sulfur mustard ( sm ) as an alkylating agent was used against iranian veterans by iraq in the 1983 - 1988 iraq it is a vesicant chemical weapon , affecting mainly the respiratory system , skin , and eyes with late complications . long - term sm - induced complications have been reported in the intoxicated patients even 16 - 20 years after exposure . there are about 100,000 surviving victims who were exposed to chemical warfare agents in iran , many with permanent pulmonary disabilities such as bronchiolitis obliterans . the mechanism of effect of sm on respiratory tract and effective medications are poorly understood . interestingly , only 40% to 50% of sm exposed subjects seem to develop the pulmonary disease . chronic obstructive pulmonary disease ( copd ) and bronchiolitis obliterans ( bo ) are the main complications due to sm exposure . sm - exposed patients ( smp ) suffer by an immune - mediated airway disease associated with airway and systemic inflammation . previous studies have shown that circulating markers of systemic inflammation , such as interleukin 6 ( il-6 ) , c - reactive protein ( crp ) , and sputum eosinophilic cationic protein ( ecp ) are elevated in this patients . crp is an important component of the innate immune response , synthesized predominantly in the liver in response to il-6 , but it is also produced in the respiratory epithelium during infection . several studies have shown that high levels of crp are associated with obstructive lung disease . smp often suffer from symptoms such as dyspnea , cough , phlegm , chest tightness , exercise intolerance , and psychosocial abnormality . common treatment and management guidance is largely based on the pulmonary function test ( pft ) and forced expiratory volume in the first second ( fev1 ) . fev1 is weakly associated with various impact of disease on pulmonary and extra - pulmonary organs . quality of life ( qol ) is directly affected by inflammatory markers or there are some steps that can possibly play a role in this pathway ? it has been postulated that the anti - inflammatory effects of statins may have relevance for the treatment of respiratory diseases george 's respiratory questionnaire ( sgrq ) are the preferred questionnaires for the assessment of qol in these patients . in a previous study , high serum level of hs - crp was found in patients injured with sm inhalation and respiratory complications . some investigators have shown that statins may be beneficial in patients with ischemic heart disease and in copd patients . statins are inhibitors of 3-hydroxymethyl-3-glutaryl coenzyme a reductase ( hmg coa reductase ) ; a rate - limiting step in cholesterol synthesis . some investigators have shown that statins may be beneficial in patients with ischemic heart disease and in copd patients . it has been postulated that the anti - inflammatory effects of statins may have benefit in the treatment of inflammatory airway disease such as smp with late pulmonary complications . a recent trial of atorvastatin showed no improvement in controlling asthma but reduces sputum inflammatory cells in atopic asthma . another study showed improvement in clinical outcome measures associated with reduction in blood inflammatory biomarkers such as crp and il-6 in rheumatoid arthritis . to the best of our knowledge , this study is the first study that assessed the effect of atorvastatin in the smp in a double blind clinical trial . the aim of this study was to evaluate efficacy of adding atorvastatin to bronchodilator and corticosteroid inhalers on lung function improvement , airway inflammation indicators such as serum level of hs - crp and qol in smp with obstructive pulmonary disease . we designed a randomized double - blind controlled trial to investigate the effect of oral atorvastatin ( 40 mg daily for 9 weeks ) on airway inflammation ( serum hs - crp ) , saturation of hemoglobin with o2 by pulse oximetry ( spo2 ) , pft , 6 min walk distance ( 6mwd ) test and qol measured by cat and sgrq test in smp with chronic obstructive pulmonary disease . although the cat is easy to use , sgrq is time consuming and requires complicated spreadsheets to calculate the scores . patients with obstructive pulmonary disease and documentation of sm exposure by military officials , the presence of respiratory complications , aged between 35 and 85 years and elevated serum hs - crp were recruited from hospital clinics in ardabil during 11 months ( 4th february 2011 to 6th december 2011 ) . all subjects should not have a history of exacerbation during last 8 weeks prior to randomization and cigarette smoking . patients were excluded from study in the case of chronic inflammatory diseases , active