This thesis examines the overarching theme of inhaled corticosteroid (ICS) dose response effects on a variety of asthma outcome measures; with further importance placed on the application of these findings to personalising ICS dosing for the individual asthmatic. The introduction provides a detailed summary of the current recommendations for the treatment of adult asthma, with particular reference to the mechanism of action and clinical utility of ICS for the treatment of asthma. Current methods of assessing ICS dose response are presented, as well as the common influences that affect these responses. Novel therapeutic theories and the identification of specific asthmatic phenotypes are also introduced, in order to demonstrate the shift towards personalising treatment for asthma. The first two studies examine the dose response of ICS on two specific factors that influence asthma. The third study presents an examination of pharmacological manipulation of the ICS dose response using an additional agent. The following two studies address: how asthma outcomes relate to each other in patients receiving ICS; in addition to an overall assessment of the ICS dose response across a broad range of both ICS moieties and outcome measures. The final study examines for any detrimental effect of an ICS dose ramp on bone metabolism, an important potential long-term adverse effect of higher ICS dosing. The discussion draws together all the results obtained in relation to ICS dose response in asthma, and how these apply to current clinical practice for the individual patient. Furthermore, hypotheses are generated for areas of future study based on the findings from this work.

Master of Science in Medicine / Rationale: Asthma management aims to achieve optimal control on the minimal effective dose of medication. We assessed the effectiveness of two algorithms to guide ICS dose in well-controlled patients on ICS+LABA in a double-blind study, comparing dose adjustment guided by exhaled nitric oxide (eNO) to clinical care algorithm(CCA) based on symptoms and lung function. Methods: We randomised non-smoking adult asthmatics on minimum FP dose 100μgs daily +LABA to ICS adjustment using eNO or CCA, assessed over 5 visits during 8 months treatment. Primary endpoints were asthma-free days and asthma related quality of life (QOL). Analysis was by mixed model regression and generalised estimating equations with log link. Results: 69 subjects were randomised (eNO:34, CCA:35) and 58 completed the study. At baseline mean FEV1 was 94% pred., mean eNO (200ml/sec) 7.1 ppb, median ACQ6 score 0.33. Median ICS dose was 500 μg (IQR 100-500) at baseline and 100 μg on both eNO (IQR 100-200) and CCA arms (IQR 100–100) at end of study. There were no significant differences between eNO and CCA groups in asthma-free days (RR=0.92, 95% CI 0.8–1.01), AQL (RRAQL<median = 0.95, 95% CI 0.8–1.1) or exacerbation-free days (HR = 1.03, 95%CI 0.6–1.7). Neither clinic FEV1 (overall mean difference FEV1 % pred. -0.24%, 95% CI -2.2–1.7) nor a.m. PEF (mean difference 1.94 L/min (95% CI -2.9–6.8) were significantly different. Similar proportions of subjects were treated for ≥1 exacerbation (eNO: 50%, 95% CI 32.1–67.9; CCA: 60%, 95% CI 43.9–76.2). Conclusion: Substantial reductions in ICS doses were achieved in well controlled asthmatics on ICS+LABA, with no significant differences in outcomes between eNO or clinically based algorithms.

