We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary ...care.
One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period.
One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001).
Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role.
ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.
There are no data comparing the relative effects of high-dose ciclesonide (CIC) and fluticasone propionate (FP) on airway and systemic outcomes in patients with moderate persistent asthma
We elected ...to evaluate the relative effects of CIC and FP on the plasma cortisol response to stimulation with human corticotropin-releasing factor (hCRF) and bronchial hyperresponsiveness to methacholine as the primary outcome variables, in addition to secondary outcomes of overnight 10-h urinary cortisol (OUC) levels, exhaled nitric oxide levels, lung function, symptoms, and quality of life
Fourteen patients with moderate persistent asthma (mean FEV1, 67% predicted prior to each randomized treatment) completed the study, which had a randomized, double-blind, double-dummy, crossover design, per protocol. Patients stopped receiving their usual inhaled corticosteroids for the duration of the study and instead began receiving salmeterol, 50 μg twice daily, and montelukast, 10 mg once daily, for the 2-week washout periods prior to each randomized treatment, in order to prevent dropouts after withdrawal from inhaled corticosteroid therapy. Patients received 4 weeks of either CIC, 200 μg ex-valve (160 μg ex-actuator) four puffs twice daily, plus FP-placebo, four puffs twice daily, or FP, 250 μg ex-valve (220 μg ex-actuator) four puffs twice daily, plus CIC-placebo, four puffs twice daily. Salmeterol and montelukast were withheld for 72 h prior to each postwashout baseline visit, and CIC or FP was withheld for 12 h prior to each posttreatment visit
FP, but not CIC, when compared to respective baseline values, significantly suppressed (p < 0.05) plasma cortisol levels as follows: FP prior to receiving hCRF: geometric mean fold difference, 1.2; 95% confidence interval (CI), 1.1 to 1.3; CIC prior to receiving hCRF: geometric mean fold difference, 0.9; 95% CI, 0.8 to 1.0; FP 30 min after receiving hCRF: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; CIC 30 min after receiving hCRF: geometric mean fold difference, 1.0; 95% CI, 0.9 to 1.2; OUC after FP administration: geometric mean fold difference, 1.9; 95% CI, 1.4 to 2.6; OUC after CIC administration: geometric mean fold difference, 1.2; 95% CI, 0.9 to 1.5. There was also a significantly lower (p < 0.05) mean value for OUC levels after FP administration than after CIC administration (geometric mean fold difference, 1.5; 95% CI, 1.1 to 2.0). Therapy with CIC and FP, compared to respective baselines, significantly increased (p < 0.05) the provocative concentration of methacholine causing a 20% fall in FEV1, as follows: CIC: doubling dilution difference, 0.8; 95% CI, 0.1 to 1.6; FP: doubling dilution difference, 1.0; 95% CI, 0.1 to 2.0. It also significantly reduced (p < 0.05) exhaled nitric oxide levels, as follows: CIC: geometric mean fold difference, 1.2; 95% CI, 1.1 to 1.3; FP: geometric mean fold difference, 1.9; 95% CI, 1.3 to 2.8. There was no effect on other secondary efficacy outcomes
FP, 2,000 μg daily, but not CIC, 1,600 μg daily, significantly suppressed hypothalamic-pituitary-adrenal axis outcomes, with OUC levels being lower after FP administration than after CIC administration. Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyperresponsiveness and exhaled nitric oxide levels. The present results would therefore suggest that CIC might confer a better therapeutic ratio than FP when used at higher doses
Lowest receptor occupancy for a drug occurs at trough prior to the next dose. Previous studies have focused on the effects of triple therapy at peak dose intervals using forced expiratory maneuvers. ...Impulse oscillometry (IOS) and body plethysmography (PLETH) are more sensitive than spirometry to assess inhaled therapies in COPD.
