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1 American Thoracic Society Documents An Official ATS Clinical Practice Guieline: Interpretation of Exhale Nitric Oxie Levels (FE NO ) for Clinical Applications Rae A. Dweik, Peter B. Boggs, Serpil C. Erzurum, Charles G. Irvin, Margaret W. Leigh, Jon O. Lunberg, Anna-Carin Olin, Alan L. Plummer, D. Robin Taylor, on behalf of the American Thoracic Society Committee on Interpretation of Exhale Nitric Oxie Levels (FE NO ) for Clinical Applications THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, MAY 2011 CONTENTS Executive Summary Introuction Methos Committee Composition, Meetings, an Document Preparation Document Structure Quality of Evience an Strength of Recommenations Why Shoul a FE NO Test be Obtaine? Can FE NO Be Use to Diagnose Asthma? FE NO Is Associate with Eosinophilic Airway Inflammation FE NO Preicts Likelihoo of Corticosteroi Responsiveness FE NO Can Support a Diagnosis of Asthma FE NO May Preict AHR Is There a Normal FE NO Value? Normal Values versus Relevant Cut Points for FE NO Confouning Factors that May Affect FE NO What Are the Clinically Significant Cut Points for FE NO? Low FE NO (, 25 ppb in Aults; 20 ppb in Chilren) High FE NO (. 50 ppb in Aults, 35 ppb in Chilren) Intermeiate FE NO (between 25 ppb an 50 ppb in Aults; ppb in Chilren) Persistently High FE NO (. 50 ppb in aults, 35 ppb in Chilren) Can FE NO Be Use to Monitor Airway Inflammation? Monitoring Airway Inflammation in Asthma Minimally Important Differences, an Prognostic Significance of FE NO How Shoul a FE NO Measurement Be Interprete an Reporte? Other Situations in which FE NO May Be Useful COPD Pulmonary Hypertension Cystic Fibrosis an Nasal NO Measurements Conclusions an Future Directions Online Supplement Appenix E1: Methos Checklist Appenix E2: Technical Consierations an Sources of Variation in FE NO Appenix E3: Causes of High an Low FE NO Levels Appenix E4: Case Stuies This article has an online supplement, which is available from this issue s table of contents at Am J Respir Crit Care Me Vol 184. pp , 2011 DOI: /rccm ST Internet aress: Backgroun: Measurement of fractional nitric oxie (NO) concentration in exhale breath (FE NO ) is a quantitative, noninvasive, simple, an safe metho of measuring airway inflammation that provies a complementary tool to other ways of assessing airways isease, incluing asthma. While FE NO measurement has been stanarize, there is currently no reference guieline for practicing health care proviers to guie them in the appropriate use an interpretation of FE NO in clinical practice. Purpose: To evelop evience-base guielines for the interpretation of FE NO measurements that incorporate evience that has accumulate over the past ecae. Methos: We create a multiisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway isease an/or NO. The committee ientifie important clinical questions, synthesize the evience, an formulate recommenations. Recommenations were evelope using pragmatic systematic reviews of the literature an the GRADE approach. Results: The evience relate to the use of FE NO measurements is reviewe an clinical practice recommenations are provie. Conclusions: In the setting of chronic inflammatory airway isease incluing asthma, conventional tests such as FEV 1 reversibility or provocation tests are only inirectly associate with airway inflammation. FE NO offers ae avantages for patient care incluing, but not limite to (1) etecting of eosinophilic airway inflammation, (2) etermining the likelihoo of corticosteroi responsiveness, (3) monitoring of airway inflammation to etermine the potential nee for corticosteroi, an (4) unmasking of otherwise unsuspecte nonaherence to corticosteroi therapy. Keywors: nitric oxie; asthma; inflammation; airway isease; exhale breath; clinical application EXECUTIVE SUMMARY Nitric oxie (NO) is now recognize as a biological meiator in animals an humans. NO is prouce by the human lung an is present in the exhale breath. It has been implicate in the pathophysiology of lung iseases, incluing asthma. The measurement of exhale NO has been stanarize for clinical use. Numerous stuies have provie evience regaring the applications of NO measurements in clinical practice, together with the performance characteristics an the strengths an the weaknesses of the test. Base on this evience, this Clinical Practice Guieline is esigne to guie clinicians as to how exhale NO measurements shoul be use an interprete. EVIDENCE QUALITY AND RECOMMENDATIONS These recommenations may vary with respect to the particular target population. Where this is the case, this has been inclue

2 American Thoracic Society Documents 603 in the recommenation. If not state, then the recommenation applies to patients with asthma. We recommen the use of FE NO in the iagnosis of eosinophilic airway inflammation (strong recommenation, moerate quality of evience). We recommen the use of FE NO in etermining the likelihoo of steroi responsiveness in iniviuals with chronic respiratory symptoms possibly ue to airway inflammation (strong recommenation, low quality of evience). We suggest that FE NO may be use to support the iagnosis of asthma in situations in which objective evience is neee (weak recommenation, moerate quality of evience). We suggest the use of cut points rather than reference values when interpreting FE NO levels (weak recommenation, low quality of evience). We recommen accounting for age as a factor affecting FE NO in chilren younger than 12 years of age (strong recommenation, high quality of evience). We recommen that low FE NO less than 25 ppb (, 20 ppb in chilren) be use to inicate that eosinophilic inflammation an responsiveness to corticosterois are less likely (strong recommenation, moerate quality of evience). We recommen that FE NO greater than 50 ppb (. 35 ppb in chilren) be use to inicate that eosinophilic inflammation an, in symptomatic patients, responsiveness to corticosterois are likely (strong recommenation, moerate quality of evience). We recommen that FE NO values between 25 ppb an 50 ppb (20 35 ppb in chilren) shoul be interprete cautiously an with reference to the clinical context. (strong recommenation, low quality of evience). We recommen accounting for persistent an/or high allergen exposure as a factor associate with higher levels of FE NO (strong recommenation, moerate quality of evience). We recommen the use of FE NO in monitoring airway inflammation in patients with asthma (strong recommenation, low quality of evience). We suggest using the following values to etermine a significant increase in FE NO : greater than 20% for values over 50 ppb or more than 10 ppb for values lower than 50 ppb from one visit to the next (weak recommenation, low quality of evience). We suggest using a reuction of at least 20% in FE NO for values over 50 ppb or more than 10 ppb for values lower than 50 ppb as the cut point to inicate a significant response to antiinflammatory therapy (weak recommenation, low quality of evience). Conclusion: Avances in technology an stanarization have mae FE NO measurement simple, permitting its use as a biomarker that as a new imension to the traitional clinical tools in the assessment an management of airways iseases. These guielines for interpretation of FE NO measurements are meant to enhance their clinical utility, but more work is still neee to better efine the use of FE NO in ifferent clinical settings. INTRODUCTION NO has long been known as an atmospheric pollutant present in vehicle exhaust emissions an cigarette smoke, an more recently its clinical importance as a biological meiator in animals an humans has been recognize (1, 2). NO is present in virtually all mammalian organ systems an is prouce by the human lung. It is present in the exhale breath of all humans (3). NO is recognize to play key roles in virtually all aspects of lung biology an has been implicate in the pathophysiology of lung iseases, incluing asthma (4). The functions an effects of NO in the lung/airways reflect its key roles as a vasoilator, bronchoilator, neurotransmitter, an inflammatory meiator (3). Patients with asthma have high levels of NO in their exhale breath an high levels of inucible nitric oxie synthase (NOS2) enzyme expression in the epithelial cells of their airways, suggesting a role for NO in asthma pathogenesis (5). NO