liver and kidney diseases , cancer , cardiac diseases ( mi and unstable angina in previous 6 months ) , current smokers , ex - smokers , opium addiction , receiving statins or having an allergic history to statins , active respiratory tract infection , bronchiectasis , myositis , myopathy , hypercholesterolemia , asthma , and elevated serum cpk . this study was approved by the ethics committee of ardabil university of medical sciences ( ref : 902/6 ) and all participants signed an informed consent letter . iran war who suffered from persistent respiratory complaints ; shortness of breath and cough with chronic pulmonary airway obstruction and high serum level of hs - crp accepted to participate . subjects randomly ( using an envelope containing allocated group ) allocated in two groups of trial ( oral atorvastatin 40 mg daily ) and control ( placebo ) based on consort flow diagram ) [ see diagram 1 ] . information on spo2 , pft , 6mwd , serum hs - crp , and quality of life were collected from subjects . atorvastatin on mustard - gas - exposed patients study flow diagram at the first visit , age , respiratory symptoms , duration of symptoms , and drug history were asked . meanwhile , height and weight , spo2 and 6mwd were measured along with baseline lung function using a spirometer ( hi-801 chest spirometer , tokyo , japan ) . these respiratory tests ( spo2 , pft , and 6mwd ) were repeated in week 4 and 9 . in addition , patients were asked to fill cat and sgrq which were repeated after 9 weeks . three component scores of sgrq are calculated : symptoms , activity , impacts , and a total score . blood sample was drawn for hs - crp assay at the end of ninth week . symptoms that were considered potential adverse effects of atorvastatin were acquired by self - administered questionnaire at second and third visits . five patients did not complete the study due to incompliance to medicine ( trial 2 and control 3 ) . some researchers reported that 8 weeks of atorvastatin was long enough to show a clinical effect , as serum cholesterol levels fall within 6 weeks of statin treatment . exposure to sulfur mustard was determined by documentation of military officials , pulmonary complication , and three pulmonologists documentation . hs - crp test was done by means of cobas integra 400 , using particle enhanced turbimetric assay method , the agglutinated particles produced in 552 nanometer lenge wave was measured by turbimetric assay . all participants underwent spirometry ( hi-801 chest spirometer , tokyo , japan ) at the first visit , after 4 weeks of intervention and at the end of 9th weeks . forced expiratory volume in the first second ( fev1 ) , forced vital capacity ( fvc ) , and fev1/fvc ratio were measured to assess pulmonary function . exercise capacity was done by 6mwd test between 8:00 a.m. and 14:00 p.m. the data were analyzed using spss software version 16 . bivariate correlations between different parameters were assessed using pearson 's correlation coefficients . a value of p < 0.05 was considered as statistically significant . exposure to sulfur mustard was determined by documentation of military officials , pulmonary complication , and three pulmonologists documentation . hs - crp test was done by means of cobas integra 400 , using particle enhanced turbimetric assay method , the agglutinated particles produced in 552 nanometer lenge wave was measured by turbimetric assay . all participants underwent spirometry ( hi-801 chest spirometer , tokyo , japan ) at the first visit , after 4 weeks of intervention and at the end of 9th weeks . the spirometer was calibrated using the device provided by the manufacturer . forced expiratory volume in the first second ( fev1 ) , forced vital capacity ( fvc ) , and fev1/fvc ratio were measured to assess pulmonary function . exposure to sulfur mustard was determined by documentation of military officials , pulmonary complication , and three pulmonologists documentation . hs - crp test was done by means of cobas integra 400 , using particle enhanced turbimetric assay method , the agglutinated particles produced in 552 nanometer lenge wave was measured by turbimetric assay . all participants underwent spirometry ( hi-801 chest spirometer , tokyo , japan ) at the first visit , after 4 weeks of intervention and at the end of 9th weeks . forced expiratory volume in the first second ( fev1 ) , forced vital capacity ( fvc ) , and fev1/fvc ratio were measured to assess pulmonary function . bivariate correlations between different parameters were assessed using pearson 's correlation coefficients . a value of p < 0.05 was considered as statistically significant . a total of 50 smp with obstructive pulmonary