Lebrikizumab treatment in adults with asthma. Exhaled nitric oxide indicates poorly athlete's asthma Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study Is FENO50 useful diagnostic tool in suspected asthma? Exhaled nitric oxide as a predictor of exercise-induced bronchoconstriction. Whole-Body Plethysmography in Suspected Asthma: A Prospective Study of Its Added Diagnostic Value in 302 Patients. Portable exhaled nitric oxide as a screening tool for asthma in young adults during pollen season. Supporting the diagnosis of non-specific respiratory symptoms in primary care: the role of exhaled nitric oxide measurement and spirometry. FENO measurement and sputum analysis for diagnosing asthma in clinical practice. Validation study of asthma screening criteria based on subjective symptoms and fractional exhaled nitric oxide. Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma Exhaled nitric oxide: a predictor of steroid response. The value of exhaled nitric oxide to identify asthma in smoking patients with asthma-like symptoms.
BACKGROUND Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids . One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype . We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity . METHODS We conducted a r and omized , double-blind , placebo-controlled study of lebrikizumab , a monoclonal antibody to interleukin-13 , in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy .  The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second ( FEV(1 ) ) from baseline to week 12 . Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks . Patient subgroups were prespecified according to baseline type 2 helper T-cell ( Th2 ) status ( assessed on the basis of total IgE level and blood eosinophil count ) and serum periostin level . RESULTS At baseline , patients had a mean FEV(1 )  that was 65 % of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day ; 80 % were also taking a long-acting beta-agonist . At week 12 , the mean increase in FEV(1 ) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.02 ) . Among patients in the high-periostin subgroup , the increase from baseline FEV(1 ) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.03 ) . Among patients in the low-periostin subgroup , the increase from baseline FEV(1 ) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group ( P = 0.61 ) . Musculoskeletal side effects were more common with lebrikizumab than with placebo ( 13.2 % vs. 5.4 % , P = 0.045 ) . CONCLUSIONS Lebrikizumab treatment was associated with improved lung function . Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels . ( Funded by Genentech ; Clinical Trials.gov number , NCT00930163 . ) In athletes , exercise‐induced respiratory symptoms are common and their assessment is time and re source consuming . Objectives To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool . Design Diagnostic study performed between 2007 and 2010 . Participants had their history taken , underwent  physical examination and measurement of C reactive protein ( CRP ) and procalcitonin in venous blood  on the day they first consulted , and underwent chest radiography within seven days . Setting Primary care centres in 12 European countries . Participants Adults presenting with acute cough . Main outcome measures Pneumonia as determined by radiologists , who were blind to all other information when they judged chest radiographs . Results Of 3106 eligible patients , 286 were excluded because of missing or inadequate chest radiographs , leaving 2820 patients ( mean age 50 , 40 % men ) of whom 140 ( 5 % ) had pneumonia . Re- assessment of a subset of 1675 chest radiographs showed agreement in 94 % ( κ 0.45 , 95 % confidence interval 0.36 to 0.54 ) . Six published “ symptoms and signs models ” varied in their discrimination ( area under receiver operating characteristics curve ( ROC ) ranged from 0.55 ( 95 % confidence interval 0.50 to 0.61 ) to 0.71 ( 0.66 to 0.76 ) ) . The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness , crackles and diminished breath sounds on auscultation , tachycardia , and fever , with an ROC area of 0.70 ( 0.65 to 0.75 ) . Addition of CRP at the optimal cut off of > 30 mg/L increased the ROC area to 0.77 ( 0.73 to 0.81 ) and improved the diagnostic classification ( net reclassification improvement 28 % ) . In the 1556 patients classified according to symptoms , signs , and CRP > 30 mg/L as “ low risk ” ( < 2.5 % ) for pneumonia , the prevalence of pneumonia was 2 % . In the 132 patients classified as “ high risk ” ( > 20 % ) , the