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• W2045168308 abstract "Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response.After a screening visit, 20 patients with COPD (mean FEV1 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5min after prior inhalation of salbutamol, and 45min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV1) and inspiratory (FIV1) volumes.Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV1 was smallest at screening (P<0.01), without a significant difference between treatments. Regarding FIV1, however, the percent fall from baseline was higher after placebo (Δ=-10.1%; P<0.05) compared to screening (0.4%) or cetirizine (−4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of α2-macroglobulin after cetirizine compared to placebo (P=0.045).The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations. Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV1 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5min after prior inhalation of salbutamol, and 45min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV1) and inspiratory (FIV1) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV1 was smallest at screening (P<0.01), without a significant difference between treatments. Regarding FIV1, however, the percent fall from baseline was higher after placebo (Δ=-10.1%; P<0.05) compared to screening (0.4%) or cetirizine (−4.3%). Sputum composition showed no significant differences except for a tendency towards reduced concentrations of α2-macroglobulin after cetirizine compared to placebo (P=0.045). The present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airway obstruction in patients with moderate-to-severe COPD. In view of the mechanisms involved, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations. Inhalation challenges using hypertonic saline aerosol have been used in asthma research for a long time1Schoeffel R.E. Anderson S.D. Altounyan R.E. Bronchial hyperreactivity in response to inhalation of ultrasonic nebulised solutions of distilled water and saline.Br Med J. 1981; 283: 1285-1287Crossref PubMed Scopus (197) Google Scholar but are less commonly performed in patients with chronic obstructive pulmonary disease (COPD). In most cases the challenge has been more or less inadvertently used during sputum induction which requires inhalation of hypertonic or isotonic saline solution by a high-output nebuliser. Patients with COPD, particularly those with more severe disease, are known to develop significant airway obstruction during this procedure2Richter K. Holz O. Jörres R.A. Mücke M. Magnussen H. Sequentially induced sputum in patients with asthma or chronic obstructive pulmonary disease.Eur Respir J. 1999; 14: 697-701Crossref PubMed Scopus (37) Google Scholar, 3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar and the response to hypertonic saline aerosol has already been used to address bronchoprotective effects of a leukotriene receptor antagonist4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar or inhaled corticosteroids5Kanniess F. Böhme S. Jörres R.A. Magnussen H. Effect of fluticasone on the airway response to hypertonic saline in patients with COPD.Am J Respir Crit Care Med. 2004; (Abstract)Google Scholar in this disease. More detailed data on drug effects are available in asthma, in which cyclooxygenase inhibitors6Finnerty J.P. Wilmont C. Holgate S.T. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine.Am Rev Respir Dis. 1989; 140: 593-597Crossref PubMed Scopus (46) Google Scholar and cromones7Rodwell L.T. Anderson S.D. Du Toit J. Seale J.P. Nedocromil sodium inhibits the airway response to hyperosmolar challenge in patients with asthma.Am Rev Respir Dis. 1992; 146: 1149-1155Crossref PubMed Scopus (28) Google Scholar have shown the potential to reduce hypertonic saline-induced airway obstruction. Corticosteroids could also attenuate the response in asthma.8Du Toit J.I. Anderson S.D. Jenkins C.R. Woolcock A.J. Rodwell L.T. Airway responsiveness in asthma: bronchial challenge with histamine and 4.5% sodium chloride before and after budesonide.Allergy Asthma Proc. 1997; 18: 7-14Crossref PubMed Scopus (42) Google Scholar Interestingly, in patients with COPD their beneficial effect seemed to be due solely to increased bronchodilation by salbutamol which had been administered before the challenge.5Kanniess F. Böhme S. Jörres R.A. Magnussen H. Effect of fluticasone on the airway response to hypertonic saline in patients with COPD.Am J Respir Crit Care Med. 2004; (Abstract)Google Scholar In accordance with this, a leukotriene receptor antagonist exerted a protective effect particularly in severe COPD, independently from the presence of steroids.4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar In asthma there are also results showing a protective capacity for anti-histamines,6Finnerty J.P. Wilmont C. Holgate S.T. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine.Am Rev Respir Dis. 1989; 140: 593-597Crossref PubMed Scopus (46) Google Scholar, 9Rodwell L.T. Anderson S.D. Seale J.P. Inhaled clemastine inhibits airway narrowing caused by aerosols of non-isotonic saline.Eur Respir J. 1991; 4: 1126-1134PubMed Google Scholar but no corresponding data exist in COPD. Such data seem to be of interest, as there is release of mediators such as histamine3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar and probably cysteinyl leukotrienes during hypertonic saline challenge in COPD, in line with the effect of an anti-leukotriene.4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar In addition, data in COPD could be of interest for clinical purposes. Though it is unknown whether the response to hypertonic saline represents an effect encountered under real-life conditions, we have previously compiled arguments that it could mimic part of the functional effects occurring during exacerbations.4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar Based on these considerations we performed a trial using short-term treatment with the H1 histamine receptor antagonist cetirizine dihydrochloride to determine its effect on the airway response to hypertonic saline aerosol in patients with moderate-to-severe COPD. Twenty patients with the diagnosis of moderate-to-severe stable COPD10Pauwels R.A. Buist A.S. Calverley P.M. Jenkins C.R. Hurd S.S. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global initiative for chronic obstructive lung disease (GOLD) workshop summary.Am J Respir Crit Care Med. 2001; 163: 1256-1276Crossref PubMed Scopus (4174) Google Scholar and FEV1⩽60% of predicted normal values11Quanjer P.H. Tammeling G.J. Cotes J.E. Pedersen O.F. Peslin R. Yernault J.C. Lung volumes and forced ventilatory flows.Eur Respir J. 1993; 16: 5-40Google Scholar were enrolled into the study (Table 1). Patients were of GOLD stage II (n=9) or III (n=11),10Pauwels R.A. Buist A.S. Calverley P.M. Jenkins C.R. Hurd S.S. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global initiative for chronic obstructive lung disease (GOLD) workshop summary.Am J Respir Crit Care Med. 2001; 163: 1256-1276Crossref PubMed Scopus (4174) Google Scholar exsmokers since at least 6 weeks and had no history of asthma or allergic disease. All patients inhaled β2-adrenoceptor agonists and/or short-acting anti-cholinergics on a regular basis, while none of them had long-acting anti-cholinergics at the time of the study. Five patients took theophylline and nine received inhaled but not systemic corticosteroids; the latter had to be discontinued at least 4 weeks before inclusion. Medication was held constant over the whole course of the trial. The study was approved by the local Ethics Committee and all patients gave their written informed consent.Table 1Patients’ characteristics.Sex (f/m)3/17Age (y)62±4Weight (kg)93±21BMI (kg/m2)29.2±5.8Smoking history (Packyears)56±26FEV1 (L)1.59±0.27FEV1 (% pred)48.8±7.8FIV1 (L)3.05±0.56IVC (L)3.50±0.63FEV1/FVC (%)48.5±8.4ITGV (% pred)142.9± 30.3RV/TLC (%)54.0±4.7TLCO (% pred)71.5±22.2Arithmetic mean values±sd are given. BMI: Body Mass Index; FEV1: forced expiratory volume in 1s; FIV1: forced inspiratory volume in 1s; IVC: inspired vital capacity; FEV1/FVC : ratio of forced expiratory volume in 1s to forced vital capacity; ITGV: intrathoracic gas volume; RV/TLC: ratio of residual volume to total lung capacity; TLCO: single breath diffusion capacity for carbon monoxide. Open table in a new tab Arithmetic mean values±sd are given. BMI: Body Mass Index; FEV1: forced expiratory volume in 1s; FIV1: forced inspiratory volume in 1s; IVC: inspired vital capacity; FEV1/FVC : ratio of forced expiratory volume in 1s to forced vital capacity; ITGV: intrathoracic gas volume; RV/TLC: ratio of residual volume to total lung capacity; TLCO: single breath diffusion capacity for carbon monoxide. The study comprised a screening visit and two visits at the end of two consecutive treatment periods. Patients were asked to stop the inhalation of short- or long-acting β2-agonists for at least 6 or 12h, respectively, and