Virpi H Sidoroff

Mari K Hyvärinen

Eija Piippo-Savolainen

Matti Korppi

Sidoroff Virpi

MD Piippo-Savolainen Eija

Lung function and overweight in school aged children after early childhood wheezing

Keywords: child, spirometry, obstruction, overweight, obesity, lung function, wheezing child, spirometry, obstruction, overweight, obesity, lung function, wheezing

Background and purpose. Recently, obesity has been connected with wheezing, asthma and reduced lung function. Most previous studies have been cross-sectional. The aim of the present follow-up study was to evaluate the association of preceding or current overweight or obesity with lung function at early and late school age after early childhood wheezing. Material and methods. From the 100 children hospitalized for infection associated wheezing at <24 months of age, 83 attended the control visit at 4.0 years, 82 at 7.2 years and 81 at 12.3 years of age. Flow-volume spirometry was performed in 79 children at 7.2 years and in 80 children at 12.3 years of age. The weight status was assessed by calculating body mass index (BMI) at all visits. Age-and gender-specific BMI standard deviation scores (BMI-SDS) of >1.3 SD and > 2.0 SD were defined to mean overweight and obesity, respectively.

Results. Overweight at both 7.2 and 12.3 years of age was associated with decreased FEV 1 /FVC (forced expiratory volume in one second/ forced vital capacity). Overweight and obesity at 7.2 years of age were associated with decreased FEV 1 /FVC and MEF 50 (maximal expiratory flow at 50 % of FVC) at 12.3 years of age. The results were similar by continuous and categorized analyses, being robust to adjustments for viral findings during early childhood wheezing and asthma maintenance medication at school age.

Conclusion.

Overweight and obesity are significant risk factors for reduced lung function at school age after early childhood wheezing. Thus, early-life wheezers should avoid excessive weight gain during childhood.

Introduction

Asthma and overweight or obesity have increased concomitantly among both children and adults during the last three decades in western countries [1][2][3] . The studies have suggested an association between wheezing symptoms and obesity [4][5][6][7][8][9] , and also between asthma diagnoses and obesity [10][11][12][13] . When pulmonary function and bronchial reactivity have been studied objectively, the results have been mainly negative 5,[14][15][START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF][17][18] .

In adults, obesity decreases both lung volume, as documented by reduced total lung capacity (TLC), forced vital capacity (FVC) and functional residual capacity (FRC), and airway flows, as documented by decreased forced expiratory volume in one second (FEV 1 ) and increased airway resistance 19,20 . In addition, obesity leads to obstruction in peripheral airway 21 , as documented by decreased flows at 50% (MEF 50 ) or at 25% (MEF 25 ) of FVC. However, the largest impact seems to target at expiratory reserve volume, which means that restriction is the characteristic lung function disorder in obesity 22,23 . In addition, weight reduction in obese adults elicited an improvement of lung function 24 .

In children with asthma suggestive symptoms, high body mass index (BMI) was associated with subnormal lung function in one study 18 , but not in two others 4,5 . In healthy children, lung function was either impaired [START_REF] Li | The effect of obesity on pulmonary function[END_REF] , improved in boys and girls [START_REF] He | Respiratory Health in overweight and obese chinese children[END_REF] or improved only in girls [START_REF] Fung | Effect of overweight on lung function[END_REF] by excessive weight gain

We have prospectively followed-up a cohort of children hospitalized for infection associated wheezing at <24 months of age in 1992-1993. The weights and heights of the children were measured at follow-up visits at the median ages of 4.0, 7.2 and 12.3 years, and spirometry was performed at both visits at school age [START_REF] Reijonen | Predictors of asthma three years after hospital admission for wheezing in infancy[END_REF][START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF][START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] .

Material and methods

Study design

One-hundred consecutive children, hospitalized for wheezing associated respiratory infection at age 1-23 months, were recruited into this follow-up study in 1992 -1993 [START_REF] Reijonen | Anti-inflammatory therapy reduces wheezing after bronchiolitis[END_REF] .

Maintenance therapy for asthma was one of the exclusion criteria, and the wheezing episode was the first one in 87% of the included children [START_REF] Reijonen | One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma[END_REF] . The basic data were collected by interviewing the parents during hospitalization using a structured questionnaire. Seven respiratory viruses, including respiratory syncytial virus (RSV), were studied by antigen and antibody assays [START_REF] Reijonen | One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma[END_REF] . Later, viral studies were supplemented by polymerase chain reaction to RSV and rhinoviruses in frozen samples [START_REF] Kotaniemi-Syrjänen | Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma?[END_REF]34 . In all, RSV was identified in 29/100 and rhinovirus in 27/81 cases [START_REF] Kotaniemi-Syrjänen | Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma?[END_REF]35 .

Three follow-up visits were prospectively organized at the median ages of 4.0 years, 7.2 years and 12.3 years 28-30. Asthma was present in 33/82 (40.2%) children at the 7.2-year visit [START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF] and in 32/81 (39.5%) children at the 12.3-year visit [START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] . Data on medical history, including the use of asthma medication during the preceding 12 months, were collected by interviewing the parents.

Assessment of weight status

The weights and heights of the children, measured by an experienced nurse using standard methods, were registered in all attending children at all controls visits. Body mass index (BMI) was calculated by using the equation: weight (kg) / [height (m)] 2 . Due to the lack of Finnish references, we applied British gender-and age-specific populationbased references. BMI standard deviation score (BMI-SDS), also called Z-score, was assessed by an obesity calculator (NIBHI 2007) 36 . This calculator applies British growth references from 1990, produced by the LMS method in 1995 37,38 , and revised in 1996 39 .

The LMS method summarizes the distribution of BMI at each age by its median (M), coefficient of variation (S), and skewness expressed as a Box-Cox power (L) required to transform the data to normal 40 .

In the present study, we used the same cut-off points for overweight and obesity as proposed by the British study evaluating the limits of obesity and overweight in different populations 41 . The cut-off point for overweight was BMI >91 percentile (approximating BMI-SDS >1.3) and for obesity BMI >98 percentile (approximating BMI-SDS >2.0) 19,41 . In the British population, these cut-off points corresponds BMI 25 kg/m 2 and BMI 30 kg/m 2 levels, respectively, in the 18 years old young adults 41 .

Measurement of lung function

Lung function was studied by flow-volume spirometer (FVS) (Medikro, Kuopio, Finland) at the 7.2-year and 12.3-year study visits. The parameters were expressed as percentages of the gender-specific height-related reference values (% of predicted) for Finnish children 42,44 . The parameters registered were FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FVC, MEF 50 (maximal expiratory flow at 50 % of FVC) and MEF 25 (maximal expiratory flow at 25 % of FVC). Either the measurement with the highest FEV 1 (at the 7.2-year study) [START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF] or the composite maximal curve (at the 12.3-year study) [START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] was in each child recorded for further analyses. The cut-off limits for abnormal values were 80 % for FEV 1 , 88 % for FEV 1 /FVC, 62 % for MEF 50 and 48 % for MEF 25 17,30,43 .

F

Statistics

The data were analysed using SPSS 17.0 software (SPSS Inc. Chicago, IL, USA). Mann-Whitney U-test was used in univariate analyses and analysis of variance (ANOVA) in multivariate analyses for continuous FVS parameters. In the previous studies in this cohort, RSV etiology of wheezing in early childhood was associated with a nonreversible restrictive pattern of lung function and non-RSV etiology (mostly rhinovirus)

with an increased asthma risk and a reversible obstructive pattern of lung function at school age 43,44 . Therefore, analyses by ANOVA were adjusted also for RSV etiology of wheezing in early childhood, in addition to adjustment with anti-inflammatory asthma medication during the preceding 12 months before the study visit at school age. Logistic regression analysis, adjusted for RSV etiology of early childhood wheezing and antiinflammatory asthma medication during the 12 preceding months before the study visit, was applied for categorized (by the limits of abnormal values in % predicted) FVS parameters, and the results were expressed as adjusted odds ratios (aOR) and their 95 % confidence intervals (95% CI). In univariate analyses at 7.2 years of age, the only significant association was between current overweight and lower FEV 1 /FVC (Table 1). There were no significant associations between previous (4.0 years of age) overweight or obesity and any FVS parameter at age 7.2 years (Data not shown). In multivariate analyses, the association between obesity and lower FEV 1 /FVC changed to significant ( 3). In multivariate analyses, the association between current overweight and MEF 50 changed to non-significant ( The association between excessive weight gain and reduced lung function has been well documented in adults [14][15][START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]20,22 . In a Finnish study, weight reduction in obese adults even elicited an improvement of lung function 24 . The effect of excessive weight gain to lung function seems to depend on the degree of obesity and on the presence and severity of asthma. When lung function was studied in 52 non-asthmatic non-obese, in 53 asthmatic non-obese, in 52 obese non-asthmatic and in 53 asthmatic obese adults, lung function was reduced in patients with asthma and obesity, and in addition, FVC and FRC were reduced 13 in obese adults also with no asthma [START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF] . In a birth cohort from New Zealand, an association was found between increasing BMI and decreasing FEV 1 /FVC in 9-26 years old females, but not in males 15 . In a study on difficult-to-treat asthma, FEV 1 was increased and FRC and total lung capacity were decreased in obese patients 46 . Thus, controlled studies in adults with asthma [START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]46 , as well as population-based studies in healthy adults 15,22,23 , highlight the connection between obesity and decreased expiratory reserve volumes, which means that restriction is the characteristic lung function disorder in obesity.

