Metabolic Acidosis Improves Airway Conductance in Patients with Asthma

The objective was to investigate whether acute metabolic acidosis could cause bronchodilation in patients with asthma. Twelve patients with asthma (8 females, mean age 39 (± SD 12) years, forced expiratory volume in 1 second [FEV₁] 93 [±9] % predicted, PC₂₀ 1.9 (±1.0) mg/mL) participated in a double-blind, placebo-controlled trial. Subjects ingested calculated amounts of ammonium chloride to induce acidosis or saline as placebo, in random order, each on a separate day. Airway resistance (R_aw), specific airway conductance (sG_aw), FEV₁, and PEF were measured as primary variables. To evaluate the consequences of alterations in bronchial contractility on the airway responsiveness, the histamine provocation test (PC₂₀) was measured as secondary variable.

The intervention resulted in a mean (SD) decrease in base excess from –0.5 (±1.4) to –3.9 (±1.1) mmol/L (p < 0.01) and a decrease in pH from 7.41 (±0.02) to 7.36 (±0.02) (p < 0.01). This caused a statistically significant increase in sG_aw from 1.15 (±0.16) to 1.26 (±0.13) 1/kPa.s) (p < 0.05). Tendencies towards increase were found in PEF (7.79 (±2.2) versus 8.09 (±1.9) (NS, p = 0.10) and in FEV₁ (2.98 (±0.9) versus 3.06 (±0.9) (NS, p = 0.15). PC₂₀ did not change significantly.

It was concluded that acute metabolic acidosis has a modest bronchodilating effect in patients with asthma.     

Airway remodelling in COPD: It's not asthma!

COPD is defined as airflow limitation that is not reversed by treatment. In asthma, airflow limitation is not only reversible, but also inducible. This is called ‘airway hyperresponsiveness’ (AHR) and is associated with thickening of the airway wall, predominantly the layer of airway smooth muscle, due to more cells, bigger cells and more extracellular matrix (ECM) in proportion to the increase in smooth muscle. AHR is also observed in COPD if the changes in airflow are expressed as a percent of the baseline lung function. However, the absolute change in baseline lung function that can be induced in COPD is actually less than that seen in normal subjects, suggesting that the airways in COPD are resistant not only to opening, but also to closing. This observation agrees with physiological measures showing increased airway wall stiffness in COPD. Like asthma, airway wall thickness is increased in COPD, including the layer of smooth muscle. Unlike asthma, however, fixed airflow obstruction appears to be characterized by a disproportionate increase in the ECM within the smooth muscle layer. In this review, we summarize the studies of airway matrix deposition in COPD and put forward the proposal that the airway remodelling in COPD is different from that in asthma and call for a systematic analysis of airway matrix deposition in COPD.     

Asthma COPD Overlap Syndrome on CT Densitometry: A Distinct Phenotype from COPD

Patients with asthma COPD overlap syndrome (ACOS) are an important but poorly characterized group. This study sought to explore the distinct characteristics of ACOS on CT densitometry. The study population was randomly selected from communities via questionnaires. All participants underwent low-dose volumetric chest CT both before and after bronchodilator administration. Each CT scan was performed at full-inspiration and full-expiration for CT densitometry. Emphysema index (EI), air trapping (AT), mean lung density (MLD) and total lung volume (TLV) were measured and compared between the ACOS and COPD groups. The distributions of both EI and AT were compared between patients with ACOS and COPD. The variations between the pre- and post-BD measurements observed in patients with ACOS were compared with those in patients with COPD. A total of 71 patients completed the study, including 32 patients with COPD and 39 patients with ACOS. The patients with ACOS exhibited lower EI and more upper-zone-predominant EI distributions, compared with the patients with COPD. No significant differences were exhibited in AT and its distribution. Following bronchodilator administration, the variations in AT and expiratory MLD were greater in patients with ACOS than in patients with COPD. No differences were observed in the variations of EI and inspiratory MLD. Our results indicate that patients with ACOS have lower extent of emphysema and different emphysema distribution, as well as greater post-BD variations in air trapping, compared with patients with COPD. These findings suggest that CT densitometry characterizes ACOS as a distinct phenotype from COPD.     

Non-Invasive Measurement of Airway Inflammation in Asthma

Assessing the severity and control of a patient's asthma is of great importance to ensure that pharmacotherapy is optimized. Measures such as lung function, symptoms, and reliever use have traditionally been used as objective means of undertaking this assessment, but until now the level of airway inflammation has not been quantified. As asthma is primarily an inflammatory disorder, it would be desirable to include a measure of this process when evaluating disease control. The following article outlines methods of non-invasively measuring asthmatic airway inflammation and highlights their potential role in clinical practice.     

