in several chronic cardiopulmonary diseases independent of other exercise-related variables such as peak O2 uptake (V'O2 ). The V'E/V'CO2 slope is determined by two factors: 1) the arterial CO2 partial pressure (PaCO2 ) during exercise and 2) the fraction of the tidal volume (VT) that goes to dead space (VD) (i.e. the physiological dead space ratio (VD/VT)). An altered PaCO2 set-point and chemosensitivity are present in many cardiopulmonary diseases, which influence V'E/V'CO2 by affecting PaCO2 Increased ventilation-perfusion heterogeneity, causing inefficient gas exchange, also contributes to the abnormal V'E/V'CO2 observed in cardiopulmonary diseases by increasing VD/VT During cardiopulmonary exercise testing, the PaCO2 during exercise is often not measured and VD/VT is only estimated by taking into account the end-tidal CO2 partial pressure (PETCO2 ); however, PaCO2 is not accurately estimated from PETCO2 in patients with cardiopulmonary disease. Measuring arterial gases (PaO2 and PaCO2 ) before and during exercise provides information on the real (and not "estimated") VD/VT coupled with a true measure of gas exchange efficiency such as the difference between alveolar and arterial O2 partial pressure and the difference between arterial and end-tidal CO2 partial pressure during exercise.

Neurophysiological Evidence for a Cortical Contribution to the Wakefulness-Related Drive to Breathe Explaining Hypocapnia-Resistant Ventilation in Humans.

Spontaneous ventilation in mammals is driven by automatic brainstem networks that generate the respiratory rhythm and increase ventilation in the presence of increased carbon dioxide production. Hypocapnia decreases the drive to breathe and induces apnea. In humans, this occurs during sleep but not during wakefulness. We hypothesized that hypocapnic breathing would be associated with respiratory-related cortical activity similar to that observed during volitional breathing, inspiratory constraints, or in patients with defective automatic breathing (preinspiratory potentials). Nineteen healthy subjects were studied under passive (mechanical ventilation, n = 10) or active (voluntary hyperventilation, n = 9) profound hypocapnia. Ventilatory and electroencephalographic recordings were performed during voluntary sniff maneuvers, normocapnic breathing, hypocapnia, and after return to normocapnia. EEG recordings were analyzed with respect to the ventilatory flow signal to detect preinspiratory potentials in frontocentral electrodes and to construct time-frequency maps. After passive hyperventilation, hypocapnia was associated with apnea in 3 cases and ventilation persisted in 7 cases (3 and 6 after active hyperventilation, respectively). No respiratory-related EEG activity was observed in subjects with hypocapnia-related apneas. In contrast, preinspiratory potentials were present at vertex recording sites in 12 of the remaining 13 subjects (p < 0.001). This was corroborated by time-frequency maps. This study provides direct evidence of a cortical substrate to hypocapnic breathing in awake humans and fuels the notion of corticosubcortical cooperation to preserve human ventilation in a variety of situations. Of note, maintaining ventilatory activity at low carbon dioxide levels is among the prerequisites to speech production insofar as speech often induces hypocapnia. SIGNIFICANCE STATEMENT: Human ventilatory activity persists, during wakefulness, even when hypocapnia makes it unnecessary. This peculiarity of human breathing control is important to speech and speech-breathing insofar as speech induces hypocapnia. This study evidences a specific respiratory-related cortical activity. This suggests that human hypocapnic breathing is driven, at least in part, by cortical mechanisms similar to those involved in volitional breathing, in breathing against mechanical constraints or with weak inspiratory muscle, and in patients with defective medullary breathing pattern generators. This fuels the notion that the human ventilatory drive during wakefulness often results from a corticosubcortical cooperation, and opens new avenues to study certain ventilatory and speech disorders.

An official European Respiratory Society statement: pulmonary haemodynamics during exercise.