Ethics

F

In a population study from China, overweight had a beneficial effect on lung function in 7 to 20 years old healthy girls [START_REF] Fung | Effect of overweight on lung function[END_REF] . In a population study from Mexico, lung function improved when weight increased in 8-11 years old healthy children, but after that age, lung function first reached a plateau and then decreased among the obese youths 47 . Lung function by spirometry was compared between 657 overweight and 196 normal weight Greek children, and FVC, FEV 1 , MEF 25-75% and FEV 1 /FVC were reduced in overweight children 18 . In a population study from Australia, spirometry was performed in 2464 school children [START_REF] Lazarus | Effects of body fat on ventilatory function in children and adolecents: cross-sectional findings from a random population sample of school children[END_REF] studies in healthy children 4,5,[START_REF] Fung | Effect of overweight on lung function[END_REF]46,47 . However, the associations may be different in children with asthma; about 40% of our patients had asthma and all had wheezed in early childhood. Lung function and weight status were studied as a part of the childhood asthma management program (CAMP) in 1041 American children aged 5-12 years [START_REF] Tantisira | Childhood asthma management program research group). Association of body mass with pulmonary function in the childhood asthma management program (CAMP)[END_REF] , and increasing BMI was associated with increasing FEV 1 and FVC, but decreasing FEV 1 /FVC. The increase in FVC and decrease in FEV 1 /FVC are in accordance with the results of our present study. In the CAMP study, weight status and lung function were studied by a cross-sectional design at enrolment of the patients, and no follow-up data have been, at least thus far, published. We found no evidence for a restrictive pattern of lung function disorder in overweight or obese children, though suggested to be present in obese asthmatic adults 15,[START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]22,23,46 , and though was demonstrable after early childhood wheezing caused by RSV in 12.3 years old children of the present study 43,44 .

The mechanisms leading to lung function disorders in association with overweight or obesity may be narrowing of the small peripheral airways 21 , in line with decreased The strengths of the present study are the long, over 10 years prospective follow-up time and the fact that weights and heights of the children were measured at all control visits by experienced nurses using calibrated scales, thus allowing a reliable follow-up of the weight status of the children. Prospectively collected data on potential confounding factors, like data on viral etiology of early childhood wheezing and use of antiinflammatory medication at school age, were available for adjusted analyses. The small number of the patients is a remarkable limitation, and with no doubt, the study was underpowered to reveal all presenting associations. Our selected material, children hosptalized for wheezing at <24 months of age, can be considered as a weakness of the study lessening the generalizibility of the results. On the other hand, early childhood wheezers are at a high risk for later pulmonary disorders, and knowing the risk factors relevant in this specific group of children, like overweight and obesity according to the present results, opens new ways for preventive measures.

In

Introduction

Asthma and overweight or obesity have increased concomitantly among both children and adults during the last three decades in western countries [1][2][3] . The studies have suggested an association between wheezing symptoms and obesity [4][5][6][7][8][9] , and also between asthma diagnoses and obesity [10][11][12][13] . When pulmonary function and bronchial reactivity have been studied objectively, the results have been mainly negative 5,[14][15][START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF][17][18] .

In adults, obesity decreases both lung volume, as documented by reduced total lung capacity (TLC), forced vital capacity (FVC) and functional residual capacity (FRC), and airway flows, as documented by decreased forced expiratory volume in one second (FEV 1 ) and increased airway resistance 19,20 . In addition, obesity leads to obstruction in peripheral airway 21 , as documented by decreased flows at 50% (MEF 50 ) or at 25% (MEF 25 ) of FVC. However, the largest impact seems to target at expiratory reserve volume, which means that restriction is the characteristic lung function disorder in obesity 22,23 . In addition, weight reduction in obese adults elicited an improvement of lung function 24 .

In children with asthma suggestive symptoms, high body mass index (BMI) was associated with subnormal lung function in one study 18 , but not in two others 4,5 . In healthy children, lung function was either impaired [START_REF] Li | The effect of obesity on pulmonary function[END_REF] , improved in boys and girls [START_REF] He | Respiratory Health in overweight and obese chinese children[END_REF] or improved only in girls [START_REF] Fung | Effect of overweight on lung function[END_REF] by excessive weight gain

We have prospectively followed-up a cohort of children hospitalized for infection associated wheezing at <24 months of age in 1992-1993. The weights and heights of the children were measured at follow-up visits at the median ages of 4.0, 7.2 and 12.3 years, and spirometry was performed at both visits at school age [START_REF] Reijonen | Predictors of asthma three years after hospital admission for wheezing in infancy[END_REF][START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF][START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] .

Material and methods

Study design

One-hundred consecutive children, hospitalized for wheezing associated respiratory infection at age 1-23 months, were recruited into this follow-up study in 1992 -1993 [START_REF] Reijonen | Anti-inflammatory therapy reduces wheezing after bronchiolitis[END_REF] .

Maintenance therapy for asthma was one of the exclusion criteria, and the wheezing episode was the first one in 87% of the included children [START_REF] Reijonen | One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma[END_REF] . The basic data were collected by interviewing the parents during hospitalization using a structured questionnaire. Seven respiratory viruses, including respiratory syncytial virus (RSV), were studied by antigen and antibody assays [START_REF] Reijonen | One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma[END_REF] . Later, viral studies were supplemented by polymerase chain reaction to RSV and rhinoviruses in frozen samples [START_REF] Kotaniemi-Syrjänen | Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma?[END_REF]34 . In all, RSV was identified in 29/100 and rhinovirus in 27/81 cases [START_REF] Kotaniemi-Syrjänen | Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma?[END_REF]35 .

Three follow-up visits were prospectively organized at the median ages of 4.0 years, 7.2 years and 12.3 years 28-30. Asthma was present in 33/82 (40.2%) children at the 7.2-year visit [START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF] and in 32/81 (39.5%) children at the 12.3-year visit [START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] . Data on medical history, including the use of asthma medication during the preceding 12 months, were collected by interviewing the parents.

Assessment of weight status

The weights and heights of the children, measured by an experienced nurse using standard methods, were registered in all attending children at all controls visits. Body assessed by an obesity calculator (NIBHI 2007) 36 . This calculator applies British growth references from 1990, produced by the LMS method in 1995 37,38 , and revised in 1996 39 .

The LMS method summarizes the distribution of BMI at each age by its median (M), coefficient of variation (S), and skewness expressed as a Box-Cox power (L) required to transform the data to normal 40 .

In the present study, we used the same cut-off points for overweight and obesity as proposed by the British study evaluating the limits of obesity and overweight in different populations 41 . The cut-off point for overweight was BMI >91 percentile (approximating BMI-SDS >1.3) and for obesity BMI >98 percentile (approximating BMI-SDS >2.0) 19,41 .

In the British population, these cut-off points corresponds BMI 25 kg/m 2 and BMI 30 kg/m 2 levels, respectively, in the 18 years old young adults 41 .

Measurement of lung function

Lung function was studied by flow-volume spirometer (FVS) (Medikro, Kuopio, Finland) at the 7.2-year and 12.3-year study visits. The parameters were expressed as percentages of the gender-specific height-related reference values (% of predicted) for Finnish children 42,44 . The parameters registered were FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FVC, MEF 50 (maximal expiratory flow at 50 % of FVC) and MEF 25 (maximal expiratory flow at 25 % of FVC). Either the measurement with the highest FEV 1 (at the 7.2-year study) [START_REF] Kotaniemi-Syrjänen | Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up[END_REF] or the composite maximal curve (at the 12.3-year study) [START_REF] Hyvärinen | Teenage asthma after severe early childhood wheezing: an 11-year prospective followup[END_REF] was in each child recorded for further analyses. The cut-off limits for abnormal values were 80 % for FEV 1 , 88 % for FEV 1 /FVC, 62 % for MEF 50 and 48 % for MEF 25 17,30,43 .