Non-Invasive Measurement of Airway Inflammation in Asthma

Assessing the severity and control of a patient's asthma is of great importance to ensure that pharmacotherapy is optimized. Measures such as lung function, symptoms, and reliever use have traditionally been used as objective means of undertaking this assessment, but until now the level of airway inflammation has not been quantified. As asthma is primarily an inflammatory disorder, it would be desirable to include a measure of this process when evaluating disease control. The following article outlines methods of non-invasively measuring asthmatic airway inflammation and highlights their potential role in clinical practice.     

Once-Daily Fluticasone Propionate in Stable Asthma: Study on Airway Inflammation

Children with stable asthma receiving twice-daily fluticasone propionate (FP) were studied. Spirometry, exhaled nitric oxide (eNO) and sputum eosinophils were measured at baseline and 8 weeks after FP was changed to once-daily use while keeping the same total dosage. Visual analogue scores on asthma severity, symptoms, and dosing regimen preference were obtained. Twenty-nine children of mean age 10.6 years (SD 2.5) were recruited. There was significant improvement in eNO (47.1 ppb [30.3] vs. 39.9 ppb [27.1], p = 0.037), and sputum eosinophils (5.7% [6.5] vs. 2.5% [3.9], p = 0.024] after 8 weeks. All subjects preferred the once-daily dosing regimen. Once-daily FP is effective in controlling airway inflammation. This frequency of medication use is also the preferred regimen.     

Once-Daily Fluticasone Propionate in Stable Asthma: Study on Airway Inflammation

Children with stable asthma receiving twice-daily fluticasone propionate (FP) were studied. Spirometry, exhaled nitric oxide (eNO) and sputum eosinophils were measured at baseline and 8 weeks after FP was changed to once-daily use while keeping the same total dosage. Visual analogue scores on asthma severity, symptoms, and dosing regimen preference were obtained. Twenty-nine children of mean age 10.6 years (SD 2.5) were recruited. There was significant improvement in eNO (47.1 ppb [30.3] vs. 39.9 ppb [27.1], p = 0.037), and sputum eosinophils (5.7% [6.5] vs. 2.5% [3.9], p = 0.024] after 8 weeks. All subjects preferred the once-daily dosing regimen. Once-daily FP is effective in controlling airway inflammation. This frequency of medication use is also the preferred regimen.     

Lack of Benefit of Continuous Positive Airway Pressure on Lung Function in Patients with Overlap Syndrome

Obstructive sleep apnea (OSA) has been shown to be an inflammatory stimulus and may potentially result in a deterioration in the respiratory status of patients with coexistent chronic obstructive pulmonary disease (COPD) (overlap syndrome). We hypothesized that with treatment of OSA, there would be an improvement in coexistent COPD in overlap patients. We also sought to characterize overlap patients by comparing them with patients with either OSA or COPD alone. We performed a retrospective study of patients who attended a university-affiliated Veterans Affairs hospital. Demographic and clinical data were obtained from the medical charts and pharmacy records for the preceding two years and for the two years following the initiation of continuous positive airway pressure (CPAP) therapy. Overlap patients had moderately severe sleep apnea (AHI 28.6 ± 4.2) and moderately severe COPD (FEV₁= 1.94 ± 0.10 L). The prevalence of overlap syndrome in COPD patients was 11.9%, and 41% in OSA patients. Overlap patients who were compliant with CPAP therapy experienced a greater decrease in FEV₁, percent predicted FEV₁, percent decrease in FEV₁, FVC, percent predicted FVC, and percent decrease in FVC when compared with noncompliant patients. A very strong correlation was found between the average hours of CPAP use per day and the percent decrease in FEV₁ (r = 0.69, p = 0.003). There was a similar strong correlation for the decrease in FEV₁ and percent predicted FEV₁. OSA is common in COPD patients; similarly, COPD is common in OSA patients. Treatment of OSA with CPAP therapy in patients with overlap syndrome may not lead to an improvement in the coexistent COPD.     

The Airway Pathophysiology of COPD: Implications for Treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting β₂-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II–GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.     