Nineteen patients with COPD (FEV1/FVC ratio < 0.7; FEV1 < 60%) completed a double-blind randomized crossover trial of tiotropium 18 μg/d or placebo for 2 weeks each, with a 1-week washout. Prior to this procedure, there was a nonrandomized 4 week run-in of budesonide/formoterol 200/6 2 puffs bid, which continued throughout the study. Spirometry, IOS, and PLETH were performed both before pre- and post-budesonide/formoterol run-in and at trough following the first and last dose of tiotropium (ie, 24 h posttiotropium and 12 h post-budesonide/formoterol).
Mean ± SEM for age and FEV1 were 65 ± 2 years and 42 ± 2%, respectively. Following initial budesonide/formoterol, there were no significant changes in spirometry; however, all measures of IOS and PLETH deteriorated (P < .01 for all outcomes). Compared with placebo, tiotropium was additive to budesonide/formoterol after single and chronic dosing measured by FEV1 (P < .001 and P = .014, respectively) and forced expiratory flow, midexpiratory phase (P = .001; P= .026), whereas specific airway resistance, reactance, resonant frequency, and area under the reactance curve showed additive benefits at a single dose only.
Budesonide/formoterol caused an unexpected worsening of IOS and PLETH outcomes compared with a washed-out baseline in the nonplacebo-controlled run-in. This finding was not observed with spirometry. Subsequent addition of tiotropium improved lung function with all techniques after a single dose and for spirometry after chronic dosing. These paradoxical findings may reflect β2-adrenoceptor downregulation and muscarinic 3 receptor cross talk. Placebo-controlled studies are required to explore this result.
Background We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in ...primary care. Methods One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV1 (PD10 ) (AHR strategy) or a control group (reference strategy) over a 1-year period. Results One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD10 and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD10 between AHR vs control groups. The final mean daily ciclesonide dose was higher ( P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV1 ( P < .05), salivary eosinophilic cationic protein ( P < .05), exhaled nitric oxide ( P < .05), symptoms ( P < .005), and reliever use ( P < .001). Conclusions Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. Trial registration ClinicalTrials.gov ; No.: NCT01216579 ; URL: www.clinicaltrials.gov
The use of extracorporeal membrane oxygenation (ECMO) for reversible pulmonary failure in critically ill patients has increased over the last few decades. Nosocomial infections are a major ...complication of ECMO and fungi have been found to be a common cause. Herein, we describe a case of invasive pulmonary aspergillosis following ECMO, which was successfully treated with combination antifungal therapy and interferon-gamma.
This study assessed if bronchiectasis (BR) and rheumatoid arthritis (RA), when manifesting as an overlap syndrome (BROS), were associated with worse outcomes than other BR etiologies applying the ...Bronchiectasis Severity Index (BSI).
Data were collected from the BSI databases of 1,716 adult patients with BR across six centers: Edinburgh, United Kingdom (608 patients); Dundee, United Kingdom (n = 286); Leuven, Belgium (n = 253); Monza, Italy (n = 201); Galway, Ireland (n = 242); and Newcastle, United Kingdom (n = 126). Patients were categorized as having BROS (those with RA and BR without interstitial lung disease), idiopathic BR, bronchiectasis-COPD overlap syndrome (BCOS), and “other” BR etiologies. Mortality rates, hospitalization, and exacerbation frequency were recorded.
A total of 147 patients with BROS (8.5% of the cohort) were identified. There was a statistically significant relationship between BROS and mortality, although this relationship was not associated with higher rates of BR exacerbations or BR-related hospitalizations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with other causes of BR, 18% for RA, and 28.5% for BCOS. Mortality was statistically higher in patients with BROS and BCOS compared with those with all other etiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS compared with those with idiopathic BR (BSI mean, 7.7 vs 7.1, respectively; P < .05). Patients with BCOS had significantly higher BSI scores (mean, 10.4), Pseudomonas aeruginosa colonization rates (24%), and previous hospitalization rates (58%).
Both the BROS and BCOS groups have an excess of mortality. The mechanisms for this finding may be complex, but these data emphasize that these subgroups require additional study to understand this excess mortality.
Background
The effects of single or combined histamine H1‐receptor and leukotriene CysLT1‐receptor antagonism on nasal adenosine monophosphate (AMP) challenge in allergic rhinitis are unknown.
