asthma is defined as a chronic disorder of airways with inflammation and bronchial hyperresponsiveness as major underlying phenomena . for many years , asthmatics have been regarded as a heterogeneous population , and as a consequence , asthma has been a vague term describing a group of several clinical symptoms rather than a single pathologic process . some decades ago , this was reflected in the concept of extrinsic and intrinsic asthma . the former was usually developed in childhood , was atopic with identifiable allergens affecting course of the disease , and was accompanied by other atopic diseases . the latter was developed later in the lifetime , more often by women , and was not associated with allergy . as this division did not make it possible to predict the response to treatment or the course of the disease , it was abandoned . however , in recent years , the concept of subtypes of asthma has been debated once again with proposals of phenotypes ( observable properties of an organism produced by interactions of the genotype and the environment ) and endotypes ( pathological pathways explaining properties of phenotype ) [ 4 , 5 ] . although there is no generally accepted consensus on phenotypes of asthma , some variables differentiate asthmatics strongly in many studies , including age of asthma onset , atopy , gender , obesity , sputum eosinophilia or neutrophilia , etc . on their basis , the following phenotypes have been proposed : early - onset allergic , late - onset eosinophilic , exercise - induced , obesity - related , neutrophilic . better understanding of asthma phenotypes and endotypes seems crucial at the dawn of the era of biologicals . as there is no general pattern of asthmatic inflammation , efficacy of given drug may vary between phenotypes . potential effect of therapy should be monitored with the use of biomarkers specific for the given phenotype . it is associated with th2-type inflammation and is often accompanied by other atopic diseases , such as allergic rhinitis or atopic dermatitis . sputum eosinophils and feno are considered good biomarkers of allergic asthma as they correlate with clinical outcome and therapy with inhaled steroids [ 7 , 8 ] . in contrast to early - onset allergic asthma , phenotypes not related to th2-type inflammation have not been precisely defined e.g. , there are no generally accepted criteria for diagnosing obesity- or exercise - induced asthma . , several questions have been raised on the role of chitinases and chitinase - like proteins ( clps ) in chronic bronchial inflammation . among the clps , ykl-40 was found to correlate with asthma but is not specific with high serum levels in numerous infectious diseases and malignancies [ 1013 ] . in studies on asthma , some authors found dubious relations with clinical features and biomarkers ( fev1 , severity level , eosinophilia , etc ) [ 10 , 14 , 15 ] . it is not known whether ykl-40 is typical for some phenotypes of asthma . however , this hypothesis may be confirmed by studies showing its high concentration in allergic inflammation [ 16 , 17 ] . the aim of the present study was to investigate the role of ykl-40 as a possible marker of asthma and its associations with factors differentiating phenotypes of asthma . the study group comprised 167 patients , including 116 women and 51 men aged 1888  years ( mean age : 50.1  years ) with chronic asthma , confirmed by reversibility test and treated for at least 12  months . patients were recruited in the in- and out - patient departments of allergology , medical university of gdansk , poland , from march 2013 to february 2014 . exclusion criteria were episodic asthma , concomitant chronic respiratory disease ( copd , interstitial disease , etc . ) , cancer diagnosed or treated within previous 5  years , current immunosuppression or immunodeficiency , and hepatic or renal insufficiency . the control group comprised 81 healthy individuals , including 50 women and 31 men aged 1986  years ( mean age : 48.6  years ) . they were recruited among patients and employees of the university clinical centre , gdansk , poland . exclusion criteria included : chronic respiratory disorders , current or past history of allergy , and all chronic diseases mentioned in reference to study group . characteristics of study groups have been shown in table  1.table  1characteristics of the study groupsasthma groupcontrol group 
 p valueage ( years)50.1    15.348.6    15.30.44gender ( women : men)116:5150:310.22fev1/fev1 predicted ( % ) 79.9    20.099.44    9.7 < 0.001 
 bmi ( kg / m)25.7    3.125.1    3.20.64white blood count ( 10/l)8.1    3.56.67    2.2 < 0.001 
 number of eosinophils ( 10/l)0.37    0.850.16    0.16 
 0.03 
 number of neutrophils ( 10/l)5.61    7.35.07    10.00.63crp ( mg / l)4.7 9.82.1    3.8 
 0.02 
