Clinical applications of exhaled nitric oxide for the diagnosis and management of asthma: A consensus report

Consensus Statement

Clinical Applications of Exhaled Nitric Oxide for the Diagnosis and Management of Asthma: A Consensus Report Myron Zitt, MD

Allergy and Immunology, Queen's Long Island Medical Group, North Babylon, New York ABSTRACT

Background: Patients with asthma routinely exhibit elevated levels of fractionated exhaled nitric oxide (FENo), and this observation has led to studies investigating FENo as a potential marker of airway inflammation. FENo has been shown to enhance the diagnosis of asthma, detect deterioration in control of patients with asthma, and monitor response to antiinflammatory therapy. Objectives: The aim of this work was to determine if FENo measurement provides a noninvasive, welltolerated, and standardized technique to monitor airway inflammation, and if it has the potential to complement standard asthma monitoring tools (eg, symptom diaries, control questionnaires, and pulmonary function testing) and to improve asthma control and patient outcomes. Methods: Thirteen experts in the diagnosis and treatment of asthma met to discuss the use of FENo in the diagnosis and management of patients with asthma. Participants were selected by Aerocrine, a medical, technical company with headquarters in Stockholm, Sweden, in consultation with their medical education partner Cadent Medical Communications located in Irving, Texas, to represent a diversity of specialists, including both clinicians and investigators, in the fields of allergy, immunology, and pulmonology. All participants were nominally compensated for their time to attend this closed scientific roundtable discussion. The meeting was supported by an educational grant from Aerocrine. This report represents the overall consensus reached by the participants on the clinical applicability of this technique. Results: Our understanding of asthma has expanded so that investigators are now focusing on inflammation in addition to airway obstruction and hyperreactivity. Whereas patient history, symptoms, and pulmonary function testing can assist in diagnosing

asthma, they are not direct measures of the extent of airway inflammation. Elevated FENo levels have been shown to reflect airway inflammation and to occur together with other conventional markers used to detect inflammation. Studies have confirmed increased levels of FENo in both adults and children with asthma. In most studies, FENo was found to be elevated 2- to 3-fold compared with normal controls. There are many determinants of FENo levels, however, and factors other than inflammation must be considered when FENo measurement is used to diagnose and monitor asthma. FENo measurement alone is not sufficient for diagnosing or monitoring asthma, but it can be a valuable addition to current clinical tools. Conclusions: EENo measurement is a noninvasive and reproducible test that is a surrogate measure of airway inflammation in patients with asthma. The test has demonstrated utility in diagnosing and managing asthma and in predicting response to therapy and, therefore, may be an important tool to incorporate into clinical care. (Clin Ther. 2005;27:1238-1250) Copyright © 2005 Excerpta Medica, Inc. Key words: exhaled nitric oxide, asthma, monitoring, airway inflammation.

INTRODUCTION Asthma is a chronic, inflammatory disorder of the airways. 1 Chronically inflamed airways are hyperresponsive and airflow becomes limited when the airways become obstructed by bronchoconstriction, mucus plugs, and further inflammation. Airflow also

AcceptedforpublicationJune20, 2005. ExpressTrack online publicationJuly20, 2005. doi:10.1016/j.clinthera.2005.07.005 0149-2918/05/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2005 Excerpta Medica, Inc.

M.

is limited when airways are exposed to such irritants as dust, mold, and tobacco smoke and when patients are exposed to risk factors such as infections, abrupt changes in weather, and exercise for those affected by exercise-induced asthma. While asthma episodes, or flares, occur at irregular intervals, airway inflammation is always present. 2 Episodes can vary from mild to life-threatening and represent a significant health care burden. In 2002, it was estimated that approximately 31 million people in the United States (111 people per 1000 population) had been diagnosed with asthma. 1 In that same year, nearly 500,000 hospitalizations, about 2 million emergency hospital visits, and 4261 deaths were attributed to asthma. 1 While asthma is commonly associated with a classic triad of symptoms, including cough, dyspnea, and wheezing, one or more of these symptoms may be absent. In addition, similar symptoms can occur in other conditions such as congestive heart failure or bronchitis. 3 Diagnosis, therefore, often requires a patient and family history, a physical examination, and spirometry. 4 However, pulmonary function testing only focuses on the identification of abnormal airway physiology and airflow obstruction. It does not measure the inflammatory status of the airways, thus, important diagnostic clues may be overlooked, s This report represents the overall consensus of 13 clinical and investigational experts representing the diverse specialties of allergy, immunology, and pulmonology on the clinical applications of fractionated exhaled nitric oxide (FENo), a potential marker of airway inflammation, in the diagnosis and management of asthma. METHODS