is a highly reactive molecule/free raical an may have oxiant properties irectly or in the form of the more noxious peroxynitrite. These properties give NO its bactericial an cytotoxic effects an may participate in host efense by meiating antimicrobial activity an cytotoxicity for tumor cells (4). The exact pathophysiological role of NO in the airways an lungs is complex (4, 6 8). On the one han, it may act as a proinflammatory meiator preisposing to the evelopment of airway hyperresponsiveness (AHR) (4, 9). On the other, uner physiological conitions NO acts as a weak meiator of smooth muscle relaxation, an protects against AHR (4, 10). In exhale air, NO appears to originate in the airway epithelium (5, 11 15), as a result of NOS2 up-regulation which occurs with inflammation (5, 12, 13, 16). Thus, exhale NO may be regare as an inirect marker for up-regulation of airway inflammation. The fiel of exhale NO measurement has evelope remarkably over the last 15 years. The use of chemiluminescence analyzers allowe for the etection of NO in exhale breath in the early 1990s (17). Patients with asthma were foun to have high FE NO in their exhale breath (18 20) that ecrease in response to treatment with corticosterois (21). This quickly prompte the evaluation of FE NO as a potential noninvasive metho to iagnose asthma an monitor the response to antiinflammatory therapy. Avantages for FE NO inclue the noninvasive nature of the test, ease of repeat measurements, an the relatively easy use in patients with severe airflow obstruction where other techniques are ifficult to perform (22). By proviing information about airway inflammation (23, 24), FE NO as a new imension to the traitional clinical tools (history, physical exam, an lung function tests). Before FE NO coul become useful as a clinical tool, several issues neee to be aresse (25). In particular, the methos an equipment for measuring FE NO neee to be stanarize (26, 27). Large population stuies were neee to etermine effect of confouning factors an provie the normal range or useful cutoff points of FE NO levels (22, 25). Most of these issues have either alreay been aresse or are currently uner investigation, allowing FE NO measurement to make the transition from research into the clinical arena. Last, but not least, interpretative strategies nee to be evise an put in place for the ifferent potential uses an applications (28). The purpose of this ocument is to aress this last requirement. Wherever possible, the recommenations are base on publishe material, incluing abstracts, as reference, but they are supplemente by nonsystematic observations of experts in the fiel. The guielines are provie with the clear unerstaning that this will be a rapily evolving area an that perioic upating will be require. METHODS Committee Composition, Meetings, an Document Preparation The project Chair (R.A.D.) assemble a group of international experts in exhale nitric oxie. Their expertise was in clinical

3 604 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL care, clinical research, or basic science in the area of asthma an/ or nitric oxie (five pulmonologists [R.A.D., S.C.E., A.C.O., A.L.P., D.R.T.], an allergist [P.B.B.], two physiologists [C.G.I., J.O.L.], an one peiatric pulmonologist [M.W.L.]). The outline of the Report was propose by the Chair an moifie an agree upon following input from all Committee members. The Committee was ivie into subgroups, each was assigne a specific section, an preliminary rafts were evelope. Three face-to-face meetings an nine teleconferences were hel. The outline an the rafts were reviewe, an evience-base recommenations were iscusse an finalize by consensus. Committee members isclose all potential conflicts of interest. All isclose conflicts of interests were reporte to the Chair of the Ethics an Conflict of Interest Committee of the ATS. These were reviewe in etail, an members with perceive conflicts abstaine from the iscussion of specific questions relate to their conflicts of interest. Furthermore, members were remine to consier their own an other members potential conflicts of interest uring the meetings. The Chair (R.A.D.) integrate the raft sections an compose the entire ocument into a preliminary ocument that was circulate among the committee members for further input. The revise ocument incorporate the comments an input from all Committee members. Document Structure This ocument is structure to provie an evience-base review of the current state of knowlege regaring the application an interpretation of FE NO measurements in clinical practice. The recommenations regaring interpretive strategy were organize aroun specific questions accoring to the GRADE approach to assessing the quality of the evience (Summary Table E1 in Appenix in online supplement) (29, 30). Relevant section topics an questions were ientifie by the Committee. Committee members were aske to review the current evience by inepenently completing a pragmatic systematic review of the literature using PubMe an OVID. Each Committee member was aske to assess the ientifie literature relevant to his/her section, an ecie about inclusion of iniviual articles. MED- LINE searches from 1993 to December 2008 were performe by Committee members, with perioic upates uring ocument evelopment an finalization. Searching the literature before 1993 was not one systematically since the iscovery of nitric oxie in asthma was first reporte in The search was augmente by searches of Committee member files. The literature search was limite to all relevant stuies incluing ranomize controlle trials, cohort stuies, case-control stuies, an cross-sectional stuies publishe in the English language. Sections that i not yiel specific recommenations were written after a thorough review of the available literature in a narrative review format. Quality of Evience an Strength of Recommenations The quality of evience was etermine accoring to the ATS GRADE criteria (30). For each question, the Committee grae the quality of the evience available (high, moerate, low, or very low), an mae a recommenation for or against. Recommenations were ecie by consensus. Recommenations were either strong or weak. The strength of a recommenation reflects the extent to which one can, across the range of patients for whom the recommenation is intene, be confient that esirable effects outweigh unesirable effects (30). Consensus on the recommenations was reache among all the members of the Committee. The strength of a recommenation has important implications for patients, clinicians, an policy makers (30). Strong recommenation. Patients: Most people in this situation woul want the recommene course of action an only a small proportion woul not Clinicians: Most patients shoul receive the recommene course of action Policy makers: The recommenation can be aopte as a policy in most situations Weak recommenation. Patients: The majority of people in this situation woul want the recommene course of action, but many woul not Clinicians: Be more prepare to help patients to make a ecision that is consistent with the patient s own values Policy makers: There is a nee for substantial ebate an involvement of stakeholers Why Shoul a FE NO Test Be Obtaine? Common reasons for measuring FE NO. To assist in assessing the etiology of respiratory symptoms To help ientify the eosinophilic asthma phenotype To assess potential response or failure to respon to antiinflammatory agents, notably inhale corticosterois (ICS) To establish a baseline FE NO uring clinical stability for subsequent monitoring of chronic persistent asthma To guie changes in oses of antiinflammatory meications: stepown osing, step-up osing, or iscontinuation of antiinflammatory meications To assist in the evaluation of aherence to antiinflammatory meications To assess whether airway inflammation is contributing to poor asthma control particularly in the presence of other contributors (e.g., rhinosinusitis, anxiety, gastro-esophageal reflux, obesity, or continue allergen exposure). Can FE NO Be Use to Diagnose Asthma? Asthma is a clinical iagnosis an there is no single iagnostic test for the isease. The backgroun pathology of asthma is often but not always ue to eosinophilic airway inflammation. The two are not synonymous. This is extremely important in the interpretation of FE NO measurements. It is often claime that FE NO is a iagnostic test for asthma, but in cases of asthma not ue to airway eosinophilia, FE NO may be low. Similarly, the value of exhale FE NO as a preictor of steroi responsiveness is high even in the absence of inuce sputum eosinophils (31). - Recommenations: We recommen the use of FE NO in the iagnosis of eosinophilic airway inflammation (strong recommenation, moerate quality of evience). We recommen the use of FE NO in etermining the likelihoo of steroi responsiveness in iniviuals with chronic respiratory symptoms possibly ue to airway inflammation (strong recommenation, low quality of evience). We suggest that FE NO may be use to support the iagnosis of asthma in situations in which objective evience is neee (weak recommenation, moerate quality of evience). FE NO is associate with eosinophilic airway inflammation. There are several inflammatory phenotypes in asthma most commonly escribe as eosinophilic, neutrophilic, mixe, an paucigranulocytic (32). Determination of the subtype may help a physician

