Airway Responsiveness to Indirect Challenges in COPD

ABSTRACT

Patients with chronic obstructive pulmonary disease (COPD) demonstrate airway hyperresponsiveness to a number of indirect stimuli. Hyperresponsiveness to cold air hyperventilation, exercise, and drugs like propranalol and methoxamine seem to be able to distinguish patients with COPD from those with asthma, whereas hyperresponsiveness to stimuli like adenosine 5-monophosphate (AMP) and hypertonic saline seem unable to do so. The relationship of airway responsiveness to indirect stimuli and airway inflammation has received little study. The clinical relevance of hyperresponsiveness to an indirect challenge, including the impact on the natural history, relation to types of bronchitis, baseline airway calibre, and response to treatment need to be studied.     

Immunological Status May Predict Clinical Outcome in BCG Treated Melanoma

Summary: Immunological status may predict clinical outcome in BCG treated melanoma. P. M. Reynolds. G. Grimsley. R. L. Dawkins, M. J. Byrne and P. J. Zilko. Aust. N.Z. J. Med ., 1980, 10 , pp. 39–43.
Twenty-seven patients with surgically reseated stage Il or III malignant melanoma were treated with bacillus Calmette-Guérin (BCG) and followed prospectively to determine whether relapse could be predicted. Peripheral blood mononuclear (lymphocyte plus monocyte) counts (PBM), T and B cell counts, phyto-haemagglutinin (PHA) cytotoxicity, PHA transformation, antibody-dependent cell-mediated cytotoxicity (ADCC) and serum immunoglobulin concentrations were studied before and during therapy. Patients ultimately classified as having a poor clinical outcome (inoperable recurrence) were compared with those with a more favourable outcome. Prior to therapy, poor outcome patients had lower PBM and T cell counts but there was some overlap. After three months, these differences were more pronounced. Low PHA cytotoxicity was also associated with poor outcome; again the differences were more apparent at 3 months than prior to therapy.
These results suggest that PBM, T cell counts and PHA cytotoxicity may predict poor outcome some months before inoperable recurrence is apparent clinically     

Atopic Status and Level of Bronchial Responsiveness in Parents of Children with Acute Bronchiolitis

To examine whether children with a genetic predisposition to asthma are more likely to be afflicted with bronchiolitis, we studied 122 parents of infants who were hospitalized with the diagnosis of acute bronchiolitis (index group) and 120 parents of children who had never suffered from this disease (control group). The parents underwent bronchial challenge testing with methacholine and skin prick testing with common airborne allergens, and gave blood specimens for measurement of serum total IgE. There was no difference in atopic status, as assessed by the prevalence of atopy (at least one positive response to the allergens tested) or by serum total IgE levels, between index and control parents. The prevalence of bronchial hyperresponsiveness (BHR) (concentration of methacholine causing a 20% reduction in forced expiratory volume in 1 sec [PC₂₀] < 18 mg/mL) was higher in index parents than in control parents (17.2% vs. 7.5%, p = 0.02). Bronchial responsiveness (BR) index was significantly higher in index parents than in control parents (1.135 ± 0.088 vs. 1.104 ± 0.071, p < 0.01). Parents of children who were hospitalized with acute bronchiolitis showed a higher level of BR, but not atopy. This suggests that in terms of BHR, there may be a genetic predisposition to the development of bronchiolitis.     

Development of Lung Function in Relation to Increased Degree of Bronchial Responsiveness

