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.
Background The occurrence and mechanisms of nocturnal hypoxemia in precapillary pulmonary hypertension (PH) are not clearly defined. Methods In an observational, prospective, and transversal design, ...we studied 46 clinically stable patients with PH and a BMI < 35 kg/m2 , an FEV1 > 60% predicted, and idiopathic pulmonary arterial hypertension (n = 29) or chronic thromboembolic pulmonary hypertension (n = 17). They underwent nocturnal polysomnography with transcutaneous capnography. Results Most patients (69.6%) had New York Heart Association functional class II disease. Mean pulmonary artery pressure was 44 ± 13 mm Hg, and the cardiac index was 3.2 ± 0.6 L/min/m2 . Duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90% was 48.9% ± 35.9%, and 38 of 46 patients (82.6%) had nocturnal hypoxemia. Mean apnea-hypopnea index was 24.9 ± 22.1/h, and 41 patients (89%) had sleep apnea. The major mechanism of nocturnal hypoxemia was a ventilation/perfusion mismatch alone or associated with obstructive apneic events. Multivariate logistic regression identified both FEV25%–75% (OR, 0.9519; 95% CI, 0.9089-0.9968; P = .036) and mean pulmonary artery pressure (OR, 1.1068; 95% CI, 1.0062-1.2175; P = .037) as significant predictors of nocturnal hypoxemia. Clinical symptoms were not predictive of nocturnal hypoxemia. Conclusions The occurrence of nocturnal hypoxemia is high in PH and should be screened for systematically. Further studies are needed to determine the impact of nocturnal hypoxemia on the outcome of patients with PH. Trial registry ClinicalTrials.gov ; No.: NCT01371669 ; URL: www.clinicaltrials.gov
Background While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is ...reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. Methods Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. Results Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 ( P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. Conclusions Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. Trial registry ClinicalTrials.gov ; No.: NCT01007149 ; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In ...2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP > 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2-3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). This review discusses the current state of art regarding to epidemiologic aspects of PH, diagnostic approaches and the current classification of PH. In addition, currently available specific PAH therapy is discussed as well as future treatments.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ObjectiveTo characterise uncontrolled severe asthma and compare the disease burden with the general and asthmatic populations.DesignRetrospective observational study using a national sample of a ...French healthcare database (Echantillon Généraliste des Bénéficiaires (EGB)).SettingThe EGB, an anonymised permanent sample of health insurance databases, representing 1/97th of the French population.ParticipantsPatients (≥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 measuresMortality, healthcare use and associated costs were studied in the 2 years of follow-up.ResultsAmong 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).ConclusionsThis 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.
Characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) who benefit from long-term calcium channel blockers (CCB) are unknown.
Acute pulmonary vasodilator testing with ...epoprostenol or nitric oxide was performed in 557 IPAH patients. Acute responders, defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) >20%, received long-term oral CCB. Patients who benefit from long-term CCB were defined as those being in New York Heart Association (NYHA) functional class I or II after at least 1 year on CCB monotherapy. Among the 70 patients who displayed acute pulmonary vasoreactivity (12.6%; 95% CI, 9.8% to 15.3%) and received CCB therapy, only 38 showed long-term improvement (6.8%; 95% CI, 4.7% to 8.9%). Long-term CCB responders had less severe disease at baseline than patients who failed. During acute vasodilator testing, long-term CCB responders displayed a more pronounced fall in mean PAP (-39+/-11% versus -26+/-7%; P<0.0001), reaching an absolute value of mean PAP lower than that measured in patients who failed (33+/-8 versus 46+/-10 mm Hg; P<0.0001). After 7.0+/-4.1 years, all but 1 long-term CCB responders were alive in NYHA class I or II, with a sustained hemodynamic improvement. In the group of patients who failed on CCB, the 5-year survival rate was 48%.
Long-term CCB responders represent <10% of IPAH patients evaluated in a pulmonary vascular referral center. During acute vasodilator testing, these patients showed significantly lower levels of both mean PAP and PVR, which reached near-normal values.
Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. ...The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key "research statement proposals" were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn't be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year
should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop.
Anti-interleukin-5 therapy in severe asthma Garcia, Gilles; Taillé, Camille; Laveneziana, Pierantonio ...