4 American Thoracic Society Documents 605 ecie which therapies to select or stop (33 35). Given the longestablishe relationship between eosinophilic inflammation an steroi responsiveness in airways isease, the fining that FE NO correlates with eosinophilic inflammation suggests its use as inirect inicator not only of eosinophilic inflammation, but more importantly of the potential for steroi responsiveness (36 42). There is little evience irectly emonstrating that eosinophilic airway inflammation increases FE NO by increasing NOS2 expression or activity (43). However, eosinophilic airway inflammation may affect FE NO inirectly through NOS2 or via other enzyme pathways. Numerous stuies escribe the relationship between FE NO an eosinophilic airway inflammation. Eosinophils can be measure in sputum, bronchoalveolar lavage, an biopsies. There are also reports of correlation between FE NO an bloo eosinophils (44 46). Warke an coworkers reporte that in bronchoalveolar lavage flui the correlation between eosinophils an FE NO was 0.78 (P, 0.001) (40). Payne an colleagues reporte that the correlation between FE NO an eosinophils in bronchial biopsies was 0.54 (P ¼ 0.03) (47), but in contrast Lim an coworkers were unable to fin a significant correlation in the biopsies (48). In inuce sputum, the correlation between FE NO levels an eosinophils ranges from 0.35 (n ¼ 25, P ¼ 0.09)(36)to0.48(n¼ 35, P ¼ 0.003) (49) to 0.62 (n ¼ 78, P, 0.001) (50). In the largest stuy to ate (n ¼ 566), the correlation was of a similar orer (0.59, P, 0.001) (39). In this last stuy, FE NO of 36 ppb (at a flow rate of 50 ml/s) ha a sensitivity an specificity for sputum eosinophilia of more than 3% (the cut point eeme by the authors to be clinically significant) of 78% an 72%, respectively. In the stuy by Shaw an colleagues, a FE NO of less than 26 ppb ha a negative preictive value of 85% for sputum eosinophils less than 3% (51). Similarly, Porsbjerg an coworkers have reporte that with FE NO less than 27ppb, it is unlikely that sputum eosinophils will be greater than 1% (52). Thus a low FE NO is of value in etermining the absence of eosinophilic, an, by inference, the likely absence of steroi-responsive airway inflammation. These limite correlations reflect the fact that whereas sputum eosinophilia is always abnormal, exhale nitric oxie is present even in health with its istribution skewe to the right. It is also necessary to bear in min that negative an positive preictive values are limite in their generalizablity, given that they epen on the prevalence of the conition in the teste population. Importantly, two stuies have shown that the relationship between FE NO levels an airway eosinophilia is inepenent of the iagnosis of asthma as reporte in patients with chronic obstructive pulmonary isease (COPD) (53), an with eosinophilic bronchitis (54). Furthermore, NO an NO metabolites in the airway (e.g., peroxynitrite) alter the REDOX balance in the airways, may cause inflammation, an are in some part steroi sensitive. Thus NO prouction is to some extent inepenent of eosinophilic inflammation (4). FE NO preicts likelihoo of corticosteroi responsiveness. Treatment response in asthma is heterogeneous (55). Not all patients respon to corticosterois an an important reason to use FE NO is to help ecie who might benefit from steroi treatment, an who shoul try other meications (e.g., leukotriene moifiers). FE NO may also be use to etermine patients in whom steroi therapy may be safely withrawn. FE NO has been shown to preict the likelihoo of steroi responsiveness more consistently than spirometry, bronchoilator response, peak flow variation, or AHR to methacholine (56 58). The optimum cut point in the stuy by Smith an coworkers (56), was 47 ppb, with a negative preictive value of 89% for the change in FEV 1 with inhale sterois. The preictive values were similar for alternative enpoints. Even when patients o not emonstrate sputum eosinophilia, FE NO is highly preictive of steroi response (at a cut point of 33 ppb) (31). These ata are consistent with stuies in which high FE NO (. 47 ppb) preicts the likelihoo of loss of control when inhale sterois are reuce or withrawn in chilren with a confirme iagnosis of asthma (59). Conversely, low FE NO (, 22 ppb) preicts the likelihoo of successful reuction or withrawal of inhale sterois (positive preictive value, 92%) (60). Again, these outcomes may iffer somewhat epening on the target population: for the most part these ata are erive from patients with mil to moerate asthma. In summary, epening on the prevalence of eosinophilic airway inflammation in the target population, FE NO measurements may provie a signal that is helpful in ientifying patients with asthma-like symptoms who are likely to benefit (or not) from corticosteroi treatment. FE NO can support a iagnosis of asthma. The iagnosis of asthma is well efine, an the backgroun pathology is often but not always ue to eosinophilic airway inflammation. Early stuies in populations comprising mainly patients with eosinophilic asthma explore the performance characteristics of FE NO as a iagnostic test. The preictive values for FE NO (usually at cut points of. 25 ppb) were shown to be sufficiently robust for it to be use in this context (23, 61, 62). Further, the preictive values for FE NO are higher than for conventional measurements such as peak flows an spirometry (23), an similar to those associate with bronchial challenge tests (62). However, in general, in patients presenting with variable cough, wheeze, an shortness of breath, an increase FE NO provies supportive rather than conclusive evience for an asthma iagnosis. As state, the limitations to the iagnostic role of FE NO arise principally because airway inflammation in asthma is heterogeneous an is not always associate with increase FE NO (e.g., neutrophilic airway inflammation). Similarly, in patients who have alreay been treate with inhale sterois, the test may be falsely negative. Thus, the importance of FE NO lies in its potential to ientify steroi responsiveness, rather than the exact clinical iagnosis. This information is much more clinically relevant because it enables the clinician to bypass an empiric trial of sterois or unnecessary long-term corticosteroi treatment. FE NO may preict AHR. Irrespective of the specific unerlying inflammatory signal which FE NO represents, measurements appear to reflect the ynamic interrelationships between the response to allergen or other triggers an evolving eosinophilic airway inflammation/ahr (4, 7, 8, 63). Serial FE NO levels increase progressively in response to allergen exposure an the avent of airway symptoms (63). Because of the practical ifficulties involve in measuring AHR, especially in chilren, it was initially thought that FE NO might be use as a surrogate marker for AHR. The relationship between NO metabolism an AHR in asthma is complex (64). When FE NO was use to preict the presence of AHR, the stuies reveal inconsistent relationships an correlations are generally low. The clinical interpretation of FE NO in relation to AHR is even more problematic in subjects who are taking ICS (9, 65) an with long-staning as oppose to recently evelope asthma (66). This is emonstrate in stuies esigne to evaluate pathophysiological relationships in clinical asthma using factor analysis: AHR, airway inflammation, an FE NO belong to ifferent omains (66 68). However, in one stuy FE NO has been use as a surrogate for AHR testing to support the iagnosis of asthma in chilren, an the ata appear to support its use in this limite context (62). Is There a Normal FE NO Value? This section will iscuss the normal ranges of FE NO. We will also iscuss the important clinical cut points an the rationale for selecting these cut points to be use in the interpretation of an