prevalence of pneumonia was 31 % . The positive likelihood ratio of low , intermediate , and high risk for pneumonia was 0.4 , 1.2 , and 8.6 respectively . Measurement of procalcitonin added no relevant additional diagnostic information . A simplified diagnostic score based on symptoms , signs , and CRP > 30 mg/L result ed in proportions of pneumonia of 0.7 % , 3.8 % , and 18.2 % in the low , intermediate , and high risk group respectively . Conclusions A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation . Addition of CRP concentration at the optimal cut off of > 30 mg/L improved diagnostic information , but measurement of procalcitonin  concentration did not add clinical ly relevant information in this group 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 ) ; PC20 M ≤ 16 mg/ml ) and to establish whether or not symptoms relate to FE(NO50 ) and PC20 M in patients with no demonstrated reversibility to β(2 ) -agonist . METHODS We conducted a prospect i ve study on 174 steroid naive patients with respiratory symptoms , forced expiratory volume in 1 s ( FEV(1 ) ) ≥ 70 % predicted and no demonstrated reversibility to β(2 ) -agonist . Patients answered to a st and ardised symptom question naire and underwent FE(NO50 ) and methacholine challenge . Receiver-operating characteristic ( ROC ) curve and logistic regression analysis assessed the relationship between PC20 M and FE(NO50 ) , taking into account covariates ( smoking , atopy , age , gender and FEV(1 ) ) . RESULTS A total of 82 patients had a PC20 M ≤ 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 PC20 M < 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 INTRODUCTION Exercise-induced bronchoconstriction ( EIB ) is present in 40 to 90 % of patients with asthma .  Exhaled NO ( eNO ) levels have been correlated with bronchial hyperresponsiveness to methacholine , and have correlated with the degree of decrease in FEV(1 ) with exercise . The purpose of our study was to examine whether eNO measurements prior to or after exercise could be used as a surrogate marker of exertional bronchoconstriction in a population referred specifically for the evaluation of EIB . METHODS We studied 50 consecutive subjects without a history of asthma who were referred for the clinical evaluation of EIB .  eNO levels were measured prior to exercise challenge and every 5 min for a total of 30 min after exercise . Forced expiratory flows were measured prior to and serially after exercise challenge . RESULTS Seven subjects had a decrease in FEV(1 ) of > or = 15 % with exercise . The mean eNO level prior to exercise was 41 parts per billion ( ppb ) [ median + /- SD , 23 + /- 42.2 ppb ] in the EIB group and 25.6 ppb ( median , 19.95 + /- 18.47 ppb ) in the group without EIB . A receiver operator characteristic curve yielded a value of 0.636 . When using an eNO level of < 12 ppb , the sensitivity , specificity , negative predictive value , and positive predictive value for EIB were 1.0 , 0.31 , 0.19 , and 1.0 , respectively ; therefore , no one with a baseline eNO of < 12 ppb demonstrated EIB . CONCLUSIONS No subjects with very low pre-exercise eNO levels ( < 12 ppb ) demonstrated bronchial hyperresponsiveness to exercise . eNO measurement may obviate the need for bronchoprovocation testing in patients who complain of exertional dyspnea BACKGROUND Whole-body plethysmography ( WBP ) with bronchial challenge testing to measure the ( specific ) airway resistance , (s)R(AW ) , is considered to be a more sensitive diagnostic procedure than spirometry , which can only measure the forced expiratory volume in one second ( FEV1 ) . The evidence for the added diagnostic value of WBP is not yet conclusive . METHODS In a prospect i ve diagnostic study , we carried out WBP with bronchial challenge testing as well as a bronchodilation test in 400 patients with suspected asthma from June 2010 to October 2011 . The bronchial provocation test was considered positive if the FEV1 fell by at least 20 % and /or the airway resistance doubled , with an increase of the sR(AW ) to at least 2.0 kPA × s and /or of the R(AW ) to 0.5 kPA × s/L. Follow-up evaluation was performed one year later . RESULTS The prevalence of asthma in the 302 patients who completed follow-up was 27.5 % .  