that of short-acting anti-cholinergics at least 6h before measurements, while maintaining all other medication including inhaled corticosteroids and theophylline. The screening visit was used to assess medical history and clinical state as well as lung function values. Challenges with saline aerosol were performed as “twin challenges” separated by 45min, whereby the first inhalation was used for provoking the lung function response and the second inhalation for inducing sputum. Prior to the first inhalation, patients inhaled 200μg salbutamol, and 10min later, after further lung function measurement, they inhaled 0.9% saline for 5min. The aerosol was generated by an ultrasonic nebuliser (NE-U12, Omron, Tokyo, Japan) as used in sputum induction.12Holz O. Jörres R.A. Koschyk S. Speckin P. Welker L. Magnussen H. Changes in sputum composition during sputum induction in healthy and asthmatic subjects.Clin Exp Allergy. 1998; 28: 284-292Crossref PubMed Scopus (85) Google Scholar Lung function was measured 2, 5, 15, 25, 35 and 45min after inhalation to monitor the acute response as well as recovery. The second inhalation, again of 0.9% saline and comprising two consecutive 5-min inhalation periods, was started after the last measurement had been performed (45min). Lung function was monitored until 25min afterwards. Patients were then randomized to a double-blind, cross-over treatment with either 10mg cetirizine dihydrochloride twice daily or placebo over a time period of 1 week (7–10 days) duration. The short treatment period was chosen to improve patients’ compliance, as we expected effects of the anti-histamine to occur within short time. Treatment periods followed immediately one after the other and the resulting washout period of about 1 week was considered adequate from available data.13Frossard N. Benabdesselam O. Purohit A. Mounedji N. Pauli G. Activity of ebastine (10 and 20mg) and cetirizine at 24h of a steady state treatment in the skin of healthy volunteers.Fundam Clin Pharmacol. 2000; 14: 409-413Crossref PubMed Scopus (25) Google Scholar Patients used their regular medication during both treatment periods. At the end of each period, they visited the laboratory again for the assessment of clinical state and lung function. The procedure followed at screening, including inhalation of salbutamol and two saline inhalations 45min apart, was performed again. However, different from screening, 3% saline was administered in the first 5-min challenge, whereas the second inhalation 45min later again used 0.9% saline over 2×5min. Forced expiratory volume in 1s (FEV1) was assessed following established guidelines14American Thoracic SocietyStandardization of spirometry, 1994 update.Am J Respir Crit Care Med. 1995; 152: 1107-1136Crossref PubMed Scopus (5904) Google Scholar using a pneumotachograph (Masterlab, Jaeger, Würzburg, Germany). In addition, the forced inspiratory volume in 1s (FIV1) was determined following previously defined criteria.15Taube C. Lehnigk B. Paasch K. Kirsten D.K. Jörres R.A. Magnussen H. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2000; 162: 216-220Crossref PubMed Scopus (107) Google Scholar Inspired vital capacity (IVC), intrathoracic gas volume (ITGV), the ratio of residual volume to total lung capacity (RV/TLC) and the transfer factor for carbon monoxide (TLCO) were additionally measured upon inclusion. Patients were asked to produce sputum after the two 5-min periods of inhaling 0.9% saline that took place 45min after the first challenge. Basically, sputum processing followed previously used procedures.12Holz O. Jörres R.A. Koschyk S. Speckin P. Welker L. Magnussen H. Changes in sputum composition during sputum induction in healthy and asthmatic subjects.Clin Exp Allergy. 1998; 28: 284-292Crossref PubMed Scopus (85) Google Scholar Material that could be recognised macroscopically as originating from the lower airways was separated from saliva under a microscope. Samples were homogenised by mixing one part of sputum with two parts of 0.1% dithiothreitol (Sputolysin®) according to weight, incubated for 15min at 37°C and diluted by addition of phosphate-buffered saline (PBS) to achieve a 20-fold dilution. Samples were then centrifuged twice at 4°C. The resulting supernatants were stored at −80°C until analysis. After thawing, the concentration of α2-macroglobulin, as a potential marker of protein leakage, was determined.16Nocker R.E. Out T.A. Weller F.R. de Riemer M.J. Jansen H.M. van der Zee J.S. Induced sputum and