5 606 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Schematic representation of the istribution of FE NO levels in an unselecte population of 2,200 male an female subjects. The meian value was 16.0 ppb with a range of 2.4 to 199 ppb. The cut point of 26 ppb is the optimum cut point for significant sputum eosinophilia, inicating that up to 20% of iniviuals with an FE NO greater than 25 ppb may not necessarily have sputum eosinophilia, an that the clinical context requires to be taken into account. The ata use to prepare this composite figure were obtaine from Shaw an colleagues (51) an Olin an colleagues (73) after consultation with the authors. elevate or reuce FE NO value. It is important to choose the appropriate cut point in relation to the clinical setting an question. While this section an the accompanying tables (see Tables 3 5) focus on asthma an airway iseases/inflammation, other causes of high an low FE NO levels are liste in the Appenix in the online supplement. - Recommenations: We suggest the use of cut points rather than reference values when interpreting FE NO levels (weak recommenation, low quality of evience). We recommen accounting for age as a factor affecting FE NO in chilren younger than 12 years of age (strong recommenation, high quality of evience). Normal Values versus Relevant Cut Points for FE NO This section will iscuss the normal ranges of FE NO an what are the important clinical cut points to be use in the interpretation of an elevate or reuce FE NO value. It is unlikely that reference values erive from a normal population will be as helpful as cut points in patients with airways isease or respiratory symptoms. The istribution of FE NO in an unselecte population is skewe to the right (see Figure 1). Even when iniviuals with atopy or iagnose asthma are exclue, the upper limit of normal ranges from 27 to 57 ppb epening on sex (69). This overlaps with the range of values obtaine in populations with asthma in relation to sputum eosinophilia (see Figure 1). In a clinical stuy, Shaw an colleagues reporte that the optimum cut point for a clinically significant FE NO (corresponing to a sputum eosinophil count of > 2%) was 26 ppb (51). Similarly, stuies esigne to etermine the optimum cut point to iagnose asthma using FE NO have usually pointe to a iagnostic cut point ranging from 20 to 25 ppb (23, 70 72). However, in patients with stable, well-controlle asthma, FE NO values range from 22 to 44 ppb (73). Clearly, there is consierable overlap between mean FE NO levels in healthy an populations with stable asthma. This is illustrate in Figure 2. Confouning factors that may affect FE NO. As iscusse in the Appenix in the online supplement, FE NO values can be affecte by several factors, incluing measurement technique, exhalation flow rate, nasal NO contamination, the NO analyzer use (74), age, height, smoking, an antiinflammatory meications. A number of recent publications have reporte reference values for FE NO in aults (69, 75 79) (Table 1) an chilren (76, 80 83). There are important ifferences between these stuies with regar to the size of the examine population, as well as the range of statistical variables that have been inclue or exclue, limiting their value (76, 77, 80 83). Factors affecting population FE NO levels may be ue to one or more variables incluing genetics, age, sex, atopy, weight an height, current smoking, an iet. The importance of current smoking an atopic status is generally agree upon (28), but there are inconsistencies between the stuies regaring which other factors ought to be accounte for when eriving an applying reference values (Table 1). More etaile information on these biological sources of variability is provie in the Appenix in the online supplement. Age seems to be important in chilren (81), but there is less agreement across the stuies regaring age in aults, sex, an height. In the largest stuy to ate, Olin an coworkers ientifie the importance of age an height as factors affecting FE NO, but i not fin any ifferences between males an females (69). In contrast, Travers an colleagues (78) an Taylor an coworkers (84) reporte consistently higher levels in males. The magnitue of the effect of the patient-relate factors alone or in combination is potentially clinically significant. This is emonstrate in Table 2 (ata from Reference 69). Thus, in our present state of knowlege the problems of multiple confouning factors an overlap between normal populations an populations with asthma preclue the routine application of reference values in the clinical setting. The Committee felt that it is more relevant to ientify clinically meaningful cut points rather than reference values to interpret FE NO levels as outline below, keeping in min that very few of these cut points are well valiate. At any one time, however, the most important consieration is whether or not the patient has current respiratory symptoms or a prior iagnosis of airways isease; that is, the Figure 2. An amplification of Figure 1 in which the istribution of FE NO in stable asthma is epicte as a otte line. Taken from Olin an colleagues (73). In that stuy, the 95% confience intervals for FE NO in stable asthma was reporte to be 22 to 44 ppb. The cut point of 47 ppb is the optimum cut point for steroi responsiveness in patients with nonspecific respiratory symptoms. The other ata use to prepare this composite figure were obtaine from Smith an colleagues (56) after consultation with the authors.

6 American Thoracic Society Documents 607 TABLE 1. STUDIES OF ONLINE FRACTION OF EXHALED NITRIC OXIDE VALUES AT EXHALATION FLOW RATE OF 50 ml/s IN HEALTHY SUBJECTS Author an Reference N Groups for which Reference Values Are Given Normal Values (ppb) Analyzer Kharitonov 2003 (75) 59 Mixe population of aults an chilren Mean 16.3 ppb, ULN 33. NIOX (Aerocrine AB, Stockholm, Sween) Buchval 2005 (76) 405 Chilren age 4 17 yr Mean 9.7 ppb, NIOX (Aerocrine AB, Stockholm, Sween) Data also available by age stratification Upper 95% CI: 25.2 Olivieri 2006 (77) 204 Male, nonsmoker, nonasthmatic (CLD88, Ecomeics, Switzerlan) Female, nonsmoker, nonasthmatic (note: atopy not consiere) (note: values quote are 5th an 95th centiles) Olin 2007 (69) 3,376 Ranom population See Table 2 NIOX (Aerocrine AB, Stockholm, Sween) 1,131 never-smoking subjects not reporting any asthma symptom, ry cough or the use of inhale corticosterois Travers 2007 (78) 3,500 Male, nonsmoker, nonatopic NIOX (Aerocrine AB, Stockholm, Sween) Male, nonsmoker, atopic Male, smoker, nonatopic Male, smoker, atopic Female, nonsmoker, nonatopic Female, nonsmoker, atopic Female, smoker, nonatopic Female, smoker, atopic (note: values quote are 90% confience interval) Dressel 2008 (79) 897 Male, nonsmoker, nonatopic, 165 cm 19.5 (NOA 280, Sievers, Bouler, CO) Male, nonsmoker, atopic, 165 cm 29.1 Male, smoker, nonatopic, 165 cm 12.2 Male, smoker, atopic, 165 cm 18.3 Female, nonsmoker, nonatopic, 160 cm 15.7 Female, nonsmoker, atopic, 160 cm 23.5 Female, smoker, nonatopic, 160 cm 9.9 Female, smoker, atopic, 160 cm 14.7 interpretation of FE NO levels shoul be etermine in iniviual patients with reference to the context in which the measurement is being obtaine. What Are the Clinically Significant Cut Points for FE NO? It is important to choose the appropriate cut point in relation to the clinical setting an question. In this section, we iscuss the rationale for selecting these cut points (see Tables 3 5). While this section an the accompanying tables focus on asthma an airway iseases/inflammation, other causes of high an low FE NO levels are liste in the Appenix in the online supplement. - Recommenations: We recommen that low FE NO (, 25 ppb [, 20 ppb in chilren]) be use to inicate that eosinophilic inflammation an TABLE 2. FRACTION OF EXHALED NITRIC OXIDE 95% UPPER LIMITS, STRATIFIED FOR SEX AND ATOPY, ACCORDING TO HEIGHT AND AGE AMONG 1,131 HEALTHY LIFELONG NEVER- SMOKING SUBJECTS Height Age yr Age yr (cm) Women Men Women Men Subjects without Atopy (n ¼ 845) Subjects with Atopy (n ¼ 286) Data taken from Reference 69. responsiveness to corticosterois are less likely (strong recommenation, moerate quality of evience). We recommen that FE NO. 50ppb (. 