Interval versus constant-load exercise training in adults with Cystic Fibrosis.

BACKGROUND: The efficacy of interval exercise (IE) compared to constant-load exercise (CLE) training remains unsettled in adults with Cystic Fibrosis (CF). METHODS: Twenty-four adults with CF were randomised to 30-min IE (100 % peak work capacity (WRpeak) for 30-s alternated with 40 % WRpeak for 30-s; n = 12) or 30-min CLE (70 % WRpeak; n = 12) training, 3 times weekly, for 12 weeks. Isometric quadriceps muscle strength was assessed using a strain gauge Myometer. RESULTS: The magnitude of improvement in quadriceps muscle strength was greater (p = 0.037) in the IE (by 32 ±â€¯13 Nm) compared to the CLE (by 23 ±â€¯12 Nm) groups. Maximum inspiratory and expiratory mouth pressures were significantly improved only in the IE group (by 30 ±â€¯10 cmH2O; p = 0.009 and 13 ±â€¯4 cmH2O; p = 0.007, respectively). Arterial oxygen saturation during training was higher (p = 0.002) for IE (94 ±â€¯1%) compared to CLE (91 ±â€¯1%), whereas dyspnoea scores were lower (p = 0.001) for IE (3.8 ±â€¯0.7) compared to CLE (5.9 ±â€¯0.8) CONCLUSIONS: IE is superior to CLE in improving peripheral and respiratory muscle strength and preferable to CLE because it is associated with lower exercise-induced arterial oxygen desaturation and breathlessness.

Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: Comparison with different sputum phenotypes.

BACKGROUND: According to induced sputum cell count, four different asthma phenotypes have been recognized (eosinophilic, neutrophilic, mixed and paucigranulocytic). The aim of this study was to detect functional and inflammatory characteristics of patients with paucigranulocytic asthma. METHODS: A total of 240 asthmatic patients were categorized into the four phenotypes according to cell counts in induced sputum. All patients underwent pulmonary function tests, and measurement of fraction of exhaled nitric oxide (FeNO). The levels of IL-8, IL-13 and eosinophilic cationic protein (ECP) were also measured in sputum supernatant. Treatment, asthma control and the presence of severe refractory asthma (SRA) were also recorded. RESULTS: Patients were categorized into the four phenotypes as follows: eosinophilic (40%), mixed (6.7%), neutrophilic (5.4%) and paucigranulocytic (47.9%). Although asthma control test did not differ between groups (P=.288), patients with paucigranulocytic asthma had better lung function (FEV1 % pred) [median (IQR): 71.5 (59.0-88.75) vs 69.0 (59.0-77.6) vs 68.0 (60.0-85.5) vs 80.5 (69.7-95.0), P=.009] for eosinophilic, mixed, neutrophilic and paucigranulocytic asthma, respectively, P=.009). SRA occurred more frequently in the eosinophilic and mixed phenotype (41.6% and 43.7%, respectively) and less frequently in the neutrophilic and paucigranulocytic phenotype (25% and 21.7%, respectively, P=.01). FeNO, ECP and IL-8 were all low in the paucigranulocytic, whereas as expected FeNO and ECP were higher in eosinophilic and mixed asthma, while IL-8 was higher in patients with neutrophilic and mixed asthma (P<.001 for all comparisons). Interestingly, 14.8% of patients with paucigranulocytic asthma had poor asthma control. CONCLUSION: Paucigranulocytic asthma most likely represents a "benign" asthma phenotype, related to a good response to treatment, rather than a "true" phenotype of asthma. However, paucigranulocytic patients that remain not well controlled despite optimal treatment represent an asthmatic population that requires further study for potential novel targeted interventions.

Sputum interleukin-13 as a biomarker for the evaluation of asthma control.

