Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).
SCHLEICH, FLorence ; ; Louis, Renaud et al
in Respiratory medicine (2014), 108(12), 1723-32
The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its ... [more ▼]
The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 +/- 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (>/=40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio <70%. The median blood eosinophil count was 240/mm(3). The median FENO was 26 ppb (IQR: 15-43) and 22% of SA had FENO >/= 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos >/= 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu >/= 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20 and 77% with ACQ > 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies. [less ▲]Detailed reference viewed: 11 (0 ULg)
Importance of concomitant local and systemic eosinophilia in uncontrolled asthma.
SCHLEICH, FLorence ; ; et al
in The European respiratory journal (2014), 44
Systemic and airway eosinophilia are recognised features of asthma. There are, however, patients who exhibit discordance between local and systemic eosinophilia. In this study, we sought to determine the ... [more ▼]
Systemic and airway eosinophilia are recognised features of asthma. There are, however, patients who exhibit discordance between local and systemic eosinophilia. In this study, we sought to determine the prevalence and characteristics of patients with concordant and discordant systemic and bronchial eosinophilia.We conducted a retrospective study on 508 asthmatics with successful sputum induction. We assessed the relationship between blood and sputum eosinophils by breaking down the population into four groups according to blood (>/=400 cells per mm3) and sputum (>/=3%) eosinophils. Then, we prospectively reassessed the link between eosinophils and asthma control (Asthma Control Questionnaire (ACQ)) and exacerbation rate in a new cohort of 250 matched asthmatics.In our retrospective cohort, asthmatics without eosinophilic inflammation were the largest group (49%). The group with isolated sputum eosinophilia (25%) was, compared with noneosinophilic asthma, associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity ratio and higher bronchial hyperresponsiveness and exhaled nitric oxide fraction (FeNO). Asthmatics exhibiting isolated systemic eosinophilia (7%) had similar characteristics as noneosinophilic asthmatics. The group with concordant systemic and airway eosinophilia (19%) showed remarkable male predominance, and had the lowest airway calibre, ACQ score and quality of life, and the highest bronchial hyperresponsiveness, FeNO and exacerbation rate. The prospective cohort confirmed the different subgroup proportions and the higher ACQ and exacerbation rates in cases of diffuse eosinophilia compared with noneosinophilic asthmatics.Concomitant systemic and bronchial eosinophilic inflammation contribute to poor asthma control. [less ▲]Detailed reference viewed: 30 (22 ULg)
Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation.
SCHLEICH, FLorence ; Manise, Maïté ; et al
in BMC Pulmonary Medicine (2013), 13(1), 11
ABSTRACT: BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors ... [more ▼]
ABSTRACT: BACKGROUND: Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics. METHODS: This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics. RESULTS: Eosinophilic (>=3%) and neutrophilic (>=76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia >=3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen's kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia >=3%. Independent predictors of sputum neutrophilia were advanced age and high FRC but not blood neutrophil count. CONCLUSION: Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils. [less ▲]Detailed reference viewed: 19 (2 ULg)
Sputum IgE and Cytokines in Asthma: Relationship with Sputum Cellular Profile.
Manise, Maïté ; ; et al
in PLoS ONE (2013), 8(3), 58388
BACKGROUND: Local IgE production may play a role in asthma pathogenesis. The aim of the study was to assess sputum total IgE and cytokines in asthmatics according to sputum cellular phenotype. METHODS: We ... [more ▼]
BACKGROUND: Local IgE production may play a role in asthma pathogenesis. The aim of the study was to assess sputum total IgE and cytokines in asthmatics according to sputum cellular phenotype. METHODS: We studied 122 subjects including 22 non atopic healthy subjects, 41 eosinophilic (sputum eosinophils >/=3%), 16 neutrophilic (sputum neutrophils >76%) and 43 pauci-granulocytic asthmatics (sputum eosinophils <3% and sputum neutrophils </=76%) recruited from the asthma clinic at CHU Liege. Sputum supernatant total IgE (tIgE) was measured by ImmunoCAP and sputum supernatant cytokines (IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IFN-gamma and TNF-alpha) were measured with the Luminex xMAP Technology by using commercially available Fluorokine MAP kits. RESULTS: After concentrating sputum samples, total IgE was detectable in the majority of subjects. Sputum IgE was raised in asthmatics when compared to healthy subjects. Overall, asthmatics did not significantly differ from healthy subjects with respect to cytokine levels. The eosinophilic asthma phenotype, however, was characterised by raised sputum tIgE, IL-5 and IL-13 compared to healthy subjects (p<0.001, p<0.001 and p<0.05 respectively) and pauci-granulocytic asthma (p<0.01, p<0.001 and p<0.05 respectively) and raised IL-5 compared to neutrophilic asthma (p<0.01). When patients were classified according to sputum IgE levels, it appeared that IL-5, IL-6, IL-17 and TNF-alpha sputum supernatant levels were raised in the "IgE high" asthmatics (IgE >/=0.1 kU/l) when compared to "IgE low" asthmatics (IgE<0.1 kU/l). CONCLUSION: The eosinophilic asthma phenotype was associated with raised sputum IgE and a Th2 cytokine profile. Raised sputum IgE was associated with a heterogeneous cytokine overproduction. [less ▲]Detailed reference viewed: 23 (4 ULg)
Increased glutaredoxin-1 and decreased protein S-glutathionylation in sputum of asthmatics.
