Frequent exacerbators--a distinct phenotype of severe asthma.

BACKGROUND: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. OBJECTIVE: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. METHODS: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. RESULTS: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 µg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). CONCLUSION AND CLINICAL RELEVANCE: We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.

EAACI position statement on asthma exacerbations and severe asthma.

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial.

BACKGROUND: Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways. OBJECTIVE: To investigate the safety and efficacy of SCH527123, a selective CXCR2 receptor antagonist, in patients with severe asthma and increased number of neutrophils in sputum. METHODS: In a randomized, double-blind, parallel study, patients with severe asthma and sputum total cell count < 10 × 10(6) /g and neutrophils > 40% were randomized to SCH527123, 30 mg daily PO (n = 22) or placebo (n = 12) for 4 weeks. Primary end-points were safety and change in sputum and blood neutrophil counts. Secondary end-points were change in asthma control questionnaire (ACQ) score, minor and major exacerbations, spirometry and sputum neutrophil activation markers. RESULTS: The SCH 527123 caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (mean difference between groups of 0.42 points, P = 0.053). No statistically significant changes were observed in forced expiratory volume in 1 s (FEV (1)), sputum myeloperoxidase, IL8 or elastase. CONCLUSIONS: The SCH527123 is safe and reduces sputum neutrophils in patients with severe asthma. CLINICAL RELEVANCE: This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations.

Multiple tuberculous abscesses and mediastinal lymphadenitis with no pulmonary involvement in an immunocompetent patient.

Tubercular cold abscesses secondary to neighbouring bone involvement are a well-known clinical manifestation of extra-pulmonary tuberculosis. However, primary soft tissue tuberculous abscesses with no pulmonary involvement in immuno-competent patients are very uncommon. A rare case of multiple primary intrathoracic and extraperitoneal soft tissue tuberculous abscesses and mediastinal lymph node tuberculosis with no pulmonary involvement is reported. This case demonstrates the need for a high index of suspicion for such rare presentations of extra-pulmonary tuberculosis in patients from endemic areas.

Osteopontin expression and relation to disease severity in human asthma.

Recent studies have associated osteopontin (OPN) with allergic inflammation; however, its role in human asthma remains unclear. The aim of this study was to measure OPN levels in the serum, bronchoalveolar lavage fluid (BALF) and bronchial tissue of healthy controls and asthmatics, identify cellular sources of OPN and examine possible correlations between OPN expression, disease severity and airway remodelling. Serum samples were obtained from 35 mild-to-moderate asthmatics, 19 severe asthmatics and 17 healthy controls in the steady state and in cases of exacerbation. Of these subjects, 29 asthmatics and nine controls underwent bronchoscopy with endobronchial biopsy and BALF collection. OPN expression was determined by ELISA and immunohistochemistry/immunofluorescence. Reticular basement membrane thickness and goblet cell hyperplasia were also determined. Serum and BALF OPN levels were significantly increased in all asthmatics in the steady state, whereas serum levels decreased during exacerbations. OPN was upregulated in the bronchial tissue of all patients, and expressed by epithelial, airway and vascular smooth muscle cells, myofibroblasts, T-lymphocytes and mast cells. OPN expression correlated with reticular basement membrane thickness and was more prominent in subepithelial inflammatory cells in severe compared to mild-to-moderate asthma. OPN expression is upregulated in human asthma and associated with remodelling changes, and its subepithelial expression correlates with disease severity.

IL-5 expression and release from human CD34 cells in vitro; ex vivo evidence from cases of asthma and Churg-Strauss syndrome.

BACKGROUND: Eosinophils develop from hematopoietic CD34(+) progenitor cells in the bone marrow (BM) under the influence of Interleukin-5 (IL-5). The primary source of IL-5 is T-lymphocytes, although other sources may exist. The aims of this study were to determine whether CD34(+) cells from human peripheral blood (PB) and BM have the capacity to produce IL-5 when stimulated in vitro, and secondly, whether an elevated number of IL-5-producing CD34(+) cells can be found in situ in ongoing eosinophilic disease. METHODS: CD34(+) cells from PB and BM were stimulated in vitro, and IL-5 production and release was assessed by ELISA, ELISPOT, flow cytometry and immunocytochemistry. Blood and BM from a patient with Churg-Strauss syndrome were analyzed by flow cytometry for CD34(+)/IL-5(+) cells, and immunohistochemical staining of CD34(+)/IL-5(+) cells in bronchial biopsies from an asthmatic patient was performed. RESULTS: Both PB and BM CD34(+) cells can produce and release IL-5 when stimulated in vitro. In the Churg-Strauss patient, IL-5-producing CD34(+) cells were found in PB and BM. Oral glucocorticoid treatment markedly decreased the number of IL-5-positive CD34 cells in the BM. CD34(+)/IL-5(+) cells were present in a patient with asthma. CONCLUSION: CD34(+) cells in blood and BM are capable of producing IL-5 both in vitro and in vivo in humans, arguing that these cells may have the capacity to contribute to eosinophilic inflammation. Consequently, targeting CD34(+) progenitor cells that produce and release IL-5 may be effective in reducing the mobilization of eosinophil lineage-committed cells in eosinophilic-driven diseases.