F

Statistics

The data were analysed using SPSS 17.0 software (SPSS Inc. Chicago, IL, USA). Mann-Whitney U-test was used in univariate analyses and analysis of variance (ANOVA) in multivariate analyses for continuous FVS parameters. In the previous studies in this cohort, RSV etiology of wheezing in early childhood was associated with a nonreversible restrictive pattern of lung function and non-RSV etiology (mostly rhinovirus)

with an increased asthma risk and a reversible obstructive pattern of lung function at school age 43,44 . Therefore, analyses by ANOVA were adjusted also for RSV etiology of wheezing in early childhood, in addition to adjustment with anti-inflammatory asthma medication during the preceding 12 months before the study visit at school age. Logistic regression analysis, adjusted for RSV etiology of early childhood wheezing and antiinflammatory asthma medication during the 12 preceding months before the study visit, was applied for categorized (by the limits of abnormal values in % predicted) FVS parameters, and the results were expressed as adjusted odds ratios (aOR) and their 95 % confidence intervals (95% CI). In univariate analyses at 7.2 years of age, the only significant association was between current overweight and lower FEV 1 /FVC (Table 1). There were no significant associations between previous (4.0 years of age) overweight or obesity and any FVS parameter at age 7.2 years (Data not shown). In multivariate analyses, the association between obesity and lower FEV 1 /FVC changed to significant (Table 1). All other associations between previous or current overweight or obesity and FVS remained as unchanged.

Ethics

In The association between excessive weight gain and reduced lung function has been well documented in adults [14][15][START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]20,22 . In a Finnish study, weight reduction in obese adults even elicited an improvement of lung function 24 . The effect of excessive weight gain to lung function seems to depend on the degree of obesity and on the presence and severity of asthma. When lung function was studied in 52 non-asthmatic non-obese, in 53 asthmatic non-obese, in 52 obese non-asthmatic and in 53 asthmatic obese adults, lung function was reduced in patients with asthma and obesity, and in addition, FVC and FRC were reduced 13 in obese adults also with no asthma [START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF] . In a birth cohort from New Zealand, an association was found between increasing BMI and decreasing FEV 1 /FVC in 9-26 years old females, but not in males 15 . In a study on difficult-to-treat asthma, FEV 1 was increased and FRC and total lung capacity were decreased in obese patients 46 . Thus, controlled studies in adults with asthma [START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]46 , as well as population-based studies in healthy adults 15,22,23 , highlight the connection between obesity and decreased expiratory reserve volumes, which means that restriction is the characteristic lung function disorder in obesity.

In a population study from China, overweight had a beneficial effect on lung function in 7 to 20 years old healthy girls [START_REF] Fung | Effect of overweight on lung function[END_REF] . In a population study from Mexico, lung function improved when weight increased in 8-11 years old healthy children, but after that age, lung function first reached a plateau and then decreased among the obese youths 47 . Lung function by spirometry was compared between 657 overweight and 196 normal weight Greek children, and FVC, FEV 1 , MEF 25-75% and FEV 1 /FVC were reduced in overweight children 18 . In a population study from Australia, spirometry was performed in 2464 school children [START_REF] Lazarus | Effects of body fat on ventilatory function in children and adolecents: cross-sectional findings from a random population sample of school children[END_REF] . Height-related FVC and FEV 1 increased by growth, but both FVC and FEV 1 decreased in relation to increasing overweight. The result was opposite in an other Australian population study in 5993 children; all variables in the FVS were, irrespective of BMI, within normal limits, but FEV 1 and FVC in the lowest BMI quintile were significantly lower than in other quintiles 4 . All these studies are cross-sectional with no follow-up available. The results seem confusing, but there may be following consistency; mild overweight may be beneficial but when substantial overweight or obesity develops, the effect turns to non-beneficial. The results of the present follow-up study after early childhood wheezing showed that overweight was associated with reduced FEV 1 /FVC at 7.2 and 12.3 years of age and reduced MEF 50 and MEF 25 at 12.3 years of age, in disagreement with most population studies in healthy children 4,5,[START_REF] Fung | Effect of overweight on lung function[END_REF]46,47 . However, the associations may be different in children with asthma; about 40% of our patients had asthma and all had wheezed in early childhood. Lung function and weight status were studied as a part of the childhood asthma management program (CAMP) in 1041 American children aged 5-12 years [START_REF] Tantisira | Childhood asthma management program research group). Association of body mass with pulmonary function in the childhood asthma management program (CAMP)[END_REF] , and increasing BMI was associated with increasing FEV 1 and FVC, but decreasing FEV 1 /FVC. The increase in FVC and decrease in FEV 1 /FVC are in accordance with the results of our present study. In the CAMP study, weight status and lung function were studied by a cross-sectional design at enrolment of the patients, and no follow-up data have been, at least thus far, published. We found no evidence for a restrictive pattern of lung function disorder in overweight or obese children, though suggested to be present in obese asthmatic adults 15,[START_REF] Nicolacakis | Observevation on the physiological interactions between obesity and asthma[END_REF]22,23,46 , and though was demonstrable after early childhood wheezing caused by RSV in 12.3 years old children of the present study 43,44 .

The mechanisms leading to lung function disorders in association with overweight or obesity may be narrowing of the small peripheral airways 21 , in line with decreased The strengths of the present study are the long, over 10 years prospective follow-up time and the fact that weights and heights of the children were measured at all control visits by experienced nurses using calibrated scales, thus allowing a reliable follow-up of the weight status of the children. Prospectively collected data on potential confounding factors, like data on viral etiology of early childhood wheezing and use of antiinflammatory medication at school age, were available for adjusted analyses. The small number of the patients is a remarkable limitation, and with no doubt, the study was underpowered to reveal all presenting associations. Our selected material, children hosptalized for wheezing at <24 months of age, can be considered as a weakness of the study lessening the generalizibility of the results. On the other hand, early childhood wheezers are at a high risk for later pulmonary disorders, and knowing the risk factors relevant in this specific group of children, like overweight and obesity according to the present results, opens new ways for preventive measures.

In (maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted. c Odds ratio (95% confidence interval) adjusted for RSV etiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months)

MEF 50 and

 50 MEF 25 values in the overweight and obese children at the 12.3-year visit of the present study. In addition, decreased compliance of either the lungs due to narrow peripheral airways or the chest wall due to body adiposity may lead to subnormal lung function, including both decreased airway flows which mean an obstructive lung function disorder and decreased lung volumes which means a restrictive lung function disorder[START_REF] Lazarus | Effects of body fat on ventilatory function in children and adolecents: cross-sectional findings from a random population sample of school children[END_REF] .The effect of excessive weight gain on lung function may be age-dependent, which mechanisms may influence in children and in adults and in children at different ages. In a case-control study from Denmark, FEV 1 and FVC were reduced in 193 obese men, compared with normal weight 215 controls, at 27 years of age, but after adjustments with current BMI, childhood BMI at 7 years of age was positively associated with both FEV 1 and FVC[START_REF] Bua | Weight history from birth through childhood and youth in relation to adult lung function, in Danish juvenile obese and non-obese men[END_REF] .

  the present study was to evaluate the association between overweight or obesity and lung function at school age in former early-life wheezers, with a special focus on the influence of an emerging overweight.

  mass index (BMI) was calculated by using the equation: weight (kg) / [height (m)] 2 . Due to the lack of Finnish references, we applied British gender-and age-specific populationbased references. BMI standard deviation score (BMI-SDS), also called Z-score, was

MEF 50 and

 50 MEF 25 values in the overweight and obese children at the 12.3-year visit of the present study. In addition, decreased compliance of either the lungs due to narrow peripheral airways or the chest wall due to body adiposity may lead to subnormal lung function, including both decreased airway flows which mean an obstructive lung function disorder and decreased lung volumes which means a restrictive lung function disorder[START_REF] Lazarus | Effects of body fat on ventilatory function in children and adolecents: cross-sectional findings from a random population sample of school children[END_REF] .The effect of excessive weight gain on lung function may be age-dependent, which mechanisms may influence in children and in adults and in children at different ages. In a case-control study from Denmark, FEV 1 and FVC were reduced in 193 obese men, compared with normal weight 215 controls, at 27 years of age, but after adjustments with current BMI, childhood BMI at 7 years of age was positively associated with both FEV 1 and FVC[START_REF] Bua | Weight history from birth through childhood and youth in relation to adult lung function, in Danish juvenile obese and non-obese men[END_REF] .

(

  maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted. c Odds ratio (95% confidence interval) adjusted for RSV etiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months)

  Lung function data were available from 79 children at the 7.2-year and from 81 children at the 12.3-year study visits. The numbers of children with anti-inflammatory maintenance medication for asthma during the 12 preceding months were 29/79 (36.77%) at age of 7.2 years and 18/80 (22.5%) at age of 12.3 years. At the 4.0-year visit, weight status was assessed for 74 children with lung function data available at the 7.2-year visit.

	8
	o
	r
	P
	e e r
	R e v i e w

  The study was approved by the joint Research Ethics Committee of Kuopio University and Kuopio University Hospital. Informed written consent was obtained from the parents of the children.

