Nitric Oxide In Exhaled Breath Research Articles

Exhaled Nitric Oxide: A Valuable Tool for Early Diagnosis and Phenotyping of Bronchiolitis Obliterans Syndrome

To the Editor: Thank you very much for the opportunity to write a letter of response with respect to the letter of Antus et al. regarding possible limitations of fraction of nitric oxide in exhaled breath (FeNO) for the early detection of chronic graft dysfunction after lung transplantation (LTX; Ref. 1). We speculate that several factors might have contributed to the lack of demonstration of clinical utility for FeNO in this relatively small cohort of LTX recipients. In our study, population underlying disease was not identified as a variable contributing to the variance of FeNO. However, the percentage of cystic fibrosis (CF) patients in our study cohort was only 16.7% in comparison to 43.3% in the Hungarian cohort. Although subgroup analysis of FeNO performance is limited because of the overall small sample size, we cannot definitely rule out a significant impact of the underlying disease on FeNO performance as a marker for bronchiolitis obliterans syndrome (BOS; Ref. 2). Despite the fact that FeNO readings of recipients with overt infection were excluded from the analysis, a significant rate of colonization and subclinical infections in CF patients may be important confounders for the interpretation of FeNO measurements (3). In accordance with the findings of Antus et al., our data demonstrated that a relevant percentage of patients displayed only slightly elevated FeNO values in spite of developing BOS. We suggest that dividing BOS patients on the basis of BAL neutrophilia into neutrophilic reversible allograft dysfunction and fibroproliferative BOS (fBOS) could reveal a lack of detectable FeNO increase in fBOS patients because FeNO is mainly a marker of airway inflammation (4). Moreover, Antus and colleagues do not report the prophylactic or therapeutic use of azithromycin in CF and nonCF recipients which is the standard of care in many centers for patients during early stages of BOS that might result in a significant reduction of FeNO (5). The authors report an impressively high number of FeNO measurements without finding an unambiguous association of FeNO and BOS during long-term follow-up. However, assessment of FeNO readings as a mean of all values recorded during 6-month intervals as depicted by Antus and colleagues might hamper the performance of FeNO as a predictive marker because the average time from FeNO readingto onsetofBOSwas only 117 ±9 days in ourstudy. In this respect, we wish to emphasize the high negative predictive value of elevated FeNO (96.9%) in comparison to its rather intermediate positive predictive value (69.0%) in our cohort. In summary, we clearly recognize the relevant limitations of FeNO as a predictive marker in the context of the overall highly variable course of BOS. Nevertheless, FeNO is a valuable tool to improve our understanding for different phenotypes of BOS with potentially important clinical applications.

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter-individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti-inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

Measurement of Exhaled Nitric Oxide in a General Population Sample: A Comparison of the Medisoft HypAir FENO and Aerocrine NIOX Analyzers

Background and objective. Measuring the fraction of nitric oxide in exhaled breath (FENO) is increasingly utilized to assess airway inflammation in asthma. The primary aim of this study was to compare exhaled nitric oxide measurements obtained using two devices from different manufacturers, that is, the recently marketed portable and electrochemical-based Medisoft HypAir FENO and the well-established chemiluminescence-based Aerocrine NIOX analyzer, in an unselected population. Methods. FENO measurements were conducted in 106 subjects (86 healthy; 20 asthmatic; 56.6% atopic). Atopy and health status were assessed by skin prick tests and questionnaire, respectively. Results. The two instruments showed strong correlation over a wide range of FENO measurements (8–261.3 ppb with the HypAir, 5.6–156.8 ppb with the NIOX; r = 0.98; p < .0001). This correlation was observed in the population as a whole, as well as in healthy non-atopics, healthy atopics, and atopic asthmatics when considered separately. The measurements on the HypAir FENO were consistently 1.6 times (95% CI 1.11–2.05) higher than those obtained with the NIOX. Conclusions. FENO measurements obtained with the HypAir FENO correlated well with the NIOX, but were approximately 1.6 times higher. Therefore, a conversion factor is required if results are to be compared with the NIOX instrument.