This report is based on the proceedings of a closed scientific roundtable discussion supported by an educational grant from Aerocrine, a clinically based medical, technical company with headquarters in Stockholm, Sweden. Thirteen experts in the diagnosis and treatment of asthma met to discuss the use of FENo measurement in the diagnosis and management of patients with asthma. Participants were selected by Aerocrine, in consultation with their medical education partner Cadent Medical Communications located in Irving, Texas, to represent a diversity of specialists, including both clinicians and investigators, in the fields of allergy, immunology, and pulmonology. Participants were nominally compensated for their time to attend the

Zitt

meeting. While individual participants may hold differing opinions, the statements included in this report represent the final overall consensus of all participants on the clinical applicability of this technique. All references used in this manuscript were obtained through the use of a MEDLINE search (key words: asthma,

exhaled nitric oxide, nitric oxide, asthma monitoring, airway inflammation, pulmonary function testing, remission, adherence, asthma diagnosis; language: English; years: 1990-2005). A s t h m a as an I n f l a m m a t o r y D i s o r d e r

Asthma, as initially defined by the 1995 Global Initiative for Asthma Management and Prevention panel of the National Institutes of Health and restated in a 2002 update, is "a chronic, inflammatory disorder of the airways in which many cells play a role, in particular, mast cells, eosinophils, and T lymphocytes. "2 A paradigm shift in our understanding of asthma has occurred within the past few years, so that investigators are now focusing on inflammation, in addition to airway obstruction and hyperreactivity. 6 Using techniques that monitor the inflammatory state of the bronchial passages may be helpful in the management and early detection of potential asthma flares. 7-9 Measuring the levels of FENo, a potential marker of airway inflammation, has been shown to enhance the diagnosis of asthma, detect deterioration in asthma control, and monitor response to anti-inflammatory therapy. 1°-13

Diagnosing Asthma: History and Physical Examination Asthma patients may not experience all 3 of the classic symptoms of wheezing, coughing, and dyspnea; therefore, the use of these parameters alone is not sufficient for a diagnosis of asthma. In prospective studies among patients reporting persistent wheeze, chronic cough, or chronic dyspnea, only 35%, 14 24%, is and 29%, 16 respectively, were ultimately diagnosed with asthma. In addition, the presence or absence of wheezing does not predict severity of airflow obstruction in patients with asthma; in one prospective study, wheezing was found to be predictive of hyperreactive airways only 35 % of the time. ~4 Wheezing may be observed in patients who are experiencing various levels of asthma severity and has been reported in patients with mild, moderate, and severe airway narrowing. 17 Furthermore, patients with airway narrowing may not demonstrate wheezing during physical

examination. Practitioners, therefore, cannot rely on patient histories alone when diagnosing asthma, since seemingly obvious associations may not be clinically relevant, while important associations may not be clinically obvious.

Pulmonary Function Testing Pulmonary function testing is currently a cornerstone in the diagnosis and management of asthma and provides a measure of airflow limitation related to airway caliber and the elastic properties of the lung tissue. The Global Initiative for Asthma (GINA) guidelines state that these measurements enhance diagnostic confidence in patients suspected of having asthma. 4 Peak expiratory flow rate (PEFR) is measured as a maximal exhalation immediately following a maximal inhalation. While this test is relatively simple and inexpensive to perform, measurements are highly dependent on the patient's technique and effort, which can be problematic, especially in children) 8 Furthermore, the variability of PEFR among individuals can be great, and in some individuals, PEFR may not adequately reflect airflow limitation. Yet PEFR is useful for monitoring changes or trends in a patient's lung function. Spirometry involves the measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). The technique is rapid, relatively inexpensive, and noninvasive. However, as with PEFR, this approach does not measure airway inflammation. In a study reported by Kitch et aP 9 among adults with FEV 1 <60% of predicted, only 58% to 65% of patients experienced an asthma episode. Thus, while pulmonary function testing is useful, additional tests with greater predictive value are needed to ensure an accurate diagnosis.

Bronchoprovocation Another strategy that can be used to optimize asthma treatment is bronchoprovocation. With this strategy, airway sensitivity can be evaluated and therapy can be adjusted based on responsiveness to bronchial challenge with chemical agents such as methacholine, histamine, or adenosine. Studies have demonstrated that airway hyperresponsiveness (AHR) persists during bronchial challenge in patients whose asthma is considered to be controlled. 2° Chronic AHR may lead to airway remodeling, including a thickening and loss of elasticity of the airway wall, and thereby worsen asthma outcome. 21 Based on these data, investigation of