Modulation of the epithelial inflammatory response to rhinovirus in an atopic environment.

BACKGROUND: Immune responses to rhinovirus (RV) as well as direct effects of RV on respiratory epithelium may contribute to the induction of asthma exacerbations. OBJECTIVE: To evaluate the effect of the environment resulting from an atopic immune response on RV-induced epithelial inflammation, replication and cytotoxicity. METHODS: Peripheral blood mononuclear cells (PBMC) from atopic asthmatic subjects and matched controls (12 pairs) were isolated and stimulated by RVs. Human bronchial epithelial (BEAS-2B) cells were infected with RV in the presence of conditioned media from RV-stimulated PBMC cultures. IL-6, IL-8, RANTES and TGF-beta1 levels were measured by ELISA, RV-induced cytotoxicity by a colorimetric method and RV titres on Ohio-HeLa cells. RESULTS: RV-induced epithelial production of IL-6, IL-8 and RANTES was significantly lower, while TGF-beta1 was higher when cells were exposed to conditioned media from atopic asthmatic subjects compared with those from normal controls. Exposure to the 'atopic' environment also resulted in elevated RV titres and increased RV-induced cytotoxicity. CONCLUSIONS: Under the influence of an atopic environment, the epithelial inflammatory response to RV is down-regulated, associated with increased viral proliferation and augmented cell damage, while TGF is up-regulated. These changes may help explain the propensity of atopic asthmatic individuals to develop lower airway symptoms after respiratory infections and indicate a mechanism through which viral infections may promote airway remodelling.

Skin reactivity and local cell recruitment in human atopic and nonatopic subjects by CCL2/MCP-1 and CCL3/MIP-1alpha.

BACKGROUND: Monocyte chemotactic protein (MCP-1/CCL2), the ligand for CCR2 and CCR5, and macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3), the ligand for CCR1 and CCR5, are potent chemo-attractants in vitro and produce lesions in experimental animals, which resemble immediate and delayed-type hypersensitivity (DTH) reactions. CCL3 induces mononuclear cell and granulocyte infiltration in human atopic and nonatopic skin. Whether CCL2 (MCP-1) has comparable activity in man is uncertain as is the capacity of both the chemokines to elicit immediate- and DTH-like reactions in humans. METHODS: Inflammatory cells were counted by immunohistochemistry in 24 and 48-h skin biopsies from atopics and nonatopics after intradermal injection of CCL2 and CCL3. Immediate (15 min) wheals-and-flares and delayed (24 and 48 h) indurations were also recorded. RESULTS: Both chemokines induced immediate- (15 min) and delayed (24 and 48 h) reactions, which were associated with significant infiltrations of CD68+ macrophages, CD3+, CD4+ (but not CD8+) T cells, neutrophils, and eosinophils in biopsies from injection sites. CCL2, but not CCL3, also induced infiltration of basophils. Neither chemokine produced significant changes in the numbers of tryptase+ cutaneous mast cells. There were no differences in the pattern of skin reactivity or the numbers of infiltrating leukocytes in response to CCL2 and CCL3 between atopic and nonatopic subjects. In general, maximal infiltration of inflammatory cells was observed at the 24-h, rather than the 48-h, time point. CONCLUSIONS: CCL2 and CCL3 induce both immediate and delayed skin reactions in atopics and nonatopics, and evoke a similar profile of local T cell/macrophage and granulocyte recruitment which, in general, confirm previous in vitro findings and in vivo experimental animal data.

Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease.

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.

Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.