disease from ardabil university hospital clinics were invited to participate in the study . there were not significant differences at baseline between two groups in demographic characteristics , anthropometrics and history of disease [ table 1 ] . there were not differences between two groups in terms of age , bmi , and hs - crp at the beginning of study ( p = 0.22 , p = 0.33 , p = 0.32 , respectively ) . distribution of basic information in two groups there were no significant baseline hs - crp differences between the placebo and trial groups . atorvastatin did not reduce serum level of hs - crp compared to placebo [ table 2 ] . distribution of hs - crp levels at baseline and week 9 despite a significant decrease in serum hs - crp which was found within both groups of control and trial after study ( p < 0.01 and p = 0.01 , respectively ) [ figure 1 ] , a significant difference between two groups was not observed at 9th week . ( mean difference = 2.93 ; 95% ci : -9.25  3.38 ) ( p = 0.35 ) ) . serum hs - crp within both groups of control and trial at beginning and after study table 3 demonstrates of fev1 , fef 2575% , spo2 , 6mwd , cat score , and sgrq total score in both groups at baseline and after 4 and 9 weeks . parameters of subjects there was no significant difference in fev1 between atorvastatin and placebo group in 9 weeks ( p = 0.94 ) [ figure 2 ] . spo2 and 6mwd test did not also improve by atorvastatin ( p = 0.28 and p = 0.43 , respectively ) . fev1 in both groups of control and trial at baseline and 9 week there was statically significant improvement with atorvastatin in quality of life with cat score , and sgrq total score compared with placebo ( p < 0.001 and p = 0.004 , respectively ) . it is found that severity of airflow limitation increase cat and sgrq total scores significantly ( p < 0.001 and p < 0.001 , respectively ) . the sgrq score and cat scores show a positive linear correlation between two different tests assessing quality of life ( p < 0.001 , r = 0.97 ) . patients under atorvastatin had a better quality of life measured by cat and sgrq test compared to the control group [ figures 3 and 4 ] . cat score in control and trial groups at baseline and 9 week sgrq total score in control and trial groups at baseline and 9 week in this study , we observed a significant improvement on qol measured with cat and sgrq by atorvastatin in the management of smp with obstructive pulmonary disease while it was worse in placebo groups . on the other hand , despite qol improvement in this study there were no statically difference in hs - crp and fev1 between atorvastatin and placebo group . this suggests that perhaps these patients may benefit from long - term treatment with atorvastatin . although a significant decrease of hs - crp was observed , it is unclear and may happen due to seasonal variation . previous studies have shown that statins may be beneficial in patients with systemic inflammation such as coronary artery disease and cause a significant decrease in hs - crp over the course of the study in copd patients . study by soyseth et al . showed mortality reduction with atorvastatin in copd patients . in some studies short - term treatment with atorvastatin does not alter lung function but improve quality of life in smokers with mild to moderate asthma . hothersall et al . reported a significant reduction of sputum inflammatory cells in asthma patients after the addition of atorvastatin to inhaled corticosteroids but did not improve asthma control in short term . study by ghanei et al . found a significant improvement of severity of pulmonary symptoms and ventilator parameters after 4 months treatment with n - acetyl cysteine , their conclude that the beneficial effect of n - acetyl cysteine may be mediated by its antioxidative properties . some studies suggest that tissue remodeling is involved in sm - exposed lung damage patients . numerous studies have revealed that this disorder is strongly associated with systemic inflammation and oxidative stress and decreased levels of endogenous antioxidants . firstly , statins may improve cardiovascular function ; it is likely that some of the smp had unrecognized ihd . secondly , the lower score of cat and sgrq in patients treated with atorvastatin may be due to extra - pulmonary effect of statins and finally , statins may decrease the sputum inflammatory cells , and may reduce release of cytokines and inflammatory marker other than hs - crp including il-6 and tnfa from monocytes and endothelial cells . thus , the beneficial effect of atorvastatin may be mediated by an anti - inflammatory effect in the airway . pathophysiology of sm respiratory complication has not been