To study the relationship between development of lung function and bronchial responsiveness, we examined 106 subjects recruited from a random sample of 527 subjects, aged 8-18 years, from Copenhagen. Lung function and bronchial responsiveness to inhaled histamine were measured at two occasions, in 1986 and 1988. The participating subjects (n = 106) were divided into three groups: (a) 20 asthmatics with bronchial hyperresponsiveness (BHR), (b) 42 nonasthmatic subjects with BHR in 1986, and (c) 44 controls without BHR. In 1986, FEV₁ expressed as percentage of predicted value, was found to be similar in the three groups (91%, 94%, and 99%, respectively). The increase in height during the observation period was found to be 5, 6, and 6 cm, respectively, in the three groups. However, at the second examination, in 1988, FEV₁ was found to be significantly reduced in both asthmatics (87%) and nonasthmatic subjects (85%) compared with the controls (103%). In 1988, 16 asthmatics (80%) and 24 (57%) nonasthmatic subjects were found to have BHR, whereas none of the controls were found to have BHR. A multiple regression analysis was used to determine the correlation between change in FEV₁ and potential factors of importance. The change in FEV₁ was highly correlated with the presence of BHR in 1986, however, no correlation was found between change in FEV₁ and change in bronchial responsiveness. In conclusion, nonasthmatic subjects with former BHR showed signs of airflow obstruction and less increase in lung function during growth irrespective of the change in level of bronchial responsiveness, which may suggest a risk for subsequent development of obstructive lung disease.     

A Screening Study to Determine the Prevalence of Airway Disease in Heroin Smokers

Over the last 20 years smoking has become the most common method of heroin use and increasing numbers of heroin smokers are presenting to local medical services, before the age of 40 years, with severe airway disease. To determine COPD prevalence we recruited 129 subjects from two local community drug services, of whom 107 were heroin smokers. We collected demographic, medical and treatment data, smoking history (including cannabis and opiates) and details of symptoms including MRC dyspnoea. Subjects completed the COPD Assessment Tool and spirometry. Thirty heroin smokers were identified as having COPD resulting in a COPD prevalence of 28%. Mean age was 43 (4) Cygan J, Trunsky M, Corbridge T. Inhaled heroin-induced status Asthmaticus: Five cases and a review of the literature. Chest 2000; 117:272–275.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar] years and FEV₁ was 2.71 (0.98) L; 70 (23) Doshi V, Shenoy S, Ganesh A, Lankala S, Henkle J. Near fatal asthma in an inner city population. Am J Ther 2014; Oct 3. [Epub ahead of print].[Web of Science ®] , [Google Scholar] %predicted. Breathlessness and wheeze were more common in subjects with COPD (p < 0.04 and p < 0.05) but symptoms were common in all heroin smokers. MRC score was higher (3 vs. 2.4; p < 0.04) in those with COPD and health status appeared poorer (CAT 20.4 vs. 15.8; p < 0.07). Only 4 (11%) had previously been diagnosed with COPD and only 16 (53%) received any inhaled medication. Asthma prevalence was also high at 33% and asthmatic subjects had similar symptoms and health status compared with the COPD subjects, and were also significantly undertreated. COPD and asthma are common in current and former heroin smokers. They are often present at a young age and are underdiagnosed and undertreated. Awareness of this issue should be highlighted within drug services and in particular to heroin smokers. Screening this high-risk population with spirometry should be considered.     

A Low Serum CCL4/MIP-1β Level May Predict a Severe Asthmatic Responsiveness to Mepolizumab

Objective Mepolizumab, a humanized anti-interleukin-5 monoclonal antibody, is effective for treating eosinophilic severe asthma. However, there is a need for more biomarkers that can predict the patient response to mepolizumab before starting therapy. This study aimed to identify a new biomarker in the serum that is able to accurately predict the responsiveness to mepolizumab. Methods This study enrolled 11 patients who had all been diagnosed with severe eosinophilic asthma and were then administered mepolizumab every 4 weeks for at least 4 months. Blood samples were collected, and pulmonary function tests and questionnaires were administered at baseline and after 4, 8 and 16 weeks of treatment. The response to mepolizumab was then assessed based on the difference in the Asthma Quality of Life Questionnaire (AQLQ) score after 16 weeks of mepolizumab therapy compared with that at baseline. Patients with an increase in the AQLQ score of more than 0.5 were defined as responders. The cytokine levels in the blood were measured by LUMINEX 200 and ELISA. Results There were 6 responders and 5 non-responders. The responders showed a significantly lower serum level of chemokine (C-C motif) ligand 4/macrophage inflammatory protein-1β (CCL4/MIP-1β) at baseline compared to the non-responders. Receiver operating characteristic curves to distinguish responders from non-responders using the baseline serum CCL4/MIP-1β level showed a good area under the curve of 0.9. The non-responders showed a significant increase in the level of CCL4/MIP-1β after 4 weeks compared to the baseline. Conclusion A low baseline serum CCL4/MIP-1β level may be useful for predicting a good mepolizumab response in severe eosinophilic asthma.     