	9
	Results
	Overweight was present in 6.0% of children at 4.0 years, in 22.2% at 7.3 years and in
	33.3% at 12.3 years of age. Less than 4% of children were obese at 4.0 years of age. The
	proportion of obese children was 8.6 % at 7.3 years and 19.8% at 12.3 years of age. Three
	of 5 overweight children at age 4.0 years were overweight at age 7.2 years, and all 3
	obese children were obese, respectively. Fifteen of the 16 overweight children at age 7.2
	o years were overweight at age 12.3 years, and 4 of the 6 obese children were obese, F o respectively.
	r r
	P P
	e e r e e r
	R e v i e w R e v i e w

Table

Table 2

 2

	11
	.
	In the logistic regression analyses, both previous and current overweight were significant
	risk factors for FEV 1 /FVC <88% at both 7.2 years (Table 4) and at 12.3 years of age
	(Table 5). Since overweight was highly permanent from 4.0 to 7.3 years of age and from
	7.2 to 12.3 years of age, respectively, previous and current overweight could not be
	incorporated as variables in the same model. Therefore, the design of the study did not
	allow to asses their influences separately. Current obesity was a significant risk factor for F o FEV 1 /FVC <88% (aOR 8.07, 95% CI 2.10-31.05) and for MEF 25 <48% (aOR 4.34, 95%
	r CI 1.06-17.79) at 12.3 years of age.
	P
	e e r
	R e v i e w

). All other associations between previous or current overweight or obesity and FVS remained as unchanged.

  The results of the present follow-up study after early childhood wheezing showed that overweight was associated with reduced FEV 1 /FVC at 7.2 and 12.3 years of age and reduced MEF 50 and MEF 25 at 12.3 years of age, in disagreement with most population

	14
	F o
	r
	P
	e e r
	. Height-related FVC and FEV 1 increased by growth, but both FVC and FEV 1 decreased in relation to increasing overweight. The result was opposite in an other Australian population study in 5993 children; all variables in the FVS were, irrespective R e v i e w
	of BMI, within normal limits, but FEV 1 and FVC in the lowest BMI quintile were
	significantly lower than in other quintiles 4 . All these studies are cross-sectional with no
	follow-up available. The results seem confusing, but there may be following consistency;
	mild overweight may be beneficial but when substantial overweight or obesity develops,
	the effect turns to non-beneficial.

  Our results stress the importance of the prevention of excessive weight gain at pre-school and school age in children with early childhood wheezing. Li AM, Chan D, Wong E, Yin J, Nelson EAS, Fok TF. The effect of obesity on pulmonary function. Arch Dis Child 2003; 88: 361-363.

		Pediatric Pulmonology
			16 21 24 2 3
	F o r 25. 26. He Q, Qong T, Du L, Jiang Z, Qui H, Gao Y, Liu J, Wu J, Yu IT . Respiratory Health in overweight and obese chinese children. Pediatr Pulmonol. 2009: 44: 997-1002 27. Fung KP, Lau SP, Chow OKW, Lee J, Wong TW. Effect of overweight on lung function. Arch Dis Child. 1990; 65: 512-515. 48. Lazarus R, Colditz G, Berkey C, Speizer F. Effects of body fat on ventilatory function in children and adolecents: cross-sectional findings from a random population sample of school children. Pediatr Pulmon. 1997; 24: 187-194. 49. Tantisira KG, Litonjua AA, Weiss ST, Fuhlbrigge AL (Childhood asthma management program research group). Association of body mass with pulmonary function in the childhood asthma management program (CAMP). Thorax. 2003; 58: Summary Background and purpose. Recently, obesity has been connected with wheezing, asthma and reduced lung function. Most previous studies have been cross-sectional. The aim of the present follow-up study was to evaluate the association of preceding or current overweight or obesity with lung function at early and late school age after early childhood wheezing. Keywords: child, spirometry, obstruction, overweight, obesity, lung function, wheezing Abbreviations: BMI body mass index BMI-SDS body mass index standard deviation score TLC total lung capacity FRC functional residual capacity FVC forced vital capacity of age. F o r F o r F o r F o r F o r 28. Reijonen TM, Kotaniemi-Syrjanen A, Korhonen K, Korppi M. Predictors of asthma F o r F o r F o r 1036-1041. F o r FEV 1 forced expiratory volume in one second F o r FEV 1 /FVC forced expiratory volume in one second/forced vital capacity
	MEF 50 MEF 25 aOR CI	P e e r P e e r P e e r P e e r P e e r P e e r P e e r P e e r P e e r P e e r maximal expiratory flow at 50% of FVC P maximal expiratory flow at 25% of FVC e adjusted odds ratios e r confidence intervals
	RSV	respiratory syncytial virus	R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w R e v i e w w e i v e R
	32. Reijonen TM, Korppi M. One-year follow-up of young children hospitalized for
	wheezing: the influence of early anti-inflammatory therapy and risk factors for Conclusion. Overweight and obesity are significant risk factors for reduced lung function
	subsequent wheezing and asthma. Pediatr Pulmonol. 1998; 26: 113-119. at school age after early childhood wheezing. Thus, early-life wheezers should avoid
	excessive weight gain during childhood.

conclusion, overweight and obesity increased constantly by age during follow-up after wheezing in early childhood until the median age of 12.3 years. Overweight at school age was associated with bronchial obstruction, as manifested by decreased FEV 1 /FVC at 7.2 years and 12.3 years of age, and also with decreased flows in small airways at 12.3 years three years after hospital admission for wheezing in infancy. Pediatrics. 2000; 106: 1406-1412 29. Kotaniemi-Syrjänen A, Reijonen TM, Korhonen K, Korppi M. Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up. Pediatr Allergy Immunol. 2002; 13: 418-425. 30. Hyvärinen MK, Kotaniemi-Syrjänen A, Reijonen TM, Korhonen K, Korppi MO. Teenage asthma after severe early childhood wheezing: an 11-year prospective followup. Pediatr Pulmonol. 2005; 40: 316-323. 31. Reijonen T, Korppi M, Kuikka L, Remes K. Anti-inflammatory therapy reduces wheezing after bronchiolitis. Arch Pediatr Adolesc Med. 1996; 150: 512-517. Page 21 of 58 John Wiley & Sons, Inc.

50. Bua J, Prescott E, Schack-Nielsen L, Petersen L, Godtfredsen NS, Sørensen TI, Osler M. Weight history from birth through childhood and youth in relation to adult lung function, in Danish juvenile obese and non-obese men. Int J Obes (Lond). 2005; 29: 1055-1062. Material and methods. From the 100 children hospitalized for infection associated wheezing at <24 months of age, 83 attended the control visit at 4.0 years, 82 at 7.2 years and 81 at 12.3 years of age. Flow-volume spirometry was performed in 79 children at 7.2 years and in 80 children at 12.3 years of age. The weight status was assessed by calculating body mass index (BMI) at all visits. Age-and gender-specific BMI standard deviation scores (BMI-SDS) of >1.3 SD and > 2.0 SD were defined to mean overweight and obesity, respectively. Results. Overweight at both 7.2 and 12.3 years of age was associated with decreased FEV 1 /FVC (forced expiratory volume in one second/ forced vital capacity). Overweight and obesity at 7.2 years of age were associated with decreased FEV 1 /FVC and MEF 50 (maximal expiratory flow at 50 % of FVC) at 12.3 years of age. The results were similar by continuous and categorized analyses, being robust to adjustments for viral findings during early childhood wheezing and asthma maintenance medication at school age.

Page 32 of 58 John Wiley & Sons, Inc.

	Pediatric Pulmonology
	9
	The study was approved by the joint Research Ethics Committee of Kuopio University Results
	and Kuopio University Hospital. Informed written consent was obtained from the parents Overweight was present in 6.0% of children at 4.0 years, in 22.2% at 7.3 years and in
	of the children. 33.3% at 12.3 years of age. Less than 4% of children were obese at 4.0 years of age. The
	proportion of obese children was 8.6 % at 7.3 years and 19.8% at 12.3 years of age. Three
	of 5 overweight children at age 4.0 years were overweight at age 7.2 years, and all 3
	obese children were obese, respectively. Fifteen of the 16 overweight children at age 7.2
	F o years were overweight at age 12.3 years, and 4 of the 6 obese children were obese, F o respectively.
	r r
	P P
	e e r e e r
	R e v i e w R e v i e w

  DiscussionThere are three main results in the present study. First, the number of overweight and obese children increased constantly by age during the follow-up after early childhood wheezing until the median age of 12.3 years. Finally, a third was overweight, and about 20% were obese. The figures are higher than those calculated from self-reported weights and heights in 12-18 years old Finnish children in 1999, when 16.7% of the boys and 9.8% of the girls were overweight, and 1.4% and 0.4% were obese, assessed by using age-and gender-related international reference values45 . Second, current overweight was associated with decreased FEV 1 /FVC at both 7.2 and 12.3 years of age. Overweight children had also reduced flows in small airways by MEF 25 and obese children by MEF25