Exhaled breath condensate (EBC) is a non-invasive method of investigating airway inflammation associated with nitric oxide (NO) and the metabolites nitrite/nitrates (NOx) in diseases such as chronic obstructive pulmonary disease (COPD), but some of the variables affecting the results are unknown. It was hypothesised that 1) EBC would be influenced by lung volumes and the type of EBC collection device; 2) fractional exhaled NO (FENO) and EBC NOx in COPD patients would be altered by smoking and glucocorticosteroids (GCS); 3) cigarette smoke could contribute to the EBC NOx concentration while it may also decrease FENO indirectly by converting airway NO to NOx. It was found that EBC volume was significantly correlated with both tidal volume and minute volume. Comparing four EBC collection devices demonstrated greater efficiency with the ECoScreen?? than siliconised glass tubes or RTube?? but it gave factitiously high NOx levels. Total EBC protein levels over a 10-minute collection were significantly higher using the ECoScreen?? than either glass or RTube?? devices. A cross-sectional study of 96 COPD patients and 80 age-matched control subjects demonstrated that FENO levels in COPD patients were significantly higher than normal subjects when comparing either the combined groups or appropriate two subgroups: ex-smokers and smokers. GCS treatment demonstrated no significant effect on either FENO levels or EBC NOx, but EBC NOx was elevated in smokers. In vitro, cigarette smoke extract (CSE) induced significantly higher NOx and asymmetric dimethylarginine (ADMA) levels in A549 cells when compared with control media. The anti-oxidant, NAC pre-treatment partially reversed the elevated NOx levels but not the ADMA levels. This thesis is the first to report FENO and EBC NOx in COPD patients in an appropriate sample size to be able to evaluate each subgroup, and the increased EBC NOx levels found in smokers in vivo was consistent with the elevated NOx level in response to CSE observed in vitro. These data indicate that smoking-related airway inflammation and activation of the NO pathway are complex with both an increase in ADMA, NO, NOx and may be regulated by oxidative stress rather than the nitric oxide synthase (NOS) pathway.

Master of Science in Medicine / Rationale: Asthma management aims to achieve optimal control on the minimal effective dose of medication. We assessed the effectiveness of two algorithms to guide ICS dose in well-controlled patients on ICS+LABA in a double-blind study, comparing dose adjustment guided by exhaled nitric oxide (eNO) to clinical care algorithm(CCA) based on symptoms and lung function. Methods: We randomised non-smoking adult asthmatics on minimum FP dose 100μgs daily +LABA to ICS adjustment using eNO or CCA, assessed over 5 visits during 8 months treatment. Primary endpoints were asthma-free days and asthma related quality of life (QOL). Analysis was by mixed model regression and generalised estimating equations with log link. Results: 69 subjects were randomised (eNO:34, CCA:35) and 58 completed the study. At baseline mean FEV1 was 94% pred., mean eNO (200ml/sec) 7.1 ppb, median ACQ6 score 0.33. Median ICS dose was 500 μg (IQR 100-500) at baseline and 100 μg on both eNO (IQR 100-200) and CCA arms (IQR 100–100) at end of study. There were no significant differences between eNO and CCA groups in asthma-free days (RR=0.92, 95% CI 0.8–1.01), AQL (RRAQL<median = 0.95, 95% CI 0.8–1.1) or exacerbation-free days (HR = 1.03, 95%CI 0.6–1.7). Neither clinic FEV1 (overall mean difference FEV1 % pred. -0.24%, 95% CI -2.2–1.7) nor a.m. PEF (mean difference 1.94 L/min (95% CI -2.9–6.8) were significantly different. Similar proportions of subjects were treated for ≥1 exacerbation (eNO: 50%, 95% CI 32.1–67.9; CCA: 60%, 95% CI 43.9–76.2). Conclusion: Substantial reductions in ICS doses were achieved in well controlled asthmatics on ICS+LABA, with no significant differences in outcomes between eNO or clinically based algorithms.

Inhalation of organic dust, including endotoxin, has been associated with inflammatory response of the pulmonary system. Limited studies have evaluated the work shift effects of endotoxin on respiratory outcomes for workers in the dairy industry, such as spirometry changes. Measurement techniques for exhaled nitric oxide (eNO) have been standardized by the American Thoracic Society (ATS) and used as a biomarker to identify diseases marked with lung inflammation. Dairy parlor workers are known to work long hours in one location with little job variability. The objectives of this study were to quantify exposure concentrations of inhalable dust and endotoxin among dairy parlor workers, evaluate acute cross-shift changes in respiratory status using spirometry, and assess the effectiveness of exhaled nitric oxide for detecting cross-shift bronchial inflammation changes. The cross-sectional study recruited 62 dairy parlor workers from 10 large herd dairy farms across Iowa, Minnesota, Wisconsin, and South Dakota. Data collected before and after the work shifts included spirometry tests, eNO measurements, and pulmonary symptom questionnaires. Personal breathing zone exposure to inhalable dust was assessed during the shift using Button Aerosol Samplers. Gravimetric analysis was used to determine airborne concentrations of inhalable dust and endotoxin concentration was determined using the recombinant factor C assay. Inhalable dust concentrations ranged from 0.09 - 4.95 mg/m3 with a geometric mean of 0.58 mg/m3. Inhalable endotoxin concentrations ranged from 4-1968 EU/m3 with a geometric mean of 117 EU/m3. The study participants pre-shift forced expiratory volume in the first second (FEV1) as a percentage of predicted was an average of 93.4%. Study group cross-shift FEV1 decreased by -1.16%. Six participants with moderate post-shift concentrations of eNO had an average FEV1 cross-shift change of -3.19%. Dairy parlor workers are exposed to concentrations of organic dusts that may adversely impact health. Future studies should test interventions in milking parlors to reduce dust exposure among dairy workers.