 positive skin prick tests830n / adata are presented as mean values    sdbold values are statistically significant ( p  <  0.005 ) characteristics of the study groups data are presented as mean values    sd bold values are statistically significant ( p  < 0.005 ) having given informed consent , all the subjects underwent clinical assessment , skin prick tests , and spirometry ( lungtest 1000 , mes , poland ) . medical history was analyzed for information on asthma onset , atopy , coexisting diseases , etc . exacerbation of asthma was defined as worsening of patients condition requiring hospitalization or introduction of systemic steroids ( in patients taking systemic steroids regularly  increase of the dose ) . as the precise date of asthma diagnosis was impossible to acquire in the vast majority of cases , onset of the disease was recorded in one of four options : 12  years of age or earlier ( early onset ) , 1330 , 3140  years , and after 40th year of life ( late onset ) . skin prick tests were performed with common airborne allergens : grass , trees , weeds , cat , dog , dermatophagoides farinae , dermatophagoides pteronyssinus , and molds ( allergopharma , reinbek , germany ) . atopy was defined as at least one positive result ( mean wheal diameter 3  mm ) . consecutively , three samples ( 15  ml ) of venous blood were collected from every participant . 5  ml of blood was centrifuged and serum was stored at the temperature of 20  c for 17  months . ykl-40 was detected by means of elisa test ( quidel , san diego , usa . ) in accordance with manufacturer s instructions . all data were analyzed using statistica 10.0 statistical software ( stat soft , tulsa , usa ) . concentration of ykl-40 was compared in asthmatics and controls as well as in subgroups of asthmatics . for these analyses , u mann study protocol was approved by the local bioethics committee at the medical university of gdask ( no . nkbbn 396/2013 ) and was performed in accordance with the ethical standards of the declaration of helsinki . having given informed consent , all the subjects underwent clinical assessment , skin prick tests , and spirometry ( lungtest 1000 , mes , poland ) . medical history was analyzed for information on asthma onset , atopy , coexisting diseases , etc . exacerbation of asthma was defined as worsening of patients condition requiring hospitalization or introduction of systemic steroids ( in patients taking systemic steroids regularly  increase of the dose ) . as the precise date of asthma diagnosis was impossible to acquire in the vast majority of cases , onset of the disease was recorded in one of four options : 12  years of age or earlier ( early onset ) , 1330 , 3140  years , and after 40th year of life ( late onset ) . skin prick tests were performed with common airborne allergens : grass , trees , weeds , cat , dog , dermatophagoides farinae , dermatophagoides pteronyssinus , and molds ( allergopharma , reinbek , germany ) . atopy was defined as at least one positive result ( mean wheal diameter 3  mm ) . consecutively , three samples ( 15  ml ) of venous blood were collected from every participant . 5  ml of blood was centrifuged and serum was stored at the temperature of 20  c for 17  months . ykl-40 was detected by means of elisa test ( quidel , san diego , usa . ) in accordance with manufacturer s instructions . the remaining samples were used for determination of crp and total blood count . all data were analyzed using statistica 10.0 statistical software ( stat soft , tulsa , usa ) . concentration of ykl-40 was compared in asthmatics and controls as well as in subgroups of asthmatics . for these analyses , u mann study protocol was approved by the local bioethics committee at the medical university of gdask ( no . nkbbn 396/2013 ) and was performed in accordance with the ethical standards of the declaration of helsinki . out of 167 patients , symptoms of asthma were found to be controlled in 49 ( 29.3  % ) , partly controlled in 37 ( 22.1  % ) , and uncontrolled in 81 ( 48.6  % ) patients . patients condition was assessed as stable in 130 cases , and criteria of exacerbation were met in 37 cases . atopy was found in 83 patients with sensitizations to house dust mites , grass , and weeds as the most common . in 12 cases , there was aspirin hypersensitivity confirmed by oral provocation test . in nine patients , churg strauss syndrome was diagnosed either before or shortly after the blood collection . reported time of asthma onset was 12  years of age42 patients ; 1330  years40 ; 3140  years33 ; and > 40  years52 . mean serum ykl-40 level was 59.7    48.2  ng / ml ( 53.665.7  ng / ml ; 95  % ci ) with significant difference between asthmatics and healthy controls ( mean values 66.8    53.8 vs. 44.9    29.4  ng / ml ; p  <  0.001 ) . in the whole group of study participants , there was weak correlation with age ( r  =  0.24 ; p  <  0.05 ) or gender ( women vs. men : mean 61.3    50.5 vs. 56.3    43.6  ng / ml , respectively ; p  =  0.14 ) and moderate correlation with bmi ( r  =  0.44 ; p  <  0.05 ) . in asthmatics , serum concentration of ykl-40 was significantly higher in subgroup with poor control of symptoms ( fig .  1 ) . ykl-40 levels were also higher in patients with asthma exacerbation compared to patients with the stable disease ( 91.8    57.1 vs. 59.6    50.8  ng / ml ; p  <  0.001 ) . the full comparison of exacerbation and stable groups is presented in table  2.fig . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars)table  2comparison of patients with stable asthma and exacerbationstable asthmaasthma exacerbation 