; LOUIS, Renaud ; Manise, Maïté et al
in The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology (2013), 41(2), 469-72Detailed reference viewed: 11 (5 ULg)
Immuno-inflammatory mechanisms in refractory asthma
Doctoral thesis (2012)Detailed reference viewed: 30 (7 ULg)
Is FE(NO50) useful diagnostic tool in suspected asthma?
SCHLEICH, FLorence ; ASANDEI, Raluca ; Manise, Maïté et al
in International Journal of Clinical Practice (2012), 66(2), 158-65
Background: Asthma diagnosis is based on the presence of symptoms and the demonstration of airflow variability. Airway inflammation measured by fractional exhaled nitric oxide, measured at a flow rate of ... [more ▼]
Background: Asthma diagnosis is based on the presence of symptoms and the demonstration of airflow variability. Airway inflammation measured by fractional exhaled nitric oxide, measured at a flow rate of 50 ml/s (FE(NO50) ) remains a controversial diagnostic tool. Aim: To assess the ability of FE(NO50) to identify bronchial hyperresponsiveness (BHR) to methacholine (provocative concentration of methacholine causing a 20% fall in FEV(1) ; PC20M </= 16 mg/ml) and to establish whether or not symptoms relate to FE(NO50) and PC20M in patients with no demonstrated reversibility to beta(2) -agonist. Methods: We conducted a prospective study on 174 steroid naive patients with respiratory symptoms, forced expiratory volume in 1 s (FEV(1) ) >/= 70% predicted and no demonstrated reversibility to beta(2) -agonist. Patients answered to a standardised symptom questionnaire and underwent FE(NO50) and methacholine challenge. Receiver-operating characteristic (ROC) curve and logistic regression analysis assessed the relationship between PC20M and FE(NO50) , taking into account covariates (smoking, atopy, age, gender and FEV(1) ). Results: A total of 82 patients had a PC20M </= 16 mg/ml and had significantly higher FE(NO50) (19 ppb vs. 15 ppb; p < 0.05). By constructing ROC curve, we found that FE(NO50) cut-off value of 34 ppb was able to identify not only BHR with high specificity (95%) and positive predictive value (88%) but low sensitivity (35%) and negative predictive value (62%). When combining all variables into the logistic model, FE(NO50) (p = 0.0011) and FEV(1) (p < 0.0001) were independent predictors of BHR whereas age, gender, smoking and atopy had no influence. The presence of diurnal and nocturnal wheezing was associated with raised FE(NO50) (p < 0.001 and p < 0.05, respectively). Conclusion: The value of FE(NO50) > 34 ppb has high predictive value of PC20M < 16 in patients with suspected asthma in whom bronchodilating test failed to demonstrate reversibility or was not indicated. However, FE(NO50) </= 34 ppb does not rule out BHR and should prompt the clinician to ask for a methacholine challenge. [less ▲]Detailed reference viewed: 39 (12 ULg)
Disturbed Cytokine Production at the Systemic Level in Difficult-to-Control Atopic Asthma: Evidence for Raised Interleukin-4 and Decreased Interferon-gamma Release following Lipopolysaccharide Stimulation.
