Arnaud Bourdin

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

Are overweight asthmatics more difficult to control

The relationship between asthma and obesity appears to be quite complex. The aim of this study was to assess the effect of excess weight on asthma control evolution in a cohort of asthmatics. A prospective database was set up, which enrolled adult asthmatics with persistent (mild, moderate or severe) asthma. The control of asthma was defined as a binary variable, acceptable or unacceptable. In order to evaluate the effect of body mass index (BMI; <25 or ≥25), data were analysed using a continuous time homogeneous Markov model in which the forces ruling the transition between the two health states were estimated. The following confounding covariates were also evaluated in the model: severity of asthma, current treatment with oral corticosteroids (OCS) and history of OCS over the year preceding inclusion. About 406 asthmatics were included who made a total of 1639 consultations; the median length of follow up was 182 days. Using a univariate model, overweight patients had a lower risk of transiting from the unacceptable to the acceptable health state (RR = 0.45; P < 0.01). The effect of weight remained significant (RR = 0.53; P < 0.01) in the multivariate model including the other covariates. Moreover, transition probabilities stabilized more rapidly for patients with BMI < 25 (200 vs 300 days). In this study, we thus demonstrated that there is an association between excess weight and transition from unacceptable to acceptable control. Because control of asthma clearly drives asthma management, this finding has consequences for defining original new strategies for managing asthma in overweight patients.

Severe community-acquired pneumonia: assessment of microbial aetiology as mortality factor

Community-acquired pneumonia (CAP) remains a major cause of mortality. The aetiology of CAP has rarely been identified as a mortality risk factor. A prospective study was conducted to assess the prognostic factors of CAP patients admitted to the intensive care unit (Centre Hospitalier Departmental Félix Guyon, St Denis de la Réunion, France), with a special emphasis on microbial aetiology. All variables assessing severity were collected, with a special emphasis on microbial investigations. Among 112 immunocompetent patients (mean±sd age 54.7±15.1 yrs), 84% were male. Severity of CAP was demonstrated by mortality rate (43%), shock (48%), simplified acute physiology score (SAPS; 46.4±21.6) and mechanical ventilation support (82%). Mean risk factor score was 2.2±1.2. Microbiological identification was obtained in 78.6% of cases, with positive blood culture in 33%. Most frequently, microbial agents were Streptococcus pneumoniae and Klebsiella pneumoniae (42% and 22%, respectively). The univariate analysis recorded the usual mortality variables: age, alcohol consumption, SAPS, shock, mechanical ventilation, positive end expiratory pressure level, positive blood culture, multilobar infiltrates on chest radiograph, neutropenia, and acidosis, and found K. pneumoniae (versus S. pneumoniae, and all CAP) as a mortality factor. The multivariate analysis demonstrated that septic shock (relative risk (RR) 141), K. pneumoniae CAP (RR 27), SAPS (RR 10.7) and positive blood culture (RR 2.7) were independent factors related to death. In conclusion, the present study found that the microbial aetiology, Klebsiella pneumoniae, was an independent risk factor for mortality in severe community-acquired pneumonia.

Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma

BACKGROUND Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin‐5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid–sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. METHODS In a 28‐week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. RESULTS Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. CONCLUSIONS Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255.)

Nitrogen washout slope in poorly controlled asthma.