L-Arginine Supplementation and Metabolism in Asthma

l-Arginine, the amino acid substrate for nitric oxide synthase, has been tested as a therapeutic intervention in a variety of chronic diseases and is commonly used as a nutritional supplement. In this study, we hypothesized that a subset of moderate to severe persistent asthma patients would benefit from supplementation with l-arginine by transiently increasing nitric oxide levels, resulting in bronchodilation and a reduction in inflammation. The pilot study consisted of a 3 month randomized, double-blind, placebo-controlled trial of l-arginine (0.05 g/kg twice daily) in patients with moderate to severe asthma. We measured spirometry, exhaled breath nitric oxide, serum arginine metabolites, questionnaire scores, daily medication use and PEFR with the primary endpoint being the number of minor exacerbations at three months. Interim analysis of the 20 subjects showed no difference in the number of exacerbations, exhaled nitric oxide levels or lung function between groups, though participants in the l-arginine group had higher serum l-arginine at day 60 (2.0 ± 0.6 × 10−3 vs. 1.1 ± 0.2 × 10−3 μmol/L, p < 0.05), ornithine at day 30 (2.4 ± 0.9 vs. 1.2 ± 0.3 μmol/L serum, p < 0.05) and ADMA at day 30 (6.0 ± 1.5 × 10−1 vs. 2.6 ± 0.6 × 10−1 μmol/L serum, p < 0.05) on average compared to the placebo group. The study was terminated prematurely. Supplementing asthma subjects with l-arginine increases plasma levels; whether subgroups might benefit from such supplementation requires further study.

Exhaled nitric oxide in the diagnosis and management of bronchial asthma: From bench to bedside?

The identification of nitric oxide in exhaled breath and its role as a surrogate marker of eosinophilic inflammation of the airways led to rapid development in the area of its measurement. Standardized measurement techniques have been developed as well as simple, cheap, and reliable equipments. Although a number of factors have been identified as affecting its assay, fractional exhaled nitric oxide (FENO) can reliably be used to distinguish eosinophilic from non-eosinophilic airway inflammation. Unlike the other indirect measures of airway inflammation such as FEV1 reversibility and bronchoprovocative tests, FENO is noninvasive and gives a direct measure of inflammation. There are sufficient data supporting its role in the diagnosis of asthma, monitoring of disease, prediction of relapse, and level of compliance. Measurement of FENO has therefore made the transition from the bench to the bedside. Of recent, there are attempts at devising interpretative strategies for its use in day to day clinical practice.

Acute effects of motor vehicle traffic‐related air pollution exposures on measures of oxidative stress in human airways

Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. In controlled-exposure studies of animals and humans, emissions from diesel engines, a major source of traffic-related air pollutants, cause pulmonary and systemic inflammation that is mediated by redox-sensitive signaling pathways. Assessment of human responses to traffic-related air pollution under realistic conditions is challenging due to the complex, dynamic nature of near-roadway exposure. Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate.

Two variants of occupational asthma separable by exhaled breath nitric oxide level