Airway dimensions and pulmonary function in chronic obstructive pulmonary disease and bronchial asthma

Background and objective: COPD and bronchial asthma are chronic airway diseases with a different pathogenesis. Comparisons of differences in airway calibre by bronchial generation between these diseases and their importance to pulmonary function have not been fully studied. We investigated airway calibre and wall thickness in relation to pulmonary function in patients with asthma, COPD, asthma plus emphysema and normal subjects using CT. Methods: Sixty‐three asthmatic patients, 46 COPD, 23 patients with asthma plus emphysema and 61 control subjects were studied cross‐sectionally. We used a software with curved multiplanar reconstruction to measure airway dimensions from 3rd‐ to 6th‐generation bronchi of the right lower posterior bronchus. Results: Patients with COPD had increased wall thickness, but the airway was not narrow from the 3rd‐(subsegmental) to 6th‐generation bronchi. Mean bronchial inner diameter (Di) of 3rd‐ to 6th‐generation bronchi in patients with asthma or asthma plus emphysema was smaller than that of COPD patients and normal subjects. Airway luminal area (Ai) of 5th‐generation bronchi most closely correlated with pulmonary function in patients with stable asthma. Although Di was similar in patients with asthma and asthma plus emphysema, the Ai of 6th‐generation bronchi correlated significantly with pulmonary function in patients with asthma plus emphysema. Conclusions: Airway calibre in asthma may be smaller than in COPD. Airflow limitations correlated more closely with peripheral Ai in patients with asthma plus emphysema than in patients with asthma alone.     

Disease Burden of Patients with Asthma/COPD Overlap in a US Claims Database: Impact of ICD-9 Coding-based Definitions

The inclusion of an asthma/chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) population in the 2015 Global Initiative for Chronic Obstructive Lung Disease strategic documents has raised questions about the profile of these patients in clinical practice, as they are mostly excluded from asthma and COPD clinical trials. We estimated the disease burden, co-morbidities, and respiratory treatments of patients with asthma/COPD overlap, utilizing the Truven MarketScan commercial and Medicare databases. Patients with ≥1 COPD or chronic obstructive asthma diagnostic code were identified between January 1, 2008, and December 31, 2011. The asthma/COPD overlap group was defined and stratified based upon type and frequency of asthma diagnostic code (chronic obstructive asthma only, COPD and chronic obstructive asthma, and COPD and ≥1 asthma code). 1,488,613 patients were identified; of these, 1,171,626 were diagnosed with COPD alone and 316,987 with asthma/COPD overlap. Patients with asthma and COPD had higher disease burden indicators and inhaled corticosteroid/long-acting beta-agonist use compared with COPD alone. This trend was consistent for all definitions of asthma/COPD overlap. Patients with obstructive asthma and COPD tended to be older, with greater disease burden compared with other definitions; this population may represent a more severe form of asthma/COPD overlap. Disease burden and treatment also varied based on the codes defining asthma/COPD overlap, indicating possible phenotypic differences. More clinical insight and detailed phenotyping is needed to determine the reasons for coding variation in asthma/COPD overlap, with implications for further research to address unmet needs.     

The Overlap Syndrome of Depression and Delirium in Older Hospitalized Patients

OBJECTIVES: To measure the prevalence, predictors, and posthospitalization outcomes associated with the overlap syndrome of coexisting depression and incident delirium in older hospitalized patients.
DESIGN: Secondary analysis of prospective cohort data from the control group of the Delirium Prevention Trial.
SETTING: General medical service of an academic medical center. Follow-up interviews at 1 month and 1 year post-hospital discharge.
PARTICIPANTS: Four hundred fifty-nine patients aged 70 and older who were not delirious at hospital admission.
MEASUREMENTS: Depressive symptoms assessed at hospital admission using the 15-item Geriatric Depression Scale (cutoff score of 6 used to define depression), daily assessments of incident delirium from admission to discharge using the Confusion Assessment Method, activities of daily living at admission and 1 month postdischarge, and new nursing home placement and mortality determined at 1 year.
RESULTS: Of 459 participants, 23 (5.0%) had the overlap syndrome, 39 (8.5%) delirium alone, 121 (26.3%) depression alone, and 276 (60.1%) neither condition. In adjusted analysis, patients with the overlap syndrome had higher odds of new nursing home placement or death at 1 year (adjusted odds ratio (AOR)=5.38, 95% confidence interval (CI)=1.57–18.38) and 1-month functional decline (AOR=3.30, 95% CI=1.14–9.56) than patients with neither condition.
CONCLUSION: The overlap syndrome of depression and delirium is associated with significant risk of functional decline, institutionalization, and death. Efforts to identify, prevent, and treat this condition may reduce the risk of adverse outcomes in older hospitalized patients.     