Short‐term control of asthma is often lacking even though forced expiratory volume in 1 s (FEV1) remains above normal value. Small airways are a potential key site of persistent inflammation and structural modification. Noninvasive assessment of small airways was found to be difficult, but the computerized single breath nitrogen washout test (SBNT) has been recently successfully reintroduced with this aim. Twenty‐four asthmatics (13 females) of various severity but with normal FEV1 were compared with 24 healthy volunteers (13 females) and studied at steady‐state after bronchodilatation (400 μg salbutamol). Spirometric values, plethysmographic data, phase III (slope of phase III of the SBNT, dN2) and IV [closing volume (CV), with closing capacity (CC) = CV + residual volume (RV)] of the SBNT were checked. Asthma severity, recent control, exacerbation rate, and therapy requirements were assessed on the basis of validated questionnaires (ACQ) and international guidelines. Patients were prospectively pooled into two equal groups according to their exacerbation rate. The reproducibility of the measurements obtained on 2 following days was assessed. All plethysmographic values, except total lung capacity (TLC), differentiated asthmatic patients from controls. The CC/TLC [124 (117–148) vs 117 (112–123), P = 0.04] and dN2 [110 (99–190) vs 94 (75–111), P = 0.02] were increased in asthma. The dN2 was significantly increased in patients with frequent exacerbations [100 (83–105) vs 195 (141–212), P = 0.0005]. A correlation was obtained between dN2 and recent asthma control (ρ: 0.62; P = 0.003), number of exacerbations (ρ: 0.71, P = 0.0008), and RV/TLC (ρ: 0.49, P = 0.026). This study demonstrated that ventilation inequalities assessed by dN2 represent an important indicator of poor asthma control and high exacerbation rate in high symptom perceivers. New therapies focused on small airways should now be developed.

Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial

IMPORTANCE Therapeutic options for severe emphysema are limited. Lung volume reduction using nitinol coils is a bronchoscopic intervention inducing regional parenchymal volume reduction and restoring lung recoil. OBJECTIVE To evaluate the efficacy, safety, cost, and cost-effectiveness of nitinol coils in treatment of severe emphysema. DESIGN, SETTING, AND PARTICIPANTS Multicenter 1:1 randomized superiority trial comparing coils with usual care at 10 university hospitals in France. Enrollment of patients with emphysema occurred from March to October 2013, with 12-month follow-up (last follow-up, December 2014). INTERVENTIONS Patients randomized to usual care (n = 50) received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen; those randomized to bilateral coil treatment (n = 50) received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures. MAIN OUTCOMES AND MEASURES The primary outcome was improvement of at least 54 m in the 6-minute walk test at 6 months (1-sided hypothesis test). Secondary outcomes included changes at 6 and 12 months in the 6-minute walk test, lung function, quality of life as assessed by St Georges Respiratory Questionnaire (range, 0-100; 0 being the best and 100 being the worst quality of life; minimal clinically important difference, ≥4), morbidity, mortality, total cost, and cost-effectiveness. RESULTS Among 100 patients, 71 men and 29 women (mean age, 62 years) were included. At 6 months, improvement of at least 54 m was observed in 18 patients (36%) in the coil group and 9 patients (18%) in the usual care group, for a between-group difference of 18% (1-sided 95% CI, 4% to ∞; P = .03). Mean between-group differences at 6 and 12 months in the coil and usual care groups were +0.09 L (95% CI, 0.05 L to ∞) (P = .001) and +0.08 L (95% CI, 0.03 L to ∞) (P = .002) for forced expiratory volume in the first second, +21 m (95% CI, -4 m to ∞) (P = .06) and +21 m (95% CI, -5 m to ∞) (P = .12) for 6-minute walk distance, and -13.4 points (95% CI, -8 points to ∞) and -10.6 points (95% CI, -5.8 points to ∞) for St Georges Respiratory Questionnaire (1-sided P < .001 for both). Within 12 months, 4 deaths occurred in the coil group and 3 in the usual care group. The mean total 1-year per-patient cost difference between groups was

Anti-interleukin-5 therapy in severe asthma

47,908 (95% CI,

Bronchial epithelium as a target for innovative treatments in asthma

47,879-

Pulmonary hypertension associated with benfluorex exposure

48,073) (P < .001); the incremental cost-effectiveness ratio was

Update on the roles of distal airways in COPD

782,598 per additional quality-adjusted life-year. CONCLUSIONS AND RELEVANCE In this preliminary study of patients with severe emphysema followed up for 6 months, bronchoscopic treatment with nitinol coils compared with usual care resulted in improved exercise capacity with high short-term costs. Further investigation is needed to assess durability of benefit and long-term cost implications. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01822795.