Guus A. Westerhof

Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis

BACKGROUND Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary. METHODS We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy. FINDINGS We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0·75 [95% CI 0·72-0·78]); blood eosinophils (14 studies; 2405 patients; 0·78 [0·74-0·82]); total IgE (seven studies; 942 patients; 0·65 [0·61-0·69]). In children, only FeNO (six studies; 349 patients; summary AUC 0·81 [0·72-0·89]) and blood eosinophils (three studies; 192 patients; 0·78 [0·71-0·85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0·66 (0·57-0·75) and 0·76 (0·65-0·85) for FeNO; 0·71 (0·65-0·76) and 0·77 (0·70-0·83) for blood eosinophils; and 0·64 (0·42-0·81) and 0·71 (0·42-0·89) for IgE. INTERPRETATION FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives. FUNDING None.

Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes

Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (≥3%) in different adult asthma phenotypes. Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex-)smoking and never-smoking asthma patients. Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78–0.87) for blood eosinophils, 0.82 (0.77–0.87) for FeNO and 0.69 (0.63–0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients. Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma. FeNO and blood eosinophils can be used to detect sputum eosinophilia in adult asthma patients regardless of phenotype http://ow.ly/MnGqF

Predictors for the development of progressive severity in new-onset adult asthma

BACKGROUND A proportion of patients with adult-onset asthma have severe disease. Risk factors for an increase in asthma severity are poorly known. OBJECTIVE We sought to identify predictors for the development of severe asthma in adults. METHODS A cohort of 200 adults with new-onset asthma was prospectively followed for 2 years. At baseline, patients underwent a comprehensive assessment of clinical, functional, and inflammatory parameters. After 2 years, change in asthma severity was assessed by using the Global Initiative for Asthma score (range, 1-4), which is based on asthma control (Asthma Control Questionnaire), lung function (FEV1), and inhaled corticosteroid requirement. ANOVA and multiple regression equations were used in the analysis. RESULTS One hundred twenty-eight patients completed 2 years of follow-up. Seventeen (13.3%) patients had an increase in asthma severity, whereas 53 (41.4%) patients had a decrease. A lower postbronchodilator FEV1/forced vital capacity ratio and a higher number of cigarette pack years smoked at baseline were significantly associated with an increase in asthma severity at follow-up. Multiple regression equations showed that only the number of cigarette pack years smoked was independently associated with an increase in asthma severity, with an odds ratio of 1.4 (95% CI, 1.02-1.91) for every 10 pack years smoked. CONCLUSION A history of cigarette smoking in patients with new-onset adult asthma predicts an increase in asthma severity during the first 2 years of the disease in a dose-dependent manner.

Clinical predictors of remission and persistence of adult-onset asthma

Background: Adult‐onset asthma is an important but relatively understudied asthma phenotype and little is known about its natural course and prognosis. The remission rate is believed to be low, and it is still obscure which factors predict remission or persistence of the disease. Objective: This study sought to determine the remission rate and identify predictors of persistence and remission of adult‐onset asthma. Methods: Two hundred adult patients with recently diagnosed (<1 year) asthma were recruited from secondary and tertiary pulmonary clinics and prospectively followed for 5 years. Clinical, functional, and inflammatory parameters were assessed at baseline and at yearly visits. Asthma remission was defined as absence of asthma symptoms for ≥1 year and no asthma medication use for ≥1 year. Descriptive statistics and logistic regression analysis were performed. Results: Five‐year follow‐up data of 170 patients (85%) was available. Of these, 27 patients (15.9%) experienced asthma remission. Patients with asthma persistence were older, had worse asthma control, required higher doses of inhaled corticosteroids, had more severe airway hyperresponsiveness, more often nasal polyps, and higher levels of blood neutrophils as compared to patients who experienced clinical remission. In a multivariable logistic regression analysis, only moderate to severe bronchial hyperresponsiveness and nasal polyps were independent predictors of asthma persistence. Patients with these 2 characteristics had <1% chance of asthma remission. Conclusions: One in 6 patients with adult‐onset asthma experiences remission within the first 5 years of the disease. In patients with moderate to severe bronchial hyperresponsiveness and nasal polyposis, the chance of remission is close to zero.

