The effect of aging and cardiorespiratory fitness on the lung diffusing capacity response to exercise in healthy humans

Aging is associated with deterioration in the structure and function of the pulmonary circulation. We characterized the lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm(CO)), and pulmonary-capillary blood volume (V(C)) response to discontinuous incremental exercise at 25, 50, 75, and 90% of peak work (Wpeak) in four groups: 1) Young [27 ± 3 y, maximal oxygen consumption (V̇O₂max) 110 ± 18% age-predicted]; 2) Young Highly-Fit (27 ± 3 y, V̇O₂max 147 ± 8% age-predicted); 3) Old (69 ± 5 y, V̇O₂max 116 ± 13% age-predicted); and 4) Old Highly-Fit (65 ± 5 y, V̇O₂max 162 ± 18% age-predicted). At rest and at 90% Wpeak, DLCO, Dm(CO), and VC were decreased with age. At 90% Wpeak, DLCO, Dm(CO) and VC were greater in Old Highly-Fit vs. Old adults. The slope of the DLCO-cardiac output (Q̇) relationship from rest to end-exercise at 90% Wpeak was not different between Young, Young Highly-Fit, Old and Old Highly-Fit (1.35 vs. 1.44 vs. 1.10 vs. 1.35 mlCO·mmHg⁻¹·Lblood⁻¹, P = 0.388), with no evidence of a plateau in this relationship during exercise; this was also true for Dm(CO)-Q̇ and V(C)-Q̇. V̇O2max was positively correlated with: 1) DLCO, Dm(CO), and V(C) at rest; 2) the rest to end-exercise change in DLCO, Dm(CO), and V(C). In conclusion, these data suggest that despite the age-associated deterioration in the structure and function of the pulmonary circulation, expansion of the pulmonary capillary network does not become limited during exercise in healthy individuals regardless of age or cardiorespiratory fitness level

Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

Increased exhalation of hydrogen peroxide in healthy subjects following cigarette consumption

CONTEXT: Increased hydrogen peroxide has been described in the expired breath condensate (H2O2-E) of several lung conditions, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. This technique has been advocated as being a simple method for documenting airway inflammation. OBJECTIVE: To evaluate H2O2-E in healthy cigarette smokers, and to determine the acute effects of the consumption of one cigarette on H2O2-E levels. TYPE OF STUDY: Prospective, controlled trial. SETTING: A pulmonary function laboratory in a University Hospital. PARTICIPANTS: Two groups of healthy volunteers: individuals who had never smoked (NS; n=10; 4 men; age = 30.6 ± 6.2 years) and current cigarette smokers (S; n=12; 7 men; age = 38.7 ± 9.8). None of the volunteers had respiratory symptoms and all showed normal spirometric tests. INTERVENTION: Expired air was collected from all volunteers through a face mask and a plastic collecting system leading into a flask with dry ice and pure ethanol. Samples from the group S were collected twice, before and half an hour after the combustion of one cigarette. MAIN MEASUREMENTS: Expired hydrogen peroxide using the Gallati and Pracht method. RESULTS: The S and NS groups showed comparable levels of H2O2-E at basal conditions [NS = 0.74 muM (DP 0.24) vs. S = 0.75 muM (DP 0.31)]. The smokers showed a significant increase in H2O2-E levels half an hour after the consumption of only one cigarette [0.75 muM (DP 0.31) vs. 0.95 muM (DP 0.22)]. CONCLUSION: The present results are consistent with the concept that smokers increase oxidative stress with elevated production of reactive oxygen species, contributing to the development of smoking-related disorders.CONTEXTO: Elevações do peróxido de hidrogênio exalado (H2O2-E) tem sido descritas em diversas doenças pulmonares tais como a síndrome do desconforto respiratório agudo, doença pulmonar obstrutiva crônica e asma. Essa técnica tem sido preconizada como um método simples capaz de refletir inflamação ao nível das vias aéreas. OBJETIVO: Avaliar os níveis de H2O2-E em indivíduos normais e determinar os efeitos agudos do consumo de um cigarro sobre seus valores. TIPO DE ESTUDO: Ensaio clínico, prospectivo, controlado. LOCAL: Laboratório de função pulmonar de um Hospital Universitário. PARTICIPANTES: Dois grupos de voluntários sadios: indivíduos que nunca fumaram [NS; n = 10; 4 homens; idade = 30,6 anos (DP 6,2)] e indivíduos fumantes atuais [S; n = 12; 7 homens; idade = 38,7 anos (DP 9,8)]. Todos os voluntários não apresentavam sintomas respiratórios e exibiam testes espirométricos dentro da normalidade. INTERVENÇÃO: Ar expirado foi coletado de todos os voluntários utilizando-se uma máscara facial e um sistema colocado em um frasco com gelo seco e etanol absoluto. Amostras do grupo S foram coletadas duas vezes, antes e meia hora após o consumo de um cigarro. VARIÁVEIS ESTUDADAS: Peróxido de hidrogênio expirado utilizando-se o método de Gallati e Pracht. RESULTADOS: Ambos os grupos mostraram níveis comparáveis de H2O2-E em condições basais [NS = 0,74 miM (DP 0,24) vs. S = 0,75 miM (DP 0,31)]. Os fumantes mostraram um aumento significante dos níveis de H2O2-E meia hora após o consumo de apenas um cigarro [0,75 miM (DP 0,31) vs. 0,95 miM (DP 0,22)]. CONCLUSÃO: Os resultados obtidos estão de acordo com o conceito de que o consumo de cigarros aumenta o estresse oxidativo com produção elevada de espécies reativas do oxigênio (ROS) contribuindo para o desenvolvimento de doenças relacionadas ao tabagismo.Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) Pulmonary DivisionUniversity of São Paulo Medical School of Ribeirão Preto Department of MedicineUNIFESP, EPM, Pulmonary DivisionSciEL

Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness

<p>Abstract</p> <p>Background</p> <p>Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R_min) is abnormally elevated in subjects with airway hyperresponsiveness.</p> <p>Methods</p> <p>The R_minwas measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R_minand spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R_minvalues.</p> <p>Results</p> <p>Asthmatics had a higher baseline R_min% predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R_minwas able to identify subjects with airway hyperresponsiveness (PC₂₀< 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R_min% predicted, FEV₁% predicted, and FEF_25-75% predicted, respectively). Also, 80% of the subjects with baseline R_min< 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R_min> 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic.</p> <p>Conclusions</p> <p>These findings suggest that baseline R_min, a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R_minto asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R_mincould provide a clinically useful tool for assessing asthma and monitoring response to treatment.</p

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Pulmonary function testing in quadriplegic subjects

Study design: Cross-sectional study.Objective: Pulmonary functional capacity in 23 Brazilian quadriplegic subjects (ASIA A), aged 30 (9.5) years, weight 66 (10.75) kg, height 176 (7) cm, was investigated at 42 ( 64) months postinjury.Setting: University Hospital-UNICAMP, Campinas, Brazil.Method: Subjects performed forced vital capacity ( FVC) and maximal voluntary ventilation (MVV) tests while seated in their standard wheelchairs. Forced Expired Volume after 1 s (FEV1) and FVC/FEV1 ratio were calculated from these tests. Values obtained were compared to three prediction equations from the literature that are used specifically for spinal cord subjects and include different variables in their formulae, such as age, gender, height, postinjury time and injury level. Data are expressed as median (interquartile interval). Differences between values were demonstrated by median confidence interval with significance level set at a 0.05.Results: Obtained data were statistically different from prediction equation results, with FVC 3.11 ( 0.81), 4.46 (0.28), 4.16 (0.33), 4.26 (0.42); FEV1 2.77 (1.03), 3.67 (0.21), 3.66 (0.30), 3.45 (0.39) and MVV 92 (27), 154.2 (11.9), 156.6 (14),157.3 (16.8), where the first value is obtained experimentally and the second, third and fourth values correspond to predicted values. the results obtained from spirometry test in this study differed significantly from the results obtained when prediction equations were used.Conclusion: the use of prediction equations developed to estimate pulmonary function in wheelchair users significantly overestimates pulmonary function of quadriplegic individuals with complete lesions (ASIA group A), in comparison to measured values.Univ Estadual Campinas, Dept Orthopedia & Traumatol, FCM, BR-13083970 Campinas, SP, BrazilUniv Estadual Campinas, Fac Phys Educ, BR-13083970 Campinas, SP, BrazilUniversidade Federal de São Paulo, Santos, SP, BrazilUniv São Paulo, Fac Med, Dept Biomech Med & Rehabil Locomotor Syst, BR-14049 Ribeirao Preto, BrazilUniv São Paulo, Dept Elect Engn, Sao Carlos, SP, BrazilUniversidade Federal de São Paulo, Santos, SP, BrazilWeb of Scienc

Eucapnic Voluntary Hyperpnea: Gold Standard for Diagnosing Exercise-Induced Bronchoconstriction in Athletes?

In athletes, a secure diagnos is of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Evaluating spirometric indices of airflow before and following an exercise bout is intuitively the optimal means for the diagnosis; however, this approach is recognized as having several key limitations. Accordingly, alternative indirect bronchoprovocation tests have been recommended as surrogate means for obtaining a diagnosis of EIB. Of these tests, it is often argued that the eucapnic voluntary hyperpnea (EVH) challenge represents the ‘gold standard’. This article provides a state-of-the-art review of EVH, including an overview of the test methodology and its interpretation. We also address the performance of EVH against the other functional and clinical approaches commonly adopted for the diagnosis of EIB. The published evidence supports a key role for EVH in the diagnostic algorithm for EIB testing in athletes. However, its wide sensitivity and specificity and poor repeatability preclude EVH from being termed a ‘gold standard’ test for EIB

Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma

<p>Abstract</p> <p>Background</p> <p>Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV₁and area under the FEV₁time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions.</p> <p>Methods</p> <p>Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval.</p> <p>Results</p> <p>Of 373 subjects challenged twice 161 were positive (≥10% fall FEV₁on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (< 10% fall FEV₁) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV₁and AUC_0-30min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV₁and AUC_{0-30 min}for the 72 subjects with two tests ≥10% fall FEV₁was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥15% fall FEV₁it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative.</p> <p>Conclusions</p> <p>Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when prescribing prophylactic treatment to prevent EIB and when designing protocols for clinical trials.</p

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

<p>Abstract</p> <p>Background</p> <p>Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.</p> <p>Methods</p> <p>509 people (6–50 yr) were enrolled, 78% were atopic, median FEV₁92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV₁on at least one of two tests, to methacholine a PC₂₀≤ 16 mg/ml and to mannitol a 15% fall in FEV₁at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.</p> <p>Results</p> <p>Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV₁in subjects positive to exercise was 19%, (SD 9.2), mannitol PD₁₅158 (CI:129,193) mg, and methacholine PC₂₀2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.</p> <p>Conclusion</p> <p>In this group with normal FEV₁, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.</p> <p>Trial registration</p> <p>This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).</p

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials.

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.Bone Marrow Transplantation advance online publication, 29 June 2009; doi:10.1038/bmt.2009.129