	11
	.
	In the logistic regression analyses, both previous and current overweight were significant
	risk factors for FEV 1 /FVC <88% at both 7.2 years (Table 4) and at 12.3 years of age
	(Table 5). Since overweight was highly permanent from 4.0 to 7.3 years of age and from
	7.2 to 12.3 years of age, respectively, previous and current overweight could not be
	incorporated as variables in the same model. Therefore, the design of the study did not
	F o allow to asses their influences separately. Current obesity was a significant risk factor for FEV 1 /FVC <88% (aOR 8.07, 95% CI 2.10-31.05) and for MEF 25 <48% (aOR 4.34, 95% F o
	r CI 1.06-17.79) at 12.3 years of age. r
	P P
	e e r e e r
	univariate analyses at 12.3 years of age, previous (7.2 years of age) overweight was associated with lower FEV 1 /FVC, and current (12.3 years of age) overweight was R e v i e w R e v i e w
	associated with lower FEV 1 /FVC, MEF 50 and MEF 25 (Tables 2). Similarly, previous
	obesity was associated with lower FEV 1 /FVC, and current obesity was associated with
	lower FEV 1 /FVC, MEF 50 and MEF 25 (Table 3). In multivariate analyses, the association
	between current overweight and MEF 50 changed to non-significant (Table 2). All other
	associations between previous or current overweight or obesity and FVS remained as
	unchanged.

and MEF 50 at age 12.3 years. FEV 1 /FVC is considered as the most sensitive and reliable measure of obstruction, but the reliability of MEF 25 has been questioned. Third, overweight and obesity at early school age preceded reduced FEV 1 /FVC at age 12.3 years. But, since overweight was highly permanent from early to late school age, the influences of previous and current overweight could not be assessed separately.

Table 1 .

 1 conclusion, overweight and obesity increased constantly by age during follow-up after wheezing in early childhood until the median age of 12.3 years. Overweight at school age was associated with bronchial obstruction, as manifested by decreased FEV 1 /FVC at 7.2 years and 12.3 years of age, and also with decreased flows in small airways at 12.3 years Our results stress the importance of the prevention of excessive weight gain at pre-school and school age in children with early childhood wheezing. Flow-volume spirometry (FVS, % of predicted, mean, SD) in 74 study subjects at 7.2 years of age, in relation to current overweight or obesity (at 7.2 years of age).

	16
	of age.
	F o
	r
	P
	e e r
	R e v i e w

Table 2 .

 2 Flow-volume spirometry (FVS, % of predicted, mean, SD) in 80 study subjects at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) overweight.

	Previous
	overweight a

Table 3 .

 3 Flow-volume spirometry (FVS, % of predicted, mean, SD) in 80 study subjects at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) obesity.

		Previous			Current
		obesity a			obesity a
	Parameters in FVS b	Yes (N=6)	No (N=68)	Univariate p c	Multivariate p d	Yes (N=16)	No (N=64)	Univariate p c	Multivariate p d
		Mean,	Mean,			Mean,	Mean,
		(SD)	(SD)			(SD)	(SD)
	FVC	99.05 (9.47)	97.95 (12.65)	0.797	0.769	98.39 (9.12)	97.64 (13.12)	0.674	0.837
	FEV 1	87.28 (13.30)	92.87 (12.89)	0.434	0.318	87.44 (12.69)	93.43 (12.86)	0.136	0.116
	FEV 1 /FVC	87.76 (6.99)	95.12 (8.57)	0.022	0.026	88.85 (9.78)	95.97 (7.51)	0.010	0.002
	MEF 50	70.46 (15.72)	82.97 (19.52)	0.132	0.107	71.68 (18.81)	83.87 (18.41)	0.025	0.028
	MEF 25	60.03 (10.59)	72.34 (20.84)	0.113	0.130	61.02 (21.40)	74.35 (19.68)	0.021	0.024
	a BMI-SDS >2
	b FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50
	(maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC),
	expressed as % of predicted.
	c Mann-Whitney U -test

d Analysis of variance, adjusted for RSV etiology of early wheezing and current anti-inflammatory asthma medication (during the preceding 12 months).

Table 4 .

 4 Logistic regression: abnormal lung function in flow-volume spirometry (FVS) at 7.2 years of age, in relation to previous (at 4.0 years of age) and current (at 7.2 years of age) overweight. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50(maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted. c Odds ratio (95% confidence interval) adjusted for RSV etiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months)

		Previous		Current
	Abnormal FVS b	overweight a Yes No	aOR c (95% CI)	overweight a Yes No	aOR c (95% CI)
		(N=5)	(N=69)		(N=17)	(N=57)
	FEV 1 <80%	0	4	-	1	3	1.01 (0.10-10.58)
	FEV 1 /FVC<88%	3	10	15.46 (1.65-145.26)	6	7	3.71 (1.01-13.60)
	MEF 50 <62%	2	11	6.46 (0.772-33.95)	3	11	0.89 (0.21-3.80)
	MEF 25 <48%	2	12	4.74 (0.61-36.76)	3	11	0.89 (0.22-3.70)
	At least one abnormal parameter	3	16	6.63 (0.89-49.46)	6	14	1.63 (0.51-5.22)
	a BMI-SDS >1.3

b

Table 5 .

 5 Logistic regression: abnormal lung function in flow-volume spirometry (FVS) at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) overweight. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50(maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted. c Odds ratio (95% confidence interval) adjusted for RSV etiology of early wheezing and current antiinflammatory asthma medication (during the preceding 12 months)

		Previous		Current
	Abnormal FVS b	overweight a Yes No	aOR c (95% CI)	overweight a Yes No	aOR c (95% CI)
		(N=16)	(N=58)		(N=24)	(N=50)
	FEV 1 <80%	2	10	0.70 (0.13-3.60)	5	9	1.00 (0.29-3.46)
	FEV 1 /FVC<88%	6	6	5.64 (1.43-22.20)	8	5	4.02 (1.14-14.22)
	MEF 50 <62%	3	9	1.29 (0.30-5.54)	7	6	2.64 (0.78-8.97)
	MEF 25 <48%	4	6	3.51 (0.76-16.13)	6	5	2.47 (0.65-9.38)
	At least one abnormal parameter	6	17	1.45 (0.45-4.67)	11	15	1.70 (0.63-4.55)
	a BMI-SDS >1.3

b

Table 1 .

 1 Flow-volume spirometry (FVS, % of predicted, mean, SD) in 74 study subjects at 7.2 years of age, in relation to current overweight or obesity (at 7.2 years of age).

	Parameters	Current			Current obesity a
	in FVS b	overweight a
		Yes	No	Univariate	Multivariate	Yes	No	Univariate	Multivariate
		(N=16) Mean, (SD)	(N=58) (SD) Mean,	p	p d	(SD) (N=7) Mean,	(SD) (N=72) Mean,	p c	p d
	FVC	108.71	102.06	0.252	0.219	106.73	103.27	0.448	0.467
		(19.75)	(16.48)			(8.78)	(18.00)
	FEV 1	100.16	99.95	0.977	0.890	96.58	100.33	0.523	0.574
		(14.16)	(13.94)			(4.78)	(14.46)
	FEV 1 /FVC	92.63	98.47	0.017	0.025	90.81	97.76	0.076	0.034
		(8.95)	(8.93)			(7.62)	(9.17)
	MEF 50	84.00	85.10	0.700	0.814	81.30	85.19	0.546	0.615
		(17.73)	(20.39)			(19.03)	(19.87)
	MEF 25	66.00	71.27	0.394	0.454	62.77	70.78	0.398	0.305
		(19.85)	(22.76)			(17.30)	(22.50)
	a Overweight BMI-SDS >1.3 (obese children included); obesity BMI-SDS > 2,0
	b FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV1/FCV, MEF 50
	(maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC),
	expressed as % of predicted.
	c Mann-Whitney U -test
	d Analysis of variance, adjusted for RSV etiology of early wheezing and current anti-inflammatory
	asthma medication (during the preceding 12 months).

Table 2 .

 2 Flow-volume spirometry (FVS, % of predicted, mean, SD) in 80 study subjects at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) overweight. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50 (maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted.

	Previous
	overweight a

b c Mann-Whitney U -test d Analysis of variance, adjusted for RSV etiology of early wheezing and current anti-inflammatory asthma medication (during the preceding 12 months).

Table 3 .

 3 Flow-volume spirometry (FVS, % of predicted, mean, SD) in 80 study subjects at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) obesity. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50 (maximal expiratory flow at 50% of FVC) and MEF 25 (maximal expiratory flow at 25% of FVC), expressed as % of predicted. Analysis of variance, adjusted for RSV etiology of early wheezing and current anti-inflammatory asthma medication (during the preceding 12 months).