 p valueage ( years)49.7    14.751.8    17.40.49gender ( women : men)89:4127:100.59fev1/fev1 predicted ( % ) 83.7    18.466.5    19.8 < 0.001 
 white blood count ( 10/l)7.5    2.410.1    5.3 < 0.001 
 number of eosinophils ( 10/l)0.41    0.90.22    0.290.07number of neutrophils ( 10/l)5.2    7.87.1    5.4 < 0.001 
 crp ( mg / l)4.2    10.46.4    7.0 < 0.001 
 ykl-40 ( u / l)59.6    50.891.8    57.1 
 < 0.001 
 data are presented as mean values    sdbold values are statistically significant ( p  <  0.005 ) ykl-40 levels in relation to level of asthma control . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars ) comparison of patients with stable asthma and exacerbation data are presented as mean values    sd bold values are statistically significant ( p  <  0.005 ) significant differences were found in ykl-40 concentration in relation to the phenotype of asthma . when the division into atopic , non - atopic , aspirin , and vasculitis - associated asthma was applied , the highest levels were found in atopic subgroup ( fig .  2 ) . slightly different findings were revealed when the analysis was limited to three subgroups with strictly defined phenotypes described previously : early - onset atopic , late - onset non - atopic , and obesity - related . although the difference between early - developed atopic and late - onset non - atopic asthma was still significant , the highest values were observed in cases of obesity - related asthma ( 80.62    46.9 , 51.6    24.9 vs. 168.1    71.5  ng / ml , respectively ; fig .  3 ) . in fact , in the whole asthmatic group , obesity was an important determinant of ykl-40 level , as its mean value in obese asthmatics was 135.6  ng / ml compared to 50.0  ng / ml in non - obese ( p  <  0.001 ) . in non - obese asthmatics , ykl-40 level was similar to controls ( 50.0 vs. 44.9  ng / ml ; p  =  0.14 ) . difference between obese and non - obese non - asthmatics was larger ( 54.2 vs. 43.9  ng / ml ) but still not significant ( p  =  0.07 ) . conversely , no correlations with blood eosinophilia , neutrophilia , or crp were found.fig . 2ykl-40 levels in relation to asthma phenotypes : aspirin asthma , atopic asthma , non - atopic asthma , asthma accompanying vasculitis . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars)fig . 3ykl-40 levels in relation to phenotypes of asthma : late - onset non - atopic , obesity - related , and early - onset atopic . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars ) ykl-40 levels in relation to asthma phenotypes : aspirin asthma , atopic asthma , non - atopic asthma , asthma accompanying vasculitis . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars ) ykl-40 levels in relation to phenotypes of asthma : late - onset non - atopic , obesity - related , and early - onset atopic . data are presented as median ( central square ) , 25th and 75th percentiles ( top and bottom of boxes ) , 10th and 90th percentiles ( top and bottom of bars ) , they play an important role in controlling homeostasis in lower life forms  crabs , insects , and spiders . mammalian chitinases and clps ( acidic mammalian chitinase , chitotriosidase , oviductin , and human cartilage glycoprotein - hcgp / ykl-40 ) are produced by monocytes , macrophages , and neutrophils in response to parasitic or fungal infection . elevated levels of ykl-40 were also observed in numerous pathologies , including rheumatoid arthritis , myocardial infarction , diabetes , and several types of cancer [ 11 , 13 , 19 ] . however , expression at inflammation sites suggests that they play a role in antiparasitic defense and repair mechanisms . difference in ykl-40 levels between asthmatics and healthy controls has been demonstrated in several studies [ 10 , 14 ] . however , the increase is not specific , and there are studies showing no correlations in some groups of asthmatics . as asthma is a heterogenous disease , it may lead to the hypothesis that ykl-40 is elevated only in some of its phenotypes . in this study , we confirmed increased level of ykl-40 in asthmatics and its correlation with clinical course of the disease . the higher levels were found in patients with current exacerbation and long - term poor control of symptoms . konradsen found the highest concentrations of ykl-40 in patients with severe therapy - resistant asthma with elevated feno . significant differences were revealed when patients with asthma were divided into subgroups varied in terms of disease onset , atopy , aspirin hypersensitivity , obesity etc . owing to the lack of one , generally accepted classification of phenotypes and endotypes of asthma , we initially divided patients into four groups : atopic , non - atopic , aspirin asthma , and asthma coexisting with vasculitis . consecutively , we applied modified classification proposed by wenzel to select  the