35 ppb in chilren) be use to inicate that eosinophilic inflammation an, in symptomatic patients, responsiveness to corticosterois are likely (strong recommenation, moerate quality of evience). We recommen that FE NO values between 25 ppb an 50 ppb (20 35 ppb in chilren) shoul be interprete cautiously with reference to the clinical context (strong recommenation, low quality of evience). Low FE NO (, 25 ppb in aults; 20 ppb in chilren). In a symptomatic ault patient with a FE NO of less than 25 ppb (20 ppb in chilren), eosinophilic airway inflammation is unlikely. This cut point is base on evience from a number of sources incluing the stuy by Shaw an colleagues (51) an Porsbjerg an coworkers (52), stuies investigating the role of FE NO measurements to iagnose asthma (23, 70 72), an stuies esigne to optimize ICS use (56, 60). The ifferential iagnosis for symptomatic patients with a low FE NO is given in Table 3. In patients presenting with nonspecific respiratory symptoms, low FE NO suggests alternative iagnoses which are not amenable to an increase in inhale or oral steroi therapy. High FE NO (. 50 ppb in aults, 35 ppb in chilren). High FE NO is likely to inicate significant airway eosinophilia. It is also likely to inicate that a symptomatic patient has steroi-responsive airways inflammation (56, 57, 85, 86). The clinically significant cut point of 50 ppb is base on the results of pragmatic stuies. However, this is a general guie an may vary slightly in iniviual patients. Symptomatic steroi-naïve patients with high FE NO are more likely to exhibit responsiveness to inhale steroi therapy, irrespective of the iagnostic label (e.g., asthma or nonasthma), with an optimum cut point of 47 ppb (56). In asymptomatic patients with stable asthma, the likelihoo of relapse following withrawal of ICS therapy is greatest in patients whose FE NO increases to above 49 ppb uring the 4 weeks after

7 608 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 3. LOW FE NO (, 25 ppb [, 20 ppb IN CHILDREN]): IMPLIES NONEOSINOPHILIC OR NO AIRWAY INFLAMMATION* Diagnosis In a symptomatic patient (chronic cough an/or wheeze an/or shortness of breath for. 6 wk) presenting for the first time, the patient is unlikely to benefit from a trial of inhale corticosteroi treatment, possible etiologies: Other pulmonary/airway causes: Rhinosinusitis Noneosinophilic asthma Reactive airways ysfunction synrome COPD Bronchiectasis Cystic fibrosis, primary ciliary yskinesia Extene post-viral bronchial hyperresponsiveness synrome Vocal cor ysfunction Nonpulmonary/airway causes: Anxiety-hyperventilation Gastroesophageal reflux isease Cariac isease/pulmonary hypertension/pulmonary embolism Confouning factors: Smoking Obesity Monitoring In a symptomatic patient with an establishe iagnosis of asthma, possible etiologies: Asthma: Noneosinophilic asthma (probably steroi unresponsive) Aitional or alternative iagnosis? Vocal cor ysfunction Anxiety-hyperventilation Bronchiectasis, Cariac isease Rhinosinusitis, Gastroesophageal reflux isease In an asymptomatic patient with an establishe iagnosis of asthma: Implies aequate osing an goo aherence to antiinflammatory therapy Inhale corticosteroi ose may possibly be reuce (repeat FE NO 4wklaterto confirm this jugment; if it remains low then relapse is unlikely). Definition of abbreviations: COPD ¼ chronic obstructive pulmonary isease; FE NO ¼ fraction of exhale nitric oxie. *The interpretation of FE NO is an ajunct measure to history, physical exam, an lung function assessment. For intermeiate FE NO levels (in the range ppb [20 35 ppb in chilren]), refer to Table 5. steroi withrawal (59). The ifferential iagnosis for high FE NO is shown in Table 4. Intermeiate FE NO (between 25 ppb an 50 ppb in aults; ppb in chilren). The above ata inicate that for FE NO values between 25 an 50 ppb, cautious interpretation is require. The weight place on an FE NO result within this range will epen on whether the test is being use iagnostically in a symptomatic steroi-naïve subject, or whether the patient s FE NO has increase or ecrease from a previous value by what is eeme to be a clinically significant amount in a patient who is being monitore over time. - Recommenation We recommen accounting for persistent an/or high allergen exposure as a factor associate with higher levels of FE NO (strong recommenation, moerate quality of evience). Persistently high FE NO (. 50 ppb in aults, 35 ppb in chilren). In a patient with ongoing asthma, symptoms may occur espite apparently aequate antiinflammatory treatment (87). In the collective experience of the Committee, a common cause of persistently high FE NO is poor aherence to ICS therapy. Other explanations coul be poor inhale rug elivery or continue exposure to allergen (7, 8). Continuing or increasing exposure to aeroallergens to which a patient is sensitize may result in a rise in FE NO, or the TABLE 4. HIGH FE NO (. 50 ppb [. 35 ppb IN CHILDREN]) OR RISING FE NO (. 40% CHANGE FROM PREVIOUSLY STABLE LEVELS): IMPLIES UNCONTROLLED OR DETERIORATING EOSINOPHILIC AIRWAY INFLAMMATION* Diagnosis In a symptomatic patient (chronic cough an/or wheeze an/or shortness of breath uring past. 6 wk) presenting for the first time, possible etiologies: Atopic asthma Eosinophilic bronchitis COPD with mixe inflammatory phenotype That the patient is likely to benefit from a trial of inhale corticosteroi treatment Monitoring In a symptomatic patient with an establishe iagnosis of asthma, possible etiologies: High persistent allergen exposure Inhale corticosteroi elivery problems: Poor aherence Poor inhaler technique Proximal rug eposition, with untreate istal airway/alveolar inflammation Inaequate inhale corticosteroi ose: Likely to respon to increase inhale corticosteroi ose OR prenisone Rarely: truly steroi resistant asthma (a trial of systemic steroi will confirm this: FE NO will remain high Rarely: Churg Strauss synrome, pulmonary eosinophilia In an asymptomatic patient: No change in inhale corticosteroi osing, but refer to FE NO tren over time in iniviual patient Withrawing inhale corticosteroi is likely to be followe by relapse An increase in therapy is inicate as some patients are asymptomatic, but the high FE NO coul be a risk factor for an upcoming exacerbation. High F E NO may be normal in a certain percent of the population (Figure 1). Definition of abbreviation: FE NO ¼ fraction of exhale nitric oxie. *The interpretation of FE NO is an ajunct measure to history, physical exam, an lung function assessment. For intermeiate FE NO (levels in the range ppb [20 35 ppb in chilren]), refer to Table 5. persistence of an elevate FE NO. The magnitue of the effect may be sufficient for FE NO levels to increase beyon the cut point of 50 ppb, an in some patients may occur even in the absence of respiratory symptoms (88 91). More recent evience suggests that persistent high FE NO in corticosteroi-treate iniviuals with asthma may also reflect a highly reactive asthma phenotype, an such patients nee to be manage with caution (35). However, if the patient is asymptomatic an has a high FE NO, then no change in treatment is require. There is a small group of patients whose FE NO remains high espite goo asthma control. This probably results from the fact that more than one factor (i.e., not just eosinophilic airway inflammation) is responsiblefortheelevatefe NO. Another explanation may be that the high exhale NO is erive from constitutive NOS sources which are steroi insensitive. Thus, levels greater than 50 ppb in a welltreate asymptomatic patient may be normal for that specific patient. Can FE NO Be Use to Monitor Airway Inflammation? The change in FE NO value following corticosteroi intervention may be more vali than the absolute FE NO value. The efinition of a clinically significant change in FE NO, however, remains to be establishe. - Recommenations We recommen the use of FE NO in monitoring airway inflammation in patients with asthma (strong recommenation, low quality of evience).