Exhaled nitric oxide (FE(NO)) has been used as a marker of asthmatic inflammation in non-occupational asthma, but some asthmatics have a normal FE(NO). In this study we investigated whether, normal FE(NO) variants have less reactivity in methacholine challenge and smaller peak expiratory flow (PEF) responses than high FE(NO) variants in a group of occupational asthmatics. We measured FE(NO) and PD(20) in methacholine challenge in 60 workers currently exposed to occupational agents, who were referred consecutively to a specialist occupational lung disease clinic and whose serial PEF records confirmed occupational asthma. Bronchial responsiveness (PD(20) in methacholine challenge) and the degree of PEF change to occupational exposures, (measured by calculating diurnal variation and the area between curves score of the serial PEF record in Oasys), were compared between those with normal and raised FE(NO). Potential confounding factors such as smoking, atopy and inhaled corticosteroid use were adjusted for. There was a significant correlation between FE(NO) and bronchial hyper-responsiveness in methacholine challenge (p = 0.011), after controlling for confounders. Reactivity to methacholine was significantly lower in the normal FE(NO) group compared to the raised FE(NO) group (p = 0.035). The two FE(NO) variants did not differ significantly according to the causal agent, the magnitude of the response in PEF to the asthmagen at work, or diurnal variation. Occupational asthma patients present as two different variants based on FE(NO). The group with normal FE(NO) have less reactivity in methacholine challenge, while the PEF changes in relation to work are similar.

Adherence to HAART (Highly Active Antiretroviral Therapy) by HIV-1 Infected Patients with Allergic Asthma is Associated with Selective Suppression of Serum IgE but Not of Exhaled Breath Nitric Oxide (NO).

Adherence to HAART (Highly Active Antiretroviral Therapy) by HIV-1 Infected Patients with Allergic Asthma is Associated with Selective Suppression of Serum IgE but Not of Exhaled Breath Nitric Oxide (NO).

Selective Inducible Nitric Oxide Synthase Inhibition Has No Effect on Allergen Challenge in Asthma

Exhaled breath nitric oxide (Fe(NO)) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. Fe(NO) was assessed predose on Days 1, 7, 10, and 14. Adenosine 5'-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. GW274150 reduced predose Fe(NO) by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce Fe(NO). GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced Fe(NO) levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. Selective iNOS inhibition effectively reduces Fe(NO) but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00273013).

The Use of Exhaled Nitric Oxide to Guide Asthma Management

Rationale: Current asthma guidelines recommend adjusting antiinflammatory treatment on the basis of the results of lung function tests and symptom assessment, neither of which are closely associated with airway inflammation.Objectives: We tested the hypothesis that titrating corticosteroid dose using the concentration of exhaled nitric oxide in exhaled breath (FeNO) results in fewer asthma exacerbations and more efficient use of corticosteroids, when compared with traditional management.Methods: One hundred eighteen participants with a primary care diagnosis of asthma were randomized to a single-blind trial of corticosteroid therapy based on either FeNO measurements (n = 58) or British Thoracic Society guidelines (n = 60). Participants were assessed monthly for 4 months and then every 2 months for a further 8 months. The primary outcome was the number of severe asthma exacerbations. Analyses were by intention to treat.Measurements and Main Results: The estimated mean (SD) exacerbation frequency was 0.33 per patient per year (0.69) in the FeNO group and 0.42 (0.79) in the control group (mean difference, −21%; 95% confidence interval [CI], −57 to 43%; p = 0.43). Overall the FeNO group used 11% more inhaled corticosteroid (95% CI, −17 to 42%; p = 0.40), although the final daily dose of inhaled corticosteroid was lower in the FeNO group (557 vs. 895 μg; mean difference, 338 μg; 95% CI, −640 to −37; p = 0.028).Conclusions: An asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used over 12 mo, when compared with current asthma guidelines.Clinical trial registered with www.controlled-trials.com (ISRCTN08067387).

Mouse Models of Asthma: Can They Give Us Mechanistic Insights into the Role of Nitric oxide?