MANISE, Maïté ; SCHLEICH, FLorence ; QUAEDVLIEG, Valérie et al
in International Archives of Allergy & Immunology (2012), 158(1), 1-8
Background: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between ... [more ▼]
Background: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between cytokine production from blood leucocytes and the level of asthma control. Methods: We compared the production of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor-alpha from peripheral blood leucocytes in non-atopic healthy subjects (n = 22), atopic non-asthmatics (n = 10), well-controlled asthmatics [Juniper asthma control questionnaire (ACQ) score <1.5; n = 20] and patients with uncontrolled asthma despite inhaled or oral corticoids (ACQ score >/=1.5; n = 20). Fifty microlitres of peripheral blood was incubated for 24 h with RPMIc, lipopolysaccharide (LPS; 1 ng/ml) or phytohaemagglutinin (1 mug/ml), and cytokines were measured by immunotrapping (ELISA). Results: Both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously produced more IL-4 than non-atopic healthy subjects (p < 0.001). IL-4 production induced by LPS was significantly greater (p < 0.05) in both asthma groups compared to atopic non-asthmatics and non-atopic healthy subjects. By contrast, IFN-gamma release induced by LPS was lower in uncontrolled asthmatics than in non-atopic healthy subjects (p < 0.05) and controlled asthmatics (p < 0.05). IL-10 release after LPS was greater in uncontrolled asthmatics than in atopic non-asthmatics (p < 0.05). No difference was observed regarding other cytokines. Conclusion: Blood cells from patients with difficult-to-control atopic asthma display highly skewed Th2 cytokine release following LPS stimulation. [less ▲]Detailed reference viewed: 35 (7 ULg)
Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease.
Moermans, Catherine ; HEINEN, Vincent ; NGUYEN DANG, Delphine et al
in Cytokine (2011), 56(2), 298-304
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also ... [more ▼]
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. METHODS: Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-alpha and IFN-gamma produced by 24h sputum and blood cell cultures were measured. RESULTS: Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-alpha release deficiency that contrasted with a raised IFN-gamma production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-gamma, IL-10 and TNF-alpha. Furthermore, sputum neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-alpha release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-alpha and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. CONCLUSIONS: COPD is characterized by prominent neutrophilic inflammation and raised IFN-gamma production at both bronchial and systemic level. Overproduction of TNF-alpha at systemic level correlates with disease severity and inversely with body mass index. [less ▲]Detailed reference viewed: 51 (16 ULg)
Inertie et observance therapeutiques en tant que facteurs influencant le controle de l'asthme.
Louis, Renaud ; Manise, Maïté ; Sele, Jocelyne et al
in Revue Médicale de Liège (2010), 65(5-6), 338-42
Asthma is a chronic inflammatory disease which can be most often adequately controlled by current medications as demonstrated by multiple randomised clinical trials. Yet most of the recent surveys ... [more ▼]
Asthma is a chronic inflammatory disease which can be most often adequately controlled by current medications as demonstrated by multiple randomised clinical trials. Yet most of the recent surveys conducted in the real life setting point to an inadequate control in the majority of asthmatics. In addition to factors linked to the hygiene of life, clinician's inertia and patient's lack of adherence to the treatment certainly contribute to poor asthma control. [less ▲]Detailed reference viewed: 70 (8 ULg)
Exhaled nitric oxide thresholds associated with a sputum eosinophil count >=3% in a cohort of unselected patients with asthma.
Schleich, FLorence ; Seidel, Laurence ; Sele, Jocelyne et al
in Thorax (2010), 65(12), 1039-1044
Background It has been claimed that exhaled nitric oxide (FeNO) could be regarded as a surrogate marker for sputum eosinophil count in patients with asthma. However, the FeNO threshold value that ... [more ▼]
Background It has been claimed that exhaled nitric oxide (FeNO) could be regarded as a surrogate marker for sputum eosinophil count in patients with asthma. However, the FeNO threshold value that identifies a sputum eosinophil count >/=3% in an unselected population of patients with asthma has been poorly studied. Methods This retrospective study was conducted in 295 patients with asthma aged 15-84 years recruited from the asthma clinic of University Hospital of Liege. Receiver-operating characteristic (ROC) curve and logistic regression analysis were used to assess the relationship between sputum eosinophil count and FeNO, taking into account covariates such as inhaled corticosteroids (ICS), smoking, atopy, age and sex. Results Derived from the ROC curve, FeNO >/=41 ppb gave 65% sensitivity and 79% specificity (AUC=0.777, p=0.0001) for identifying a sputum eosinophil count >/=3%. Using logistic regression analysis, a threshold of 42 ppb was found to discriminate between eosinophilic and non-eosinophilic asthma (p<0.0001). Patients receiving high doses of ICS (>/=1000 mug beclometasone) had a significantly lower FeNO threshold (27 ppb) than the rest of the group (48 ppb, p<0.05). Atopy also significantly altered the threshold (49 ppb for atopic vs 30 ppb for non-atopic patients, p<0.05) and there was a trend for a lower threshold in smokers (27 ppb) compared with non-smokers (46 ppb, p=0.066). Age and sex did not affect the relationship between FeNO and sputum eosinophilia. When combining all variables into the logistic model, FeNO (p<0.0001), high-dose ICS (p<0.05) and smoking (p<0.05) were independent predictors of sputum eosinophilia, while there was a trend for atopy (p=0.086). Conclusion FeNO is able to identify a sputum eosinophil count >/=3% with reasonable accuracy and thresholds which vary according to dose of ICS, smoking and atopy. [less ▲]Detailed reference viewed: 50 (19 ULg)
Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity.