BACKGROUND: Asthma control refers to the extent to which the manifestations of asthma have been reduced or eradicated by treatment. Interleukin-13 (IL-13) has a central role in Th2 response and serves as a possible therapeutic target in uncontrolled asthma. Fraction of exhaled nitric oxide (FeNO) and sputum eosinophils have modest performance in the evaluation of asthma control. OBJECTIVE: To assess the diagnostic performance of sputum IL-13 for the evaluation of asthma control and furthermore to investigate the performance of sputum eosinophils and FeNO. METHODS: One hundred and seventy patients with asthma were studied. All subjects underwent assessment of asthma control by asthma control test (ACT), lung function tests, FeNO measurement and sputum induction for cell count identification and IL-13 measurement in supernatants. RESULTS: IL-13 (pg/mL) levels in sputum supernatant differed significantly among patients with well-controlled asthma and those with not well-controlled asthma [median IQR 78 (66-102) vs. 213 (180-265), P < 0.001]. Receiver operating characteristic (ROC) analysis showed that, for the whole study population, the diagnostic performance of IL-13 was superior to both sputum eosinophils and FeNO levels [area under the curve (AUC) 0.92, 95% CI 0.87 to 0.95 vs. AUC 0.65, 95% CI 0.58 to 0.72 vs. AUC 0.65, 95% CI 0.55 to 0.72, respectively]. CONCLUSION: The diagnostic performance of sputum IL-13 was superior to both sputum eosinophils and FeNO levels for the identification of well-controlled asthma. Sputum IL-13 levels could serve as a useful biomarker for asthma control assessment.

Hemodynamic effects of high intensity interval training in COPD patients exhibiting exercise-induced dynamic hyperinflation.

Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n = 25) and without (n = 11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRT(ON)) and offset (QMRT(OFF)) of CLET. Post-rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRT(ON) (from 82.2 ± 4.3 to 61.7 ± 4.2 s) and QMRT(OFF) (from 80.5 ± 3.8 to 57.2 ± 4.9 s ). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients.

Sputum and BAL Clara cell secretory protein and surfactant protein D levels in asthma.

Clara cell secretory protein (CC16) is associated with Th2 modulation. Surfactant protein D (SPD) plays an important role in surfactant homeostasis and eosinophil chemotaxis. We measured CC16 and SPD in sputum supernatants of 84 asthmatic patients and 12 healthy controls. In 22 asthmatics, we additionally measured CC16 and SPD levels in BAL and assessed smooth muscle area (SMA), reticular basement membrane (RBM) thickness, and epithelial detachment (ED) in bronchial biopsies. Induced sputum CC16 and SPD were significantly higher in patients with severe asthma (SRA) compared to mild-moderate and healthy controls. BAL CC16 and SPD levels were also higher in SRA compared to mild-moderate asthma. CC16 BAL levels correlated with ED, while SPD BAL levels correlated with SMA and RBM. Severity represented a significant covariate for these associations. CC16 and SPD levels are upregulated in SRA and correlate with remodeling indices, suggesting a possible role of these biomarkers in the remodeling process.

High intensity, interval exercise improves quality of life of patients with chronic heart failure: a randomized controlled trial.

BACKGROUND: The aim of this study was to evaluate the effect of high intensity, interval exercise on quality of life (QoL) and depression status, in chronic heart failure (CHF) patients. METHODS: A randomized controlled trial (phase III). Of the 100 consecutive CHF patients (NYHA classes II-IV, ejection fraction ≤ 50%) that were randomly allocated to exercise intervention (n = 50, high-intensity intermittent endurance training 30 s at 100% of max workload, 30 s at rest, for 45 min/day-by-12 weeks) or no exercise advice (n = 50), 72 (exercise group, n = 33, 63 ± 9 years, 88% men, 70% ischemic CHF and control group, n = 39, 56 ± 11 years, 82% men, 70% ischemic CHF) completed the study. QoL was assessed using the validated and translated Minnesota Living with Heart Failure questionnaire. Depressive symptomatology was evaluated using the validated and translated Zung Depression Rating Scale (ZDRS). Maximal oxygen uptake (VO(2max)) and carbon dioxide production (VCO(2max)) were also measured breath-by-breath. RESULTS: Data analysis demonstrated that in the intervention group MLHFQ score was reduced by 66% (P = 0.003); 6-min-walk distance increased by 13% (P < 0.05), VO(2max) level increased by 31% (P = 0.001), VCO(2max) level increased by 28% (P = 0.001) and peak power output increased by 25% (P = 0.001), as compared with the control group. CONCLUSION: High intensity, systematic aerobic training, could be strongly encouraged in CHF patients, since it improves QoL, by favorably modifying their fitness level.