There is growing recognition of the clinical importance of pulmonary haemodynamics during exercise, but several questions remain to be elucidated. The goal of this statement is to assess the scientific evidence in this field in order to provide a basis for future recommendations.Right heart catheterisation is the gold standard method to assess pulmonary haemodynamics at rest and during exercise. Exercise echocardiography and cardiopulmonary exercise testing represent non-invasive tools with evolving clinical applications. The term "exercise pulmonary hypertension" may be the most adequate to describe an abnormal pulmonary haemodynamic response characterised by an excessive pulmonary arterial pressure (PAP) increase in relation to flow during exercise. Exercise pulmonary hypertension may be defined as the presence of resting mean PAP <25 mmHg and mean PAP >30 mmHg during exercise with total pulmonary resistance >3 Wood units. Exercise pulmonary hypertension represents the haemodynamic appearance of early pulmonary vascular disease, left heart disease, lung disease or a combination of these conditions. Exercise pulmonary hypertension is associated with the presence of a modest elevation of resting mean PAP and requires clinical follow-up, particularly if risk factors for pulmonary hypertension are present. There is a lack of robust clinical evidence on targeted medical therapy for exercise pulmonary hypertension.

Novel targets of omalizumab in asthma.

PURPOSE OF REVIEW: Omalizumab is a recombinant humanized anti-IgE monoclonal antibody approved in the US for moderate to severe persistent allergic asthma (severe persistent asthma in the European Union), uncontrolled despite treatment with inhaled corticosteroids and long-acting beta2 agonists. It reduces asthma exacerbations, symptoms, oral corticosteroid doses, and improves quality of life. RECENT FINDINGS: Omalizumab may have an antiviral effect when used as a preventive therapy for fall exacerbations in children and teenagers. Two proof-of-concept studies have evaluated omalizumab in nonatopic asthma and showed that it is safe and possibly efficacious in some patients. Omalizumab has been successfully studied as add-on to specific immunotherapy in moderate allergic asthma. Its safety in pregnancy has been assessed in the EXPECT registry. Case series also report positive effects in cases of allergic bronchopulmonary aspergillosis, and in nasal disorders frequently associated with asthma. Last, omalizumab may have corticosteroid-sparing effect in a subset of patients with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). SUMMARY: Recent studies argue in favor of positive effects of omalizumab beyond its current indications in asthma. Well-designed studies are needed in order to demonstrate the safety and efficacy of omalizumab in these possible novel indications.

Pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients.

Severe asthma care trajectories: the French RAMSES cohort.

Background: The French RAMSES study is an observational prospective multicentre real-life cohort including severe asthmatic subjects. The objective of the study was to compare the characteristics of patients, in terms of phenotype and asthma care trajectories, between those managed by tertiary referral centres (TRCs) or secondary care centres (SCCs). Methods: Patients were prospectively recruited and enrolled for a 5-year follow-up. Patients' characteristics were analysed at inclusion and compared between TRCs and SCCs. Results: 52 centres (24 TRCs and 28 SCCs) included 2046 patients: 1502 (73.4%) were included by a TRC and 544 (26.6%) by a SCC. Patients were mainly women (62%), 53±15 years old, 67% with Asthma Control Test <20; at inclusion, 14% received oral corticosteroids (OCS) and 66% biologics. Compared with the SCC group, the TRC group had more frequent comorbidities and lower blood eosinophil counts (262 versus 340 mm-3; p=0.0036). OCS and biologics use did not differ between groups, but patients in the TRC group benefited more frequently from an educational programme (26% versus 18%; p=0.0008) and received more frequently two or more sequential lines of biologics (33% versus 24%; p=0.0105). In-depth investigations were more frequently performed in the TRC group (allergy tests: 74% versus 62%; p<0.0001; exhaled nitric oxide fraction: 56% versus 21%; p<0.0001; induced sputum: 6% versus 3%; p=0.0390). Conclusions: Phenotypes and care trajectories differed in the RAMSES cohort between SCCs and TRCs, probably related to different levels of asthma severity and differences in medical resources and practices among centres. This highlights the need for standardisation of severe asthma care.