		Previous			Current
		obesity a			obesity a
	Parameters in FVS b	Yes (N=6)	No (N=68)	Univariate p c	Multivariate p d	Yes (N=16)	No (N=64)	Univariate p c	Multivariate p d
		Mean,	Mean,			Mean,	Mean,
		(SD)	(SD)			(SD)	(SD)
	FVC	99.05 (9.47)	97.95 (12.65)	0.797	0.769	98.39 (9.12)	97.64 (13.12)	0.674	0.837
	FEV 1	87.28 (13.30)	92.87 (12.89)	0.434	0.318	87.44 (12.69)	93.43 (12.86)	0.136	0.116
	FEV 1 /FVC	87.76 (6.99)	95.12 (8.57)	0.022	0.026	88.85 (9.78)	95.97 (7.51)	0.010	0.002
	MEF 50	70.46 (15.72)	82.97 (19.52)	0.132	0.107	71.68 (18.81)	83.87 (18.41)	0.025	0.028
	MEF 25	60.03 (10.59)	72.34 (20.84)	0.113	0.130	61.02 (21.40)	74.35 (19.68)	0.021	0.024

a BMI-SDS >2 b c Mann-Whitney U -test d

Table 4 .

 4 Logistic regression: abnormal lung function in flow-volume spirometry (FVS) at 7.2 years of age, in relation to previous (at 4.0 years of age) and current (at 7.2 years of age) overweight. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50

		Previous		Current
	Abnormal FVS b	overweight a Yes No	aOR c (95% CI)	overweight a Yes No	aOR c (95% CI)
		(N=5)	(N=69)		(N=17)	(N=57)
	FEV 1 <80%	0	4	-	1	3	1.01 (0.10-10.58)
	FEV 1 /FVC<88%	3	10	15.46 (1.65-145.26)	6	7	3.71 (1.01-13.60)
	MEF 50 <62%	2	11	6.46 (0.772-33.95)	3	11	0.89 (0.21-3.80)
	MEF 25 <48%	2	12	4.74 (0.61-36.76)	3	11	0.89 (0.22-3.70)
	At least one abnormal parameter	3	16	6.63 (0.89-49.46)	6	14	1.63 (0.51-5.22)
	a BMI-SDS >1.3

b

Table 5 .

 5 Logistic regression: abnormal lung function in flow-volume spirometry (FVS) at 12.3 years of age, in relation to previous (at 7.2 years of age) and current (at 12.3 years of age) overweight. FVC (forced vital capacity), FEV 1 (forced expiratory volume in one second), FEV 1 /FCV, MEF 50

		Previous		Current
	Abnormal FVS b	overweight a Yes No	aOR c (95% CI)	overweight a Yes No	aOR c (95% CI)
		(N=16)	(N=58)		(N=24)	(N=50)
	FEV 1 <80%	2	10	0.70 (0.13-3.60)	5	9	1.00 (0.29-3.46)
	FEV 1 /FVC<88%	6	6	5.64 (1.43-22.20)	8	5	4.02 (1.14-14.22)
	MEF 50 <62%	3	9	1.29 (0.30-5.54)	7	6	2.64 (0.78-8.97)
	MEF 25 <48%	4	6	3.51 (0.76-16.13)	6	5	2.47 (0.65-9.38)
	At least one abnormal parameter	6	17	1.45 (0.45-4.67)	11	15	1.70 (0.63-4.55)
	a BMI-SDS >1.3

b

John Wiley & Sons, Inc.

John Wiley & Sons, Inc.Pediatric Pulmonology

Acknowledgements:

We thank Vesa Kiviniemi, Ph.Lic., for statistical advice, Kuopio University Hospital, The National Foundation for Pediatric Research in Finland and Tampere Tuberculosis Foundation for financial support.

The authors do not have a financial relationship with any commercial entity that has an interest in the subjects of this manuscript.

Acknowledgements: We thank Vesa Kiviniemi, Ph.Lic., for statistical advice, Kuopio University Hospital, The National Foundation for Pediatric Research in Finland and Tampere Tuberculosis Foundation for financial support.

The authors do not have a financial relationship with any commercial entity that has an interest in the subjects of this manuscript.


Atul Gupta

Rosemary Marsh

Simon Jordan

Simon Padley

Kareem Aboualfa

Ola Smith

Cyril Fisher

Andrew G Nicholson

Andrew 1 Bush

Gupta Atul

Marsh Rosemary

Jordan Simon

Padley Simon

Aboualfa Kareem

Fisher Cyril

John Wiley

Inc Sons

Endobronchial fibrosarcoma

Keywords: Endobronchial, fibrosarcoma, Polyp, Pneumonia, Tumor

come

Introduction

Community-acquired pneumonia is relatively common in children, with an incidence of 10-40 cases per 1000 per year 1 . It is usually due to viral or bacterial infection in an otherwise healthy child and resolves completely 1 . Typically, such infections are clinically resolved before radiological resolution is complete 2 . When infections have an atypical course (such as recurrent episodes, incomplete resolution or atypical radiological appearances) or atypical features (for example failure to thrive, positive family history, gastrointestinal symptoms) further investigations are warranted to exclude diseases like Cystic Fibrosis, immunodeficiency, Primary Ciliary Dyskinesia and aspiration. We describe an unusual case of recurrent pneumonia which highlights two important lessons. A fully immunised six year old girl was referred to Royal Brompton Hospital for investigation of multiple episodes of a pneumonia-like illness over the previous three years.

Case

At three and a half years of age she had presented to the local hospital with a short history of fever, cough and vomiting. Chest radiography showed left-sided opacification. She was treated for community-acquired pneumonia with intravenous antibiotics and was discharged home on oral antibiotics after clinical improvement.

Ten days later she was readmitted with respiratory distress and fever. Chest radiograph showed persistent left sided opacification and was treated with 2 weeks of broad spectrum intravenous antibiotics. Within three weeks of her recovery from this episode, she was again admitted with respiratory exacerbation for intravenous antibiotics.

Follow up chest radiograph (two months after last episode of illness) showed some but not complete resolution of left sided opacification. Further investigations were done to exclude tuberculosis, Cystic Fibrosis and immune deficiency. Six months later she was discharged from follow-up after clinical resolution of her illness. Three years later, at six and a half years of age, she presented again with intermittent dry cough for several weeks and short history of fever. She was treated with intravenous and oral antibiotics. Chest radiograph showed extensive left lung consolidation. After this episode she was referred to Royal Brompton Hospital for further management.

Clinical assessment showed dramatically reduced breath sounds throughout the left hemithorax with the apex beat displaced to the left axilla. There was a mild scoliosis concave to the left. Spirometry revealed an FEV1 of 0.82L, 67% predicted, FVC 1.05L, 79% predicted. Chest radiograph (figure 1) showed a collapse of the left lung with a soft tissue opacity protruding into the left main bronchus. Contrast enhanced chest CT scan (figure 2) confirmed obstruction of the left main bronchus by a mass.

Three small soft tissue nodules measuring 2-3mm were also noted in the right lung.

Flexible bronchoscopy (figure 3) revealed an endobronchial polypoid mass, completely occluding the left main bronchus. Following biopsy confirmation of neoplasia, classified at that time as low-grade spindle cell neoplasm not otherwise specified, the patient underwent left pneumonectomy. At thoracotomy, the tumour was found to be arising from a broad base within the left main bronchus and so a sleeve resection was not possible. A left pneumonectomy was therefore performed with resection of a firm broad-based mass measuring 30x25x20mm obstructing the left main bronchus and involving the bronchial wall. The proximal bronchial resection margin was examined by frozen section microscopy during the operation, and showed no evidence of disease.

Microscopy showed a submucosal proliferation of mildly pleomorphic spindle cells arranged in sheets, stroriform whorls and fascicles with scattered multinucleate giant cells and some peripheral inflammatory cells (figure 4). There were occasional mitoses present but no necrosis. Staining for CD34 was very focally positive, although positivity for this antibody was not viewed as specific for a tumour type in this context. The tumour was negative for SMA and ALK-1, arguing strongly against an inflammatory myofibroblastic tumour. Staining for MNF116 and EMA was negative, thus excluding carcinoma from the diagnosis. Neural and perineural tumours were excluded based on the lack of S-100 and claudin-1 positivity. There was no

Discussion

Community-acquired pneumonia is a common in young children and usually resolves completely with antibiotic treatment and supportive care 1 . In most cases it is usually not essential to investigate for an underlying cause. In adults chest radiography is routinely repeated after convalescence from community acquired pneumonia to screen for underlying neoplastic disease 3 . Current guidelines on management of community acquired pneumonia in children state that, ''follow up chest radiography should only be performed after lobar collapse, an apparent round pneumonia, or for continuing symptoms' 1 . This recommendation is supported by prospective studies of which demonstrate no need for routine follow-up chest radiography 2,4-6 .