New clinical practice guidelines for patients with asthma include the recommendation to monitor exhaled breath nitric oxide (NO) levels. NO concentrations in exhaled breath are increased in asthmatics and increased NO levels correlate with worsening airway inflammation and asthma symptoms. The multiple roles of NO in the lung have not been delineated clearly. Clinical trials are being performed presently that test the apparently conflicting hypotheses that either donors or inhibitors of NO in the lung are effective strategies for treating asthma. These strategies evolved, in part, from results of pre-clinical studies performed in mice and other animal models. This review evaluates the existing literature with regard to mouse models of asthma and explores the often conflicting data on the role of NO, the nitric oxide synthase (NOS) enzymes, and the arginase enzymes in allergic airway inflammation. While we will emphasize the ovalbumin exposure mouse model, we will also examine other models. Where inconsistencies are identified among the studies, we attempt to determine whether such inconsistencies arise from methodological differences or alternative mechanisms. Ultimately, we address whether the allergen-exposed mouse is a suitable model for identifying promising new drugs for the treatment of human asthma. While a consensus is building that NO is beneficial or protective in subsets of asthmatics, results from studies using mouse models to investigate the individual roles of NO and the NOS enzymes in airway inflammation are often contradictory. Further research efforts with this model will allow us to distinguish which asthma patients may benefit best from NO donors and which may benefit from NO inhibitors.

Reference Ranges for Exhaled Nitric Oxide Derived from a Random Community Survey of Adults

Measurement of the fraction of nitric oxide in exhaled breath (Fe(NO)) has been proposed as a noninvasive marker of airway inflammation. Before the widespread use of this test, there is a need to develop reference ranges to allow clinicians to interpret Fe(NO) measurements. To derive reference ranges for Fe(NO) and to determine which factors in health and disease influence Fe(NO) levels. Subjects aged between 25 and 75 years were drawn from a random sample of the predominantly white population of Wellington, New Zealand. Fe(NO) was measured using an online nitric oxide monitor in accordance with international guidelines. A detailed respiratory questionnaire and pulmonary function tests were performed. The geometric mean Fe(NO) was 17.9 parts per billion (ppb) with a 90% confidence interval for an individual prediction (reference range) for normal subjects of 7.8 to 41.1 ppb. Sex, atopy, and smoking status significantly affected Fe(NO) levels, and several reference ranges are presented adjusting for these factors. Asthma and allergic rhinitis were associated with higher Fe(NO). Measurement of Fe(NO) had poor discriminant ability to identify steroid-naive subjects with asthma. The reference ranges presented may be used to assist in the interpretation of Fe(NO) measurements in white adults.

Tetracyclines tigecycline and doxycycline inhibit LPS-induced nitric oxide production by RAW 264.7 murine macrophages. (101.3)

Abstract We previously reported that minocycline and doxycycline strongly suppress serum IgE and decrease IgE production by PBMC from patients with asthma (Smith-Norowitz et al, Ann Allergy, Asthma, &amp; Immunol 2002; 89:172–9; Durkin et al, AAAAI Annual Meeting San Diego, Feb 23–27, 2007). We have now studied the effects of doxycycline and tigecycline on LPS-induced nitric oxide (NO) production by murine macrophages (RAW 264.7). Cell cultures were incubated for 1 – 5 days with or without LPS (200ng/mL, phenol extracted from Salmonella typhimurium) and doxycycline or tigecycline (1 – 10 μg/ml). Accumulation of nitrite, stable metabolite of NO, was determined using a modified colorimetric Griess reaction. Both doxycycline, and to a lesser extent tigecycline, consistently suppressed LPS-induced nitric oxide production in dose-dependent manner (doxycycline: 23–30%, tigecycline: 10–23%). The tetracycline mediated suppression of NO production by macrophages in culture is independent of antimicrobial activities, but the underlying mechanism of this effect remains to be elucidated. Since nitric oxide is an important mediator of inflammatory responses, our results suggest that the anti-inflammatory effects of tetracyclines may be utilized in the treatment of IgE mediated allergic disorders and may decrease exhaled breath nitric oxide, an emerging biomarker of allergic airway disease.