clearly understood but these complications are induced by airway disease with systemic inflammation . in particular , complications occur on the respiratory tract , skin , eyes , and immune system . our study demonstrated that airway obstruction and ventilator parameters did not improved after 9 weeks administration of 40 mg atorvastatin . atorvastatin is widely used as anti - inflammatory agents in cardiovascular and pulmonary disease ( especially in copd ) does not show a significant benefit in pulmonary function in obstructive pulmonary complication due to sulfur mustard gas . reported exercise capacity improvement and serum hs - crp reduction with statins after 6 months intervention in copd patients . however , the finding of our study did not support this result . in this study , we did not find significantly improvement of fev1 by atorvastatin in smp . the possible reason for lack of association is that smp - like subjects with copd have a persistent and irreversible airflow limitation as was suggested by previous studies . therefore , it can be assumed that fev1 and pft are not a reliable test for evaluating multiple consequences of systemic inflammation in pulmonary diseases . although pft is a valuable diagnostic instrument for evaluation of severity of airflow obstruction this test can not be used for evaluation of treatment efficacy on extra - pulmonary consequence of sm injured patients during regular follow - up . some investigators have reported a significant association between cat and disease severity obtained by lung function in smp with airflow obstruction . the cat and sgrq were designed to measure qol in copd patients in clinical practice . we observed that both cat and sgrq exhibit significant correlation with airflow limitation and can be used as a reliable tools to assess quality of life in smp . patients with severe airflow limitation reported worse quality of life , measured with both cat and sgrq similarly to other studies in copd patients . in addition , we noticed that atorvastatin do not have beneficial effect on sm patients exercise capacity measured by 6mwd test and spo2 . first , the time of intervention and follow - up was not long , that may alter the study finding . second , the serum level of other inflammatory markers such as il-6 and tnfa has not been measured . therefore , a complementary study with large sample size and long - term intervention with atorvastatin is appreciated . in conclusion , we have shown that atorvastatin in smp who suffered from chronic respiratory complications did not alter serum hs - crp , pft , and 6mwd and did not increase spo2 at air room but associated with qol improvement using cat and sgrq . in summary , improvement in qol suggests that atorvastatin could be used in addition to the conventional therapies in these patients .
background : statins have anti - inflammatory effects in patients with chronic obstructive pulmonary disease ( copd ) . this study designed to evaluate the effects of atorvastatin on serum highly sensitive c - reactive protein ( hs - crp ) and pulmonary function in sulfur 
 mustard exposed patients with copd.materials and methods : fifty patients with chronic obstructive pulmonary disease due to sulfur mustard and high serum hs - crp entered in this study . 
 participants were randomized to receive 40 mg atorvastatin or placebo in a double - blind clinical trial . 
 forty - five patients completed the study ( n = 23 atorvastatin and n = 22 placebo ) . 
 pulse oximetry ( spo2 ) , pulmonary function test ( pft ) , and 6 min walk distance test ( 6mwd ) was measured . 
 copd assessment test ( cat ) and st . 
 george 's respiratory questionnaire ( sgrq ) were also completed by patients at the beginning of trial and after 9 weeks of prescription of 40 mg / day atorvastatin or placebo . at fourth week , spo2 , pft , and 6mwd were again measured . 
 after 9 weeks serum hs - crp was re-measured.results:there was no significant difference between atorvastatin and the placebo group in spo2 , fev1 , and 6mwd after fourth week ( p = 0.79 , p = 0.12 , p = 0.12 , respectively ) . 
 the difference between baseline and ninth week was calculated for two groups of trial and control in term of serum hs - crp , spo2 , fev1 , and 6mwd . 
 significant improvement was not observed between two groups in above mentioned variables ( p = 0.35 , p = 0.28 , p = 0.94 , p = 0.43 , respectively ) . 
 however , the quality of life was improved by administration of atorvastatin using the cat score ( p < 0.001 ) and sgrq total score ( p = 0.004).conclusion : atorvastatin does not alter serum hs - crp and lung functions but may improve quality of life in sm - injured patients with copd .