diagnosis in infants often proves difficult treatment , although well - codified , poses complex practical issues at such an early age . early childhood wheezing disorders follow different time courses , probably corresponding to different endophenotypes [ 1 , 3 , 4 ] . thus , wheezing phenotype is assessed retrospectively , making it impossible to integrate phenotype - specific features into asthma management policy for infants under 36 months of age [ 1 , 5 ] . however , it is essential to target the population of wheezing infants likely to remain long - term active asthmatics in order to deliver appropriate adapted treatment and followup . evidence from neonatal cohort studies suggests early - onset persistent asthma has the worst long - term prognosis , because of a faster decline in respiratory function during adolescence [ 68 ] . asthma predictive scores established in these populations are not necessarily transposable to the most severe cases of asthma followed by specialists in tertiary care . for these reasons , we performed a study of a cohort of wheezing infants in a tertiary care centre to determine long - term prognosis and to identify risk factors for asthma at adolescence . this retrospective study was performed in two tertiary care centres : the asthma and allergies centre , armand - trousseau hospital , paris ( france ) , and the centre for airborne allergies in infants , chu - estaing ( university teaching hospital ) , clermont - ferrand ( france ) . we recruited infants aged under 36 months who had a history of at least three wheezing episodes and who had been assessed for respiratory wheezing disease via a doctor - led isaac questionnaire [ 10 , 11 ] and a standardized allergy testing programme . infants born premature or presenting other causes of chronic airway obstruction ( e.g. , cystic fibrosis or bronchopulmonary dysplasia ) were excluded from the study . the patients were contacted at the age of 13 years by a doctor , who used the isaac questionnaire in a telephone interview to assess the pattern of active asthma symptoms over the preceding 12 months . the predictive parameters measured and collated were ( i ) demographic characteristics : age , gender ; ( ii ) parental documented history , when available , of doctor - diagnosed asthma and infant 's personal history of atopic dermatitis ; ( iii ) severe recurrent wheezing indicated by at least two previous hospital admissions due to exacerbation ; ( iv ) biological markers of atopy : eosinophilia ( hypereosinophilia was defined as an absolute eosinophil count of 470/mm ) , total serum ige ( total serum ige was defined as high at 45  iu / ml ) and allergen sensitization , as defined by the presence of allergen - specific ige 0.35  ku / l ( cap system ; pharmacia & upjohn , saint - quentin - en - yvelines , france ) to at least one of the common aeroallergens ( dust mites , cat or dog dander , seed plant , or birch pollen ) or one of the common food allergens ( cow 's milk , eggs , peanuts , wheat , soybean , fish ) . allergen sensitization was single or multiple ( 2 specific food allergen - positive ige or 2 specific airborne allergen - positive ige ) . allergen polysensitization was defined as 2 allergen - specific ige , regardless of allergen class . positivity of the modified asthma predictive index ( api ) was assessed for each infant . persistent active asthma in the previous 12 months was defined as the presence of asthma symptoms and/or antiasthma medication taken during that period . the study was performed in accordance with french and international best practices for epidemiological research . consent forms were collected from the parents for every questionnaire . the saint - antoine hospital ( paris ) institutional review board for biomedical research did not require approval from an ethics committee , since the study protocol did not feature any investigations other than those routinely used in the day - to - day management of the patient . data analysis was managed in such a way as to protect confidentiality as stipulated in the french commission nationale d'informatique et liberts data privacy law . statistical analysis was performed using stata v11 for windows ( statacorp , tex , usa ) . continuous quantitative variables were expressed as means  standard deviation and qualitative variables as numbers and percentages . the dependent variable studied was active asthma symptoms at age of 13 .   under univariate analysis , continuous variables from the asthmatic versus nonasthmatic groups were compared using either a student 's t - test or kruskal - wallis test ( for non - gaussian data ) . categorical variables were compared by chi - squared test or , if the conditions were unsuitable , fischer 's exact test . predictive variables for persistence of asthma at age 13 after univariate analysis ( p < 0.05 ) were introduced into a multivariate logistic regression model , allowing for correlation issues . a step - down procedure was used to establish which of the predictive variables were independent prognostic factors for persistent asthma at 13 years by calculating odds ratios and their confidence intervals . sensitivity , specificity , and positive and negative predictive values were calculated and the receiver operating characteristic ( roc ) curve was used for modified api . the two centres recruited a combined total of 541 patients , for 436 of whom fully workable datasets were compiled . we were able to recontact 227 of the 436 at age 13 , who then formed the final study population . of the remaining patients , 206 were registered as lost - to - followup ( no valid address at call - up or three or four calls left without a reply ) and 3 responded to call - up but declined to complete the questionnaire . the age of children lost - to - followup was significatively lower at initial diagnosis than the average age of recruits ( 22  8,6 months , p < 0.001 ) , and the children had a significantly lower incidence of atopic dermatitis ( p < 0.001 ) . there were no statistically significant differences in terms of initial allergen sensitization ( particularly sensitization to multiple airborne allergen triggers ) , hypereosinophilia , family history of asthma , gender , and initial severity assessment based on hospital admission history . average age at the intake assessment was 26 months ( sd :  8.8 ) . average age at the follow - up end point was 13.1 years ( sd :  0.9 ) , and over the previous 12-month period , 121 patients ( 55.8% ) had had active asthma . the factors significantly associated with active asthma at the follow - up end point were presence of initial atopic dermatitis ( p < 0.001 ) , sensitization to multiple aeroallergens ( p < 0.001 ) and to multiple food allergens ( p = 0.02 ) , allergen polysensitization ( p < 0.001 ) , hypereosinophilia ( p = 0.001 ) , high total serum ige ( p = 0.002 ) , and severe recurrent wheezing ( p = 0.004 ) . in contrast , neither infant age nor infant gender was predictive of persistently - active asthma at the follow - up end point . the most relevant risk factors for persistent asthma were : sensitization to multiple aeroallergen ( or 4.6 , ci-95% ( 1.911.2 ) p = 0.001 ) ,   previous history of atopic dermatitis ( or 3.4 , ci-95% ( 1.96.3 ) p < 0.001 ) ,   initial severity ( or 2.3 , ci-95% ( 1.34.2 ) p = 0.007 ) ,   hypereosinophilia 470/mm ( or 2.2 , ci-95% ( 1.074.7 ) p = 0.033 ) .   finally , of the asthmatic infants presenting all these risk factors , 95.6% remained active asthmatics in adolescence , with 81% of the cases being classifiable as mild to severe persistent . sensitivity , specificity , negative and positive negative values , and roc curve area are given in table 2 . modified api was able to correctly classify 68.7% of recurrent wheezing infants for risk of active asthma in adolescence . the main advantage of this study is that it was performed bicentrically , with cohorts of patients submitted to the same management procedure for both the questionnaire and the allergy testing programme . however , our findings have some limitations because of the retrospective nature of the study and the percentage of cases lost to followup ( 52.2% ) . this percentage is high but needs to be seen in the perspective of the length of the follow - up period , which ran to over 10 years . other long - term follow - up studies have reported similar findings [ 13 , 14 ] . the main characteristics of the lost - to - followup population differ from those of the final population by a lower rate of atopic dermatitis and a younger age at diagnosis , but allergen sensitization and initial severity were strictly the same . the lower incidence of atopic dermatitis in the lost cases is a bias for our result . unfortunately , we have no data on respiratory function parameters to corroborate persistently active asthma in the previous 12 months [ 5 , 15 ] and it is known that asthma symptoms are frequently underestimated by patients and their family [ 16 , 17 ] . another potential biasing factor in this study is the lack of data on environmental factors ( intercurrent viral infections , passive smoking ) that may play a role in the persistence of symptoms in asthmatic children [ 1820 ] .   at the age of 13 , 121 patients ( 55.8% ) have had active asthma over the previous 12-month period . in an earlier study of the paris - based cohort , asthma symptoms were observed in only 1/3 of the children at age of 6 yrs ; the time course of asthma tends to show fluctuating patterns over the patient 's lifetime . studies demonstrate that periods of remission may only be transient   and that periods of relapse are common . the risk factors associated with persistent childhood asthma symptoms were consistent with those in the literature : multiple sensitization to aeroallergens in recurrent wheezing infants as a major risk factor for active asthma in adolescence [ 2225 ] , atopic dermatitis as an asthma - specific vulnerability - marker phenotype [ 3 , 23 , 2628 ] , hypereosinophilia [ 12 , 2931 ] , and initial - intake severity [ 4 , 6 , 7 ] , which indicate a probable genetic predisposition associated with specific vulnerability to environmental factors [ 32 , 33 ] . several authors had tried to establish scores to predict the long - term persistence of asthma . however , these scores do not have high statistical predictive power , especially when used in cohorts of wheezing infants instead of general - population infants . the most widely used score , the modified asthma predictive index ( api ) , offers the benefit of being easy to use , but sensitivity , specificity , and positive predictive value are quite low , as demonstrated in our study . negative predictive value is higher , but this value has little effect in term of clinical disease management . predicting the long - term course of asthma is still difficult , although atopy is confirmed as a major predictive risk factor . predictive scores are unfortunately not reliable enough performances to have a real value at an individual level . early identification of clinical and biological signs of atopy is essential to target the population of wheezing infants who will need specialized long - term followup and who would greatly benefit from specific treatment .
background . in recurrent wheezing infants , 
 it is important to identify those likely to remain asthmatic in order to propose appropriate long - term management . 
 objective . to establish predictive factors for persistent asthma at adolescence in a population of recurrent wheezing infants 
 . 
 methods . 
 retrospective study of 227 infants . 
 inclusion criteria were age under 36 months , a history of at least three wheezing episodes assessed via a doctor - led isaac questionnaire and a standardized allergy testing programme . at 13 years , active asthma was assessed by questionnaire . 
 results 
 . risk factors for asthma persisting into adolescence were allergic sensitization to multiple airborne allergens ( or 4.6 , ci-95% ( 1.911.2 ) p = 0.001 ) , initial atopic dermatitis ( or 3.4 , ci-95% ( 1.96.3 ) p < 0.001 ) , severe recurrent wheezing ( or 2.3 , ci-95% ( 1.34.2 ) p = 0.007 ) , and hypereosinophilia 470/mm3 ( or 2.2 , ci-95% ( 1.074.7 ) p = 0.033 ) . 
 conclusion . 
 while it is still difficult to predict the long - term course of asthma , atopy remains the major risk factor for persistent asthma .