BACKGROUND: Pulmonary Hypertension (PH) is a common form of high blood pressure in the lungs. It affects the pulmonary arteries, which normally allow blood to flow from the right heart to the lungs. Nitric Oxide (NO) is a potential mediator for establishing PH and decreasing its availability is implicated in the pathogenesis of PH. HYPOTHESIS: We tested the hypothesis that Fractional Exhaled Nitric Oxide (FeNO) is a good indicator to assess disease severity that may add to understanding the disease. METHODS: The aim of the study was to measure FeNO levels in consecutive PH patients and seek correlations with the 6 Minute walk distance (6MWD) within different World Health Organization (WHO) groups and New York Health Association Function Class (NYHA FC). Assignment to groups I or IV was done respecting the current guidelines. All values were taken at Tufts Medical Center PAH clinic visits. FeNO levels were measured utilizing the NIOX device. RESULTS: FeNO levels were highest in WHO Group 1 and lowest in WHO Group 5 patients. There was a strong inverse correlation between FeNO and 6MWD for each NYHA FC. (Pearson correlation of -0.986, p = 0.014). Within WHO Groups, we found significantly inverse correlations between FeNO and 6MWD in PH Group 4 (p= 0.012) and PH Group 5 (p=0.001). NYHA FC correlated with 6MWD across all WHO Groups (P=0.001). CONCLUSION: We report for the first time FeNO levels in all WHO Groups of PH. FeNO levels are low in early disease. FeNO levels correlate inversely with the severity of PH in WHO Group 4 and 5 patients. The increase in FeNO in more severe patients may reflect the degree of oxidative stress and inflammation in severe PH. Further studies to determine whether FeNO may be a biomarker in early disease, especially in PH Group 4 and 5 warrants further investigation.