AHR measurement as a standard technique for asthma management has been initiated. Sont et al 9 conducted a randomized study in 75 adults with mild to moderate asthma to investigate whether a treatment strategy aimed at reducing AHR in addition to employing standard guidelines would lead to more effective control of asthma and greater improvement in chronic airway inflammation. All 75 patients received treatment based on the 1995 GINA guidelines, 22 including initial assessment of FEV 1 and AHR to methacholine, PEFR assessment every 3 months for 2 years, treatment with a ~2-agonist, and monitoring of patient symptom diaries. Following each assessment, corticosteroid treatment was adjusted according to: (1) a stepwise approach (n = 41, reference strategy) based on 4 predetermined severity levels of patient symptoms, bronchodilator use, PEFR variability, and FEV 1 measurement; or (2) a stepwise approach (n = 34, AHR strategy) based on 4 classes of severity according to AHR. Patients in the AHR treatment group experienced a 1.8-fold lower rate of mild episodes compared with the standard treatment group (P = 0.03). Lung function, characterized by FEV1, also was significantly more improved in patients in the AHR treatment group (P ___0.05). Bronchial biopsy revealed a decrease in the thickness of the subepithelial reticular layer in the AHR treatment group only. Despite its usefulness, bronchial challenge can be impractical in a clinical setting; it cannot be performed routinely in patients with severe asthma or in those experiencing an asthma flare. 23

Sputum Eosinophil Induction Eosinophils are considered to be important proinflammatory mediators in the pathogenesis of asthma. Eosinophils consistently have been reported to be present in the airways of people with asthma but not in the airways of individuals without atopic asthma. 24 Furthermore, the suppression of eosinophil infiltration through the use of glucocorticoids is a reflection of symptom improvement and amelioration of abnormal airway function. 25 Studies have shown that sputum eosinophilia develops several weeks prior to the onset of an asthma flare, 26 which has led investigators to explore the sputum eosinophil measurement as a potential means of monitoring inflammation and impending episodes in patients with asthma. 8 In a randomized controlled study that included 74 patients with moderate to severe asthma, patients

were assigned to receive treatment either by normalization of sputum eosinophil count or by standard British Thoracic Society (BTS) asthma guidelines. 8 Treatment for patients managed according to BTS guidelines was based on assessment of symptoms, PEFR, and the use of 132-agonists. Patients in the sputum eosinophil management group were monitored with the goal of maintaining a sputum eosinophil count <3%. For patients with counts >3%, antiinflammatory therapy was increased. For patients unable to produce sputum, FENo measurements were used as a surrogate marker of airway inflammation. Patients in the sputum eosinophil management group maintained a 63% lower sputum eosinophil count over 12 months compared with those in the BTS management group (P -- 0.002). Of note, sputum eosinophil management resulted in improved airway responsiveness, with significantly fewer severe asthma flares compared with those in the BTS management group (35 vs 109; P = 0.01). This improvement further translated into significantly fewer hospital admissions in the sputum eosinophil management group (P = 0.047). Although this technique proved efficacious in this setting, its extrapolation to the management of patients with milder disease may not be accurate, s Furthermore, the induction of sputum in a primary care setting may not always be feasible. The authors of this study recommended the use of FENo measurement, a surrogate marker of airway inflammation, as a more practical alternative to monitoring induced sputum eosinophils. 8 Specifically, correlations between FENo levels and sputum eosinophil counts recently have been reported in patients with asthma (r = -0.40), particularly in those naive to corticosteroid therapy. 27,28 Based on this correlation, it may be possible to use FENo as a standard surrogate for induced sputum eosinophil counts in patients in whom sputum production is difficult to achieve.

Exhaled Nitric Oxide Nitric oxide (NO) is an endogenous regulatory molecule widely distributed throughout the body. The synthesis of NO is mediated by a family of enzymes, the NO synthases (NOS), which can exist as constitutively expressed isoforms (cNOS), including endothelial NOS (eNOS) and neural NOS, or as an inducible isoform (iNOS). Whereas all 3 isoforms (cNOS, eNOS, and iNOS) have been identified in the airways of humans, 29 iNOS is found in airway epithelium, and the