Responsiveness of Health Status Measures and Utility-based Methods in Patients with Rheumatoid Arthritis

The aim of the study was to compare the responsiveness of disease-specific (Arthritis Impact Measurement Scale 2, AIMS2), generic (Medical Outcome Study Short Form Health Survey, SF-36) and preference-based instruments (rating scale, RS and time tradeoff, TTO) to changes in articular status and perceived health in patients with rheumatoid arthritis (RA). Seventy-eight consecutive patients with RA, attending the care facilities of the Department of Rheumatology of Ancona, were recruited in this longitudinal study. In order to assess the responsiveness three strategies were used: effect size (ES), standardised response mean (SRM) and receiver operating characteristic (ROC). There were 55 women and 23 men with a mean age of 56 years (range 19–78) and arthritis duration of 7.1 years (range 6 months to 24 years). Using three-category EULAR criteria as external indicators of improvement/response, 21 patients (27%) reported a significant improvement, 23 (29.5%) moderate improvement, and 34 (43.5%) no change over the 12-month period. The mean change scores in generic and specific health status instruments and utility measures were significantly related to response category. The AIMS2 subscales (physical function, pain, psychological function and social interaction) were slightly more responsive than those of SF-36. The physical and pain dimensions were most sensitive for measuring change over a 12-month period, followed by psychological and social dimensions. For the utility measurement, RS scores were found to be significantly more responsive in detecting changes in preferences than TTO scores. These results may have implications for the application of the health status and utility measures in clinical trials in patients with RA. Received: 10 September 2001 / Accepted: 27 May 2002 Correspondence and offprint requests to: Dr F. Salaffi, Department of Rheumatology, University of Ancona, Ospedale A. Murri, Via dei Colli 52, 60035 Jesi, Ancona, Italy. Tel: +39 0731-534128/32/25; Fax: +39 0731-534124; E-mail:fsalaff@tin.it     

Modulation of Airway Responsiveness to Acetylcholine by Nitric Oxide in a Rabbit Model

Nitric oxide (NO) is an important mediator in the regulation of bronchial muscle tone and airway responsiveness. We investigated the influence of exogenous NO on airway responsiveness to acetylcholine aerosols (ACH) in normal and in hyperresponsive rabbits. White New Zealand rabbits were anesthetized, intubated, and breathed room air spontaneously. Responses of respiratory parameters in ACH challenge tests were measured. In group A the influence of NO on ACH infusion-induced airway constriction was measured. Airway responses to aerosols from 0.25 to 8.0% ACH solutions in saline were measured with 150 and 300 ppm NO inhalation (groups B and C) and compared with the same animals' responses without NO. Moreover, we examined the influence of NO synthase inhibition on airway responsiveness (group D) and the modulatory effect of NO in hyperresponsive animals (group E). 300 ppm NO inhalation significantly decreased the bronchoconstrictor response to intravenously administered ACH (group A). However, the baseline value of dynamic elastance (E_dyn) was only marginally lower under the influence of 300 ppm NO. During inhalation of 150 or 300 ppm NO, responses to nebulized 2.0% and less ACH solutions remained nearly unaltered. Responses to aerosols of 4.0 and 8.0% diminished significantly (groups B and C). Following 40 min of aerosolized N-nitro-l-arginine-methyl ester (l-NAME) solution (a NO synthase inhibitor, 1.2 mM) inhalation, the response of E_dyn to ACH increased significantly in group D. In group E, animals inhaled 500 mg/m³ ammonium persulfate (APS), an oxidant with various industrial applications, after the first ACH challenge test (0.2, 1.0, and 2.0% ACH). After 2 h of APS exposure, the ACH-induced broncho constriction was increased significantly in the challenge test. After another 2 h of APS inhalation, the airway responsiveness to ACH was tested under the influence of 300 ppm NO. NO significantly decreased the response to ACH to almost the same level as before APS exposure. The results indicate that responses to high ACH concentrations as well as an APS-induced increase in ACH responsiveness were effectively reduced by high concentrations of inhaled NO. Accepted for publication: 11 February 1997     

