FLorence Schleich

Exhaled nitric oxide thresholds associated with a sputum eosinophil count ≥3% in a cohort of unselected patients with asthma

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 μg 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.

Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation.

BackgroundPhenotyping 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.MethodsThis 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.ResultsEosinophilic (≥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.ConclusionEosinophilic 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.

Importance of concomitant local and systemic eosinophilia in uncontrolled asthma

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, asthma control 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. Concomitant systemic and bronchial eosinophilic inflammation contributes to poor asthma control http://ow.ly/sLtYr

Lung-resident eosinophils represent a distinct regulatory eosinophil subset.

Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions.

Induced sputum in asthma: from bench to bedside.

During recent years there has been a growing interest in using non-invasive biomarkers to understand and monitor the airway inflammation in subjects with respiratory tract disorders and mainly asthma and chronic obstructive pulmonary disease (COPD). Sputum induction is generally a well-tolerated and safe procedure and a European Respiratory Society Task Force has published a comprehensive review on sputum methodology. Induced sputum cell count and, to a lesser extent, mediator measurements have been particularly well validated. In asthma, the sputum and the cell culture supernatant can be used for the measurement of a variety of soluble mediators, including eosinophil-derived proteins, nitric oxide (NO) derivatives, cytokines and remodelling-associated proteins. Sputum eosinophilia (> 3%) is a classic feature of asthma although half of the patients seems to be non eosinophilic. Measuring the percentage of sputum eosinophils has proved to be useful in the clinical arena in helping to predict short term response to inhaled corticosteroids (ICS) and tailor the dose of ICS in the severe patients but there is scope for the application of other induced sputum markers potentially useful in clinical practice. The widespread application of induced sputum in asthma across the spectrum of disease severity has given insight into the relationship between airway function and airway inflammation, proposed new disease phenotypes and defined which of these phenotypes respond to current therapy, and perhaps most importantly provided an additional tool to guide the clinical management of asthmatic patients. To date sputum induction is the only non-invasive measure of airway inflammation that has a clearly proven role in asthma management.

Corticosteroids: still at the frontline in asthma treatment?

Inhaled corticosteroids (ICS) have led to improved asthma control and reduced asthma mortality in the Western world. ICS are effective in combating T-helper type 2-driven inflammation featuring mast cell and eosinophilic airway infiltration. Their effect on innate immunity-driven neutrophilic inflammation is poor and their ability to prevent airway remodeling and accelerated lung decline is controversial. Although ICS remain pivotal drugs in asthma management, research is needed to find drugs complementary to the combination ICS/long-acting β2-agonist in refractory asthma and perhaps a new class of drugs as a first-line treatment in mild to moderate noneosinophilic asthma.

Sputum IgE and Cytokines in Asthma: Relationship with Sputum Cellular Profile

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-γ and TNF-α) 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-α 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.

Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory?

BackgroundThe technique of induced sputum has allowed to subdivide asthma patients into inflammatory phenotypes according to their level of granulocyte airway infiltration. There are very few studies which looked at detailed sputum and blood cell counts in a large cohort of asthmatics divided into inflammatory phenotypes. The purpose of this study was to analyze sputum cell counts, blood leukocytes and systemic inflammatory markers in these phenotypes, and investigate how those groups compared with healthy subjects.MethodsWe conducted a retrospective cross-sectional study on 833 asthmatics recruited from the University Asthma Clinic of Liege and compared them with 194 healthy subjects. Asthmatics were classified into inflammatory phenotypes.ResultsThe total non-squamous cell count per gram of sputum was greater in mixed granulocytic and neutrophilic phenotypes as compared to eosinophilic, paucigranulocytic asthma and healthy subjects (p < 0.005). Sputum eosinophils (in absolute values and percentages) were increased in all asthma phenotypes including paucigranulocytic asthma, compared to healthy subjects (p < 0.005). Eosinophilic asthma showed higher absolute sputum neutrophil and lymphocyte counts than healthy subjects (p < 0.005), while neutrophilic asthmatics had a particularly low number of sputum macrophages and epithelial cells. All asthma phenotypes showed an increased blood leukocyte count compared to healthy subjects (p < 0.005), with paucigranulocytic asthmatics having also increased absolute blood eosinophils compared to healthy subjects (p < 0.005). Neutrophilic asthma had raised CRP and fibrinogen while eosinophilic asthma only showed raised fibrinogen compared to healthy subjects (p < 0.005).ConclusionsThis study demonstrates that a significant eosinophilic inflammation is present across all categories of asthma, and that paucigranulocytic asthma may be seen as a low grade inflammatory disease.

Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity

To cite this article: Manise M, Schleich F, Gusbin N, Godinas L, Henket M, Antoine N, Corhay JL, Louis R. Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity. Allergy 2010; 65: 889–896.

Clinically relevant subgroups in COPD and asthma

As knowledge of airways disease has grown, it has become apparent that neither chronic obstructive pulmonary disease (COPD) nor asthma is a simple, easily defined disease. In the past, treatment options for both diseases were limited; thus, there was less need to define subgroups. As treatment options have grown, so has our need to predict who will respond to new drugs. To date, identifying subgroups has been largely reported by detailed clinical characterisation or differences in pathobiology. These subgroups are commonly called “phenotypes”; however, the problem of defining what constitutes a phenotype, whether this should include comorbid diseases and how to handle changes over time has led to the term being used loosely. In this review, we describe subgroups of COPD and asthma patients whose clinical characteristics we believe have therapeutic or major prognostic implications specific to the lung, and whether these subgroups are constant over time. Finally, we will discuss whether the subgroups we describe are common to both asthma and COPD, and give some examples of how treatment might be tailored in patients where the subgroup is clear, but the label of asthma or COPD is not. Summary of subgroups of airways disease that can be found in COPD and asthma, and their management http:///ow.ly/KiDvo