8 American Thoracic Society Documents 609 TABLE 5. GENERAL OUTLINE FOR FE NO INTERPRETATION: SYMPTOMS REFER TO COUGH AND/OR WHEEZE AND/OR SHORTNESS OF BREATH* FE NO, 25ppb FE NO ppb FE NO. 50 ppb (,20 ppb in chilren) (20 35 ppb in chilren) (.35 ppb in chilren) Diagnosis Symptoms present uring past 61 wk Eosinophilic airway inflammation unlikely Be cautious Evaluate clinical context Eosinophilic airway inflammation present Alternative iagnoses Monitor change in FE NO over time Likely to benefit from ICS Unlikely to benefit from ICS Monitoring (in Patients with Diagnose Asthma) Symptoms present Possible alternative iagnoses Persistent allergen exposure Persistent allergen exposure Unlikely to benefit from increase in ICS Inaequate ICS ose Poor aherence Poor aherence or inhaler technique Inaequate ICS ose Steroi resistance Risk for exacerbation Steroi resistance Symptoms absent Aequate ICS ose Goo aherence ICS taper Aequate ICS osing Goo aherence Monitor change in FE NO ICS withrawal or ose reuction may result in relapse Poor aherence or inhaler technique Definition of abbreviations: FE NO ¼ fraction of exhale nitric oxie; ICS ¼ inhale corticosteroi. * The interpretation of FE NO is an ajunct measure to history, physical exam, an lung function assessment. See text an Tables 3 an 4 for other etails. We suggest using the following values to etermine a significant increase in FE NO : greater than 20% for values over 50 ppb or more than 10 ppb for values lower than 50 ppb from one visit to the next (weak recommenation, low quality of evience). We suggest using a reuction of at least 20% in FE NO for values over 50 ppb or more than 10 ppb for values lower than 50 ppb as the cut point to inicate a significant response to antiinflammatory therapy (weak recommenation, low quality of evience). Monitoring Airway Inflammation in Asthma Serial measurements obtaine when patients asthma is both stable an unstable allows each patient to act as his/her own control when assessing subsequent measurements an as a result personal best can be use (92). The same cut points use in etecting airway inflammation apply when monitoring patients with asthma. In asymptomatic iniviuals, incluing patients with well-controlle asthma, low FE NO suggests that ICS ose coul be reuce or even that ICS treatment may be withrawn altogether. In a stuy of chilren with stable asthma, withrawal of ICS i not result in symptom relapse when FE NO remaine consistently low (optimum cut point 22 ppb) when measure 2 to 4 weeks after treatment withrawal (60). In symptomatic patients with low FE NO, strategies other than increasing the ICS ose shoul be pursue. Thus, FE NO values which are either high or low are informative as to the etiology of current symptoms particularly in patients with ifficult asthma. Sequential measurements may be important in etermining trens. The relatively rapi change in FE NO in response to ICS is thought to a to its utility in monitoring aherence to an response to such therapy (93). However, as a preictor of asthma control, FE NO is no better than more conventional lung function tests (51, 87, 94, 95). The preictive values of a single measurement of FE NO for loss of asthma control are insufficiently sensitive or specific to justify its use for this specific purpose (51, 94, 95). Minimally Important Differences, an Prognostic Significance of FE NO The within-subject coefficient of variation for FE NO in healthy subjects is approximately 10%, or up to 4 ppb (75, 96). The variation increases to approximately 20% in patients with asthma (75, 96, 97). Since a change of 20% coul be ue to the variation in the FE NO measurement, the Committee recommens a change of at least 20% to inicate a significant rise or fall in FE NO over time or following an intervention. However, there are very few ata that clarify what constitutes a clinically important change in iniviual patients. In one stuy, FE NO levels were 50% higher uring acute asthma compare with when stability was restore (98). Data obtaine from steroi withrawal stuies show that the mean increase in FE NO associate with the avent of loss of control ranges from 16 ppb (99) to 25 ppb (50), the latter representing a 60% increase from baseline. However, the range of the increase in FE NO between stability an loss of control is high (up to 141 ppb) (50). More recently, Michils an colleagues have reporte that the transition from goo control to poorly controlle asthma is likely to be associate with a rise in FE NO of 40% or greater (100). An acute rise (over h) in FE NO may occur after infection or exposure to an allergen to which the patient is sensitize. The magnitue of the rise may be as high as 150 ppb. Ieally, one woul wish that a minimally important change in FE NO to a level that is above or below a particular cut point woul provie justification for a specific interpretation. Unfortunately, there are insufficient ata to recommen this approach. Rather, the current FE NO level, the irection an magnitue of any recent change, an where the measure level sits in relation to the cut points for high or low values nee to be taken into account. Ranomize trials esigne to assess whether asthma outcomes are improve using regular FE NO measurements as the basis for ajusting the ose of ICS therapy have faile to show important benefits (51, 87, 95, 101, 102), although in one stuy ICS ose reuction was facilitate without compromising asthma control (103). Thus in general, FE NO measurements cannot be recommene for this purpose. A recent systematic assessment of publishe ranomize trials of asthma therapy guie by FE NO conclue that the mixe results of these stuies (the ASTRAL stuies, an acronym for ASthma ranomize TReatment ALgorighm stuies) were ue to specific esign an methoological issues that may have le to incorrect conclusions (104). In his summary, Gibson highlights the following problems: (1) the ose response relationship of the rugs use in relation to the outcomes measure; (2) the effects of aherence an nonaherence; (3) the algorithms use an their agreement with clinical ecision making; (4) the selection of FE NO cut points/ecision points. Gibson states that future stuies woul require the use of an aitional metric to assess the likelihoo that any two algorithms (conventional an biomarkerguie) will give ifferent ICS osing ecisions (104). In a more

9 610 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL recent stuy, investigators aime to evaluate the accuracy of baseline FE NO to recognize iniviuals with ifficult-to-treat asthma who have the potential to achieve control with a guieline-base stepwise strategy (105). One hunre two consecutive patients with suboptimal asthma control unerwent stepwise increase in the treatment with maximal inhale corticosterois for 1 month. Then, those who remaine uncontrolle receive oral corticosterois for an aitional month. With this approach, 53 patients (52%) gaine control. A FE NO cut point greater than or equal to 30 ppb emonstrate a sensitivity of 88% an a specificity of 91% for the ientification of responsive iniviuals with asthma, an a value less than or equal to 30ppb ha a negative preictive value for steroi response of 92% (105). Thus, incorporating optimal esign features into future FE NO stuies shoul help in obtaining a better estimate of the value of FE NO -guie asthma therapy (104). Otherwise, a stuy is unlikely to etect a positive result in favor of one ecision-making algorithm versus the other, even if one truly exists. How Shoul a FE NO Measurement Be Interprete an Reporte? 1. Assure proper methoology: follow ATS/ERS guielines. ATS/ERS guielines for the measurement of FE NO have been publishe an are the current stanar (26, 27). These guielines shoul be followe carefully to obtain accurate an reproucible measurements. These guielines shoul be use in conjunction with FDAapprove instructions for the use of specific nitric oxie analyzers. As aitional instruments using ifferent technologies to measure FE NO become available, these guielines as well as the scope of FDA enorsements are likely to change. 