BACKGROUND: Severe and difficult to treat asthma impairs health status and accounts for about half of asthma expenditure. In 1994, a European Network For Understanding Mechanisms of Severe Asthma (ENFUMOSA) was formed. A large group of patients from nine European countries has been selected. OBJECTIVE: To examine the risk factors and symptoms associated with a phenotype of severe/difficult to treat asthma. METHODS: The present report presents data assessed through the use of the European Community Respiratory Health Survey (ECRHS) Questionnaire in 148 mild-moderate controlled and 155 severe asthmatics from the ENFUMOSA group. RESULTS: There is a negative association of severe asthma with reported allergy and with a family history of allergy (Odds ratio (OR)=0.45). Sharing a bedroom before the age of five is associated with a higher risk of severe asthma (OR=1.5) while childhood infections, play school attendance and exposure to allergens or animals are not. A larger proportion of severe asthma patients report symptoms at work (OR=2.7) or have to change jobs (OR=4.3) and fewer severe than mild patients are currently employed (OR=0.39). Smoking and exposure to smoke is similar in mild and severe asthma. Dietary habits do not differ between the groups, but severe asthmatics report eating less savoury snacks and there is a trend for lower intake of sweets. CONCLUSIONS: Analysis of the ECRHS questionnaire in the ENFUMOSA study shows that severe asthma patients experience more symptoms and their health status is impaired by their inability to work and perhaps eat freely. Personal and maternal history of allergy is associated with mild but not severe asthma. Other than sharing a bedroom before the age of 5 years, no childhood exposure risk factors associated with severe asthma could be identified from this analysis.

Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura.

BACKGROUND: Adenosine deaminase (ADA) is a commonly used marker in the diagnosis of tuberculous effusion and there is evidence that its production is linked to T cells and monocytes. Data on the correlation between ADA and T cells or macrophages in tuberculous effusions are conflicting. Furthermore, no studies have examined a possible correlation between pleural tissue infiltration and ADA. OBJECTIVES: We undertook this study to examine cell subsets in the fluid and the pleura in tuberculous effusion and their correlation to ADA. The use of cell subsets as a marker in the differential diagnosis was also examined. METHODS: Pleural fluid from 36 patients with tuberculous and 34 patients with malignant effusion as well as pleural tissue biopsies from 16 patients with tuberculous pleurisy were examined. The APAAP and the avidin-biotin complex immunocytochemical methods were used to examine CD4+ T cells and macrophages (CD68+), while ADA activity was measured by the Giusti colorimetric method. RESULTS: Our results showed that, in pleural fluid, CD4+ cells and ADA were significantly higher in tuberculous compared to malignant effusion (p<0.001 for all measurements). In pleural tissue biopsies, macrophages were the predominant cells but CD4+ T cells were also abundant. A significant correlation was found between ADA and CD4+ numbers in pleural fluid and tissue (r=0.45, p<0.01; r=0.75, p<0.001, respectively). ADA had high sensitivity and specificity for differential diagnosis while cell subsets did not. CONCLUSIONS: These results indicate that ADA activity correlates to CD4+ T cell infiltration in the pleura and the fluid. Moreover, ADA but no cell subsets may be used as markers of tuberculous effusion.

Exercise-induced flow limitation, dynamic hyperinflation and exercise capacity in patients with bronchial asthma.

It is known that, in stable asthmatics at rest, tidal expiratory flow limitation (EFL) and dynamic hyperinflation (DH) are seldom present. This study investigated whether stable asthmatics develop tidal EFL and DH during exercise with concurrent limitation of maximal exercise work rate (WRmax). A total of 20 asthmatics in a stable condition and aged 32+/-13 yrs (mean+/-SD) with a forced expiratory volume in one second (FEV1) of 101+/-21% of the predicted value were studied. Only three patients exhibited an FEV1 below the normal limits. On a first visit, patients performed a symptom-limited incremental (20 W.min(-1)) bicycle exercise test. On the second visit, the occurrence of EFL (using the negative expiratory pressure technique) and DH (via reduction in inspiratory capacity) were assessed at rest and when cycling at 33, 66 and 90% of their predetermined WRmax. FEV1 was measured to detect exercise-induced asthma, 5 and 15 min after stopping exercise at 90% WRmax. Only one patient showed EFL at rest, whereas 13 showed EFL and DH during exercise. In these 13 asthmatics, exercise capacity was significantly reduced (WRmax 75+/-9% pred) compared to the seven non-EFL patients (WRmax 95+/-13% pred). Moreover, a significant correlation of WRmax (% pred) to the change in inspiratory capacity (percentage of resting value) from rest to 90% WRmax was found. Tidal EFL during exercise was not associated with exercise-induced asthma, which was detected in only three patients. In conclusion, tidal expiratory flow limitation and dynamic hyperinflation during exercise are common in stable asthmatics with normal spirometric results and without exercise-induced asthma, and may contribute to reduction in exercise capacity.