Manise, Maïté ; Schleich, FLorence ; Gusbin, Natacha et al
in Allergy (2010), 65(7), 889-96
BACKGROUND: Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. METHODS: The aim of our study was to assess the ... [more ▼]
BACKGROUND: Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. METHODS: The aim of our study was to assess the cytokine production by sputum and blood cells from 15 refractory asthmatics (American Thoracic Society Criteria) compared to 15 mild untreated and 17 moderate treated asthmatics and 22 healthy subjects. Spontaneous production of interleukin (IL)-4, IL-6, IL-10, interferon-gamma, and tumor necrosis factor alpha was measured by immunotrapping after 24 h sputum or blood cell culture. RESULTS: Moderate and refractory asthmatics were both characterized by a lower production of IL-6 from their airway cells compared to healthy subjects. However, the difference was no longer significant when expressing the results per gram of sputum. No significant difference between the three groups was found regarding other cytokines. As for cytokine production from blood, the three groups of asthmatics exhibited raised production of IL-4 when compared to healthy subjects, and this was true when results were expressed per blood volume or after normalization for total leukocyte cell count. Moderate asthmatics exhibited greater production of IL-10 when compared to refractory asthmatics and healthy subjects when results were normalized for total leukocyte cell count. CONCLUSIONS: Sputum cells from moderate and refractory asthmatics release less IL-6. While the systemic overproduction of IL-4 was observed through the all spectrum of asthma severity, moderate asthmatics exhibited greater systemic IL-10 production compared to refractory asthmatics. [less ▲]Detailed reference viewed: 36 (9 ULg)
L'omalizumab (Xolair) dans le traitement de l'asthme allergique persistant severe.
Schleich, FLorence ; Manise, Maïté ; Louis, Renaud
in Revue Médicale de Liège (2009), 64(5-6), 313-7
L’asthme est une maladie chronique des voies aériennes. La plupart des asthmatiques ont une inflammation bronchique liée à un processus immunologique faisant intervenir les immunoglobulines E (IgE). En ... [more ▼]
L’asthme est une maladie chronique des voies aériennes. La plupart des asthmatiques ont une inflammation bronchique liée à un processus immunologique faisant intervenir les immunoglobulines E (IgE). En dépit des thérapeutiques existantes, les patients atteints d’asthme sévère ont une qualité de vie sérieusement altérée et présentent un risque élevé d’exacerbations graves pouvant parfois être fatales. L’omalizumab est un anticorps (Ac) monoclonal humanisé dirigé contre les IgE circulantes, interférant ainsi avec une des cascades moléculaires importantes dans la pathogénie de l’asthme. L’omalizumab a montré qu’il était capable d’améliorer la qualité de vie et de réduire la fréquence des exacerbations ainsi que le recours aux corticoïdes inhalés et systémiques. Selon les nouvelles recommandations de l’asthme du GINA 2006, cet agent biologique est indiqué dans l’asthme allergique persistant sévère. [less ▲]Detailed reference viewed: 149 (10 ULg)
Asthme réfractaire : mécanismes sous-jacents, diagnostics et nouvelles approches thérapeutiques.
Manise, Maïté ; Louis, Renaud
in Revue Médicale de Liège (2008), 63(7-8), 494-499
There has been a recent increase in the prevalence of asthma worldwide. Most cases can be satisfactorily managed with a combination of inhaled corticoids and bronchodilators. However, some 10% of patients ... [more ▼]
There has been a recent increase in the prevalence of asthma worldwide. Most cases can be satisfactorily managed with a combination of inhaled corticoids and bronchodilators. However, some 10% of patients remain symptomatic despite high doses of inhaled corticosteroids and long-acting β-2 agonists. They represent a heterogeneous group consisting of those who are either undertreated, or really refractory to current available treatment. [less ▲]Detailed reference viewed: 84 (21 ULg)