Biomedical subjects
K Parameswaran
Publications and source records attributed to K Parameswaran.
Problems with using exhaled nitric oxide to guide asthma treatment.
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Effects of intranasal fluticasone and salmeterol on allergen-induced nasal responses.
BACKGROUND: Combination of inhaled steroid and long-acting beta-agonists has synergistic effects in asthma. OBJECTIVE: To investigate whether nasal corticosteroid and long-acting beta-agonists have synergistic effects on allergen-induced nasal responses. METHODS: The effects of intranasal treatment with fluticasone p-MDI (50 microg bid), salmeterol p-MDI (25 microg bid), their combination, and placebo, on nasal symptoms, eosinophil differential cell count and albumin in nasal lavage fluid (measures of inflammation and leakage respectively) and nasal electrical potential difference (measure of epithelial integrity) were studied in 11 atopic subjects with rhinitis, in a randomized, partially-blinded, 4-period, cross-over study. The measurements were made at baseline, at the end of 1 week of treatment, and immediately after a nasal allergen provocation. RESULTS: Allergen-induced sneeze, postnasal drip and nasal obstruction were significantly reduced by fluticasone, but not by salmeterol. Eosinophil count in postallergen nasal lavage fluid was significantly less after fluticasone (median 1.9%, IQR 4.6) and salmeterol treatment (median 2.5%, IQR 8.5) compared with placebo (median 12.5%, IQR 27.9). Compared with placebo, both fluticasone and salmeterol attenuated allergen-induced change in nasal potential (mean change from baseline -18.5, +0.4 and -7.2% respectively) and the increase in nasal albumin (median 154, 119 and 130 ng/ml respectively). Combination treatment did not have any additional benefits over the individual therapies. CONCLUSIONS: Although salmeterol has anti-inflammatory properties, intranasal salmeterol or its combination with fluticasone do not offer any added benefit over intranasal fluticasone alone for allergen-induced nasal responses.
Asthma, COPD and bronchitis are just components of airway disease.
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Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations.
One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal. A total of 117 adults with asthma were entered into a multicentre, randomised, parallel group-effectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils 250 microg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups. Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.
Efficacy of fluticasone on cough.
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Extracellular matrix regulates human airway smooth muscle cell migration.
Extracellular matrix proteins regulate the survival and proliferation of smooth muscle cells. Their effect on airway smooth muscle cell migration is not known. Their role in leukotriene-primed (0.1 microM leukotriene E4) chemotaxis of cultured human airway smooth muscle cells towards platelet-derived growth factor BB (1 ng.mL(-1)) was investigated. Migration of cells was greater on membranes coated with collagens III and V and fibronectin compared to collagen I, elastin and laminin (all 10 microg.mL(-1)). Concentration-dependent promotion of migration was observed on collagen I (1,000>10 microg.mL(-1)), which was associated with increased phosphorylation of Src kinase. This was not observed on laminin or elastin. The role of Src kinase was further confirmed by demonstrating that its inhibitor, PP1 analogue (1 microM), inhibited chemotaxis. Collagen I itself was not a chemoattractant; however, haptokinesis was observed when cells were primed with leukotriene E4, and haptotaxis when cells were primed with platelet-derived growth factor. The priming effect of leukotrienes on chemotaxis was not elicited by promoting adhesion, increasing surface expression of beta1, alphav and alpha5 integrin, or Src kinase phosphorylation. These experiments demonstrate that the extracellular matrix, along with growth factors and cysteinyl leukotrienes, can regulate human airway smooth muscle cell migration. This may be relevant in the remodelling process in chronic airway diseases, such as asthma.
Two siblings with Allgrove's syndrome and extrapyramidal features.
We report two siblings with Allgrove's syndrome and extrapyramidal features. Though various neurological abnormalities have been described in this disorder, we report the first patient of Allgrove's syndrome associated with dystonia and chorea.
Clinical applications of assessment of airway inflammation using induced sputum.
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The use of induced sputum in clinical trials.
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The use of sputum cell counts to evaluate asthma medications.
Total and differential cell counts from hypertonic-induced, dithiothreitol-dispersed sputum provide reproducible measurements of airway inflammatory cell counts, which are responsive to treatment with anti-inflammatory drugs. They have helped to understand the kinetics of inflammatory cell changes in asthma after the reduction of corticosteroids and the subsequent re-introduction of treatment. They have identified that the presence of sputum eosinophilia in asthma, chronic cough and chronic airflow limitation is a predictor of steroid-responsiveness and of lack of 'asthma control'. They can be used to study the dose-response effect of inhaled corticosteroids and may be useful to establish the relative potency of different corticosteroid formulations and delivery devices. Sputum cell counts are also useful to study the potential anti-inflammatory effects of drugs like theophylline, long-acting beta-adrenoceptor agonists, leukotriene antagonists and newer drugs in development. They may be helpful to select add-on therapy to corticosteroids in 'difficult-to-control' asthma.