most typical patients with early - onset ( < 12  years of age ) atopic , late - onset ( > 40  years of age ) non - atopic , and obesity - associated asthma . only three phenotypes were compared as we did not analyze sputum , and as a consequence , differentiating neutrophilic and eosinophilic pattern of inflammation was not possible . in this comparison , the highest mean value was found in obesity - related asthma followed by atopic asthma . relations between chitinases and atopy have already been investigated several times . that started with the observation that reaction to parasitic infection is in some aspects similar to mechanisms of allergic inflammation , which would explain the role of chitinases in both processes . its concentration was elevated in bronchoalveolar lavage fluid after allergen challenge . in the study on the murine asthma model , acidic mammalian chitinase ( amc ) was found to be upregulated and its expression was induced by cytokines il-4 and il-13 . inhibition of amc activity prevented from airway hyperresponsiveness . in another animal model , oral administration of chitin downregulated th2 inflammation . ykl-40 was found to promote proliferation of bronchial smooth muscle cells , which is one of the characteristics of bronchial remodeling . single nucleotide polymorphisms in chi3l1 promoter were found to be associated with elevated ykl-40 levels as well as atopy , asthma , and bronchial hyperresponsiveness [ 28 , 29 ] . on the other hand , it needs to be emphasized that in many papers , ykl-40 was also found elevated in patients with copd , who have pattern of inflammation not related to th2 mechanisms , and smokers who had not developed this disease . there were some studies showing that circulating ykl-40 was associated with levels and decline in lung function in the general population . their authors hypothesized that this could be a biomarker of susceptibility to the long - term effect of cigarette smoking . obesity was found to correlate with ykl-40 , and in the group of obesity - related asthma , we found the highest mean level . it is generally recognized that obesity has substantial impact on asthma . however , whether it is a driving factor initiating the disease , a mere confounder or just a frequent co - morbidity is debatable . surely , obesity may enhance the perception of breathlessness in asthmatics due to greater energy expenditure while breathing . by leading to gastroesophageal reflux in contrast , in severe asthma requiring systemic steroids , obesity is one of their common side - effects rather than the cause of the pathology . many authors emphasize associations between obesity and general inflammation with elevated levels of tnf , il-6 , and leptins [ 31 , 32 ] . pro - inflammatory tendency in obese asthmatics may be another explanation for high levels of ykl-40 . it seems that chitinases are upregulated mostly in atopic asthma and in obese patients . however , the level of ykl-40 correlates with clinical features ( exacerbation , lack of control , and fev1 ) in the whole asthmatic population . although not specific for asthma , ykl-40 could have its practical application in assessment of disease control and phenotype . further studies would be useful to assess whether monitoring of its levels could facilitate making successful clinical decisions .
purposeykl-40 is a chitinase - like protein found to correlate with asthma as well as numerous infectious and autoimmune diseases or cancer . 
 the aim of the present study was to investigate the role of ykl-40 as a possible marker of asthma and its associations with factors differentiating phenotypes of asthma.methodsthe study group comprised 167 patients , including 116 women and 51 men aged 1888  years with chronic asthma . 
 the control group comprised 81 healthy individuals , including 50 women and 31 men aged 1986  years . in every participant 
 , medical history was taken ; spirometry and skin prick tests were performed . 
 ykl-40 was determined in sera by means of elisa test.resultsmean serum ykl-40 level was 59.7 ng / ml ( 53.665.7  ng / ml ; 95  % ci ) with significant difference between asthmatics and healthy controls ( mean values : 66.8    53.8 vs. 44.9    29.4  ng / ml ; p  <  0.001 ) . in asthmatics 
 , the level was significantly higher in subgroup with poor control of symptoms and exacerbations ( 91.8    57.1  ng / ml ) compared to stable asthmatics ( 59.6    50.8  ng / ml ; p  <  0.001 ) as well as in atopic compared to non - atopic asthmatics ( 77.2    53.9 vs. 61.1    57.8  ng / ml ; p  <  0.001 ) . 
 mean ykl-40 level in obese asthmatics was 135.6  ng / ml compared to 50.0  ng / ml in non - obese ( p  <  0.001 ) . 
 when phenotypes of early - onset atopic , late - onset non - atopic , and obesity - related asthma were compared , ykl-40 levels were 80.62    46.9 , 51.5    24.9 , and 168.1    71.5  ng / ml , respectively ( p  <  0.05).conclusionalthough ykl-40 is not a specific marker for asthma , it correlates with some clinical features such as exacerbation , level of control , atopy , and obesity .