expression of iNOS messenger RNA is upregulated in the airways of patients with asthma as a part of the inflammatory process. 3° All of these isoforms differ in their ability to produce NO, as well as in the final effect of the NO produced. For example, iNOS, although not constitutively active, has the capacity to generate large quantities of NO when transcriptionally upregulated by inflammatory cytokines, including tumor necrosis factor-o~, interleukin 1-13, and interferon-7. 31,32 In contrast, the constitutively expressed isoforms of NOS express constant, low levels of NO. Inducible NOS-derived NO is predominately produced in the epithelial cells of the bronchial wall, which is the key source of the increased levels of FENo seen in people with asthma. Alveolar concentrations of NO are usually low except in certain disease states, such as allergic alveolitis. 33 During an exhalation, as air from the alveolar compartment moves through the bronchial compartment, NO from the bronchial wall diffuses into the airway lumen, thereby increasing NO concentration in exhaled air. If the exhalation is slow, there will be time for NO to diffuse into the airway, thus increasing the concentration to a greater extent than if the exhalation is fast. 7 Patients with asthma commonly display elevations in FENo of up to 2- to 3-fold. 7,34 Healthy adults usually exhibit exhaled NO values between 10 and 35 ppb 3s at the standardized flow rate of 50 mL/s. 36 There are many determinants of FENo levels, and these levels vary between healthy and asthmatic individuals. In healthy individuals, FENo levels are lower in children and appear to increase with age. 37 FENo levels also appear to be higher in healthy men than in healthy women; this difference may be related to airway size. 38 Cigarette smoking may decrease FENo levels. 39 Certain foods and drinks high in nitrates may increase levels. 4° Patients with asthma, 7 atopy without asthma, 4] viral infection, 42 mycobacterial infection, 43 liver disease, 44 lung cancer, 4s bronchiectasis, 46 lung transplant rejections, 47 and chronic obstructive pulmonary disease 48,49 have been reported to have increased FENo levels. Decreases in FENo levels have been reported in patients with cystic fibrosis s° and ciliary dysmotility syndromes, sl Thus, care should be taken when interpreting FENo measurement in the diagnosis and treatment of individuals with asthma to ensure that an increase in FENo level due to factors other than inflammation are considered.

Exhaled Nitric Oxide in the Management of Asthma In patients with asthma, chronic airway inflammation characterized by increased numbers of activated eosinophils, mast cells, and T lymphocytes in the mucosa and lumen result in epithelial damage, swelling, mcreased mucus secretion, and smooth muscle contraction. 52 These phenomena, in turn, lead to AHR and asthma symptoms. When people with asthma are exposed to allergens, they experience both early and late inflammatory responses. The early response, which occurs within minutes of allergen exposure, is associated with activation of cells bearing allergen-specific immunoglobulin E that, in turn, leads to contraction of airway smooth muscle, mucus hypersecretion, and vasodilation. 53 The late response, which is a sustained response, is associated with increased levels of eosinophils and release of eosinophil cationic protein and major basic protein, which participate in the induction of heightened airway inflammation, increased numbers of local T lymphocytes, and subsequent increases in FENo levels. 29 Elevated FENo levels have been shown to reflect airway inflammation and to occur together with other conventional markers used to detect inflammation. In human studies, these markers include cellular changes seen in tissue from bronchial biopsies54; cells and cell mediators, including cytokines and chemokines, observed in bronchial lavage fluidS5; peripheral blood eosinophil Counts56; and serum eosinophil cationic protein. 34,56,57 Several studies have confirmed increased levels of FENo in both adults and children with asthma. 7,33,s6-s8 In most of these studies, FENo was found to be elevated 2- to 3-fold compared with normal controls. 7,34 Successful measurement of FENo has been obtained in adults, 29 children, 59 infants, 6° and elderly patients 29 with asthma. Because various methods have been used to measure FENo, the European Respiratory Society (ERS) published the first recommendations for standardized methods of measurement in 1997. 61 In 1999, a joint task force formed by the American Thoracic Society (ATS) and the ERS recommended that FENo measurements at a flow rate of 50 mL/s should be used. 62 Recommendations for the standard measurement of FENo were refined, updated, and adopted by the ATS and ERS in 2004. 63 Comparison of Exhaled Nitric Oxide Measurement to Conventional Tests Many of the conventional testing techniques used for the diagnosis and management of asthma have in-

herent limitations. Most notably, pulmonary function testing is not a direct measure of airway inflammation. While sputum eosinophil induction and bronchoprovocation monitor airway inflammation, these methods can be difficult to perform in a clinical setting and may not be feasible for day-to-day use. 8,23 FENo measurement, by contrast, is a noninvasive, reproducible, and well-tolerated test that accurately reflects the extent of airway inflammation. In addition, FENo levels have been shown to improve faster than FEV 1 measurement (2 weeks vs 3 months) following allergen avoidance and asthma improvement, suggesting that it may be a more sensitive diagnostic parameter. In a study of 22 asthmatic children sensitized to house dust mites, 1° FENo was measured at baseline, while the children were living in their family home, 3 months after living in a residential home essentially free of dust mites, and again 2 weeks after returning to their homes. FENo levels were shown to decrease significantly in the first 2 weeks at the residential home (P = 0.003). In contrast, FEV 1 improved gradually, with no change in FEV 1 measurement from baseline (2.006 ± 0.42 L/min) to after the first 2 weeks at the residential home (2.0075 ± 0.43 L/min). When compared with other techniques that monitor airway inflammation, for example, measurement of the provocation concentration of adenosine 5' monophosphate producing a 20% decline in FEV 1 (PC20 AMP) and percent sputum eosinophils, a significant correlation was found between FENo measurement and PC20 AMP (r = -0.64) and FENo measurement and percent sputum eosinophil (r = -0.40). 27 In a study comparing the use of FENo to conventional parameters, including respiratory symptoms, bronchodilator use, PEFR, and FEV1, in the diagnosis of asthma, the sensitivity of FENo measurement was reported to be higher (88%) than that found with the conventional parameters (0 % - 4 7%), including peak flow variation (P = 0.018). 64 While FENo measurement alone is not sufficient for diagnosing or monitoring asthma, it can be a valuable addition to current clinical tools.