The Relationship of Exhaled Nitric Oxide to Airway Inflammation and Responsiveness in Children

Exhaled nitric oxide (eNO) is a potential tool in epidemiological studies of asthma. It was hypothesized that in a cross-sectional survey of asthma in adolescent children, eNO may contribute to the detection of this disease. A cohort of Australian school children in two educational years (n = 107, aged 14.7 ± 2.3 years, 42.9% female) were surveyed in terms of exhaled nitric oxide (eNO), which was compared with other indicators of asthma: asthma symptoms, atopy [skin prick tests (SPT)], hypertonic saline bronchial reactivity, sputum inflammatory cells and eosinophilic cationic protein. Significant positive correlations were found with eNO and number of positive skin prick tests (p = 0.001; n = 98), symptoms (p = 0.05; n = 107), sputum eosinophils (p = 0.025; n = 83), and sputum eosinophilic cationic protein (p = 0.009; n = 83). There was no significant relationship with airway hyperresponsiveness (p = 0.3; n = 15). eNO had a negative predictive value for asthma of 83%, and a positive predictive value of 54%, which is comparable with most current tests for diagnosing asthma. eNO appears to be a useful indicator of atopy and airway inflammation, but in this population it was not closely related to airway hyperresponsiveness.     

Comparison of 4 AM and 4 PM Bronchial Responsiveness to Hypertonic Saline in Asthma

Bronchial responsiveness to methacholine or histamine increases at night and may contribute to the mechanisms of nocturnal asthma. Hypertonic saline (HS) is a more clinically relevant stimulus for the diagnosis and assessment of the severity of asthma, but the circadian variation in bronchial responsiveness to hypertonic challenges has not been addressed. The aim of this study was to compare the responsiveness to hypertonic saline at 4:00 AM and at 4:00 PM. Eighteen diurnally active patients (11 women) with asthma, 31 ± 9 years of age (mean ± SD) and with a forced expiratory volume in 1 s (FEV₁) of 79.11% ± 12.85%, underwent two challenge tests (4:00 AM and 4:00 PM) in random sequence separated by an interval of 7 days. The challenge test consisted of inhalations of 4.5% saline with increasing doses by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min). The inhalation continued until a drop of 20% in FEV₁ was achieved or total time of 15.5 min. The provocative dose that caused the 20% drop in FEV₁ (PD₂₀) was calculated. Differences were found between 4:00 PM and 4:00 AM values for inhalation times [3.80 ± 3.57 min and 2.19 ± 2.42 min (p = 0.001), respectively] and for PD₂₀ [4.94 ± 6.77 ml and 2.93 ± 4.74 ml (p = 0.002), respectively]. Eight patients with a home-assessed nocturnal peak expiratory flow (PEF) drop of more than 15% formed the nocturnal asthma group. The behavior of these patients was similar to that of the non-nocturnal asthma group. We conclude that the bronchial responsiveness to HS increases at night.     

Differentiation in Dose-Response Curves of Airway Responsiveness to Inhaled Methacholine Between Asthmatics and Nonasthmatics

We compared the discriminative capacity of the parameters obtained from dose-response curves of airway resistance (Raw) to inhaled methacholine (i.e., threshold dose, slope, and maximal increase in Raw) to differentiate asthmatics from nonasthmatics. Of the three parameters, maximal increase in Raw most accurately differentiated asthmatics from nonasthmatics (% correctness was 86% in asthmatics). Furthermore, an index consisting of both threshold dose and slope more clearly differentiated asthmatics from nonasthmatics (% correctness was 94% in asthmatics) than either threshold dose or slope alone (W correctness was 68% and 54% in asthmatics, respectively). We conclude, that of the three parameters, the maximal increase in Raw or an index consisting of both threshold dose and slope i s the most discriminative index in asthmatics.     