However, if there is a history suggesting progressive or persistent collapse or consolidation it is important to consider the possibility, albeit rare, of a structural abnormality including a neoplastic endobronchial lesion. Case series of endobronchial neoplasms in children suggest that the majority of these present as persistent collapse or consolidation [7][8][9][10] and that delay in diagnosis can have implications for future surgical management. Primary lung tumours in children are rare. They have a tendency to present endobronchially, in particular inflammatory myofibroblastic tumour, carcinoids, salivary-gland tumours, hamartomas, papillomas and sarcomas. Inflammatory myofibroblastic tumours are the most common primary pulmonary tumours in children under the age of sixteen 13 . This entity was excluded in our patient based on the lack of characteristic morphology, in particular an absence of inflammatory cells within the tumour, and the absence of both SMA and ALK-1 staining. Guccion and Rosen noted that the majority of endobronchial fibrosarcomas occurred in children, whereas intrapulmonary fibrosarcomas presented mostly in adults and elderly populations. They classified fibrosarcomas of the lung into endobronchial and intrapulmonary types and this classification scheme was said to have prognostic and clinical importance 11 . In another series, metastases were more common with pleuropulmonary blastoma and carcinoid being more frequently seen than mesenchymal neoplasms 12 .

Conclusion

This child had recurrent consolidation in the left lung with several relapses despite aggressive antibiotic treatment. She also never had a completely normal chest x-ray and perhaps this should have prompted earlier referral and investigation. We have reported this case because it illustrates two important lessons: firstly, the importance of following up all but the most typical cases of community acquired pneumonia to ensure complete recovery (clinical and radiological). Secondly, although rare, primary concave to the left. Spirometry revealed an FEV1 of 0.82L, 67% predicted, FVC 1.05L, 79% predicted. Chest radiograph (figure 1) showed a collapse of the left lung with a soft tissue opacity protruding into the left main bronchus. Contrast enhanced chest CT scan (figure 2) confirmed obstruction of the left main bronchus by a mass.

Three small soft tissue nodules measuring 2-3mm were also noted in the right lung.

Flexible bronchoscopy (figure 3) revealed an endobronchial polypoid mass, completely occluding the left main bronchus. Following biopsy confirmation of neoplasia, classified at that time as low-grade spindle cell neoplasm not otherwise specified, the patient underwent left pneumonectomy. At thoracotomy, the tumour was found to be arising from a broad base within the left main bronchus and so a sleeve resection was not possible. A left pneumonectomy was therefore performed with resection of a firm broad-based mass measuring 30x25x20mm obstructing the left main bronchus and involving the bronchial wall. The proximal bronchial resection margin was examined by frozen section microscopy during the operation, and showed no evidence of disease.

Microscopy showed a submucosal proliferation of mildly pleomorphic spindle cells arranged in sheets, stroriform whorls and fascicles with scattered multinucleate giant cells and some peripheral inflammatory cells (figure 4). There were occasional mitoses present but no necrosis. Staining for CD34 was very focally positive, although positivity for this antibody was not viewed as specific for a tumour type in this context. The tumour was negative for SMA and ALK-1, arguing strongly against

Discussion

Community-acquired pneumonia is a common in young children and usually resolves completely with antibiotic treatment and supportive care 1 . In most cases it is usually not essential to investigate for an underlying cause. In adults chest radiography is routinely repeated after convalescence from community acquired pneumonia to screen for underlying neoplastic disease 3 . Current guidelines on management of community acquired pneumonia in children state that, ''follow up chest radiography should only be performed after lobar collapse, an apparent round pneumonia, or for continuing symptoms' 1 . This recommendation is supported by prospective studies of which demonstrate no need for routine follow-up chest radiography 2,4-6 .

However, if there is a history suggesting progressive or persistent collapse or consolidation it is important to consider the possibility, albeit rare, of a structural abnormality including a neoplastic endobronchial lesion. Case series of endobronchial neoplasms in children suggest that the majority of these present as persistent collapse or consolidation [7][8][9][10] 13 . This entity was excluded in our patient based on the lack of characteristic morphology, in particular an absence of inflammatory cells within the tumour, and the absence of both SMA and ALK-1 staining. Guccion and Rosen noted that the majority of endobronchial fibrosarcomas occurred in children, whereas intrapulmonary fibrosarcomas presented mostly in adults and elderly populations. They classified fibrosarcomas of the lung into endobronchial and intrapulmonary types and this classification scheme was said to have prognostic and clinical importance 11 . In another series, metastases were more common with pleuropulmonary blastoma and carcinoid being more frequently seen than mesenchymal neoplasms 12 .

Conclusion

This child had recurrent consolidation in the left lung with several relapses despite aggressive antibiotic treatment. She also never had a completely normal chest x-ray and perhaps this should have prompted earlier referral and investigation. We have reported this case because it illustrates two important lessons: firstly, the importance of following up all but the most typical cases of community acquired pneumonia to ensure complete recovery (clinical and radiological). Secondly, although rare, primary Pediatric Pulmonology

  and this was corroborated by the lack of CD68 positivity within the neoplastic cells. PCR did not detect the FUS-CREB3L2 or ETV6-NTRK3 gene fusions, thus ruling out a low grade fibromyxoid sarcoma and congential fibrosarcoma. Overall, the features were regarded as those of a low-grade fibrosarcoma.Serial follow-up chest CT scans (over last 2 years) have not shown any change in the number, size or appearances of the nodules in the right lung.

Figure 1 .

 1 Figure 1. Chest x ray showing a collapse of the left lung with a soft tissue opacity, protruding into the left main bronchus.

Figure 2 .Figure 3 .

 23 Figure 2. CT scan of chest confirmed a collapsed left lower lobe and a soft tissue mass in the left main bronchus extending into the left lung

Figure 4 .Figure 1 .Figure 2 .Figure 3 .

 4123 Figure 4. Microscopic image showing spindle cells arranged in stroriform whorls and fasicles typical of a low-grade fibrosarcoma. (H&E x 100 magnification)

Figure 4 .

 4 Figure 4. Microscopic image showing spindle cells arranged in stroriform whorls and fasicles typical of a low-grade fibrosarcoma. (H&E x 100 magnification) 80x60mm (300 x 300 DPI)

  an inflammatory myofibroblastic tumour. Staining for MNF116 and EMA was negative, thus excluding carcinoma from the diagnosis. Neural and perineural tumours were excluded based on the lack of S-100 and claudin-1 positivity. There was no and this was corroborated by the lack of CD68 positivity within the neoplastic cells. PCR did not detect the FUS-CREB3L2 or ETV6-NTRK3 gene fusions, thus ruling out a low grade fibromyxoid sarcoma and congential fibrosarcoma. Overall, the features were regarded as those of a low-grade fibrosarcoma.Serial follow-up chest CT scans (over last 2 years) have not shown any change in the number, size or appearances of the nodules in the right lung.

Figure 1 .

 1 Figure 1. Chest x ray showing a collapse of the left lung with a soft tissue opacity, protruding into the left main bronchus.

Figure 2 .Figure 3 .

 23 Figure 2. CT scan of chest confirmed a collapsed left lower lobe and a soft tissue mass in the left main bronchus extending into the left lung

Figure 4 .

 4 Figure 4. Microscopic image showing spindle cells arranged in stroriform whorls and fasicles typical of a low-grade fibrosarcoma. (H&E x 100 magnification)

  and that delay in diagnosis can have implications for future Primary lung tumours in children are rare. They have a tendency to present endobronchially, in particular inflammatory myofibroblastic tumour, carcinoids, salivary-gland tumours, hamartomas, papillomas and sarcomas. Inflammatory myofibroblastic tumours are the most common primary pulmonary tumours in children under the age of sixteen

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	surgical management.

John Wiley & Sons, Inc.Pediatric Pulmonology


G Cunge

M Fouchier

M Brihoum

P Bodart

M Touzeau

N Sadeghi

Vacuum UV Broad-Band absorption spectroscopy: a powerful diagnostic tool for reactive plasma monitoring

Keywords: PACs numbers: 52, 77, Bn, 52, 70, Kz and 33, 20, Lg

Broad band UV-visible absorption spectroscopy is widely used to measure the concentration of radicals in reactive plasmas. We extended the applicability of this technique to the VUV (115 nm to 200 nm), the spectral range in which the electronic transitions from the ground state to the Rydberg or pre-dissociated states of many closed shell molecules are located. This gives access to the absolute densities of species which do not, or weakly absorb in the UV/visible range. The technique is demonstrated by measuring the densities of HBr and Br 2 molecules in HBr high-density ICP plasmas.