Repeatability and validity of cell and fluid-phase measurements in nasal fluid: a comparison of two methods of nasal lavage.
BACKGROUND: There is little information on the repeatability of cell counts and fluid-phase measurements in nasal fluid obtained by different methods of nasal lavage. OBJECTIVE: To compare the repeatability and validity of total and differential cell counts and eosinophil cationic protein (ECP) in nasal secretions obtained by two methods of nasal lavage. PATIENTS AND METHODS: Twelve healthy subjects and twelve subjects with clinically stable allergic rhinitis were randomly assigned to two nasal lavages (separated by 48 h), by one of two methods in the first week and by the second method in the following week. One method was a modification of the method described by Greiff et al. and Grunberg and coworkers and the other was that described by Naclerio and coworkers. RESULTS: Both methods of nasal lavage gave poorly repeatable eosinophil counts and ECP in normal subjects but better repeatability in subjects with rhinitis. The modified Greiff/Grunberg method gave higher and more repeatable total cell count and, in subjects with rhinitis, more reproducible ECP levels compared with the Naclerio METHOD: Both methods were able to discriminate between healthy and rhinitic subjects: mean +/- SD eosinophil percentage count and eosinophil cationic protein differences were 4.5 +/- 4% (P < 0.05) and 24.5 +/- 46.9 microg/L (P < 0.05), respectively, with the modified method and 7.0 +/- 4% (P < 0.05) and 26.9 +/- 68 microg/L (P < 0.05), respectively, with the Naclerio method. CONCLUSION: Both methods are valid and discriminate between normal and rhinitic subjects. In subjects with rhinitis, although the repeatability of eosinophil counts is similar by both methods, the modified Greiff/Grunberg method gives more reproducible ECP measurements, compared with the Naclerio method.
Coronary and laryngeal spasm provoked by methacholine inhalation.
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The trials and tribulations of IL-5, eosinophils, and allergic asthma.
Eosinophils have been suggested to be part of the pathologic process that characterizes asthma, and their recruitment into the upper or lower airways appears to be essential for the clinical manifestations of allergen inhalation. IL-5 is a cytokine necessary for the development, differentiation, recruitment, activation, and survival of eosinophils. Allergen inhalation increases the production of IL-5 in the airways as measured in bronchoalveolar lavage cells and induced sputum. The relationship between IL-5 and the development of airway eosinophilia has been firmly established in IL-5 transgenic mice, with allergen challenge models in IL-5-deficient mice, and in mice treated with blocking anti-IL-5 antibodies. In addition, an accumulation of evidence suggests that treating mice with anti-IL-5 blocking antibodies prevents allergen-induced airway hyperresponsiveness. A recently reported study examined the effects of treatment with a humanized anti-IL-5 mAb (SB-240563) on allergen-induced airway responses and inflammation in atopic subjects. The authors of the study concluded that their results call into question the role of eosinophils in mediating the allergen-induced late asthmatic response and airway hyperresponsiveness; however, because of methodologic limitations, the study cannot be used either to support or to refute the concept of an important role for eosinophils in causing allergen-induced changes in airway function.
Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma.
BACKGROUND: Aminophylline has been used extensively in acute asthma, but its role is unclear especially with respect to any additional benefit when added to beta2-agonists. OBJECTIVES: To determine the magnitude of effect of the addition of intravenous aminophylline to beta2-agonists in adult patients with acute asthma treated in the emergency setting. SEARCH STRATEGY: Studies were identified from the following sources: The Cochrane Airways Group register (derived from MEDLINE, EMBASE, CINAHL standardised searches), hand searched respiratory journals and meeting abstracts. Potentially relevant articles were obtained, and their bibliographic lists were hand searched for additional articles. The search included searches of the database up to 1999. SELECTION CRITERIA: Randomised controlled trials comparing intravenous aminophylline versus placebo in adults with acute asthma and treated with beta-adrenergic agonists. Patients could be treated with or without corticosteroids or other bronchodilators. DATA COLLECTION AND ANALYSIS: A total of 210 abstracts were identified. Two independent reviewers selected a total of 27 eligible studies for possible inclusion, in which quality assessment was performed and a third reviewer was used to adjudicate disagreements. Peak expiratory flow (PEFR) and forced expiratory volume in the first second (FEV1) data were extracted and entered in Review Manager from these studies. Information not obtained from the authors was estimated from graphs. All data were entered and double checked by two reviewers. Results are reported as weighted mean differences (WMD) or odds ratio (OR), both with 95% confidential intervals (CI). MAIN RESULTS: Fifteen trials were included. Overall, the quality of the studies was only moderate; concealment of allocation was assessed as clearly adequate in only seven (45%) of the trials. The doses of aminophylline and other medications and the severity of asthma varied between studies. There was no statistically significant effect of aminophylline on airflow outcomes at any time period. The aminophylline treated group had higher values of PEFR at 12 (PEFR 8 L/min or 2.3%) and 24 hours (PEFR 22 L/min or 6.4%), but these were not significant (p>0.05). Two subgroup analyses were performed by grouping studies according to mean baseline airflow limitation (n = 11 studies) and the use of any steroids (n = 9 studies). There was no relationship between baseline airflow limitation nor the use of steroids on the effect of aminophylline. Aminophylline treated patients reported more palpitations/arrhythmias (OR: 2.9; 95% CI: 1.5 to 5.7) and vomiting (OR: 4.2; 95% CI 2.4 to 7.4), but no difference was found in tremor or hospital admissions. REVIEWER'S CONCLUSIONS: In acute asthma, the use of intravenous aminophylline did not result in any additional bronchodilation compared to standard care with beta-agonists. The frequency of adverse effects was higher with aminophylline. No subgroups in which aminophylline might be more effective could be identified. These results should be added to consensus statements and guidelines.