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma.

BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).

Dynamic respiratory mechanics and exertional dyspnoea in pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension (PAH) may exhibit reduced expiratory flows at low lung volumes, which could promote exercise-induced dynamic hyperinflation (DH). This study aimed to examine the impact of a potential exercise-related DH on the intensity of dyspnoea in patients with PAH undergoing symptom-limited incremental cardiopulmonary cycle exercise testing (CPET). 25 young (aged mean±sd 38±12 yrs) nonsmoking PAH patients with no evidence of spirometric obstruction and 10 age-matched nonsmoking healthy subjects performed CPET to the limit of tolerance. Ventilatory pattern, operating lung volumes (derived from inspiratory capacity (IC) measurements) and dyspnoea intensity (Borg scale) were assessed throughout CPET. IC decreased (i.e. DH) progressively throughout CPET in PAH patients (average 0.15 L), whereas it increased in all the healthy subjects (0.45 L). Among PAH patients, 15 (60%) exhibited a decrease in IC throughout exercise (average 0.50 L), whereas in the remaining 10 (40%) patients IC increased (average 0.36 L). Dyspnoea intensity and ventilation were greater in PAH patients than in controls at any stage of CPET, whereas inspiratory reserve volume was lower. We conclude that DH-induced mechanical constraints and excessive ventilatory demand occurred in these young nonsmoking PAH patients with no spirometric obstruction and was associated with exertional dyspnoea.

Dyspnea-induced Limitation (DYSLIM), a new self-administered concise questionnaire to evaluate dyspnea-related activity limitation in chronic respiratory diseases.

BACKGROUND AND AIM: Few questionnaires are available for routine assessment of dyspnea. The study aimed to design a self-administered questionnaire assessing the impact of chronic dyspnea on daily activities, named DYSLIM (Dyspnea-induced Limitation). METHODS: The development followed 4 steps: 1: selection of relevant activities and related questions (focus groups); 2: clinical study: internal and concurrent validity vs. modified Medical Research Council (mMRC), Baseline Dyspnea Index (BDI) and Saint George Respiratory Questionnaire (SGRQ); 3: item reduction; 4: responsiveness. Eighteen activities (from eating to climbing stairs) were considered with 5 modalities for each: doing the task slowly, taking breaks, seeking assistance, changing habits, and activity avoidance. Each modality was graded from 5 (never) to 1 (very often). Validation study included 194 patients: COPD (FEV1 ≥ 50% pred: n = 40; FEV1 < 50% pred: n = 65); cystic fibrosis (n = 30), interstitial lung disease (n = 30), pulmonary hypertension (n = 29). Responsiveness was evaluated by post-pulmonary rehabilitation data in 52 COPD patients. RESULTS: Acceptability was high and short term (7 days) reproducibility was satisfactory (Kappa mostly above 0.7). Concurrent validity was high vs. mMRC (Spearman correlation coefficient, r = 0.71), BDI (r = - 0.75) and SGRQ (r = - 0.79). The reduced questionnaire with 8 activities (from cleaning to climbing stairs) and 3 modalities (slowly, seeking help, changing habits) showed a comparable validity and was chosen as the final short version. Effect size of rehabilitation was good for both the full (0.57) and short (0.51) versions. A significant correlation was also found between changes of SGRQ and DYSLIM post rehabilitation: r = - 0.68 and r = - 0.60 for full and reduced questionnaires, respectively. CONCLUSION: The DYSLIM questionnaire appears promising for the evaluation of dyspnea-induced limitations in chronic respiratory diseases and seems suitable for use in various contexts.

Severity and phenotypes of dyspnea in asthma: Impact of comorbidities.