Ascorbid Acid Supplementation Reduces Severity of Exercise-Induced Asthma

PURPOSE: Ascorbic acid (vitamin C) is a major antioxidant in the airways. Data on the effect of antioxidants on exercise-induced asthma (EIA) is equivocal. Therefore, the aim of this study was to determine the effects of ascorbic acid (vitamin C) supplementation on the severity of EIA. METHODS: Eight subjects with EIA participated in a randomized, placebo controlled double-blind cross-over trial. Subjects entered the study on their normal diet and were then placed on either 2 weeks of ascorbic acid supplementation (1500mg/day) or placebo, followed by a 1 week washout period, before crossing over to the alternative diet. Pre- and post-exercise pulmonary function was assessed at the conclusion of each treatment period. In addition, urine samples were collected pre- and post-exercise and assayed for the presence of pro inflammatory mediators, cysteinyl leukotrienes (LT) C4-E4 and 9α, 11β- prostaglandin (PG) F2 which have been implicated in the pathogenesis of EIA. Urine was assayed for hydrogen peroxide (H2O2), as a marker of oxidative stress. Diet was monitored through 24-hour dietary recall to ensure that diet was not significantly different between the trials. Pre- and post exhaled breath nitric oxide (FENO) was measured as a noninvasive indicator of airway inflammation. RESULTS: Ascorbic acid supplementation significantly reduced (p <0.05) the mean maximum fall in post-exercise FEV1 (−6.4 ± 2.4%) compared to normal diet (−14.3 ± 1.6%) and placebo (−12.9 ± 2.4%). Post-exercise FENO was reduced on ascorbic acid supplementation (23.8 ± 7.7 ppb) as compared to normal diet (48.4 ±16.3 ppb) and placebo (34.1 ± 7.8 ppb). Ascorbic acid supplementation induced significant reductions (p <0.05) in urinary LTC4-E4 on the ascorbic acid supplementation (5.3 ±1.7 ng/mmol of creatinine) compared to the normal diet (15.0 ±4.0 ng/mmol/creatinine) and placebo (11.1 ±3.1 ng/mmol/creatinine). Similarly, urinary 9α, 11β-PGF was significantly reduced on the ascorbic acid supplementation (8.5 ±1.7 ng/mmol/creatinine) compared to the normal diet (20.0 ±4.5 ng/mmol/creatinine) and placebo (13.0 ± 1.8 ng/mmol). Furthermore, significant reductions (p <0.05) in urinary HO were observed on the ascorbic acid supplementation (5.6 ± 1.3 mmol/L) compared to placebo (23.6 ±5.1 mmol/L) and normal diet (12.6 ±2.9 mmol/L). CONCLUSION: These data indicate that high dose ascorbic acid supplementation reduces the severity of EIA. This reduction in the severity of EIA may occur through a mechanism by which ascorbic acid reduces reactive oxygen species, thereby leading to a reduction in bronchoconstrictive mediators.

The Effects of Age on Exhaled Breath Nitric Oxide Levels

A variety of factors influence exhaled breath nitric oxide (ENO) but few studies have examined ENO at the extremes of adult age. This investigation explores whether there is a difference in ENO between groups of older and younger individuals. A total of 48 normal subjects consisting of 23 younger (median age - 24 years) and 25 older (median age - 72 years) participants were studied. Carefully defined clinical and spirometric parameters, smoking history, and drug/medication documentation were determined to insure normalcy. Measurements of ENO were made using ATS/ERS recommended methodologies. The older group consistently showed higher ENO concentrations than-the younger subjects; median ENO values were 36.9 and 18.7 ppb, respectively (p < 0.001). The statistical significance held true when adjusting for multiple testing with the Holm method and accounting for outliers and medication usage. ENO levels are significantly higher in a normal older population. Comparing ENO between individuals at the extremes of age may depict differences more decidedly. Whether elevated ENO reflects underlying airway inflammation in older persons remains unanswered. It is possible that the difference in NO concentrations between older and younger groups represents only a marker of past oxidant exposures and holds no clinical significance. Additional investigations are necessary to elucidate the mechanisms and significances of elevated NO levels in the aged.