Differentiation in Dose-Response Curves of Airway Responsiveness to Inhaled Methacholine Between Asthmatics and Nonasthmatics

We compared the discriminative capacity of the parameters obtained from dose-response curves of airway resistance (Raw) to inhaled methacholine (i.e., threshold dose, slope, and maximal increase in Raw) to differentiate asthmatics from nonasthmatics. Of the three parameters, maximal increase in Raw most accurately differentiated asthmatics from nonasthmatics (% correctness was 86% in asthmatics). Furthermore, an index consisting of both threshold dose and slope more clearly differentiated asthmatics from nonasthmatics (% correctness was 94% in asthmatics) than either threshold dose or slope alone (W correctness was 68% and 54% in asthmatics, respectively). We conclude, that of the three parameters, the maximal increase in Raw or an index consisting of both threshold dose and slope i s the most discriminative index in asthmatics.     

Contribution of CT Quantified Emphysema,Air Trapping and Airway Wall Thickness on Pulmonary Function in Male Smokers With and Without COPD

Emphysema, airway wall thickening and air trapping are associated with chronic obstructive pulmonary disease (COPD). All three can be quantified by computed tomography (CT) of the chest. The goal of the current study is to determine the relative contribution of CT derived parameters on spirometry, lung volume and lung diffusion testing. Emphysema, airway wall thickening and air trapping were quantified automatically on CT in 1,138 male smokers with and without COPD. Emphysema was quantified by the percentage of voxels below –950 Hounsfield Units (HU), airway wall thickness by the square root of wall area for a theoretical airway with 10 mm lumen perimeter (Pi10) and air trapping by the ratio of mean lung density at expiration and inspiration (E/I-ratio). Spirometry, residual volume to total lung capacity (RV/TLC) and diffusion capacity (Kco) were obtained. Standardized regression coefficients (β) were used to analyze the relative contribution of CT changes to pulmonary function measures. The independent contribution of the three CT measures differed per lung function parameter. For the FEV1 airway wall thickness was the most contributing structural lung change (β = –0.46), while for the FEV₁/FVC this was emphysema (β = –0.55). For the residual volume (RV) air trapping was most contributing (β = –0.35). Lung diffusion capacity was most influenced by emphysema (β = –0.42). In a cohort of smokers with and without COPD the effect of different CT changes varies per lung function measure and therefore emphysema, airway wall thickness and air trapping need to be taken in account.     

Effect of TRFK-5 on Airway Responsiveness in Ovalbumin-Treated Guinea Pigs Exposed to Tobacco Smoke

Tobacco smoke (TS) exposure can induce airway hyperresponsiveness, especially in asthma. A feature of asthma is eosinophilia. We hypothesized that tobacco smoke exposure enhances eosinophil responsiveness in sensitized guinea pigs. Tobacco smoke-exposed, ovalbumin (OA)-sensitized guinea pigs were treated with TRFK-5 (1.0 mg/kg, intraperitoneal), an anti-interleukin (IL)-5 agent, or its vehicle. Guinea pigs were challenged with aerosols of OA, capsaicin, histamine, and methacholine. TRFK-5 attenuated airway responsiveness to OA but not to capsaicin, histamine, or methacholine. Bronchial alveolar lavage fluid analysis confirmed TRFK-5 attenuated airway eosinophilia in OA-treated guinea pigs. Therefore, airway responsiveness to OA is enhanced by eosinophils or IL-5 itself.     

β2-Adrenergic Receptor Polymorphisms Affect Airway Responsiveness to Salbutamol in Asthmatics

We examined the β-adrenergic receptor (β₂AR) polymorphisms (Arg16 → Gly, Gln27 → Glu) and clinical status for 117 asthmatics. Airway responsiveness to methacholine and β₂-agonists was evaluated with Astograph®. The atopic factors, pulmonary function test, and airway responsiveness to methacholine did not differ significantly among the different β₂AR genotypes. Asthmatics homozygous for Glyl 6 showed significantly lower airway responsiveness to inhaled salbutamol than those heterozygous for Arg/Gly16 or homozygous for Arg16. Asthmatics heterozygous for Gln/Glu27 had significantly later asthma onsets than those homozygous for Gln27. These results suggest that β₂AR polymorphisms play an important role in the airway responsiveness to inhaled β₂- agonist and the initial asthma onset.     