O objetivo do presente estudo foi avaliar o papel de um programa de condicionamento físico nos aspectos relacionados à qualidade de vida, níveis de ansiedade e depressão, sintomas e óxido nítrico exalado de pacientes com asma persistente moderada ou grave. Foram avaliados 39 pacientes divididos aleatoriamente em grupo controle (GC; N=20) e grupo treinado (GT; N=19). Foram avaliados a capacidade aeróbica máxima (VO2max), função pulmonar, qualidade de vida, sintomas, ansiedade, depressão e percepção subjetiva de esforço e óxido nítrico exalado com um intervalo de 3 meses. Não houve diferença entre os grupos antes do tratamento. O treinamento físico melhorou as capacidades máximas e submáximas ao esforço e os níveis de depressão (p < 0,05). O treinamento físico reduziu os níveis de ansiedade-traço (p < 0,05), mas não a ansiedade-estado. O treinamento físico também melhorou os domínios limitação física, freqüência de sintomas, psicossocial e escore total dos HRQL (p < 0,001). Houve aumento no número de dias livres de sintomas (p < 0,001) e nos valores de óxido nítrico exalado (p < 0,001) no grupo treinado. Nossos resultados sugerem que o condicionamento físico para pacientes asmáticos pode ser benéfico para reduzir sintomas e melhorar os escores de qualidade de vida e a co-morbidade psicossocial. Estes dados sugerem que o treinamento físico pode ter um papel adjuvante importante no controle clínico de pacientes com asma persistente moderada ou grave / The aim of the present study was to evaluate the effect of aerobic training on quality of life, functional capacity and exhaled nitric oxide (NOex) in patients with moderate and severe asthma. Twenty nine subjects were randomly divided in control group (n 20) (educational program + breathing exercises) and training group (n 19) (control + aerobic training, 70% maximal VO2peak) and followed during 3 months, twice a week. Aerobic capacity (VO2peak), quality of life, anxiety, depression, and pulmonary function were evaluated before and after treatment. FENO and symptoms were evaluated monthly. There was no change in inhaled glucocortiscosteroid during treatment. Our results show that patients submitted to an aerobic training presented a decrease on physical limitation (p < 0.05), frequency and gravity score, decrease in psychosocial limitation an increse in global score of quality of life (p < 0.05) as well as an improvement on VO2peak (p=0,001) when compared with control group. Compared with control group, training group also presented a increase in number of days without symptoms (p < 0,001). FENO it was also decreased (p < 0,001) after training in training group. No change was observed in lung function in both groups after treatment. Our results suggest that aerobic improves quality of life and decreases symptoms and exhaled nitric oxide on asthmatic patients reinforcing its importance on asthma treatment

O objetivo do presente estudo foi avaliar o papel de um programa de condicionamento físico nos aspectos relacionados à qualidade de vida, níveis de ansiedade e depressão, sintomas e óxido nítrico exalado de pacientes com asma persistente moderada ou grave. Foram avaliados 39 pacientes divididos aleatoriamente em grupo controle (GC; N=20) e grupo treinado (GT; N=19). Foram avaliados a capacidade aeróbica máxima (VO2max), função pulmonar, qualidade de vida, sintomas, ansiedade, depressão e percepção subjetiva de esforço e óxido nítrico exalado com um intervalo de 3 meses. Não houve diferença entre os grupos antes do tratamento. O treinamento físico melhorou as capacidades máximas e submáximas ao esforço e os níveis de depressão (p < 0,05). O treinamento físico reduziu os níveis de ansiedade-traço (p < 0,05), mas não a ansiedade-estado. O treinamento físico também melhorou os domínios limitação física, freqüência de sintomas, psicossocial e escore total dos HRQL (p < 0,001). Houve aumento no número de dias livres de sintomas (p < 0,001) e nos valores de óxido nítrico exalado (p < 0,001) no grupo treinado. Nossos resultados sugerem que o condicionamento físico para pacientes asmáticos pode ser benéfico para reduzir sintomas e melhorar os escores de qualidade de vida e a co-morbidade psicossocial. Estes dados sugerem que o treinamento físico pode ter um papel adjuvante importante no controle clínico de pacientes com asma persistente moderada ou grave / The aim of the present study was to evaluate the effect of aerobic training on quality of life, functional capacity and exhaled nitric oxide (NOex) in patients with moderate and severe asthma. Twenty nine subjects were randomly divided in control group (n 20) (educational program + breathing exercises) and training group (n 19) (control + aerobic training, 70% maximal VO2peak) and followed during 3 months, twice a week. Aerobic capacity (VO2peak), quality of life, anxiety, depression, and pulmonary function were evaluated before and after treatment. FENO and symptoms were evaluated monthly. There was no change in inhaled glucocortiscosteroid during treatment. Our results show that patients submitted to an aerobic training presented a decrease on physical limitation (p < 0.05), frequency and gravity score, decrease in psychosocial limitation an increse in global score of quality of life (p < 0.05) as well as an improvement on VO2peak (p=0,001) when compared with control group. Compared with control group, training group also presented a increase in number of days without symptoms (p < 0,001). FENO it was also decreased (p < 0,001) after training in training group. No change was observed in lung function in both groups after treatment. Our results suggest that aerobic improves quality of life and decreases symptoms and exhaled nitric oxide on asthmatic patients reinforcing its importance on asthma treatment

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