Consensus Recommendations for the Clinical Application of Exhaled Nitric Oxide Measurement in the Management of Asthma This report represents the overall consensus of participants who attended a closed scientific roundtable discussion, supported by an educational grant from

Aerocrine, on the clinical applications of FENo in the management of patients with asthma, which was held in New York on April 16, 2005. Whereas these opinions may not reflect the individual opinions of all participants, they do represent the overall consensus of the group. Several key points of consensus were identified; these key points and the resulting recommendations are discussed below and are outlined in the table.

Practical Applications for the Use of FENo FENo Can Be Used as a Screening Tool for Asthma Screening for asthma in large, group settings, such as the military, is currently quite costly. A study conducted in a military setting found the use of FENo as a screening tool for asthma to be sensitive. 65 Among 172 basic trainees with signs of asthma who were screened by history, physical exam, baseline spirometry, and histamine challenge, 80% were diagnosed with asthma. When FENo measurements of 10.5 ppb (measured

at a standard flow rate of 50 mL/s) were used as a diagnostic cutoff for asthma, a sensitivity of 86% relative to positive histamine challenge was reported. The authors of this study concluded that measuring FENo as a screening technique provided a sensitive method of identifying individuals with undiagnosed asthma.

FENo, Along with Other Parameters, Can Assist in the Diagnosis of Asthma, Especially in Patients Without Spirometric Evidence of Airflow Limitation and/or Reversibility FENo levels correlate with airway inflammation in asthmatic individuals s4-57 and, thus, should be useful in the diagnosis of asthma. In a study by Dupont et al, 66 240 steroid-naive adults with symptoms suggestive of obstructive airway disease were tested for a diagnosis of asthma using either the presence of significant airways reversibility (AFEV1 >12%) and/or AHR (histamine PC20 AMP <8 mg/mL; n = 160). FENo measurement was obtained before lung function

Table. Consensus recommendations on the use offractionated exhaled nitric oxide (FENo) in asthma management. Practical Applications • Asthma screening • Asthma diagnosis -When used in conjunction with other parameters -In individuals who do not have demonstrable reversibility • Evaluation o f response to asthma controller therapy -Inhaled corticosteroids (ICS) -Leukotriene modifiers -Anti-lgE monoclonal antibodies -Oral steroids -Combination therapy (including long-acting ]3-agonists) • Selection of therapeutic agent

Potential Uses for Monitoring • Predicting asthma flares • Confirmation of apparent clinical remission • Monitoring adherence to recommended treatment regimen • Dose titration o f ICS to achieve/maintain asthma control

Parameter for Monitoring Patients with Asthma • Include FENo measurement as one of the parameters along with validated questionnaires, symptoms, physical examination, pulmonary function tests Benefits o f FENo Monitoring • ATS standardized • ATS/ERS joint recommendation • FDA-approved monitoring system -Objective -Noninvasive • Well tolerated Data Still Needed • Long-term effects on -Asthma control, patient quality of life -Hospitalization, emergency visits -Drug-associated side effects -Medication adherence -Incidence of fixed airway obstruction -Morbidity and mortality

-Health care costs (cost-effectiveness) -Physician practices and decision making

IgE = immunoglobulin E; ATS = American Thoracic Society; ERS = European Respiratory Society; FDA = US Food and Drug Administration.

was tested, and the predictive value of FENo for a diagnosis of asthma was determined by lung function measurement. In this study, a cutoff level of FENo levels >16 ppb (at a flow rate of 200 mL/s, representing -33 ppb at the standardized flow rate of 50 mL/s) for the diagnosis of asthma resulted in 90% specificity and a >90% positive predictive value. 66 Similarly, a separate study indicated that FENo can serve as a robust discriminator between asthmatic (n = 34) and healthy (n = 28) individuals (P < 0.001). 67 In this study, FENo was measured using off-line techniques on a single visit, and differences in FENo measurements between individuals were analyzed. Furthermore, as noted previously, measurement of FENo has been demonstrated in the context of a clinical trial to be more sensitive in the diagnosis of asthma than conventional parameters, including history and pulmonary function.64 Response to inhaled corticosteroids can be considered suggestive of a diagnosis of asthma. In a recent study reported by Smith et al, 68 57 patients with undiagnosed respiratory symptoms received inhaled fluticasone or placebo for 4 weeks in a single-blind, crossover trial. FENo and spirometry with bronchodilator response and adenosine PC20 AMP were measured both before and after therapy. Patients with FENo levels >49 ppb demonstrated significantly greater changes in symptom score (P = 0.001), FEV 1 (P < 0.001), morning PEFR (P = 0.004), and PC20 AMP (P < 0.001) following fluticasone treatment, compared with patients with lower FENo scores. Thus, FENo may identify patients with respiratory symptoms but without a firm diagnosis of asthma who could respond to inhaled corticosteroid therapy.