Markers of Lung Disease in Exhaled Breath: Nitric Oxide

Management of airway inflammation requires proper monitoring and treatment to improve long-term outcomes. However, achieving this goal is difficult, as current methods have limitations. Although nitric oxide (NO) was first identified 200 years ago, its physiological importance was not recognized until the early 1980s. Many studies have established the role of NO as an essential messenger molecule in body systems. In addition, studies have demonstrated a significant relationship between changes in exhaled NO levels and other markers of airway inflammation. The technique used to measure NO in exhaled breath is noninvasive, reproducible, sensitive, and easy to perform. Consequently, there is growing interest in the use of exhaled NO in the management of asthma and other pulmonary conditions. The purpose of this review is to promote a basic understanding of the physiologic actions of NO, measurement techniques, and ways that research findings might translate to future application in clinical practice. Specifically, the article will review the role of exhaled NO in regard to its historical background, mechanisms of action, measurement techniques, and implications for clinical practice and research.

Is the “instant flow” option on the NIOX ® analyser needed?

Asthmatics have increased gaseous nitric oxide in their exhaled breath. Measurements of the fraction of nitric oxide in exhaled breath (FE NO) are used for the diagnosis and management of asthma. One analyser (the NIOX ® chemiluminescence analyser) has a feature (restriction of instant flow, IF) which we suspected was responsible for reducing the success rate for obtaining FE NO measurements whilst not affecting the measurement itself. In a study involving 38 children, median age 10 years, we observed that FE NO values taken in the same individual with and without IF restriction did not differ. We also observed that the success in obtaining a FE NO measurement was higher (57%) when IF was not restricted and was lower (41%) when IF was restricted, p = 0.002. Our findings do not support the use of restriction of IF on the NIOX ® analyser.

Real-Time Analysis of Exhaled Breath via Resonance-Enhanced Multiphoton Ionization-Mass Spectrometry with a Medium Pressure Laser Ionization Source: Observed Nitric Oxide Profile

An elevated concentration of nitric oxide (NO) in alveolar ventilation is indicative of inflammatory stress within the lung. We present here the first description of time-resolved measurement of NO in breath using photoionization mass spectrometry, providing new capabilities for the medical investigator, such as isotopic tracing. Here we use resonance-enhanced multiphoton ionization (REMPI) with time-of-flight mass spectrometry (TOF-MS) coupled with a medium pressure laser ionization (MPLI) source for the selective detection of NO in breath. To demonstrate this technology, a single male subject breathes NO-free air for several minutes, and then the exhaled breath is monitored. The ability of REMPI to differentiate among three different isotopomers of NO is demonstrated, and then the concentration profile of NO in exhaled breath is measured. A similar time-dependence concentration is found as observed by previous techniques. The advantages of this approach compared to other techniques are: (1) parts-per-billion by volume (ppbV) mixing ratios of NO can be measured on a sub-second time scale, (2) since the technique operates optically as well as mass-resolved, isotopomers of NO are discernable, permitting the use of isotopic tracing, and (3) other biologically significant gas molecules can be measured via REMPI.

Lin et al. Respond to “Assessment of Respiratory Symptoms after September 11”