Activity monitoring reflects cardiovascular and metabolic variations in COPD patients across GOLD stages II to IV.

We investigated whether activity monitoring reliably reflects variations in oxygen transport and utilization during walking in COPD patients. Forty-two patients (14 in each GOLD stage II, III and IV) performed an incremental treadmill protocol to the limit of tolerance. Breath-by-breath gas exchange, central hemodynamic variables and activity monitoring were simultaneously recorded. Physiological variables and accelerometer outputs rose linearly with walking speeds. Strong correlations (r[interquartile range, IQR]) were found between treadmill walking intensity (WI: range 0.8-2.0 ms(-2)) and oxygen consumption (0.95 [IQR 0.87-0.97]), (range 7.6-15.5 ml kg(-1)min(-1)); minute ventilation (0.95 [IQR 0.86-0.98]), (range 20-37 l min(-1)); cardiac output (0.89 [IQR 0.73-0.94]), (range 6.8-11.5 l min(-1)) and arteriovenous oxygen concentration difference (0.84 [IQR 0.76-0.90]), (range 7.7-12.1 ml O2100 ml(-1)). Correlations between WI and gas exchange or central hemodynamic parameters were not different across GOLD stages. In conclusion, central hemodynamic, respiratory and muscle metabolic variations during incremental treadmill exercise are tightly associated to changes in walking intensity as recorded by accelerometry across GOLD stages II to IV. Interestingly, the magnitude of these associations is not different across GOLD stages.

Levels of prostaglandin E(2) and Cysteinyl-leukotrienes in sputum supernatant of patients with asthma: the effect of smoking.

BACKGROUND: Smoking is associated with worse asthma outcomes and may modify airway inflammation. Such modification may be mediated through an effect on prostaglandin E(2) (PGE(2)) and cysteinyl leukotrienes (Cyst-LTs). OBJECTIVE: We aimed to determine the levels of both PGE(2) and Cyst-LTs in sputum supernatants of patients with asthma and to investigate the effect of smoking habit as well as their associations with inflammatory cells, bronchial hyperresponsiveness (BHR) and lung function. METHODS: Ninety-eight patients to asthma (47 smokers) and 40 healthy subjects (20 smokers) were studied. All subjects underwent sputum induction for cell count identification, PGE(2) and Cyst-LTs levels measurement in supernatants, pulmonary function tests and BHR to methacholine. RESULTS: Patients with asthma had significantly higher levels of both Cyst-LTs and PGE(2) in sputum supernatants compared to healthy subjects [median (interquartile ranges) 432 (287, 575) vs. 91.5 (73.5, 111) pg/mL and 654 (456,789) vs. 117.5 (92,157) pg/mL, respectively, P < 0.001 for both comparisons]. Smoking asthmatics had significantly higher Cyst-LTs and PGE(2) levels compared to non-smoking asthmatics. Cyst-LTs levels in sputum supernatant of smoking asthmatics presented a significant positive association with sputum eosinophils, while PGE(2) levels were positively associated with sputum neutrophils. CONCLUSIONS: The increased concentrations of PGE(2) and Cyst-LTs in sputum supernatants of smoking asthma are consistent with an up-regulation of these two mediators in this specific phenotype of asthma. Furthermore, Cyst-LTs are associated with eosinophilic inflammation, while PGE(2) is associated with the presence of neutrophilic inflammation in smoking asthma.

On- and off-exercise kinetics of cardiac output in response to cycling and walking in COPD patients with GOLD Stages I-IV.