Using the AUDIT-PC to Predict Alcohol Withdrawal in Hospitalized Patients

BACKGROUND

Alcohol withdrawal syndrome (AWS) occurs when alcohol-dependent individuals abruptly reduce or stop drinking. Hospitalized alcohol-dependent patients are at risk. Hospitals need a validated screening tool to assess withdrawal risk, but no validated tools are currently available.

OBJECTIVE

To examine the admission Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) ability to predict the subsequent development of AWS among hospitalized medical-surgical patients admitted to a non-intensive care setting.

DESIGN

Retrospective case–control study of patients discharged from the hospital with a diagnosis of AWS. All patients with AWS were classified as presenting with AWS or developing AWS later during admission. Patients admitted to an intensive care setting and those missing AUDIT-PC scores were excluded from analysis. A hierarchical (by hospital unit) logistic regression was performed and receiver-operating characteristics were examined on those developing AWS after admission and randomly selected controls. Because those diagnosing AWS were not blinded to the AUDIT-PC scores, a sensitivity analysis was performed.

PARTICIPANTS

The study cohort included all patients age ≥18 years admitted to any medical or surgical units in a single health care system from 6 October 2009 to 7 October 2010.

KEY RESULTS

After exclusions, 414 patients were identified with AWS. The 223 (53.9 %) who developed AWS after admission were compared to 466 randomly selected controls without AWS. An AUDIT-PC score ≥4 at admission provides 91.0 % sensitivity and 89.7 % specificity (AUC?=?0.95; 95 % CI, 0.94–0.97) for AWS, and maximizes the correct classification while resulting in 17 false positives for every true positive identified. Performance remained excellent on sensitivity analysis (AUC?=?0.92; 95 % CI, 0.90–0.93). Increasing AUDIT-PC scores were associated with an increased risk of AWS (OR?=?1.68, 95 % CI 1.55–1.82, p?<?0.001).

CONCLUSIONS

The admission AUDIT-PC score is an excellent discriminator of AWS and could be an important component of future clinical prediction rules. Calibration and further validation on a large prospective cohort is indicated.     

Responsiveness of Three Instruments to Assess Self-Reported Functional Status in Patients with COPD

The study aimed to compare the responsiveness of three instruments to assess self-reported changes in functional status after exercise training in patients with COPD: Pulmonary Functional Status and Dyspnea Questionnaire –modified version (PFSDQ-M), London Chest Activity of Daily Living (LCADL) and Medical Research Council scale (MRC). Twenty-two patients (11 female, 66[62-71] years, FEV₁ 42[33-61]%predicted) participated in a 3-month high-intensity exercise program. The three instruments were applied pre- and post-program, as well as assessment of lung function, muscle strength, exercise capacity (6-minute walking test, 6MWT) and quality of life (St. George's Respiratory Questionnaire, SGRQ). SGRQ, 6MWT and quadriceps femoris, biceps and triceps brachialis strength improved significantly after the program (p < 0.05 for all). Training also yielded significant improvement in the LCADL total score and self-care, domestic and leisure domains and in the PFSDQ-M ‘change in activities’ domain, with no improvement in the MRC (p = 0.11). Calculation of effects sizes also indicated higher responsiveness in the LCADL than the other instruments. There were no significant correlations between changes in the three instruments and changes in lung function, SGRQ or 6MWT. In conclusion, PFSDQ-M's ‘change in activity’ domain and specially the LCADL (to a higher extent) showed responsiveness to detect changes in functional status after three months of high-intensity exercise training in patients with COPD, whereas the MRC scale did not. In this population, the improvement in functional status was not related with improvement in exercise capacity, lung function or quality of life.