bronchoalveolar lavage as tools for evaluating the effects of inhaled corticosteroids in patients with asthma.J Lab Clin Med. 2000; 136: 39-49Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar From the cell pellet cytospin slides were prepared and stained with Giemsa reagent. Differential cell counts were obtained from 400–500 cells by two observers on coded slides and mean values of the two counts were taken for analysis. For all variables, arithmetic mean values were computed. Standard deviations (sd) were chosen for describing the study population, whereas standard errors (sem) were used to quantify the variability of responses. Median values and interquartile distances were chosen in case of markedly skewed distributions. Both absolute and percent values of changes in FEV1 and FIV1 were computed to evaluate effects of inhalations or medication. For comparison of the three visits repeated-measures ANOVA was employed followed by Newman–Keuls post hoc multiple comparisons where appropriate. The paired t-test was used when only two values were involved, such baseline values and values assessed after recovery. Comparisons regarding the concentration of α2-macroglobulin were performed by the unpaired t-test. P-values refer to either ANOVA overall results (Table 2), or pairwise or multiple comparisons (Results). Statistical significance was assumed for P<0.05.Table 2Effects of treatment on baseline lung function and responses to the first saline challenge.Concentration of saline used (%)Value at baseline (L)Change 10min after salbutamol (mL)Saline-induced change vs post-salbutamol value (mL)Saline-induced change vs baseline value (mL)Value 45min after saline (L)FEV1FIV1FEV1FIV1FEV1FIV1FEV1FIV1FEV1FIV1Screening0.91.54±0.073.12±0.12179±43234±46−83±20**−216±64*96±50**19±55**1.71±0.093.30±0.15Placebo31.58±0.083.33±0.12139±28127±71−159±34−469±66−20±45−343±791.67±0.083.34±0.18Cetirizine31.58±0.073.20±0.14160±39192±73−176±29−347±83−16±46−156±861.68±0.083.31±0.18Mean±sem of either absolute values or absolute changes is given. FEV1: forced expiratory volume in one second; FIV1: forced inspiratory volume in one second. For percent changes and paired comparisons see Results. The saline-induced fall refers to the values measured 2min after inhalation of either 0.9% (screening) or 3% (study medications) saline over 5min.*Statistically significant difference between the three measurements (ANOVA) at the level *P<0.05, **P<0.01. Open table in a new tab Mean±sem of either absolute values or absolute changes is given. FEV1: forced expiratory volume in one second; FIV1: forced inspiratory volume in one second. For percent changes and paired comparisons see Results. The saline-induced fall refers to the values measured 2min after inhalation of either 0.9% (screening) or 3% (study medications) saline over 5min.*Statistically significant difference between the three measurements (ANOVA) at the level *P<0.05, **P<0.01. During the course of the study, no significant adverse events occurred and patients remained in a stable state without exacerbations that could have affected responses. Medication containers as returned after the study indicated acceptable compliance and showed on average 92% of the predicted weight reduction. Furthermore, the results did not depend on treatment order (placebo first: n=9). Baseline values of FEV1 and FIV1 did not show significant differences between the three study visits (Table 2). Inhalation of salbutamol caused bronchodilation in terms of both FEV1 and FIV1 at all three visits (P<0.001 each; Figure 1, Figure 2). Neither the absolute values of FEV1 measured after salbutamol inhalation nor the absolute or percent changes from baseline showed significant differences between the three visits. The same was true for FIV1.Figure 2Analogous to Fig. 1 but data on FIV1 are given. For statistical significance of ANOVA, see Results.View Large Image Figure ViewerDownload (PPT) The lowest values of FEV1 and FIV1 occurred 2min after the saline challenge (Figure 1, Figure 2); these values did not significantly differ between visits (Table 2). In contrast, the changes induced by saline inhalation were different. Specifically, absolute and percent changes of FEV1 relative to baseline showed a difference between screening on one hand and both study visits on the other (Newman–Keuls, P<0.05 each; Table 2), indicating a stronger response to 3% compared to 0.9% saline irrespective of medication. Mean percent changes were +6.1% at screening, −1.7% after