2. Determine the reason for the test an the type of subject being teste: oes the patient have asthma-like symptoms OR an alreay establishe iagnosis of asthma? The interpretation of FE NO begins with whether a patient s symptoms are nonspecific an as yet uniagnose, or whether they have a confirme iagnosis of asthma. This upfront istinction between the iagnostic an monitoring uses of FE NO allows for a more appropriate interpretation of the results as outline in Table 5. Other factors to take into account inclue whether the subject is a smoker or is on antiinflammatory meications, as well as his/her height an age. 3. Interpretation of FE NO measurement: clinically relevant cut points. The purpose of measuring FE NO is to etermine whether the value is within normal limits, high, or low. In aition, when monitoring over time, one must be able to etermine when a significant change (increase) has taken place. After correct measurement, an with reference to factors which may be affecting the measurement (e.g., current smoking). Interpretation can be mae as follows (see also Table 5):, 25ppb (, 20ppb in chilren): eosinophilic inflammation an responsiveness to ICS (post-bronchoilator FEV 1 ) are unlikely.. 50ppb (. 35ppb in chilren): eosinophilic inflammation is likely; responsiveness to ICS (post-bronchoilator FEV1) is likely. Values between 25ppb an 50ppb (20 35ppb in chilren) must be interprete cautiously with reference to the clinical context. An increase of. 20% an more than 25ppb (20ppb in chilren) may be significant but there are wie inter-iniviual ifferences. A minimally important ecrease of the F E NO value is efine as a ifference larger than 20% for values over 50ppb or more than 10ppb for values lower than 50ppb from one visit to the next. A reuction of an elevate F E NO of more than 20% that often occurs 2 6 wk after initiation of anti-inflammatory therapy supports that the treatment was successful in reuction of inflammation. 4. Minimum reporting requirements for FE NO. When reporting FE NO results, a minimum information set shoul be inclue. This shoul inclue but not be limite to: ate, time of the ay, age, sex, ethnicity, height, smoking status, reason for the test, an prior iagnosis (if known), an whether or not the patient was using inhale or oral corticosterois at the time of testing. The format of the reporting shoul inclue the evice use to make the measurement, the number of measurements mae, an the flow rate (currently approve FDA evices use 50 ml/ s flow rate). One can choose to inclue all measurements performe or just the mean value. Results of previous testing (if available) shoul be inclue. A listing of the relevant cut point values is usually helpful. Other Situations in which FE NO May Be Useful These are emerging areas for the use of FE NO in the clinical setting, but there is not enough literature to provie specific guielines for their application (106). COPD. The exact role of exhale nitric oxie measurements in patients with establishe COPD remains to be efine. In a significant number of patients, an overlap synrome comprising features of both asthma an COPD is foun (53). The airway inflammatory cell infiltrate may be mixe, incluing eosinophilic inflammation. Stuies show that, at least in the short term, the response to corticosterois is likely to be greater in patients with COPD who also have sputum eosinophilia (107, 108) or elevate FE NO (109). This raises the possibility that FE NO measurements might be use in preicting steroi responsiveness in COPD. In a small group of 19 patients, Zietkowski an coworkers reporte a significant correlation between baseline FE NO an DFEV 1 after 2 months with inhale buesonie 800mg/ay (108). e Laurentiis an colleagues (110) reporte greater FE NO variability in patients with COPD who subsequently evelop exacerbations. More recently baseline FE NO was foun to be a preictor for changes in airflow obstruction, but not improvements in functional exercise capacity or health-relate quality of life, with corticosteroi therapy (56). There is also some early evience that a raise FE NO preicts FEV 1 response to ICS in COPD (111, 112). Pulmonary hypertension. NO is one of the important pathophysiological meiators of pulmonary hypertension (113, 114). It is important to point out, however, that while NO is the most recognize prouct of NOS, it is not the only one an an activity that is inhibite by NOS inhibition is not necessarily cause by NO ( ). In the case of pulmonary hypertension for example, NO concentrations 1,000 times higher than those prouce by NOS enogenously (normally present in the airways) are require for therapy, an pulmonary hypertension can be treate by nitrogen oxies such as ethyl nitrite that o not prouce any nitric oxie at all (119). Thus in this sphere, we use NO to refer to NOS activity, recognizing that NO is a biomarker for NOS activity without always being the effector molecule. In aition to vasoilatation, NO regulates enothelial cell proliferation an angiogenesis, an maintains overall vascular health (121, 122). Interestingly, patients with pulmonary hypertension have low levels of FE NO (123). Although this is a far more complex issue than the simple lack of a vasoilator (124), giving NO therapeutically seems to work well (125). Therapies that target the NO pathway have revolutionize the treatment of this isease, incluing the wiely use phosphoiesterase type 5 (PDE5) inhibitors, which prevent the breakown of the NO effector molecule 39,59-cyclic guanosine monophosphase (cgmp), thus prolonging NO effects on tissues (122). The NO eficiency state in patients with pulmonary hypertension also improves with other therapies that o not irectly target the

10 American Thoracic Society Documents 611 NO pathway like prostacyclins an enothelin receptor antagonists (125, 126). This seems also to have a prognostic significance, with improve survival in patients who respon to therapy with higher FE NO levels compare with those who o not change their FE NO levels in response to therapy (127). The low FE NO levels in patients with pulmonary hypertension an the improvement with effective therapies suggest that monitoring NO levels over time may be a useful noninvasive marker to evaluate response to or failure of meical therapy in these patients (127). Cystic fibrosis an nasal NO measurements. Continuous an high prouction of NO takes place in the human nose an paranasal sinuses (128, 129), an this NO is reaily measurable by noninvasive techniques (130). It has been shown that the nasal NO levels are altere in several respiratory isorers incluing primary ciliary yskinesia (PCD) (129), cystic fibrosis (CF) (131, 132), an allergic rhinitis (133, 134), an this has le to the proposal that nasal NO may be clinically useful in iagnosis an monitoring of these iseases. The levels of nasal NO are uniformly extremely low in patients with PCD, an the sensitivity an specificity of the test in this setting is excellent ( ). The low levels of NO in CF are relate to the absence of NOS2 expression in the airway epithelium, which supports the concept of NOS2 contribution to much of the NO etectable in exhale breath ( ). There is now abunant evience that NO levels in CF are affecte by a variety of other pathways as well. In aition to NOS2, eterminants of exhale NO in CF inclue arginase activity (143), superoxie levels (144), S-nitrosothiol metabolism (145), an enitrification pathways/ prokaryotic nitrogen oxie metabolism (146, 147). Thus, these various eterminants are all important when it comes to clinical interpretation FE NO in CF. As such, response to arginine, response to antioxiants, response to inhale nitrosothiols, an response to antimicrobial therapy might potentially be monitore in CF, to some extent, by monitoring FE NO.AlthoughFE NO is low in PCD, the iagnostic accuracy is consierably greater for a nasal NO test. Therefore this test is attractive for screening for PCD, prior to confirmatory testing (e.g., biopsies with analysis of ciliary structure). In contrast to FE NO, a single stanarize proceure has not yet been efine for measuring nasal NO. Until this has been agree upon, nasal NO levels are not yet recommene in routine clinical practice. In summary, the use of FE NO in COPD an pulmonary hypertension an the use of nasal NO in iagnosis an monitoring of other respiratory isorers (e.g., allergic rhinitis, sinusitis, nasal polyposis, CF) are potentially of interest, but more research is neee before we know how clinically useful these tests can be for these isorers. Conclusions an Future Directions Avances in technology an stanarization have mae FE NO measurements simple, permitting their use as a biomarker in the assessment of inflammatory airways iseases. It is wiely acknowlege that asthma is a heterogeneous isease with a variety of unerlying pathophysiological