FENo Can Aid in Evaluating Responses to Asthma Controller Therapy (Corticosteroids and Leukotriene Modifiers) Several studies have demonstrated that FENo levels decrease in patients being treated with asthma controller therapy (ie, corticosteroids and leukotriene modifiers)) 1 In 14 asthmatic patients being treated with inhaled budesonide at doses ranging from 200 to 2000 lag/d, levels of FENo were reported to increase significantly when the dose was decreased by 200 lag daily (122 _+ 13 ppb - 246 _+ 52 ppb; P < 0 . 0 5 ) . 12 However, no significant decrease in spirometry or change in peak flow variability was reported, despite an increase in nocturnal symptoms. Two weeks after dose reduction, the daily dose was increased by 200 lag

to the original dose level for 2 weeks, after which it was again increased by 200 lag for 2 weeks. When the reduced inhaled steroid dose was increased to the original dose level, FENo levels and nocturnal symptoms decreased, as did diurnal variability of peak expiratory flow. As this study was relatively small, no statistical correlations were made; however, this study suggests that FENo measurement may aid in monitoring patient response to inhaled corticosteroid therapy. An asthma flare is likely due to an increase in airway inflammation,sz Therefore, measurements of FENo could be used to determine control or lack of control in patients with asthma who are currently undergoing therapy. Although FENo is reduced by inhaled corticosteroids, it is not totally suppressed and continues to show a significant correlation with severity of disease. 69,7° Stifling et a169 reported a study of 52 adult asthmatic patients who were examined to assess FENo levels as a surrogate marker of inflammatory activity. In this study, the 26 patients defined as having difficult to control asthma (ie, those who required high doses of inhaled or oral steroids) had lower FENo levels than the 30 individuals with asthma who were steroid-naive; however, FENo levels in these 26 patients were significantly higher than those for normal controls (n -- 46). FENo levels correlated closely with clinical markers of disease control (symptom frequency, r = 0.46; P = 0.03) and the need for rescue 132-agonist use (r = 0.58; P < 0.002), although not with tests of lung function (FEV1% predicted, P = 0.73; FEVJFVC, P = 0.94; peak flow variability, P = 0.85). Similarly, Artlich et al 7° found that children (n = 25) with recent asthma symptoms had high levels of FENo, even if inhaled corticosteroids were included in their treatment regimen. In a 24-week, parallel, open-label, multicenter trial, Szefler et a113 examined the benefit-risk ratio of 2 inhaled corticosteroids in 30 patients with persistent asthma. Benefit was assessed by FEV 1 and PC20 AMP, as well as FENo. An FENo level >25 ppb was a significant predictor of response to inhaled corticosteroids (significant baseline predictor of response >7.5% by univariable analysis). A positive correlation was reported between a good FEV 1 response (>15%) and FENo (17.6 ppb) compared with a poor response (>5%) and lower FENo levels (11.1 ppb). The results of this study suggest that FENo may distinguish potential responders from nonresponders to inhaled corticosteroids.

FENoCan Aid in the Selection

of Therapeudc Agents FENo measurements can signal a lack of asthma control. The identification of patients in whom FENo levels remain elevated in spite of high doses of controller therapy (ie, inhaled corticosteroid and leukotriene receptor antagonists) may influence choice of therapy. In a double-blind, placebo-controlled, 8-week, crossover trial sponsored by the National Heart, Lung, and Blood Institute, Szefler et a171 found that FENo was an independent predictor of response. The 6- to 17-year-old patients (n = 144) with mild to moderate persistent asthma included in this trial were randomized to receive treatment with an inhaled corticosteroid (fluticasone 100 pg BID) or a leukotriene receptor antagonist (montelukast 5 mg or 10 nag once nightly according to age). For each doubling of FENo level at baseline, the difference in FEV~ response (fluticasone minus montelukast) was increased, on average, by almost 2 percentage points (P -- 0.003). Moreover, a univariable odds ratio of 2.8 (P < 0.05) was observed for the odds of _>7.5% increase in FEV 1 response to fluticasone if the baseline FENo was >25 ppb versus <25 ppb. These findings suggest that FENo levels were good indicators of response to inhaled corticosteroids in these children.