Exercise-induced dynamic hyperinflation and large intrathoracic pressure swings may compromise the normal increase in cardiac output (Q) in Chronic Obstructive Pulmonary Disease (COPD). Therefore, it is anticipated that the greater the disease severity, the greater would be the impairment in cardiac output during exercise. Eighty COPD patients (20 at each GOLD Stage) and 10 healthy age-matched individuals undertook a constant-load test on a cycle-ergometer (75% WR(peak)) and a 6min walking test (6MWT). Cardiac output was measured by bioimpedance (PhysioFlow, Enduro) to determine the mean response time at the onset of exercise (MRTon) and during recovery (MRToff). Whilst cardiac output mean response time was not different between the two exercise protocols, MRT responses during cycling were slower in GOLD Stages III and IV compared to Stages I and II (MRTon: Stage I: 45±2, Stage II: 65±3, Stage III: 90±3, Stage IV: 106±3s; MRToff: Stage I: 42±2, Stage II: 68±3, Stage III: 87±3, Stage IV: 104±3s, respectively). In conclusion, the more advanced the disease severity the more impaired is the hemodynamic response to constant-load exercise and the 6MWT, possibly reflecting greater cardiovascular impairment and/or greater physical deconditioning.

Intercomparison of three recruitment maneuvers in acute respiratory distress syndrome: the role of Body Mass Index.

BACKGROUND: The aim of this paper was to investigate the effectiveness of three different recruitment maneuvers (RMs) on respiratory and hemodynamic indexes, in patients with acute respiratory distress syndrome (ARDS), and determine the impact of patients' body mass index (BMI) on RMs efficacy. METHODS: This was a prospective clinical trial conducted in a general intensive care unit. In 25 consecutive early ARDS patients arterial blood gases, respiratory system elastance (Est,rs) and hemodynamics were monitored before (T(0)), and at 3, 15, and 30 min (T(3), T(15), T(30), respectively) after each of three different RMs techniques with same airway pressures (45 cmH(2)O), randomly applied in each patient; RM-1: pressure control ventilation for 1 min, RM-2: two hyperinflations with continuous positive airway pressure for 20 sec and 1 min interval in between, RM-3: three consecutive sighs. RESULTS: All RMs improved oxygenation and Est,rs shortly (T(3)) after their application, but only RM-2 had a prolonged beneficial effect on oxygenation (T(30)). Patients were further divided according to their BMI: in the low BMI group (<27.3 Kg/m(2)) the effectiveness of RMs was similar to the whole study population, while in the high BMI group (≥ 27.3 Kg/m(2)) no sustained effect followed any RM. CONCLUSION: In our cohort, recruitment by two sustained inflations resulted in a more persistent improvement of oxygenation as compared with recruitment by pressure controlled ventilation or consecutive sighs with the same airway pressure. BMI seems to have an impact on RMs effectiveness, most probably by altering the effective transpulmonary pressure. More studies are required to elucidate this observation.

Physiological techniques for detecting expiratory flow limitation during tidal breathing.

Patients with severe chronic obstructive pulmonary disease (COPD) often exhale along the same flow-volume curve during quiet breathing as they do during the forced expiratory vital capacity manoeuvre, and this has been taken as an indicator of expiratory flow limitation at rest (EFL(T)). Therefore, EFL(T), namely attainment of maximal expiratory flow during tidal expiration, occurs when an increase in transpulmonary pressure causes no increase in expiratory flow. EFL(T) leads to small airway injury and promotes dynamic pulmonary hyperinflation, with concurrent dyspnoea and exercise limitation. In fact, EFL(T) occurs commonly in COPD patients (mainly in Global Initiative for Chronic Obstructive Lung Disease III and IV stage), in whom the latter symptoms are common, but is not exclusive to COPD, since it can also be detected in other pulmonary and nonpulmonary diseases like asthma, acute respiratory distress syndrome, heart failure and obesity, etc. The existing up to date physiological techniques of assessing EFL(T) are reviewed in the present work. Among the currently available techniques, the negative expiratory pressure has been validated in a wide variety of settings and disorders. Consequently, it should be regarded as a simple, noninvasive, practical and accurate new technique.