placebo, and −1.5% after cetirizine. Regarding FIV1, absolute changes showed a significant difference between screening and placebo only (P<0.01). In contrast, percent changes after placebo (−10.1%) were significantly (P<0.05) greater than both the effects observed after cetirizine (−4.4%) and those at screening (0.4%), thus indicating a protective effect of cetirizine in terms of FIV1. When expressed as absolute or percent change of FEV1 relative to post-salbutamol values, there was again a difference between screening vs. both medications (P<0.05 each; Table 2), demonstrating the greater response after 3% compared to 0.9% saline. Absolute changes of FIV1 differed between screening and placebo (P<0.05), with cetirizine in between, whereas percent changes were not significantly different between visits. The absolute values of either FEV1 or FIV1 as measured 45min after the hypertonic saline challenge did not significantly differ between the three study visits (Figure 1, Figure 2). Compared to baseline values there were improvements of FEV1 at screening and after placebo (paired t-test, P<0.05 each), but there were no changes regarding FIV1. Post-salbutamol values of FEV1 or FIV1 were not significantly different from 45-min values. According to FEV1 there was significant (P<0.05 each) bronchoconstriction after the second challenge comprising inhalation of 0.9% saline over 2×5min. Changes were on average −6.6% at screening, −6.4% after placebo and −4.4% after cetirizine. There were no significant changes in FIV1. With both placebo and cetirizine, values of FEV1 and FIV1 observed 25min after inhalation were no more different from those observed before (45min after the first challenge), but there remained a small difference at screening (−4.3%, P=0.032), indicating incomplete recovery. Due to lack of material of sufficient quality and/or quantity, a number of sputum samples could not be evaluated with regard to cell numbers and/or supernatants. For cell differentials, 40/60 samples yielded results with a comparable distribution between visits. There were no statistically significant differences between the three sputum samples regarding total cell counts, or the percentages of neutrophils, macrophages, or lymphocytes. The mean (±sem) percentage of neutrophils was 65.7±9.3% at screening, 57.6±8.2% after placebo, and 65.0±7.8% after cetirizine. The respective percentages of eosinophils (median and interquartile distance due to skewed distribution) were 0.6 (5.4), 1.5 (10.7) and 0.5 (1.5) %. Total cell counts were 4.18 (13.7), 5.26 (11.5) and 4.15 (4.0)×106cells/mL, respectively. Figure 3 shows the data of α2-macroglobulin that could be evaluated (33/60). Since only few patients had samples at all visits, statistical comparisons were performed using a one-tailed test for independent samples. We considered this approach applicable in a tentative analysis, as the pattern of missing values appeared to be random and as we expected protection if there should be any effect at all. The tendency towards a protection by cetirizine as suggested by Fig. 3 could be substantiated insofar as there was a difference between the levels observed after placebo and cetirizine (P=0.045). Median values were 346, 625 and 278ng/mL at baseline, after placebo and after cetirizine, respectively. In the present study, we used hypertonic saline aerosol for bronchial challenge in patients with moderate-to-severe COPD to assess the effect of a 1-week treatment with 10mg cetirizine dihydrochloride per day versus placebo. To ensure comparability with the procedure of sputum induction as well as previous studies, salbutamol was administered prior to the hypertonic saline challenge.3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar, 4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar, 5Kanniess F. Böhme S. Jörres R.A. Magnussen H. Effect of fluticasone on the airway response to hypertonic saline in patients with COPD.Am J Respir Crit Care Med. 2004; (Abstract)Google Scholar The bronchodilator effect of salbutamol was not altered by cetirizine. In accordance with previous findings, salbutamol did not prevent airway obstruction3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar, 4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar, 5Kanniess F. Böhme S. Jörres R.A. Magnussen H. Effect of fluticasone on the airway response to hypertonic saline in patients with COPD.Am J Respir Crit Care Med. 2004; (Abstract)Google Scholar and 3% saline caused greater obstruction than 