Potential Uses for FENo in the Monitoring of Patients with Asthma FENo Can Serve as a Predictor of Asthma Flare and to Confirm an Apparent Clinical Remission FENo can be used as a marker to indicate an impending asthma flare, 72,73 improvement in asthma control, 71 and reduction in inflammation.28 As such, FENo measurement could be used to complement existing measures to confirm and monitor apparent clinical improvements as well as deterioration. While apparent remission of asthma is common in children, TM there are few, if any, objective means to guide parents or patients as to when inhaled corticosteroid doses should be decreased or discontinued altogether. The FENo measurement has been studied as a means to predict relapse in children considered to be in remission. A recent study assessed 40 children with asthma after inhaled corticosteroid therapy was discontinued after asthma symptoms were not present for >6 months. 7s FENo measurements were obtained at baseline (2 weeks prior to and the week of inhaled corticosteroid withdrawal) and 2, 4, 12, and 24 weeks following withdrawal. Nine patients experienced a re-

lapse (defined as >1 asthma flare per month) after a median of 36 days. Whereas no difference in mean FENo was observed at baseline between patients who did relapse (14.8 ppb) and those who did not (10.5 ppb; P = 0.32), a significantly increased FENo level was reported at 2 weeks (35.3 ppb vs t5.7 ppb; P = 0.01) and 4 weeks (40.8 ppb vs 15.9 ppb; P = 0.009) among patients who went on to experience a relapse. This study suggests that FENo measurement may be used in children with asthma in apparent remission to predict relapse, perhaps providing a predictive tool that may guide physicians to determine when inhaled corticosteroid doses can be decreased or even discontinued.

FENo Can Be Useful in Monitoring Patient Adherence to Treatment Regimens Poor outcomes in asthma patients often result from patient nonadherence to a physician-recommended medication regimen. Estimates suggest that only 50% of asthma patients follow medication recommendations. 76 Studies have demonstrated that monitoring patient adherence and providing feedback to adult patients about medication use can improve outcomes.77,78 Health care costs were evaluated in a group of 59 asthma patients who were monitored for adherence and provided with intervention, including educational programs. Use of asthma resources, including hospital visits, physician visits, and medications, were identified retrospectively for 1 year before intervention, during intervention, and over a 4-year follow-up period after intervention. Patients served as their own controls. The median cost of care decreased by 57% within the first year and by 77.5% at 4 years.79 Studies also have shown a good correlation between FENo values and adherence to a treatment regimen of inhaled steroids. 8°,81 In one study of 6- to 16-year-old patients (n = 54) with asthma, patients were treated with inhaled budesonide 200 mg BID for 4 weeks, followed by a 4-week washout phase in which no steroid was given. 8° After the washout phase, patients were randomized to receive low-dose budesonide (200 mg QD) or no further steroid treatment. FENo was shown to decrease significantly during the washout phase and with discontinuation of inhaled steroids (P < 0.01). In patients who were randomized to receive no further steroid treatment, no change in FENo was seen (P > 0.05); however, patients randomized to receive low-dose steroids demonstrated a decrease in FENo (P < 0.01). Similar results were observed in a study of

30 asthmatic patients aged 7 to 17 years. 81 In this study, 15 patients were seen for a total of 53 physician visits. FENo measurements were shown to significantly correlate with adherence to treatment (r = 0.75; P = 0.001). The results of these studies suggest that FENo measurement may identify nonadherence to a recommended medication regimen. FENo Can Be Used to Titrate the Dose of Inhaled Corticosteroids in Patients with Asthma to Achieve or Maintain Control As previously discussed, FENo levels decrease in patients receiving asthma controller therapy and have been suggested to increase prior to an asthma episode.65,71,72 Thus, it may be possible to reduce the dose of inhaled corticosteroids in patients who exhibit low and stable FENo measurements. Similarly, increasing the dose of inhaled corticosteroids may reduce FENo levels and accompanying airway inflammation in patients receiving low doses of inhaled corticosteroids yet exhibiting high FENo measurements. In a recent prospective, observational study of 40 children with stable asthma who were evaluated every 8 weeks, FENo was found to be a significant predictor of asthma episodes following reduction of inhaled steroids to half the initial dose, 82 suggesting that FENo measurements can be useful in optimizing steroid therapy in children. Using multiple logistic regression, increased FENo levels (odds ratio [OR] = 6.3; 95% CI, 3.75-10.58; P < 0.001) and sputum eosinophils (OR = 1.38; 95% CI, 1.06-1.81; P = 0.017) were found to be significant predictors for suboptimal asthma control following inhaled corticosteroid reduction. However, the positive predictive values for loss of control were only 44% for FENo and 41% for elevated sputum eosinophils. In a separate study, 97 patients with asthma who previously had received treatment with inhaled corticosteroids were randomized to have their corticosteroid dosing optimized in a stepwise fashion using either FENo measurement or a conventional guidelines-based algorithm. 83 FENo measurement resuited in a significantly lower mean daily fluticasone dose (P = 0.003) compared with conventional management. However, exacerbation rates were not significantly different between the groups, nor were any differences in other markers of asthma control observed, including lung function or sputum eosinophils. Thus, it may be possible to use FENo to titrate the dosage of inhaled corticosteroids in asthma patients to optimize clinical outcome.