European respiratory review,
09/2013, Volume:
22, Issue:
129
Journal Article
Peer reviewed
Open access
Asthma is a chronic inflammatory disorder of the airways that leads to acute symptoms, exacerbations and sometimes, for a small part of the asthmatic population, fatal or near-fatal exacerbations. ...This as yet significant minority of individuals present with severe asthma and have persisting daily symptoms, and exacerbations despite compliance with high doses of inhaled steroids and additional treatment. For more than a decade, the pharmacological management of patients with severe asthma has focused on evaluating specific cytokines. The rationale of this approach is based on the distinguished key role played by eosinophils in the asthma inflammatory processes. Eosinophils are recruited from the circulation to airways where they cause airway damage via different mechanisms. Eosinophils are regulated in terms of their recruitment, activation, growth, differentiation and survival by interleukin (IL)-5. Abundant data from in vitro experiments, animal models and clinical trials has confirmed that IL-5 inhibition may be an effective approach for the treatment of asthma, especially severe asthma. Interfering with eosinophil function or reducing their numbers has been one of the most important goals of therapeutic monoclonal antibodies, which target cytokine receptor interactions in asthma, particularly IL-5. This review will consider new treatments options for severe asthma, particularly those targeting IL-5, that have already been evaluated in clinical trials in asthmatic patients.
Asthma is a heterogeneous condition, with dyspnoea during exercise affecting individuals to a variable degree. This narrative review explores the mechanisms and measurement of exertional dyspnoea in ...asthma and summarises the available evidence for the efficacy of various interventions on exertional dyspnoea. Studies on the mechanisms of dyspnoea in asthma have largely utilised direct bronchoprovocation challenges, rather than exercise, which may invoke different physiological mechanisms. Thus, the description of dyspnoea during methacholine challenge can differ from what is experienced during daily activities, including exercise. Dyspnoea perception during exercise is influenced by many interacting variables, such as asthma severity and phenotype, bronchoconstriction, dynamic hyperinflation, respiratory drive and psychological factors. In addition to the intensity of dyspnoea, the qualitative description of dyspnoea may give important clues as to the underlying mechanism and may be an important endpoint for future interventional studies. There is currently little evidence demonstrating whether pharmacological or non-pharmacological interventions specifically improve exertional dyspnoea, which is an important area for future research.
Cardiopulmonary exercise testing (CPET) is frequently used for the evaluation of patients with pulmonary hypertension (PH). Non-operable distal chronic thromboembolic pulmonary hypertension (CTEPH) ...represents a unique subgroup of PH where microvascular disease resembling pulmonary arterial hypertension (PAH) may predominate and efficacious medical therapy is now available. However, little is known regarding the detailed CPET profile of patients with distal CTEPH, and whether ventilation and gas exchange responses are different from PAH.
Forty-nine consecutive patients with non-operable distal CTEPH according to multidisciplinary team assessment and 45 PAH patients underwent CPET and right heart catheterization. Patients were followed up for a median of 3.2 years (interquartile range: 1.8 to 4.4).
Pulmonary hemodynamics were similar in distal CTEPH and PAH groups, but patients with distal CTEPH achieved a lower percent predicted peak oxygen consumption (59 ± 13% vs 66 ± 14%, p < 0.05). At peak exercise, higher physiologic dead-space fraction (VD/VT) (0.45 ± 0.07 vs 0.35 ± 0.07, p < 0.0001) and higher arterial-to-end-tidal carbon dioxide gradient (9 ± 3 vs 5 ± 3 mm Hg, p < 0.0001) were observed in distal CTEPH compared with PAH. Ventilatory efficiency, expressed as VE/VCO
slope, was also more impaired in distal CTEPH (52.2 ± 10.1 vs 43.8 ± 8.4 liters/min, p < 0.0001). In the distal CTEPH group only, higher VD/VT was associated with lower peak oxygen consumption (r = -0.46, p = 0.003) and worse survival.
Compared with PAH, a distinct pattern of response to exercise was observed in distal CTEPH, characterized by increased dead-space ventilation that resulted in worse ventilatory efficiency and greater impairment of exercise capacity. In distal CTEPH, dead-space ventilation correlated with exercise capacity and was associated with survival.
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