BACKGROUND: Dyspnea is a common but non-specific symptom of asthma, which in particular may be related to anxiety and hyperventilation syndrome, two frequent comorbidities of asthma. METHODS: We conducted a prospective multicentric cohort study in dyspneic asthmatic adults. Dyspnea was assessed using the Multidimensional Dyspnea Profile questionnaire. We described the sensory (QS) and affective (A2) domains of dyspnea and investigated the effect of poor asthma control, hyperventilation and anxiety on each dimension at baseline and after 6 months. RESULTS: We included 142 patients (65.5% women, age: 52 years). Dyspnea was severe and predominated on its sensory domain (median QS: 27/50; A2: 15/50). Uncontrolled asthma (ACQ≥1.5), hyperventilation symptoms (Nijmegen≥23) and anxiety (HAD-A≥10) were present in 75%, 45.7% and 39% of cases, respectively. Hyperventilation symptoms were associated with higher QS and A2 scores: QS at 28.4(10.7) vs. 21.7(12.8) (p = 0.001) and A2 at 24(14) vs. 11.3(11) (p < 0.001) in patients with vs. without hyperventilation symptoms. Anxiety was only associated with increased A2 (27(12.3) vs. 10.9(11), p < 0.001). At 6 months, QS and A2 decreased of 7 and 3 points, respectively, in relation with changes in ACQ-6 and Nijmegen scores as well as the HAD-A score for A2. CONCLUSION: In breathless asthmatics, dyspnea is severe and worsened but differentially modulated by hyperventilation symptoms and anxiety. A multidimensional phenotyping of dyspnea in asthmatics could be useful to understand its origins and personalize treatment.

Real-life impact of uncontrolled severe asthma on mortality and healthcare use in adolescents and adults: findings from the retrospective, observational RESONANCE study in France.

OBJECTIVE: To characterise uncontrolled severe asthma and compare the disease burden with the general and asthmatic populations. DESIGN: Retrospective observational study using a national sample of a French healthcare database (Echantillon Généraliste des Bénéficiaires (EGB)). SETTING: The EGB, an anonymised permanent sample of health insurance databases, representing 1/97th of the French population. PARTICIPANTS: Patients (≥12 years) were selected in year 2014 and followed 2 years. A cohort of patients with uncontrolled severe asthma was defined using an algorithm based on peer-reviewed literature and Global Initiative for Asthma recommendations. Index date was the occurrence of the first marker of uncontrolled asthma. This cohort was matched with two control cohorts, general population and asthmatic controls, on baseline characteristics. MAIN OUTCOMES MEASURES: Mortality, healthcare use and associated costs were studied in the 2 years of follow-up. RESULTS: Among 467 716 individuals in the EGB, 16 588 patients with asthma were identified, including 739 (4.5%) with uncontrolled severe disease. The survival probability at 2 years for patients with uncontrolled severe asthma (92.0%) was lower than in the general population cohort (96.6%; relative risk of death: 2.35; 95% CI: 1.70 to 3.29; p<0.0001) and tended to be lower than in the control asthmatic cohort (94.3%; p=0.07). Emergency department visits and hospitalisations were higher in patients with uncontrolled severe asthma than in the general population (64.7% vs 34.9%; p<0.0001) and asthmatic controls (64.7% vs 55.2%; p=0.0002). Other components of healthcare use (medical and paramedical visits, medications) were increased in patients with uncontrolled severe asthma compared with control populations. These increases translated into higher costs (p<0.0001 for both comparisons). CONCLUSIONS: This study demonstrates the huge burden of uncontrolled severe asthma in terms of mortality, morbidity and healthcare resource consumption compared with other patients with asthma and with the general population and emphasises the importance of appropriate management in this high-risk population.

Otological Manifestations in Adults with Primary Ciliary Dyskinesia: A Controlled Radio-Clinical Study.