Unevenness of ventilation assessed by the expired CO(2) gas volume versus V(T) curve in asthmatic patients.

Recently, we have shown that the expired CO2 gas volume versus tidal volume (VCO2-VT) curve is a useful tool for assessing unevenness of ventilation because it allows the separation of tidal volume into three functional compartments: (a) the CO2-free expired air (V0), (b) the transitional volume (Vtr), (c) the alveolar volume (VA) and the measurement of alveolar FCO2 during resting breathing in normal subjects and patients with COPD. In this paper, we have investigated whether changes pertaining to unevenness of ventilation taking place immediately after the administration of methacholine can be assessed using the VCO2-VT curve in asthmatic patients. The VCO2-VT curve was obtained during tidal breathing from 16 stable asthmatic patients who underwent a methacholine challenge test. It has been found that the Vtr, and hence Bohr's dead space (VD,Bohr = V0 + Vtr), over tidal volume ratios were significantly increased immediately after the methacholine administration, whilst the V0 over tidal volume ratio was not affected. The change of the above ratios was not related to the percentage decrease of FEV1.0 following methacholine administration.

Evidence for left ventricular dysfunction in patients with obstructive sleep apnoea syndrome.

There is limited information on the development of left ventricular (LV) dysfunction in patients with obstructive sleep apnoea (OSA) in the absence of lung and cardiac comorbidity. This study aimed to investigate whether OSA patients without heart morbidity develop LV dysfunction, and to assess the effect of continuous positive airway pressure (CPAP) on LV function. Twenty-nine OSA patients and 12 control subjects were studied using technetium-99m ventriculography to estimate LV ejection fraction (LVEF), LV peak emptying rate (LVPER), time to peak emptying rate (TPER), peak filling rate (LVPFR) and time to peak filling rate (TPFR) before and after 6 months of treatment with CPAP. A significantly lower LVEF was found in OSA patients, compared to control subjects, (53+/-7 versus 61+/-6%) along with a reduced LVPER (2.82+/-0.58 versus 3.82+/-0.77 end-diastolic volumes x s(-1)). Furthermore, OSA patients had significantly lower LVPFR (2.67+/-0.71 versus 3.93+/-0.58 end-diastolic volumes x s(-1)) and delayed TPFR (0.19+/-0.04 versus 0.15+/-0.03 s) in comparison with the control group. Six-months of CPAP treatment was effective in significantly improving LVEF, LVPER, LVPFR and TPFR. In conclusion, obstructive sleep apnoea patients without any cardiovascular disease seem to develop left ventricular systolic and diastolic dysfunction, which may be reversed, either partially or completely, after 6 months of continuous positive airway pressure treatment.

Noninvasive measurement of mean alveolar carbon dioxide tension and Bohr's dead space during tidal breathing.

The lack of methodology for measuring the alveolar carbon dioxide tension (PA,CO2) has forced investigators to make several assumptions, such as that PA,CO2 is equal to end-tidal (PET,CO2) and arterial CO2 tension (Pa,CO2). The present study measured the mean PA,CO2 and Bohr's dead space ratio (Bohr's dead space/tidal volume (VD,Bohr/VT)) during tidal breathing. The method used is a new, simple and noninvasive technique, based on the analysis of the expired CO2 volume per breath (VCO2) versus the exhaled VT. This curve was analysed in 21 normal, healthy subjects and 35 chronic obstructive pulmonary disease (COPD) patients breathing tidally through a mouthpiece apparatus in the sitting position. It is shown that: 1) PA,CO2 is similar to Pa,CO2 in normal subjects, whilst it is significantly lower than Pa,CO2 in COPD patients; 2) PA,CO2 is significantly higher than PET,CO2 in all subjects, especially in COPD patients; 3) VD,Bohr/VT is increased in COPD patients as compared to normal subjects; and 4) VD,Bohr/VT is lower than the "physiological" dead space ratio (VD,phys/VT) in COPD patients. It is concluded that the expired carbon dioxide versus tidal volume curve is a useful tool for research and clinical work, because it permits the noninvasive and accurate measurement of Bohr's dead space and mean alveolar carbon dioxide tension accurately during spontaneous breathing.