Clinical judgement of airway inflammation versus sputum cell counts in patients with asthma.
The inflammatory component of asthma is usually assessed indirectly by symptoms and spirometry, these may be inaccurate. It can now be assessed directly and reliably by the examination of sputum cell counts. There is no information on how clinical assessment of the presence and type of airway inflammation compares with actual measurements. In this single-centre observational study, sputum was collected from 76 consecutive adults with asthma attending a tertiary chest clinic after their physicians had recorded the expected cell counts in sputum. The authors examined the extent of agreement between clinical judgement of sputum cell counts and actual counts in asthmatic patients (Cohen's Kappa) and the possible predictors of agreement (multiple logistic regression). Sixty-seven of the 76 sputum samples were suitable for analysis. Agreement between expected and actual cell counts occurred in 30/67 patients. The overall agreement for the different cell types was poor (estimated K=0.14, 95% confidence interval (CI)=0.02, 0.26). The experience of the physician in using sputum cell counts in clinical practice, steroid requirement at the time of assessment, and control of asthma as assessed by the physician or by the patient could not predict the chances of agreement or disagreement. Unaware of the sputum results, the physicians often changed treatment in a way that seemed inappropriate for the cell counts present. There is poor agreement between clinical judgement of the presence and type of airway inflammation in asthmatic patients and sputum cell counts. The impact of sputum examination on the outcomes of anti-inflammatory treatment now needs investigation.
Induced sputum cell counts: their usefulness in clinical practice.
Airway inflammation is fundamental to the aetiology and persistence of asthma and other airway conditions. The presence and type of airway inflammation can be difficult to detect clinically, delaying the introduction of appropriate treatment. Induced sputum cell counts are a relatively noninvasive, safe and reliable method of identifying airway inflammation. They can accurately discriminate eosinophilic airway inflammation from noneosinophilic airway inflammation, and help guide therapy. Eosinophilic airway inflammation is steroid responsive whilst noneosinophilic (usually neutrophilic) inflammation generally is not. Macrophages containing haemosiderin can be useful in detecting left ventricular dysfunction and macrophages containing lipid are suggestive of oropharyngeal reflux with microaspiration, both of which can complicate or confuse assessment of airway disease. To date, studies using induced sputum are primarily observational. Management studies based on examination of induced sputum are now needed to validate the clinical utility of this test.
Lipid-laden macrophages in induced sputum are a marker of oropharyngeal reflux and possible gastric aspiration.
The diagnostic properties of a "lipid index" of macrophages in induced sputum as a noninvasive marker of aspiration of acidic gastric contents were evaluated. In a cross-sectional study, 33 subjects (17 with symptoms suggestive of gastrooesophageal reflux) with normal chest radiographs and no symptoms of aspiration or sinus disease, underwent dual-channel 24-h ambulatory oesophageal pH recording and sputum induction. Oropharyngeal reflux, defined as at least one episode of a fall in pH to <4 at the upper oesophageal electrode, was considered indicative of aspiration of acidic gastric contents ("gold standard"). An index for the presence of intracellular lipid in sputum macrophages, detected by oil red O stain, was obtained. The sensitivity, specificity and predictive values of this "lipid index" were calculated. The "lipid index" could be calculated in 29 of 33 samples with high interobserver repeatability (intraclass correlation coefficient 0.96). Twenty subjects showed oropharyngeal reflux and nine did not. The median "lipid index" in subjects with oropharyngeal reflux (24.5) was significantly greater than that in those without reflux (1.0) (p<0.001). A "lipid index" of 7.0 had a sensitivity of 90%, a specificity of 89%, a positive predictive value of 95% and a negative predictive value of 80%. A "lipid index" of 7.0 in the macrophages of induced sputum is a good marker of oropharyngeal reflux.