Primary ciliary dyskinesia (PCD) is a rare genetical disease characterized by an abnormal structure or function of the cilia, causing sinusitis, otitis, and bronchiectasis. Hearing loss affects 60% of PCD patients, but data are lacking concerning hearing and temporal bone imaging in adults. Our aim was to describe clinical and radiological ear disease in adults with genetically confirmed PCD. Data were recorded from January 2018 to December 2019. PCD patients were compared with controls with bronchiectasis without PCD. Clinical examination included otomicroscopy and auditory tests. A temporal bone CT scan (TBCT) was systematically performed. Seventeen patients (34 ears) were included in each group. The eardrums were abnormal in 25 (74%) PCD ears versus 8 (24%) ears in the controls (p < 0.05). Conductive hearing loss was more frequent in the PCD group (24% vs. 12% in controls). TBCT were abnormal in 94% PCD patients vs. 32% in the controls (p < 0.05). The Main CT-scan images in PCD were middle ear inflammation (65%), mastoid condensation (62%), or ossicular anomalies (35%). With its excellent sensitivity, TBCT gives typical arguments for PCD diagnosis, adding otological signs to the usual sinus CT signs (hypoplasia, aplasia). Systematic TBCT could be useful in the initial evaluation of patients with suspicion of PCD.

Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension.

AIMS: To assess the acute vasodilator response and long-term response to calcium-channel blockers (CCB) in pulmonary arterial hypertension (PAH) with associated conditions. METHODS AND RESULTS: The response to acute vasodilator testing [>20% decrease in mean pulmonary artery pressure (mPAP) and total pulmonary resistance] was assessed in 663 consecutive PAH patients with connective tissue disease (CTD; n = 168), portal hypertension (PoPH; n = 153), anorexigen use (n = 127), human immunodeficiency virus infection (HIV; n = 124), congenital heart disease (CHD; n = 50), and pulmonary veno-occlusive disease or capillary haemangiomatosis (PVOD/PCH; n = 41). An acute vasodilator response was observed in 13.4% of PAH-anorexigen patients, 12.2% of PVOD/PCH, 10.1% of CTD, 1.6% of HIV, 1.3% of PoPH, and was absent in CHD. A long-term response to CCB (marked haemodynamic improvement at 3-4 months and New York Heart Association functional class I or II after 1 year) was reported in 9.4% of PAH-anorexigen patients but was rare in HIV, PoPH, CTD (1.6, 0.7, and 0.6%, respectively) and absent in PVOD/PCH. All patients with a long-term CCB response were alive after 5 years; two deaths not related to PAH occurred after this time. Recent criteria for acute response based on the fall in mPAP to <40 mmHg are more specific to detect long-term responders to CCB. CONCLUSION: A long-term CCB response was reported in patients with PAH associated with anorexigen use, but was rare in patients with PoPH or HIV and absent in PVOD/PCH, CHD, and the vast majority of CTD. The prognosis of long-term responders was favourable and related to the underlying cause of PAH.

[Vocal cord dysfunction]. / Dysfonction des cordes vocales.

Vocal cord dysfunction is characterized by paradoxical vocal cord adduction, especially during inspiration. Clinical symptoms can mistakenly lead to a diagnosis of asthma. Some patients, thought to be asthmatic, are sometimes considered as having severe asthma. Positive diagnosis rests on the finding of paradoxical vocal cord adduction on laryngoscopic examination. The main limitation of this examination is associated with the intermittent nature of the symptoms. The diagnosis of vocal cord dysfunction can thus be mistakenly ruled out based on the absence of abnormalities on laryngoscopic examination. Therapeutic management focuses on phoniatric rehabilitation.

[Hyperventilation syndrome]. / Syndrome d'hyperventilation.

Hyperventilation syndrome is a disorder affecting children and adults, mostly women. It is frequently associated with anxiety disorders, and greatly affects quality of life. Diagnosis, which unfortunately is most often established late, is a diagnosis of elimination. It rests on a wide range of non-specific signs, on Nijmegën's clinical scale as well as on a hyperventilation provocative test. In most cases, specialized therapeutic interventions allow for an adequate control of ventilation and symptom relief.