0.9% saline,3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar in terms of forced expiratory volumes. Different from that, the analysis of forced inspiratory manoeuvres suggested that the airway obstruction elicited by 3% saline could be attenuated by cetirizine. In addition, there was a tendency towards a reduction of the concentration of α2-macroglobulin in sputum supernatants, suggesting attenuation of plasma extravasation and airway edema that is thought to be caused by the hypertonic saline challenge.4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar, 17Högman M. Almirall J. Mork A.C. Roomans G.M. Hagelqvist E. Lagerstrand L. Hedenstierna G. Nebulisation of hypertonic saline causes oedema of the airway wall.J Submicrosc Cytol Pathol. 1997; 29: 59-64PubMed Google Scholar Though the effects of cetirizine dihydrochloride were small, the direction of changes was consistent with the hypothesis that plasma leakage plays a role in hypertonic saline-induced airway obstruction in severe COPD. Functional responses were quantified by FEV1 and FIV1. FIV1 appears to be well suited for the assessment of bronchodilation in severe COPD, as it avoids the expiratory airway collapse which can mask the bronchodilator response.15Taube C. Lehnigk B. Paasch K. Kirsten D.K. Jörres R.A. Magnussen H. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2000; 162: 216-220Crossref PubMed Scopus (107) Google Scholar In contrast, bronchoconstriction is reflected in both FEV1 and FIV1.3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar In accordance with previous data we observed stronger responses after inhalation of 3% compared to 0.9% saline aerosol3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar and these differences were particularly clear in terms of FEV1 (Fig. 1). Most patients felt the forced expiratory manoeuvres less demanding than the forced inspiratory manoeuvres; thus variability of repeated measurements was slightly larger for FIV1 than for FEV1.18Taube C. Kanniess F. Grönke L. Richter K. Mücke M. Paasch K. Eichler G. Jörres R.A. Magnussen H. Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma.Respir Med. 2003; 97: 568-577Abstract Full Text PDF PubMed Scopus (18) Google Scholar The present data indicated some protective effect of cetirizine when analysing the hypertonic saline-induced fall in FIV1 (Fig. 2). One potential problem when using FIV1 is a ceiling effect in patients with only moderate airway obstruction: as forced inspiration is nearly completed within 1s and thus close to IVC, FIV1 becomes rather insensitive to changes in bronchial tone, in contrast to patients with severe obstruction. Inspection of Fig. 2 suggests that salbutamol inhalation always led to a comparable increase of FIV1 and that the greater saline-induced fall observed after placebo compared to cetirizine was not due to a ceiling effect. The difference between the time course of FEV1 (Fig. 1) and FIV1 (Fig. 2) was striking. There was a small, statistically not significant difference in baseline values of FIV1 and slightly more variability compared to FEV1.18Taube C. Kanniess F. Grönke L. Richter K. Mücke M. Paasch K. Eichler G. Jörres R.A. Magnussen H. Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma.Respir Med. 2003; 97: 568-577Abstract Full Text PDF PubMed Scopus (18) Google Scholar Nonetheless the fall in FIV1 induced by hypertonic saline turned out to be significantly different between both medications, even when applying a conservative post hoc test according to Newman–Keuls that accounted for multiple comparisons. The effect of H1 receptor antagonists on hypertonic-saline induced bronchoconstriction has been studied previously in asthma.6Finnerty J.P. Wilmont C. Holgate S.T. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine.Am Rev Respir Dis. 1989; 140: 593-597Crossref PubMed Scopus (46) Google Scholar, 9Rodwell L.T. Anderson S.D. Seale J.P. Inhaled clemastine inhibits airway narrowing caused by aerosols of non-isotonic saline.Eur Respir J. 1991; 4: 1126-1134PubMed Google Scholar Obstructive responses in terms of the percent fall in FEV1 were greater than in the patients with COPD studied by us, and at the same time protection by terfenadine was stronger.6Finnerty J.P. Wilmont C. Holgate S.T. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine.Am Rev Respir Dis. 1989; 140: 593-597Crossref PubMed Scopus (46) Google Scholar Similar data were obtained for clemastine.9Rodwell L.T. Anderson S.D. Seale J.P. Inhaled clemastine inhibits airway narrowing caused by aerosols of non-isotonic saline.Eur Respir J. 1991; 4: 1126-1134PubMed Google Scholar It is not clear whether the obstruction elicited by hypertonic saline aerosol is based on the same mechanisms in asthma and COPD. In patients with asthma and nearly normal lung function, the primary cause is probably mast cell activation with subsequent smooth muscle contraction. In patients with severe COPD, however, nonspecific reactivity of bronchial smooth muscle appears to be lower than normal.19Einhaus M. Taube C. Welker L. Branscheid D. Diemel K.D. Nakashima M. Jörres R.A. Magnussen H. Bronchial responsiveness in vitro is reduced in patients with chronic obstructive bronchitis (COPD) as compared to smokers without airway obstruction.Am J Respir Crit Care Med. 2001; 163 (Abstract): A78Google Scholar In view of the severely reduced airway lumen, other mechanisms might come into play, among them acute airway edema. Airway edema can be elicited by hypertonic saline aerosol,17Högman M. Almirall J. Mork A.C. Roomans G.M. Hagelqvist E. Lagerstrand L. Hedenstierna G. Nebulisation of hypertonic saline causes oedema of the airway wall.J Submicrosc Cytol Pathol. 1997; 29: 59-64PubMed Google Scholar and the response is largely mediated by neuropeptides in concert with cysteinyl leukotrienes and histamine.20Wedde-Beer K. Hu C. Rodriguez M.M. Piedimonte G. Leukotrienes mediate neurogenic inflammation in lungs of young rats infected with respiratory syncytial virus.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L1143-L1150PubMed Google Scholar Osmotic stimuli can lead to the release of these compounds21Silber G. Proud D. Warner J. Naclerio R. Kagey-Sobotka A. Lichtenstein L. Eggleston P. In vivo release of inflammatory mediators by hyperosmolar solutions.Am Rev Respir Dis. 1988; 137: 606-612Crossref PubMed Scopus (63) Google Scholar and mast cells are responsive to osmotic stimuli, though their responses differ between mediators.22Eggleston P.A. Kagey-Sobotka A. Proud D. Adkinson Jr, N.F. Lichtenstein L.M. Disassociation of the release of histamine and arachidonic acid metabolites from osmotically activated basophils and human lung mast cells.Am Rev Respir Dis. 1990; 141: 960-964Crossref PubMed Google Scholar This might well explain the attenuation of the obstructive airway response by an anti-leukotriene in severe COPD,4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar in line with the findings of elevated levels of histamine3Taube C. Holz O. Mücke M. Jörres R.A. Magnussen H. Airway response to inhaled hypertonic saline in patients with moderate to severe COPD.Am J Respir Crit Care Med. 2001; 164: 1810-1815Crossref PubMed Scopus (59) Google Scholar and substance P23Tomaki M. Ichinose M. Miura M. Hirayama Y. Yamauchi H. Nakajima N. Shirato K. Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis.Am J Respir Crit Care Med. 1995; 151: 613-617Crossref PubMed Google Scholar in the sputum of patients with COPD or chronic bronchitis after hypertonic saline challenge. Thus there might be a role for anti-histamines with regard to the attenuation not only of smooth muscle contraction but also of plasma extravasation. It is of particular interest that H1 receptor antagonists demonstrated inhibitory effects on plasma extravasation in animals only in large airways.24Evans T.W. Rogers D.F. Aursudkij B. Chung K.F. Barnes P.J. Inflammatory mediators involved in antigen-induced airway microvascular leakage in guinea pigs.Am Rev Respir Dis. 1988; 138: 395-399Crossref PubMed Scopus (84) Google Scholar, 25Germonpré P.R. Joos G.F. Everaert E. Kips J.C. Pauwels R.A. Characterization of neurogenic inflammation in the airways of two highly inbred rat strains.Am J Respir Crit Care Med. 1995; 152: 1796-1804Crossref PubMed Scopus (25) Google Scholar Forced expiration is likely to be more dependent on small airways obstruction than forced inspiration, and the manoeuvre of forced inspiration has long been known to be valuable for the detection of upper airways obstruction.26Davidson Jr, F.F. Burke III, G.W. Physiologic differentiation of upper and lower airway obstruction.Ann Otol Rhinol Laryngol. 