Non-invasive measurement of the mean alveolar O(2) tension from the oxygen uptake versus tidal volume curve.

AIMS: The classical equations for measuring the mean and the ideal alveolar O(2) tension are based on assumptions, which are shown to be invalid. So we thought to develop a new, non-invasive method for measuring the mean alveolar P,O(2) within the volume domain (PA,O(2(Bohr))). This method is based on the oxygen uptake vs. tidal volume curve (VO(2) vs. VT) obtained during tidal breathing of room air and/or air enriched with oxygen. METHODS: PA,O(2(Bohr)) and the ideal alveolar PO(2) (PA,O(2(ideal))) were simultaneously measured in 10 healthy subjects and 34 patients suffering from chronic obstructive pulmonary disease (COPD) breathing tidally room air at rest. Additionally, 10 subjects (three healthy subjects and seven COPD patients) were studied while breathing initially room air and subsequently air enriched with oxygen. RESULTS: According to the results, PA,O(2(Bohr)) considerably differed from PA,O(2(ideal)) (P = 0.004). The cause of the difference, at the individual's R, is: (1) the difference between the arterial and Bohr's alveolar CO(2) tension, mainly in COPD patients, and (2) the inequality between Bohr's alveolar part of the tidal volume for CO(2) and O(2). Furthermore, end-tidal gas tension (PET,CO(2) and PET,O(2)) differed from Pa,CO(2) and PA,O(2(Bohr)) respectively. CONCLUSION: The deviation of PA,O(2(Bohr)) from PA,O(2(ideal)) has a definite impact on Bohr's dead space ratio for O(2) and CO(2), and on the alveolar-arterial O(2) difference. The difference (PA,O(2(Bohr)) - PA,O(2(ideal))) is not related to the pathology of the disease. So, gas exchange within the lungs should be assessed at the subject's R from PA,O(2(Bohr)) and PA,CO(2(Bohr)) but not from PA,O(2(ideal)) nor Pa,CO(2).

Expiratory flow limitation detected by forced oscillation and negative expiratory pressure.

The within-breath change in reactance (Delta(rs)) measured by forced oscillation technique (FOT) at 5 Hz reliably detects expiratory flow limitation in chronic obstructive pulmonary disease (COPD). The present study compared this approach to the standard negative expiratory pressure (NEP) method. In total, 21 COPD patients were studied by applying both techniques to the same breath and in 15 patients the measurements were repeated after bronchodilator. For each patient and condition five NEP tests were performed and independently scored by three operators unaware of the FOT results. In 180 tests, FOT classified 53.3% as flow limited. On average, the operators scored 27.6% of tests flow limited and 47.6% non-flow limited, but could not score 24.8%. The methods disagreed in 7.9% of cases; in 78% of these the NEP scores differed between operators. Bronchodilation reduced NEP and DeltaX(rs) scores, with only the latter achieving significance. Averaging the operators' NEP scores, a threshold between 24.6-30.8% of tidal volume being flow limited by NEP produced 94% agreement between methods. In conclusion, when negative expiratory pressure and forced oscillation technique were both available they showed good agreement. As forced oscillation technique is automatic and can measure multiple breaths over long periods, it is suitable for monitoring expiratory flow limitation continuously and identifying patients' breathing close to the onset of expiratory flow limitation, where intermittent sampling may be unrepresentative.

Risk factors and characteristics associated with severe and difficult to treat asthma phenotype: an analysis of the ENFUMOSA group of patients based on the ECRHS questionnaire.