The sensitivity of WBP with sR(AW ) measurement for asthma was 95.2 % ( 95 % confidence interval [ CI ] 88.3%-98.1 % ) , and its specificity was 81.7 % ( 95 % CI 76.1%-86.3 % ) . The sensitivity of FEV1 was 44.6 % ( 95 % CI 34.4%-55.3 % ) , and its specificity was 91.3 % ( 95 % CI 86.6%-94.4 % ) . The negative predictive value ( NPV ) of WBP with sR(AW ) measurement was 97.8 % ( 95 % CI 94.5%-99.1 % ) , while that of FEV1 was 81.3 % ( 95 % CI 76.0%-85.7 % ) . The positive predictive value ( PPV ) of WBP with sR(AW ) measurement was 66.4 % ( 95 % CI 57.5%-74.2 % ) , while that of FEV1 was 66.1 % ( 95 % CI 53.0%-77.1 % ) . CONCLUSION With sR(AW ) measurement , asthma can be ruled out with high certainty . Improving the positive predictive value of testing for asthma remains a challenge , however , as sR(AW ) measurement does not yield any increase in specificity BACKGROUND The fraction of exhaled NO ( FeNO ) is valuable for the follow-up of asthmatic patients . However , its usefulness as a screening tool for asthma is not established . METHODS We screened a population of 961 university students with a modified European Community Respiratory Health Survey question naire that has been previously used for the screening of respiratory symptoms related to asthma . All subjects with a positive answer to at least one question ( n = 149 ) were su bmi tted to FeNO measurement with a portable nitric oxide analyzer . Subsequently , they were su bmi tted to spirometry and evaluated by a physician blinded to FeNO measurements . Seventy students with no respiratory symptoms served as control subjects . RESULTS Asthma was diagnosed in 63 subjects , and allergic rhinitis was diagnosed in 57 subjects . Asthmatics presented higher FeNO values than control subjects ( median , 20 parts per billion [ ppb ] ; interquartile range , 14 to 31 ppb ; vs median , 11 ppb ; interquartile range , 7 to 13 ppb , respectively ; p < 0.0001 ) , whereas they did not differ from patients with allergic rhinitis ( median , 17 ppb ; interquartile range , 12 to 23 ppb ; p = 0.28 ) . FeNO values > 19 ppb presented 85.2 % specificity and 52.4 % sensitivity for the diagnosis of asthma ( area under the curve [ AUC ] , 0.723 ) . The diagnostic performance of FeNO was better in nonsmokers ( AUC , 0.805 ) , yet FeNO values > 25 ppb were characterized by specificity > 90 % for the diagnosis of asthma both in smokers and in nonsmokers . However , FeNO was not a good marker for the differentiation between asthma and allergic rhinitis . CONCLUSIONS FeNO measurement with a portable analyzer is useful for the screening for asthma in young adults . Significant confounding factors are allergic rhinitis and current smoking AIMS To assess whether exhaled nitric oxide ( FENO ) measurements improve management and clinician confidence in patients presenting with non-specific respiratory symptoms . METHODS This observational study was based in a large primary care practice ( 15,500 patients , 14 GPs ) . Patients had non-specific respiratory symptoms for at least six weeks .  FENO and spirometry measurements  were performed at initial assessment . An algorithm was employed to assist interpretation of FENO and spirometry results . GPs evaluated the diagnostic contribution of FENO and spirometry at 3- month follow-up . RESULTS In 48/51 ( 94 % ) of cases FENO was considered significant in formulating a diagnosis . Spirometry was deemed helpful in 27/51 ( 54 % ) . CONCLUSION FENO measurements improved diagnostic confidence when assessing non-specific respiratory symptoms . This may be because , in contrast to spirometry , both low and high FENO values have clinical significance . TRIAL REGISTRATION Australian Clinical Trials Registry ACTRN012605000354684 OBJECTIVES To determine the diagnostic accuracy of fractional exhaled nitric oxide ( FENO ) measurement in pneumologists routine diagnostic work-up ; and to determine the impact of the inflammatory pattern on diagnostic accuracy . METHODS Prospect i ve diagnostic study in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease ( OAD ) . Index test was FENO measurement . Reference st and ard was the  Tiffeneau ratio ( FEV(1)/VC ) or airway resistance as assessed by whole body plethysmography , with additional bronchoprovocation or bronchodilator testing . Morning sputum was analysed with smear slides which were prepared and stained by Giemsa . RESULTS 154 patients were diagnosed as having asthma ( 145 diagnoses based on bronchial provocation , 9 based on bronchodilator results ) , 5 had COPD . For the whole group , asthma could be ruled in at FENO > 71 ppb ( PPV 80 % ; 95 % CI 63 - 90 % ) and ruled out at FENO ≤ 9 ppb ( NPV 82 % ; 95 % CI 67 - 91 % ) ( area under the curve ( AUC ) = 0.656 ; 95 % CI 0.600 - 0.712 ; p < 0.001 ) . 