Broad band absorption spectroscopy (BBAS) in the UV-visible region is a widely used technique to measure the absolute concentration of radicals in gaseous media. The application domain of this technique is wide, ranging from the detection of atmospheric gases and pollutants 1 to the measurement of the densities of small polyatomic radicals in reactive plasmas 2,3,4,5 . In the past 10 years, the sensitivity of BBAS has been enhanced by two orders of magnitude thanks to the progress in detection system and to recent availability of extremely stable light sources (UV LEDs) 6,7 . This was necessary to probe reactive plasmas, in which the absorbance by radicals is typically smaller than a few 10 -3 . However, BBAS is restricted to the detection of radicals which absorbs light in the UV-visible domain, i.e. often small polyatomic radicals. For instance, the detection of larger, closed shell molecules is impossible and relies on the use of more sophisticated laser absorption techniques in the infrared region 8,9,10,11 or on mass spectrometry 12,13 . However, many molecules have Rydberg states or pre-dissociated continuums which absorb in the Vacuum-UV (VUV) spectral range. In etching plasmas, examples of relevant molecules that could be detected in the VUV region includes Cl 2 , HBr, BrCl, Br 2 , HCl, BCl 3 , SiCl 4 , SiF 4 , CCl 4 , SF 6 , CH 2 F 2 , O 2 . Most of these molecules have no transitions accessible in the UV-visible domain, or the transition probability is not large enough for providing measurable absorption rate in low pressure plasmas. Since the electronic transitions from the ground state to the Rydberg states of molecules often have very large probabilities, the VUV absorption spectroscopy is promising to detect those molecules with a high sensitivity and it should be complementary to the typical UV-visible absorption spectroscopy. However, broad band VUV absorption spectroscopy has not yet been used for probing low pressure reactive plasmas.

Our experimental set up is shown in Fig. 1 and has been described in our previous UV-BBAS publications 14,15 . We are using an industrial, 50 cm diameter etching reactor (Advantage TM G5 silicon etcher from Applied Materials) designed to etch 300 mm diameter wafers. The light source is a high pressure deuterium (D 2 ) lamp (X2D2 from Hamamatsu) that emits a continuum radiation extending from 100 to 400 nm. A VUV grade parabolic mirror produces a collimated, 1 cm diameter, light beam at 90° from the incident light. This VUV beam crosses the reactor chamber, through two optical ports (with MgF 2 windows) facing each other, at about 5 cm below the reactor roof on which lies the rf coil used to create the plasma. At the exit of the second window, another VUV grade parabolic mirror focuses the VUV beam onto the entrance slit of a 20 cm focal length VUV monochromator (Jobin-Yvon H20-UVL), equipped with a 1200 groove/mm VUV grating. With 40 µm entrance and exit slit widths, the spectral resolution of the system is about 0.2 nm. The light intensity at the exit slit is converted to an electric signal with a solar blind Photomultiplier Tube (PMT) (R8486 from Hamamatsu) backed with a 10 6 V/A amplifier. The choice of reflective optics instead of lenses is mandatory because in the VUV the wavelength dependence of the focal length of lenses is too strong to ensure a good collimation and focussing of the beam all over the 115-200 nm range. To discard the strong plasma induced emission, the intensity of the light from D 2 lamp is modulated at 115 Hz with a tuning fork chopper placed before the first parabolic mirror (see Fig. 1) and the signal from the PMT is processed with a lock-in amplifier 6 , whose output is digitalised by an A/D converter and recorded in a computer. The entire optical path (between D 2 lamp / reactor input window and between exit window/PMT) is pumped down to 10 -4 Torr by turbomolecular pumps.

To record an absorption spectrum, the wavelength of the monochromator is scanned and the intensity I T (λ) of the transmitted light after having passed through the l = 50 cm plasma is acquired. The absorption spectrum is then deduced from the Beer Lambert law:

( ) ( ) ( ) λ - = λ A exp I I 0 T (1)
Where I 0 (λ) is the signal recorded in an empty reactor chamber, A(λ) = Nlσ(λ) is the absorbance, N the density of the absorbing species and σ the absorption cross section. Fig. 2 shows the absorption spectra of HBr at different pressures recorded without plasma. HBr is a closed-shell molecule, with (4sσ) 2 (4pσ) 2 (4pπ) 4 molecular orbital electron configuration in the X 1 Σ + ground state [START_REF] Herzberg | Molecular Spectra and Molecular Structure I[END_REF] . According to the Nee et al 17 assignment, the three strongly absorbing peaks of this spectra correspond to the 4pπ →5sσ electron excitation in the Rydberg states C 1 Π (for 137 and 143 nm peaks) and b 3 Π (for 150 nm peak), while the continuum between 154 and 235 nm results from the 4p σ σ* transition into the dissociative a 3 Π and A 1 Π states (σ* is an antibonding orbital). These authors also give the corresponding cross sections, which can be use to deduce the HBr density from the measured absorbance. However, for a stable gas like HBr, we could directly measure I T /I 0 ratio at different wavelengths as a function of HBr pressure (density) in the chamber. This possibility is of prime importance since as seen in Fig. 2, the absorbance of transitions to Rydberg states is strongly saturated even at low HBr densities (A(λ) does not vary linearly with N and is almost saturated for the 143 nm band). It should be emphasised that each of the observed peaks at 137, 143 and 150 nm is in reality composed of many rotational lines, having a Doppler width of about 0.25 pm and of non absorbing regions between these lines. As the width of these lines is much smaller than the 0.2 nm spectral resolution of the monochromator we are using, we can conclude that with the measured absorbance in the range of unity, the absorption on the position of rotational lines is almost total (for more detail see Ref. 4). So, for transitions to the Rydberg states, the medium cannot be considered as optically thin, even at low HBr density. Fortunately, this non linearity is not an issue since most of the molecules accessible in the VUV are stable (i.e. available as commercial gases): it is thus possible to experimentally determine the relation between the measured I T /I 0 and the density, shown in Fig. 2. But for the continuum part of the absorption spectrum, this artefact no more exists and the absorbance becomes proportional to the HBr density. one can distinguish a small contribution from H atoms at 121.6 nm (Lyman α). It is not straightforward to deduce the absolute density of Br 2 from this spectrum since for the same reasons than already mentioned for HBr, the absorption on rotational lines of Br 2 must be saturated and unfortunately it is not permitted to introduce Br 2 , which is liquid at room temperature, into the chamber. However, it is possible to produce known amounts of Br 2 molecules by mixing HBr and Cl 2 gases, which react totally together to form HCl and Br 2 . 9,21 So, the absorption spectrum recorded at pressure p in an stochiometric mixtures (2/1) of HBr/Cl 2 gases, will correspond to the one recorded in a mixture of 2/3.p of HCl and 1/3.p of Br 2 . Using this procedure, we were able to obtain the wavelength dependent absorption spectra of Br 2 at different pressures. So, the absorbance of Br 2 could be calibrated on an absolute scale 22 . It leads to a Br 2 density of 1.45 x 10 13 cm -3 at 600 W rf power (Fig. 3).

Fig. 4 shows the rf power dependence of the HBr and Br 2 densities in a 5 mTorr HBr plasma without etching substrate. With increasing rf power, the electron density and hence the dissociation fraction of HBr molecules increase. Furthermore, since the gas temperature also increases with the electron density 23 and since the pressure is maintained at 5 mTorr, the observed decrease of the HBr density when the rf power increases (Fig. 4) can also partially due to the neutral depletion 24 . In contrast, when the rf power is increased, the dissociation fraction of HBr increases and more Br atoms are available to recombine on the reactor walls leading to a higher Br 2 density. However, above 200 W, an equilibrium is reached between the dissociation of Br 2 by electron impact and its production by recombination on the reactor walls and the observed decay of Br 2 density must also be due to the neutral depletion by gas heating.

In conclusion, VUV absorption spectroscopy is a simple and powerful technique to measure the density of stable molecules in reactive plasmas. Giving access to novel species, it is complementary to the typical absorption spectroscopy in the UV-visible region.

Furthermore, owing to the large strength of the transitions in the VUV region, the technique appears to be highly sensitive. It follows that extremely low densities can be measured with a good accuracy. The drawback is that many absorption bands are saturated. However, this is not an issue since the molecules that can be detected are often stable gases, for which the absorbance can be directly calibrated by filling the reactor with known pressure of these gases. The detection limit of the technique can be drastically improved if the PMT detector is replaced by a VUV sensitive Diode-Array or a CCD detector. This will eliminate the nonquantum noise of the sequential scan of the monochromator and would also significantly reduce the data acquisition time. Information we are reporting in this paper are essential for a better understanding of etching processes in HBr-based plasmas, which are widely used in microelectronic industry to etch silicon, and for which information available in the literature are extremely sparse 8 .

Figure Caption

Fig. 1 : Schematic of the experimental set-up (top view).

Fig. 3

 3 Fig.3shows the absorption spectrum recorded in 5 mTorr total pressure pure HBr

Fig. 2 :

 2 Fig.2 : Absorption spectra of HBr gas at 5, 10 and 20 mTorr pressures. The insert shows in

Fig. 3 :Fig. 4 :

 34 Fig.3 : Upper part: absorption spectra of a 5mTorr / 600 W HBr plasma and absorption

Acknowledgment:

This work was supported (partially) by the European EUREKA/CATRENE program in the frame of the CT206 UTTERMOST project