We appreciate the observations made by Drs. Vlahov and Galea in their invited commentary (1) on our paper (2). Given that the World Trade Center (WTC) disaster was an unprecedented event, this was not a traditional epidemiologic study but rather a community health investigation designed to respond to the public’s concerns, as well as the first step in examining the potential health effects on local residents. Many constraints made this study difficult to design, including a lack of baseline prevalence and exposure data and unknown mobility patterns. As we explain below, most of the problems discussed by Vlahov and Galea were considered in our article and addressed to the extent possible. Selection bias is one of their main concerns. Since a significant number of residents moved out of the affected area after September 11, the actual response rate might have been higher than estimated. In addition, the response rates were similar in the affected and control areas, and the demographic distribution of the participants was similar to that of the underlying population. To estimate selection bias, we targeted a subset of buildings in the affected and control areas for increased recruitment efforts and achieved higher response rates in both areas. The risk estimates from the targeted buildings, in which the samples are assumed to be more representative, were not only consistent with but also higher than those in the nontargeted buildings. Another potential problem is information bias. We reported that ‘‘we emphasized the importance of participation for people with and without breathing problems’’ and that we used ‘‘general terms such as ‘breathing or lung problems’ rather than specific terms like ‘asthma’ ’’ (2, p. 505). We also stated that ‘‘we asked symptom questions not only qualitatively but also quantitatively, by including questions on specific time frames, severity, and frequency, which are less prone to recall bias’’ (2, p. 505). In addition, the symptom questions that we chose for the questionnaire have been validated in many epidemiologic studies. To reduce reporting bias, we asked participants about prescription medications and listed the names of the medications. We also used more objective measures by asking participants about new diagnoses by a physician, unplanned medical visits, and hospitalizations (including the dates and reasons for hospitalization). We checked the differences between the two areas for WTC-unrelated variables (e.g., physical disabilities) and excluded participants who responded affirmatively to every question. To estimate reporting bias, we compared the proportions of unplanned medical visits among participants with specific respiratory symptoms and found them be similar in the affected and control areas for most symptoms. Finally, as we described in another article (3), screening spirometry was conducted in some participants to validate self-reported symptoms. Although there were no significant differences between the affectedarea residents and the control-area residents (screening spirometry might not be sensitive for this exposure), the results of a pilot methacholine challenge test showed a higher proportion of positive findings in the participants with persistent new-onset symptoms than in asymptomatic participants. We are conducting additional studies to address some of these concerns. A follow-up study will use nitric oxide in exhaled breath (eNO) as an objective measure of airway inflammation. Self-reported symptoms will be correlated with eNO measurements and validated. Another study will estimate changes in hospitalizations (an objective indicator of outcome) for respiratory and cardiovascular diseases before and after September 11, 2001, and compare the rates in both areas. The WTC Health Registry, which has recruited a larger cohort, also plans to follow this population. The ambient air monitoring site located at the WTC was destroyed in the collapse, so ambient pollution levels immediately after September 11 were not available for exposure assessment. For this reason, we did not attribute our findings

Exhaled Nitric Oxide in Children with Asthma and Short-Term PM 2.5 Exposure in Seattle

The objective of this study was to evaluate associations between short-term (hourly) exposures to particulate matter with aerodynamic diameters < 2.5 μm (PM2.5) and the fractional concentration of nitric oxide in exhaled breath (FeNO) in children with asthma participating in an intensive panel study in Seattle, Washington. The exposure data were collected with tapered element oscillation microbalance (TEOM) PM2.5 monitors operated by the local air agency at three sites in the Seattle area. FeNO is a marker of airway inflammation and is elevated in individuals with asthma. Previously, we reported that offline measurements of FeNO are associated with 24-hr average PM2.5 in a panel of 19 children with asthma in Seattle. In the present study using the same children, we used a polynomial distributed lag model to assess the association between hourly lags in PM2.5 exposure and FeNO levels. Our model controlled for age, ambient NO levels, temperature, relative humidity, and modification by use of inhaled corticosteroids. We found that FeNO was associated with hourly averages of PM2.5 up to 10–12 hr after exposure. The sum of the coefficients for the lag times associated with PM2.5 in the distributed lag model was 7.0 ppm FeNO. The single-lag-model FeNO effect was 6.9 [95% confidence interval (CI), 3.4 to 10.6 ppb] for a 1-hr lag, 6.3 (95% CI, 2.6 to 9.9 ppb ) for a 4-hr lag, and 0.5 (95% CI, −1.1 to 2.1 ppb) for an 8-hr lag. These data provide new information concerning the lag structure between PM2.5 exposure and a respiratory health outcome in children with asthma.