Trefoil Factor 2 Regulates Airway Remodeling in Animal Models of Asthma

Background. Epithelial denudation and metaplasia are important in the pathogenesis of airway remodeling and asthma. Trefoil factor 2 (TFF2) is a member of a family of peptides involved in protection and healing of the gastrointestinal epithelium but which are also secreted in the airway mucosa. Methods. We investigated the role of TFF2 in airway remodeling by histological and morphometric analysis of lung tissue from TFF2-deficient mice subjected to two relevant animal models of asthma: an ovalbumin model of allergic airways disease and an Aspergillus fumigatus antigen sensitization model. Results. In the ovalbumin model TFF2-deficient mice had increased goblet cell hyperplasia, but not epithelial thickening compared to wild-type (WT) counterparts. In the Aspergillus model TFF2-deficient mice also had increased goblet cell hyperplasia, and epithelial thickness was also increased in the Aspergillus-sensitized mice compared to WT controls. TFF2 deficiency was also associated with increased subepithelial collagen layer thickness. Discussion. The current study demonstrates a role of TFF2 in airway remodeling in mouse models of airway disease. Further studies into the mechanisms of action of TFF2 and its role in asthma are warranted.     

Inflammatory Subtypes in Asthma are Related to Airway Hyperresponsiveness to Mannitol and Exhaled NO

Asthma may be defined as eosinophilic or non-eosinophilic based on the presence of eosinophils in sputum. Recently a further classification into four inflammatory subtypes has been suggested. The aim of the present study was to describe the association between these inflammatory subtypes and markers of airway inflammation and hyperresponsiveness. In 62 adult non-smoking asthmatics, (18–65 yr) not taking inhaled steroids, sputum induction, bronchial challenge with mannitol and measurement of exhaled NO (eNO) were performed. Based on the eosinophil and neutrophil proportions in sputum, subjects were categorised into four inflammatory subtypes: Eosinophilic asthma: i.e., sputum eosinophils > 1.0%. Neutrophilic asthma: i.e., sputum neutrophils > 61%. Mixed granulocytic asthma: both increased eosinophils and neutrophils. Paucigranulocytic asthma: i.e., normal levels of both eosinophils and neutrophils. Among subjects with non-eosinophilic asthma, neutrophilic asthma was associated with low levels of eNO (Median (IQR): 12 ppb (8–27 ppb), whereas subjects with non-eosinophilic asthma of the paucigranulocytic subtype had levels of eNO (48 ppb (29–65 ppb)) that were comparable to subjects with eosinophilic asthma of the mixed granulocytic type (47 ppb (33–112 ppb). Purely eosinophilic asthma was associated with higher levels of eNO (77 ppb (37–122 ppb)). Furthermore, a low degree of airway hyperresponsiveness to mannitol was observed in neutrophilic asthma (PD₁₅: (Median (IQR) 512 mg (291–610 mg))), whereas it was moderate in paucigranulocytic asthma (238 mg (77–467 mg)) and comparable to eosinophilic asthma of the mixed granulocytic subtype (186 mg (35–355 mg)). The highest degree of AHR to mannitol was observed in purely eosinophilic asthma (107 mg (68–245 mg)). In conclusion, further subclassification of eosinophilic and non-eosinophilic asthma showed significant differences in airway hyperresponsiveness to mannitol and exhaled NO levels among the four inflammatory subtypes.     

3-chlorotyrosine in Sputum of COPD Patients: Relationship with Airway Inflammation

ABSTRACT

The airways of patients with chronic obstructive pulmonary disease (COPD) are associated with increased numbers of inflammatory cells, in particular neutrophils and macrophages. Contained within the primary granules of neutrophils is the heme enzyme called myeloperoxidase (MPO) that has been used as a biomarker of neutrophilic inflammation in COPD and other inflammatory diseases. MPO is the only enzyme in the body that produces hypochlorous acid (HOCl), which effectively chlorinates tyrosine residues in proteins. The presence of 3-chlorotyrosine (3Cl-Tyr) in sputum of COPD patients has yet to be established. Spontaneously produced sputum was collected from 14 stable COPD patients, and ultra-centrifuged to prepare sol phase samples for analysis. Sputum 3Cl-Tyr levels were measured using Mass Spectrometry (LC-MSMS). Sputum MPO activity was measured using a standard chromogenic substrate assay. The Spearman rank correlation was used to analyse the data. We report for the first time the measurement of 3Cl-Tyr in sputum from stable COPD patients. The sputum levels of 3Cl-Tyr correlated well with sputum MPO activity (r = 0.88; p < 0.0001). The presence of 3Cl-Tyr in the sputum of stable COPD patients suggests an active process related to MPO that may play a role in the pathophysiology of this disease.