Predictors of accelerated decline in lung function in adult-onset asthma

Little is known about the prognosis of adults with new-onset asthma. Cross-sectional studies suggest that these patients may exhibit accelerated decline in forced expiratory volume in 1 s (FEV1). However, risk factors for accelerated decline in lung function have not yet been identified. We aimed to identify these risk factors in a prospective 5-year follow-up study in 200 adults with newly diagnosed asthma. In the current study, clinical, functional and inflammatory parameters were assessed annually for 5 years. Linear mixed-effects models were used to identify predictors. Evaluable lung function sets of 141 patients were available. Median (interquartile range) change in post-bronchodilator FEV1 was −17.5 (−54.2 to +22.4) mL per year. Accelerated decline in FEV1 was defined by the lower quartile of decline (>54.2 mL per year). Nasal polyps, number of blood and sputum eosinophils, body mass index, and level of exhaled nitric oxide were univariably associated with decline in lung function. Only the latter two were independently associated. Using cut-off values to identify patients at highest risk showed accelerated decline in FEV1 in all patients with combined exhaled nitric oxide fraction (FeNO) ≥57 ppb and body mass index (BMI) ≤23 kg·m−2. We conclude that adults with new-onset asthma with both high levels of exhaled nitric oxide and low BMI are at risk of accelerated decline in lung function. Exhaled nitric oxide and BMI predict accelerated decline in FEV1 in adults with new-onset asthma http://ow.ly/1yDz30hE5YE

Diagnosing persistent blood eosinophilia in asthma with single blood eosinophil or exhaled nitric oxide level

BACKGROUND Eosinophilic asthma is characterized by persistently elevated blood eosinophils, adult-onset asthma and corticosteroid resistance. For stratified medicine purposes one single measurement of blood eosinophils or exhaled nitric oxide (FeNO) is commonly used. The aim of this study was to investigate in patients with new-onset asthma whether persistent blood eosinophilia can be predicted with one single measurement of these biomarkers. METHODS Blood eosinophils and exhaled nitric oxide levels were measured at yearly intervals over 5 years in 114 adults with new-onset asthma on inhaled corticosteroid treatment. Two definitions of persistent blood eosinophilia were used (1); blood eosinophils at every visit ≥0.30 × 109/L, or (2) ≥0.40 × 109/L. Receiver operating characteristic analyses were performed. Diagnostic cut-off values were defined at a positive predictive value of 95% (or the highest achievable). RESULTS Using definition 1 (blood eosinophils ≥0.30 × 109/L) the cut-off value for a single measurement of blood eosinophils was 0.47 × 109/L. For definition 2 (≥0.40 × 109/L) the cut-off value was 0.49 × 109/L. Cut-off values for persistently low blood eosinophils were 0.17 × 109/L for definition (1) and 0.21 × 109/L for definition (2), respectively. For FeNO no cut-off values with sufficient accuracy could be defined. CONCLUSION We showed that by using high and low cut-off values, one single measurement of blood eosinophils, but not FeNO in the initial phase of new-onset asthma in adults can be used to predict persistence or absence of blood eosinophilia in asthma.

Predictors of accelerated decline in FEV1 in a prospective new-onset asthma cohort

Rationale : There is increasing evidence that adult-onset asthma is associated with accelerated decline in FEV 1 . However, it is unknown which patients are at greatest risk. Aim : To identify risk factors for FEV 1 decline in new-onset asthma in adults. Methods : 200 adults with recently diagnosed ( 1 decline ≥275ml/5years (25 th quartile). Results : Sets of lung function data of 108 (54%) patients were available; 27 patients had a pbFEV 1 decline of ≥275ml/5years. At baseline, these patients had a lower BMI (26.4 vs. 29.0 kg/m 2 p=0.032), higher pbFEV 1 (106.9% vs 91.2% p=0.004), higher exhaled nitric oxide levels (FeNO)(22.0 vs 37.2 ppb p=0.035), higher sputum eosinophil9s (7.1% vs 0.4% p=0.017) and more patients had blood eosinophilia (≥0.3x109/L) (40% vs 14% p=0.002) compared to patients with pbFEV 1 decline 1 were independently associated with pbFEV 1 decline ≥275ml/5years. FeNO>50 ppb or blood eosinophilia gave an OR(95% CI) of 6.0 (2.1-17.6) and 5.6 (1.9-16.6), respectively. pbFEV 1 ≥100% gave an OR of 4.2 (1.4-12.3). Conclusion : Adults with newly diagnosed asthma with high FeNO or blood eosinophilia, and normal pbFEV 1 are at risk of accelerated decline in FEV 1 . This suggests that the adult-onset eosinophilic asthma phenotype has a poor prognosis.