BACKGROUND: Severe and difficult to treat asthma impairs health status and accounts for about half of asthma expenditure. In 1994, a European Network For Understanding Mechanisms of Severe Asthma (ENFUMOSA) was formed. A large group of patients from nine European countries has been selected. OBJECTIVE: To examine the risk factors and symptoms associated with a phenotype of severe/difficult to treat asthma. METHODS: The present report presents data assessed through the use of the European Community Respiratory Health Survey (ECRHS) Questionnaire in 148 mild-moderate controlled and 155 severe asthmatics from the ENFUMOSA group. RESULTS: There is a negative association of severe asthma with reported allergy and with a family history of allergy (Odds ratio (OR)=0.45). Sharing a bedroom before the age of five is associated with a higher risk of severe asthma (OR=1.5) while childhood infections, play school attendance and exposure to allergens or animals are not. A larger proportion of severe asthma patients report symptoms at work (OR=2.7) or have to change jobs (OR=4.3) and fewer severe than mild patients are currently employed (OR=0.39). Smoking and exposure to smoke is similar in mild and severe asthma. Dietary habits do not differ between the groups, but severe asthmatics report eating less savoury snacks and there is a trend for lower intake of sweets. CONCLUSIONS: Analysis of the ECRHS questionnaire in the ENFUMOSA study shows that severe asthma patients experience more symptoms and their health status is impaired by their inability to work and perhaps eat freely. Personal and maternal history of allergy is associated with mild but not severe asthma. Other than sharing a bedroom before the age of 5 years, no childhood exposure risk factors associated with severe asthma could be identified from this analysis.

Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura.

BACKGROUND: Adenosine deaminase (ADA) is a commonly used marker in the diagnosis of tuberculous effusion and there is evidence that its production is linked to T cells and monocytes. Data on the correlation between ADA and T cells or macrophages in tuberculous effusions are conflicting. Furthermore, no studies have examined a possible correlation between pleural tissue infiltration and ADA. OBJECTIVES: We undertook this study to examine cell subsets in the fluid and the pleura in tuberculous effusion and their correlation to ADA. The use of cell subsets as a marker in the differential diagnosis was also examined. METHODS: Pleural fluid from 36 patients with tuberculous and 34 patients with malignant effusion as well as pleural tissue biopsies from 16 patients with tuberculous pleurisy were examined. The APAAP and the avidin-biotin complex immunocytochemical methods were used to examine CD4+ T cells and macrophages (CD68+), while ADA activity was measured by the Giusti colorimetric method. RESULTS: Our results showed that, in pleural fluid, CD4+ cells and ADA were significantly higher in tuberculous compared to malignant effusion (p<0.001 for all measurements). In pleural tissue biopsies, macrophages were the predominant cells but CD4+ T cells were also abundant. A significant correlation was found between ADA and CD4+ numbers in pleural fluid and tissue (r=0.45, p<0.01; r=0.75, p<0.001, respectively). ADA had high sensitivity and specificity for differential diagnosis while cell subsets did not. CONCLUSIONS: These results indicate that ADA activity correlates to CD4+ T cell infiltration in the pleura and the fluid. Moreover, ADA but no cell subsets may be used as markers of tuberculous effusion.

Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology.

Fashions in ideas, like clothes, come and go. From approximately 1950-1980, physiological research was seen as the key discipline in understanding lung disease and was at the cutting edge of pulmonary science. Subsequently, its importance has been down played amid a widely accepted but unfounded assumption that we now have a perfect working understanding of the physiological behaviour of the respiratory system in health and disease. Although it seems improbable that completely new disciplines within respiratory physiology will emerge with fundamentally different ways of describing the mechanical or gas exchanging function of the lung, advances in computing and new observations in disease have highlighted previously unsuspected physiological abnormalities that have changed the way we view lung disease and the interface between disordered lung mechanics, symptomatology and disability. This is especially true for the two related physiological concepts of expiratory flow limitation and dynamic hyperinflation, which are now being taken from the physiological laboratory to the bedside with dramatic effect. Each arises from well-established theoretical and practical observations first made 40 yrs ago and now adapted to a range of settings, particularly in the field of obstructive lung disease. This review focuses on how these conditions are defined and assessed and what evidence there is that they might be important in lung disease.