128 patients delivered sputum . FENO was 44.3 ppb ( sd 48.9 ) in patients with predominant eosinophilic inflammation , 18.5 ppb with neutrophilic inflammation , and 23.1 ppb in others ( p = 0.003 ) . Diagnostic accuracy of FENO increased when patients with neutrophilic inflammation were omitted from analysis ( AUC = 0.745 ; 95 % CI 0.651 - 0.838 ; p < 0.001 ) . Then asthma could be ruled in at FENO > 31 ppb ( PPV 82 % ; 95 % CI 63 - 92 % ) and ruled out at FENO ≤ 12 ppb ( NPV 81 % ; 95 % CI 62 - 91 % ) . CONCLUSIONS FENO measurement can be useful as an additional diagnostic tool in pneumologists ' practice . The diagnostic value of FENO could be improved when inflammatory patterns are taken into account BACKGROUND In the latest Global Initiative for Asthma guideline , neither sputum eosinophilia nor fractional exhaled nitric oxide ( FeNO ) have been evaluated prospect ively as an aid in asthma diagnosis , but these measurements are being evaluated for potential use in determining optimal treatment . OBJECTIVE To report criteria for screening asthma using subjective symptoms and FeNO levels and results of a prospect i ve validation study using these criteria . METHODS Sixty-one out patients with recurrent cough , wheezing , or dyspnea underwent measurements of FeNO levels , pulmonary function , methacholine airway responsiveness , and inflammatory cells in induced sputum . The sensitivity , specificity , and concordance achieved using the FeNO-based criteria ( at least 1 of the following subjective symptoms : recurrent cough , wheezing , or dyspnea and /or FeNO level ≥ 40 ppb ) were analyzed and compared with the values obtained using conventional asthma diagnostic criteria , which includes subjective symptoms with any 2 of the following conditions : airway hyperresponsiveness , reversible airflow limitation , and eosinophilia in induced sputum . RESULTS Of the 61 patients , 41 were diagnosed as having asthma by the conventional criteria , and 33 were diagnosed as having asthma by the FeNO-based criteria , which showed a sensitivity of 78.6 % , a specificity of 89.5 % , and a concordance rate of 0.62 . Nine of 42 patients were misdiagnosed as not having asthma by FeNO-based criteria ( mean [ SD ] FeNO level , 23.9 [ 8.0 ] ppb ) . Seven of 9 patients were diagnosed as having nonatopic asthma according to IgE levels . CONCLUSIONS Asthma may be accurately diagnosed in daily practice on the basis of subjective symptoms and FeNO levels , particularly in atopic patients Importance Although asthma is a chronic disease , the expected rate of spontaneous remissions of adult asthma and the stability of diagnosis are unknown . Objective To determine whether a diagnosis of current asthma could be ruled out and asthma medications safely stopped in r and omly selected adults with physician-diagnosed asthma . Design , Setting , and Participants A prospect i ve , multicenter cohort study was conducted in 10 Canadian cities from January 2012 to February 2016 . R and om digit dialing was used to recruit adult participants who reported a history of physician-diagnosed asthma established within the past 5 years . Participants using long-term oral steroids and participants unable to be tested using spirometry were excluded . Information from the diagnosing physician was obtained to determine how the diagnosis of asthma was originally made in the community . Of 1026 potential participants who fulfilled eligibility criteria during telephone screening , 701 ( 68.3 % ) agreed to enter into the study . All participants were assessed with  home peak flow and symptom monitoring , spirometry , and serial bronchial challenge tests  , and those participants using daily asthma medications had their medications gradually tapered off over 4 study visits . Participants in whom a diagnosis of current asthma was ultimately ruled out were followed up clinical ly with repeated bronchial challenge tests over 1 year . Exposure Physician-diagnosed asthma established within the past 5 years . Main Outcomes and Measures The primary outcome was the proportion of participants in whom a diagnosis of current asthma was ruled out , defined as participants who exhibited no evidence of acute worsening of asthma symptoms , reversible airflow obstruction , or bronchial hyperresponsiveness after having all asthma medications tapered off and after a study pulmonologist established an alternative diagnosis . Secondary outcomes included the proportion with asthma ruled out after 12 months and the proportion who underwent an appropriate initial diagnostic workup for asthma in the community . Results Of 701 participants ( mean [ SD ] age , 51 [ 16 ] years ; 467 women [ 67 % ] ) , 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma . Current asthma was ruled out in 203 of 613 study participants ( 33.1 % ; 95 % CI , 29.4%-36.8 % ) . Twelve participants ( 2.0 % ) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community . After an additional 12 months of follow-up , 181 participants ( 29.5 % ; 95 % CI , 25.9%-33.1 % ) continued to exhibit no clinical or laboratory evidence of asthma . Participants in whom current asthma was ruled out , compared with those in whom it was confirmed , were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis ( 43.8 % vs 55.6 % , respectively ; absolute difference , 11.8 % ; 95 % CI , 2.1%-21.5 % ) . Conclusions and Relevance Among adults with physician-diagnosed asthma , a current diagnosis of asthma could not be established in 33.1 % who were not using daily asthma medications or had medications weaned . In patients such as these , reassessing the asthma diagnosis may be warranted RATIONALE The initial management of patients who present with persistent respiratory symptoms includes recognizing those with the potential to benefit from inhaled steroid therapy . To date , this has required undertaking a " trial of steroid " to identify responders . There is increasing evidence that steroid response is more likely in patients with eosinophilic airway inflammation , and this can be assessed indirectly using exhaled nitric oxide ( FENO ) measurements . OBJECTIVES We aim ed to assess the predictive accuracy of FENO to identify steroid response in 52 patients presenting with undiagnosed respiratory symptoms in a single-blind , fixed-sequence , placebo-controlled trial of inhaled fluticasone for 4 weeks . METHODS Comparisons of predictive accuracy were made between FENO and other conventional predictors : peak flows , spirometry , bronchodilator response , and airway hyperresponsiveness measured at baseline . " Steroid response " was defined as change in symptoms , peak flows , spirometry , or airway hyperresponsiveness to adenosine based on established guidelines and recommendations . RESULTS Steroid response was significantly greater in the highest FENO tertile ( > 47 ppb ) for each endpoint . This outcome was independent of the diagnostic label . The predictive values for FENO were significantly greater than for almost all other baseline predictors , with an optimum cut point of 47 ppb . CONCLUSIONS FENO measurements greater than 47 ppb provide a means of predicting steroid response in patients with undiagnosed respiratory symptoms . Assessing airway inflammation is of more practical value than diagnostic labeling when considering the potential usefulness of inhaled antiinflammatory therapy BACKGROUND The fraction of nitric oxide in exhaled air ( FeNO ) is used in asthma diagnosis and management . Smoking reduces FeNO and 20 - 35 % of asthmatics are smoking . However no guidelines exist on the diagnostic value of FeNO in smokers . Therefore we assessed the value of FeNO to diagnose asthma in a population of subjects with asthma-like symptoms and different smoking habits . METHODS Measurements of  FeNO , lung function , bronchial responsiveness and allergy testing were performed in 282 subjects ( 108 never- , 62 ex- and 112 current smokers ) aged 14 - 44 years , with symptoms suggestive of asthma . These subjects were a subset of subjects reporting respiratory symptoms ( n = 686 ) in a r and om population sample ( n = 10,400 ) . RESULTS A diagnosis of asthma was given to 96 of the 282 subjects . Subjects with asthma had higher FeNO levels than subjects with non-specific asthma symptoms in all three smoking strata ( p < 0.001 ) , with a percentual increase of FeNO by 76 % in never- , 71 % in ex- and 60 % in current smokers . The area under the ROC-curve was similar in never- , ex- and current smokers ( 0.72 vs. 0.74 vs. 0.70 ) . The cut-offs were approximately 30 % lower for either 90 % specificity ( 22 vs. 31 ppb ) or 90 % sensitivity ( 7 vs. 10 ppb ) in current vs. never-smokers . CONCLUSIONS FeNO could differentiate asthmatic subjects from non-asthmatic subjects with asthma-like symptoms equally well in both never- and current smokers within a r and om population sample . The FeNO cut-off levels needed in order to achieve high sensitivity or specificity were lower in current smokers
OBJECTIVES Measurement of fractional exhaled nitric oxide ( FENO ) might substitute bronchial provocation for diagnosing asthma .
However , optimal FENO thresholds for diagnosing asthma remain unclear .