abnormalities. FE NO plays a role in ientifying these ifferent phenotypes (4, 7, 8, 34, 35, 148). Measurements are easily performe in ifferent settings an may be use in iagnosis an monitoring. Large population stuies have ientifie various confouners that affect FE NO incluing age, sex, an height, among others. Consistent observations inicate that atopic iniviuals have higher FE NO levels while smokers ten to have lower FE NO levels (69, 76 78). Reference values have been erive from large population stuies, but in practice they have limite application. Rather, eviencebase cut points that are shown to have iagnostic significance appear to be more relevant. When monitoring iniviual patients with asthma an assessing their treatment requirements, achieving personal best rather than normal values is more helpful. In many patients, changes in FE NO in relation to a baseline when clinically stable may be even more relevant. FE NO values of themselves o not justify a iagnosis or change in treatment. Rather, they nee to be interprete in relation to the clinical context as iscusse in this Guieline. They may be particularly useful in unerstaning patients with asthma in whom more than one factor is contributing to respiratory symptoms (e.g., obesity, anxiety) an for whom clinical ecision making is ifficult. Another potential use of FE NO might be uring inhalation challenge testing. That is, as with spirometry, giving an allergen inhalation challenge while measuring changes in FE NO before an after the challenge. This may be potentially useful in the assessment of occupational asthma (149, 150). Although these guielines for interpretation of FE NO measurements will enhance their clinical utility, we nee to continue to investigate how to interpret FE NO measurements in ifferent clinical settings. Inclusion of FE NO as an enpoint in clinical trials woul be very helpful in unerstaning the role of FE NO in monitoring response to therapy (151). Furthermore, FE NO measurement in large population-base stuies like the National Health an Nutrition Examination Survey (NHANES) woul provie more information on normative values (152). Thus, the guielines provie here will nee to be perioically upate with regar to new evelopments in this rapily evolving fiel. This official Clinical Practice Guieline was prepare by an a hoc committee of the Assembly on Allergy, Immunology an Inflammation (AII). Members of the Committee: RAED A. DWEIK (Chair), M.D. PETER B. BOGGS, M.D. SERPIL C. ERZURUM, M.D. CHARLES G. IRVIN, M.D. MARGARET W. LEIGH, M.D. JON O. LUNDBERG, PH.D. ANNA-CARIN OLIN, PH.D. ALAN L. PLUMMER, M.D. D. ROBIN TAYLOR, M.D., D.Sc. Author Disclosure: R.A.D., M.W.L., an A.L.P. reporte that they receive no payments or services from a thir party for the work submitte, an ha no relevant financial activities outsie the submitte work. C.G.I. reporte consultancies with Critical Therapeutics an Sepracor, an avisory committee service for Genentech. He also receive lecture fees from Merck, research support from Glaxo Smith Kline an Sepracor, an royalties from book publishers. P.B.B. has receive consultancy fees, lecture fees, an fees for clinical research from Aerocrine an Apieron, manufacturers of FE NO measuring equipment. S.C.E. reporte research support from Asthmatx. J.O.L. reporte ownership of shares in Aerocrine AB, which manufactures a system for measuring exhale nitric oxie. He also reporte conference support from Hope Pharmaceuticals an Ikaria. A-C.O. reporte research support from Astra Zeneca Sween an lecture fees from Aerocrine AB. D.R.T. reporte research support from Aerocrine AB. References 1. Ignarro LJ, Buga GM, Woo KS, Byrns RE, Chauhuri G. Enotheliumerive relaxing factor prouce an release from artery an vein is nitric oxie. Proc Natl Aca Sci USA 1987;84: Palmer RM, Ashton DS, Moncaa S. 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14 American Thoracic Society Documents 615 oxie an pulmonary arterial pressures in pulmonary hypertension. Free Raic Biol Me 2004;37: Lunberg JON, Farkas-Szallasi T, Weitzberg E, Riner J, Liholm J, Änggår A, Hökfelt T, Lunberg JM, Alving K. High nitric oxie prouction in human paranasal sinuses. Nat Me 1995;1: Lunberg JO, Weitzberg E, Norvall SL, Kuylenstierna R, Lunberg JM, Alving K. Primarily nasal origin of exhale nitric oxie an absence in Kartagener s synrome. Eur Respir J 1994;7: Palm JP, Graf P, Lunberg JO, Alving K. Characterization of exhale nitric oxie: introucing a new reproucible metho for nasal nitric oxie measurements. Eur Respir J 2000;16: Lunberg JON, Norvall SL, Weitzberg E, Kollberg H, Alving K. Exhale NO in peiatric asthma an cystic fibrosis. Arch Dis Chil 1996;75: Balfour-Lynn IM, Laverty A, Dinwiie R. Reuce upper airway nitric oxie in cystic fibrosis. Arch Dis Chil 1996;75: Arnal JF, Diier A, Rami J, M Rini C, Charlet JP, Serrano E, Besombes JP. Nasal nitric oxie is increase in allergic rhinitis. Clin Exp Allergy 1997;27: Kharitonov SA, Rajakulasingam K, O Connor B, Durham SR, Barnes PJ. Nasal nitric oxie is increase in patients with asthma an allergic rhinitis an may be moulate by nasal glucocorticois. J Allergy Clin Immunol 1997;99: Horvath I, Loukies S, Woehouse T, Csiszer E, Cole PJ, Kharitonov SA, Barnes PJ. Comparison of exhale an nasal nitric oxie an exhale carbon monoxie levels in bronchiectatic patients with an without primary ciliary yskinesia. Thorax 2003;58: Karaag B, James AJ, Gultekin E, Wilson NM, Bush A. Nasal an lower airway level of nitric oxie in chilren with primary ciliary yskinesia. Eur Respir J 1999;13: Woehouse T, Kharitonov SA, Mackay IS, Barnes PJ, Wilson R, Cole PJ. Nasal nitric oxie measurements for the screening of primary ciliary yskinesia. Eur Respir J 2003;21: Boini A, Rugolotto S, Praal U, Zanotto G, Peroni D. Nasal nitric oxie for early iagnosis of familial primary ciliary yskinesia. Arch Dis Chil 2008;93: Stehling F, Roll C, Ratjen F, Grasemann H. Nasal nitric oxie to iagnose primary ciliary yskinesia in newborns. Arch Dis Chil Fetal Neonatal E 2006;91:F Zheng S, Xu W, Bose S, Banerjee AK, Haque SJ, Erzurum SC. Impaire nitric oxie synthase-2 signaling pathway in cystic fibrosis airway epithelium. Am J Physiol Lung Cell Mol Physiol 2004;287: L374 L Kelley TJ, Drumm ML. Inucible nitric oxie synthase expression is reuce in cystic fibrosis murine an human airway epithelial cells. J Clin Invest 1998;102: Meng QH, Springall DR, Bishop AE, Morgan K, Evans TJ, Habib S, Gruenert DC, Gyi KM, Hoson ME, Yacoub MH, et al. Lack of inucible nitric oxie synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. J Pathol 1998;184: Grasemann H, Kurtz F, Ratjen F. Inhale L-arginine improves exhale nitric oxie an pulmonary function in patients with cystic fibrosis. Am J Respir Crit Care Me 2006;174: Jones KL, Hegab AH, Hillman BC, Simpson KL, Jinkins PA, Grisham MB, Owens MW, Sato E, Robbins RA. Elevation of nitrotyrosine an nitrate concentrations in cystic fibrosis sputum. Peiatr Pulmonol 2000;30: Snyer AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. Acute effects of aerosolize S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Me 2002;165: Yoon SS, Coakley R, Lau GW, Lymar SV, Gaston B, Karabulut AC, Hennigan RF, Hwang SH, Buettner G, Schurr MJ, et al. Anaerobic killing of mucoi Pseuomonas aeruginosa by aciifie nitrite erivatives uner cystic fibrosis airway conitions. JClinInvest2006;116: Gaston B, Ratjen F, Vaughan JW, Malhotra NR, Canay RG, Snyer AH, Hunt JF, Gaertig S, Golberg JB. Nitrogen reox balance in the cystic fibrosis airway: effects of antipseuomonal therapy. Am J Respir Crit Care Me 2002;165: Lara A, Khatri SB, Wang Z, Comhair SA, Xu W, Dweik RA, Boine M, Levison BS, Hammel J, Bleecker E, et al. Alterations of the arginine metabolome in asthma. Am J Respir Crit Care Me 2008;178: Ferrazzoni S, Scarpa MC, Guarnieri G, Corrai M, Mutti A, Maestrelli P. Exhale nitric oxie an breath conensate ph in asthmatic reactions inuce by isocyanates. Chest 2009;136: Hewitt RS, Smith AD, Cowan JO, Schofiel JC, Herbison GP, Taylor DR. Serial exhale nitric oxie measurements in the assessment of laboratory animal allergy. J Asthma 2008;45: Reel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control an exacerbations: stanarizing enpoints for clinical asthma trials an clinical practice. Am J Respir Crit Care Me 2009;180: Hankinson JL, Oencrantz JR, Fean KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Me 1999;159:

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