...Objective
We elected to study the effects of usual clinically recommended doses of fexofenadine (FEX), montelukast (ML) and FEX + ML combination, compared with placebo (PL), on nasal AMP challenge in patients with persistent allergic rhinitis.
Methods
Twelve patients with persistent allergic rhinitis (all skin prick positive to house dust mite) were randomized in a double‐blind cross‐over fashion to receive for 1 week either FEX 180 mg, ML 10 mg, FEX 180 mg + ML 10 mg combination, or PL, with nasal AMP challenge performed 12 h after dosing. There was a 1‐week washout period between each randomized treatment. The primary outcome measure was the maximum percentage peak nasal inspiratory flow (PNIF) fall from baseline over a 60‐min period after nasal challenge with a single 400 mg ml−1 dose of AMP. The area under the 60‐min time–response curve (AUC) and nasal symptoms were measured as secondary outcomes.
Results
There was significant attenuation (P < 0.05) of the mean maximum percentage PNIF fall from baseline after nasal AMP challenge vs. PL, 48; with FEX, 37; 95% confidence interval for difference 2, 20; ML, 35 (4, 22); and FEX + ML, 32 (7, 24). The AUC (%.min) was also significantly attenuated (P < 0.05) vs. PL, 1893; with FEX, 1306 (30, 1143); ML, 1246 (214, 1078); and FEX + ML, 1153 (251, 1227). There were no significant differences for FEX vs. ML vs. FEX + ML comparing either the maximum or AUC response. The total nasal symptom score (out of 12) was also significantly improved (P < 0.05) vs. PL, 3.3; with FEX, 2.1 (0.3, 2.0); ML, 2.0 (0.5, 1.9); and FEX + ML, 2.5 (0.1, 1.4).
Conclusion
FEX and ML as monotherapy significantly attenuated the response to nasal AMP challenge and improved nasal symptoms compared with PL, while combination therapy conferred no additional benefit.
Background
The effects of single or combined histamine H
1
‐receptor and leukotriene CysLT
1
‐receptor antagonism on nasal adenosine monophosphate (AMP) challenge in allergic rhinitis are unknown.
...Objective
We elected to study the effects of usual clinically recommended doses of fexofenadine (FEX), montelukast (ML) and FEX + ML combination, compared with placebo (PL), on nasal AMP challenge in patients with persistent allergic rhinitis.
Methods
Twelve patients with persistent allergic rhinitis (all skin prick positive to house dust mite) were randomized in a double‐blind cross‐over fashion to receive for 1 week either FEX 180 mg, ML 10 mg, FEX 180 mg + ML 10 mg combination, or PL, with nasal AMP challenge performed 12 h after dosing. There was a 1‐week washout period between each randomized treatment. The primary outcome measure was the maximum percentage peak nasal inspiratory flow (PNIF) fall from baseline over a 60‐min period after nasal challenge with a single 400 mg ml
−1
dose of AMP. The area under the 60‐min time–response curve (AUC) and nasal symptoms were measured as secondary outcomes.
Results
There was significant attenuation (
P <
0.05) of the mean maximum percentage PNIF fall from baseline after nasal AMP challenge
vs.
PL, 48; with FEX, 37; 95% confidence interval for difference 2, 20; ML, 35 (4, 22); and FEX + ML, 32 (7, 24). The AUC (%.min) was also significantly attenuated (
P <
0.05)
vs.
PL, 1893; with FEX, 1306 (30, 1143); ML, 1246 (214, 1078); and FEX + ML, 1153 (251, 1227). There were no significant differences for FEX
vs.
ML
vs.
FEX + ML comparing either the maximum or AUC response. The total nasal symptom score (out of 12) was also significantly improved (
P <
0.05)
vs.
PL, 3.3; with FEX, 2.1 (0.3, 2.0); ML, 2.0 (0.5, 1.9); and FEX + ML, 2.5 (0.1, 1.4).
Conclusion
FEX and ML as monotherapy significantly attenuated the response to nasal AMP challenge and improved nasal symptoms compared with PL, while combination therapy conferred no additional benefit.
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