1977; 86: 630-632PubMed Google Scholar In accordance with this differential effect and sensitivity, there was no effect of cetirizine on the course of FEV1 (Fig. 1), whereas some protection was discernible in FIV1 (Fig. 2). This was just the converse of the result observed with a leukotriene receptor antagonist,4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar where effects were more pronounced in FEV1 than FIV1, although patients had more severe disease and thus more room for change in FIV1 than the patients of the present study. The effect of cetirizine was not different between patients with and without inhaled corticosteroids. Furthermore, when comparing responses between the two subgroups with FEV1 of either >49% or ⩽49% predicted (median value of study population), the effect of cetirizine was observed only in patients with better lung function, different from the leukotriene receptor antagonist.4Zühlke I.E. Kanniess F. Richter K. Nielsen-Gode D. Böhme S. Jörres R.A. Magnussen H. Montelukast attenuates the airway response to hypertonic saline in moderate to severe COPD.Eur Respir J. 2003; 22: 926-930Crossref PubMed Scopus (18) Google Scholar This could point towards an additional effect on smooth muscle as probably occurring in asthma, or indicate insufficient dosing or a minor role for histamine compared to other mediators in more severely ill patients. We assessed the concentration of α2-macroglobulin in airway secretions as a potential marker of plasma protein leakage, though we did not have the opportunity to measure the concentrations of other proteins as a reference.1Schoeffel R.E. Anderson S.D. Altounyan R.E. Bronchial hyperreactivity in response to inhalation of ultrasonic nebulised solutions of distilled water and saline.Br Med J. 1981; 283: 1285-1287Crossref PubMed Scopus (197) Google Scholar, 27Schoonbrood D.F. Out T.A. Hart A.A. Habets F.J. Roos C.M. Jansen H.M. Nedocromil sodium in obstructive airways disease: effect on symptoms and plasma protein leakage in sputum.Eur Respir J. 1997; 10: 1500-1506Crossref PubMed Scopus (5) Google Scholar Unfortunately sputum samples were insufficient in a considerable number of cases, preventing even the determination of α2-macroglobulin. We believe that the concept of the “twin challenge”, comprising a first challenge for assessing obstruction and a second one for obtaining sputum, was responsible for this failure. The idea behind this concept was to provide more time for the release of mediators and markers into airway secretions. Probably, however, patients unwillingly produced sputum after the first challenge and swallowed the material, with the result that sputum production was handicapped in the second challenge. As we had not encountered problems in repeated sputum productions in previous work,2Richter K. Holz O. Jörres R.A. Mücke M. Magnussen H. Sequentially induced sputum in patients with asthma or chronic obstructive pulmonary disease.Eur Respir J. 1999; 14: 697-701Crossref PubMed Scopus (37) Google Scholar the twin challenge was incorporated into the study protocol. It is well possible that in the present study the repeated lung function measurements including forced inspiratory and expiratory manoeuvres have promoted an undesired effect on sputum production. Despite the handicap posed by incomplete values, there was a tendency towards elevated levels of α2-macroglobulin after inhalation of 3% compared to 0.9% saline, and in particular towards a reduction after treatment with cetirizine (Fig. 3). The result is consistent with the hypothesis of hypertonic saline-induced plasma protein leakage and a beneficial effect of the H1 receptor antagonist on this response. This is true, even if the effect should have been restricted to the larger bronchi, as sputum originates from this region.12Holz O. Jörres R.A. Koschyk S. Speckin P. Welker L. Magnussen H. Changes in sputum composition during sputum induction in healthy and asthmatic subjects.Clin Exp Allergy. 1998; 28: 284-292Crossref PubMed Scopus (85) Google Scholar If one adopts the views outlined above, the observed effects of cetirizine, small as they were, appeared to fit into a consistent picture of hypertonic-saline-induced airway obstruction in COPD. In conclusion, the present data indicate some, though small, effects of the H1 receptor antagonist cetirizine on hypertonic saline-induced airflow obstruction in moderate-to-severe COPD. In view of the mechanisms involved in hypertonic saline responses, it is an open question whether stronger effects can be elicited with higher doses and whether such effects would translate into clinical benefits, e.g. during exacerbations. The authors would like to thank Kerstin Flint and Marion Mücke as well as Marianne van der Pol (Department of Pulmonology, AMC) for their valuable technical help." @default.
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