FENo Should Be Included Among the Standard Parameters Used to Monitor Patients with Asthma Current available data suggest that monitoring airway inflammation with FENo may be useful in optimizing asthma treatment and inhaled corticosteroid reduction and withdrawal. It is likely, however, that it will be necessary to combine several measures of asthma control, including FENo , lung function, symptoms, and rescue ]3-agonist use, as well as standard asthma control questionnaires to better guide asthma management, as any one measure alone does not possess adequate predictive capacity.

Use of FENo in the Clinical Setting Several advantages are associated with the use of FENo as a standard procedure in the clinical setting. The technique of measuring FENo has been standardized by the ATS and was included in the 2005 joint recommendation statement issued by the ATS and ERS. 63 In 2003, the US Food and Drug Administration (FDA) approved a NO monitoring system for the measurement of FENo concentration in expired breath as an adjunct to established clinical and laboratory assessments. 11 The test is noninvasive and well tolerated, and it provides instant results, which can aid clinicians in making immediately actionable and informed decisions. However, FENo measurements are most meaningful when combined with other measures of asthma control and diagnosis. In addition, it has been observed that some foods, drugs, and coexisting conditions can skew FENo measurements7,39-51; therefore, it is necessary to determine if factors other than inflammation are causing an elevation in FENo measurements. Future Directions The use of FENo as a standard measurement of airway inflammation in asthmatic patients shows promise as a noninvasive, well-tolerated, standardized, and FDA-approved technique. However, further studies are needed to better understand its role in asthma management. Studies addressing FENo as a screening tool and the long-term effect of FENo measurement on asthma control, patient quality of life, hospitalization, emergency department visits, drug-associated adverse effects, medication adherence, airway obstruction, morbidity, and mortality are needed to assess the utility of FENo in asthma monitoring. Trials investigating the impact of FENo measurements on physician practices

and decision making, as well as the cost-effectiveness of this tool, are also of interest. Additional studies on the impact of FENo measurement on the outcomes of patients with fixed airway obstruction are also warranted. The National Institute of Allergy and Infectious Diseases is currently sponsoring the Inner-City Asthma Coalition trial, which is comparing asthma control achieved with and without the addition of FENo measurement to guideline-monitored therapy. This trial is similar to the trials conducted by Green et al 8 and Sont et al, 9 which used sputum eosinophil monitoring and bronchial reactivity, respectively, in addition to standard monitoring tools. Although the technology has been approved by the FDA, the use of FENo monitoring in the clinical setting is currently compromised owing to the lack of a current procedural terminology (CPT) reimbursement code. The lack of a CPT code, and therefore lack of reimbursement, may be a barrier to more common usage of this technology, without which the development of large, randomized trials to further explore the efficacy of this measurement may be hindered. 23 CONCLUSIONS FENo measurement is a noninvasive, well-tolerated, standardized, and reproducible test that is a surrogate measure of airway inflammation in patients with asthma. This test has demonstrated utility in the diagnosis and management of asthma, as well as in predicting response to therapy. These attributes suggest that it may be an important tool to incorporate into clinical care. Although further studies are needed to understand the scope and potential impact of this technique, the consensus of this group is that the measurement of FENo has potential merit in the diagnosis and management of asthma. ACKNOWLEDGM ENTS The April 2005 meeting and resulting consensus paper was supported by an educational grant provided by Aerocrine. Participants were provided with an honorarium for their participation in the meeting and thus are considered paid consultants of Aerocrine. Participants included James W. Baker, MD; William Berger, MD, MBA; Michael Blaiss, MD; Bradley Chipps, MD; Aaron Deykin, MD; Michael B. Foggs, MD; Gavin R. Graft, MD; Lanny Rosenwasser, MD; Michael Schatz, MD, MS; Philip Silkoff, MD; Mark E. Wylam, MD; Robert S. Zeiger, MD, PhD; and Myron Zitt, MD.

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Address correspondence to: M y r o n Zitt, M D , Chief, Allergy and Immunology, Queen's Long Island Medical Group, 300 Bay Shore Road, N o r t h Babylon, N Y 11703. E-maih [email protected]