Measurement of exhaled nitric oxide in young children during tidal breathing through a facemask

Measurement of exhaled nitric oxide (eNO) offers a non-invasive means for assessment of airway inflammation. The currently available methods are difficult to apply in preschool children. We evaluated four methods potentially applicable for eNO measurement during tidal breathing in young children. eNO was assessed during tidal breathing in 24 children, 2-7 yr old, using a facemask which separated nasal and oral airflow. Facemasks with and without a one-way valve allowing exhalation through the nose were used. Expiratory flow control was not attempted. Measurements of eNO were performed both on-line and off-line. In 11 children, 8-12 yr old, measurements were compared with the standard single breath on-line method. eNO was significantly lower applying the one-way valve in on-line and off-line measurements in comparison with measurements without the valve [4.6 and 3.9 parts per billion (ppb) vs. 6.9 ppb and 6.5 ppb]. The mean within subject coefficient of variation (CV) was significantly lower in on-line measurements with the one-way valve (9.6%) compared with the other three methods (18.8, 27.7 and 29.3% respectively). Measurements with a facemask fitted with a one-way valve yielded similar eNO levels as the standard single breath method (7.0 ppb vs. 6.9 ppb) and reproducibility (9.8% vs. 7.1%). In conclusion, reproducible measurements of eNO can be obtained without control of expiration flow using a facemask fitted with a one-way valve on the nasal compartment. The likely explanation to this is that the one-way valve reduces the admixture of nasal NO, thereby improving the reliability of eNO measurements.     

Exhaled nitric oxide in healthy young children during tidal breathing through a facemask

The aim of this study was to establish reference values and to examine day-to-day and within-day variations of exhaled nitric oxide (eNO) during tidal breathing in healthy children using a newly described method. Exhaled NO was measured on-line and off-line during tidal breathing through a facemask. In a subgroup of children measurements were repeated during the course of a single day and on the same time on three consecutive days. A total of 133 healthy children were included in the study and measurements were obtained from 121 children aged 2-7 yr (61 boys and 60 girls). The geometric mean eNO concentration and 95% CI was 3.9 (3.5-4.2) parts per billion (p.p.b.) for on-line measurements and 3.0 (2.7-3.3) p.p.b. for off-line measurements. Exhaled NO was independent of gender, age, height and weight. The 95% reference intervals (RI) for on-line and off-line measurements were 1.2-8.2 and 1.3-7.1 p.p.b. respectively. Twenty-three children completed measurements of within-day and day-to-day variations, none of which showed significant variation. In conclusion, the established reference values and data on variability within and between days may facilitate the clinical application for measurement of eNO during tidal breathing in young children.     

The impact of ambient NO on online measurements of exhaled and nasal NO: The PIAMA study

The guidelines of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) for standardized measurements of exhaled nitric oxide (NO) state that for online measurements the inhaled air should be free of NO. As it is not always possible to create an NO-free environment, inhalation through an NO-scrubber is used. To describe the relationship between ambient NO and measurements of fractional exhaled NO (FENO) and nasal NO (nNO) investigated according to the ATS–ERS guidelines in a large population of children. The present work makes use of data collected during the 8-yr follow-up of the Dutch PIAMA birth cohort study. FENO and nNO were measured in three hospitals in a total of 1005 children with a NIOX chemiluminescence analyser. In two hospitals, almost half of the measured ambient NO levels exceeded 5 p.p.b. Maximum levels were >100 p.p.b. in all hospitals. Despite its large variation, ambient NO did not have an effect on FENO, but it did have a significant impact on nNO in two of the three centres. The currently recommended technique including inhalation through an NO scrubber effectively deals with variable levels of ambient NO on FENO. In contrast, ambient NO has an effect on measurements of nNO.     

Single breath analysis of endogenous nitric oxide in the newborn

Nitric oxide (NO) is found in the exhaled gas of humans immediately after birth. However, variations of endogenous NO concentration during the breathing cycle have not been studied in newborns. We examined 24 newborns without acute respiratory compromise during spontaneous nasal breathing. Gas was sampled from the tip of a thin nasal catheter placed in the hypopharynx. Endogenous NO concentrations measured by chemiluminescence were assigned to the breathing cycle using synchronized CO2 recording. Exhaled NO could reproducibly be measured at 1.9 +/- 0.2 parts per billion (ppb, mean +/- SEM). Autoinhaled nasal NO peaks during regular breathing were 12.0 +/- 1.7 ppb and reached intermittent maxima of 52.2 +/- 5.8 ppb. During regular breathing 6 infants exhibited sudden decreases of nasal NO peaks to periods with <50% amplitude suggesting transient shortage of autoinhaled nasal NO. We conclude that tidal NO analysis can be used to assess upper and lower airway NO production noninvasively during spontaneous breathing in the newborn.     

Tidal off-line exhaled nitric oxide measurements in a pre-school population

Exhaled nitric oxide (ENO) is used as a non-invasive marker of airway inflammation. The aim of this study was to measure ENO in a pre-school population using a relatively novel method, the off-line tidal breathing method, and to investigate differences in ENO between subjects with different presentations of wheezing. ENO was measured in 129 children (median age 4.4 years, quartiles 4.0-4.8 years) through a mouth mask attached to a two-way valve with an expiratory resistance of 5 cm H(2)0. Mean tidal ENO concentration (tENO) was calculated from triplicate measurements. Mean +/- SEM tENO for 89 control subjects was 13+/-0.4 ppb (95%CI 11.8-13.7 ppb); this level was significantly different from tENO in 15 children with a history of recurrent wheezing (18.6+/-1.9 ppb; 95%CI 14.5-22.7 ppb; t-test P<0.0001). Mean tENO in 16 children with a single wheezing episode was 11.4+/-1.0 ppb (95%CI 9.2-13.6 ppb) and thus significantly different from the recurrent wheezing group (t-test P=0.0024). CONCLUSION: The off-line tidal breathing method is a feasible and appealing method for measuring exhaled nitric oxide in pre-school children. With this method, higher tidal exhaled nitric oxide levels were found in children with recurrent wheezing.     

High prevalence and young onset of allergic rhinitis in children with bronchial asthma

Bronchial asthma and allergic rhinitis often co-exist, and rhinitis is a major risk factor for the development of asthma. However, the reported incidence of allergic rhinitis in asthmatic children varies widely. The aim of this study was to elucidate the incidence of allergic rhinitis, the onset age of chronic upper and lower airway symptoms, and the correlation of these two symptoms in asthmatic children. A cohort of 130 consecutive children (ages 2–10) with asthma was evaluated. A questionnaire regarding upper and lower airway symptoms was filled out by the parents. Objective diagnosis of allergic rhinitis was also made on the basis of rhinoscopy, nasal cytology, nasal challenge, and specific serum IgE (CAP-RAST). Persistent nasal symptoms were present in 83.8% of the asthmatic children. The incidence of allergic rhinitis was 77.7% based on the objective findings. The mean onset age of asthma was 2.8 yr, and that of rhinitis was 2.9 yr. Nasal symptoms started as early as the first year of life in 8.9% of the children. In children with comorbid asthma and allergic rhinitis, rhinitis preceded in 33.7%, asthma preceded in 31.7%, and both started in the same year in 26.7%. In 7.9%, rhinitis was asymptomatic. Concomitant exacerbation of the upper and lower airways occurred in 34.6% of the total 130 children. These results demonstrate that allergic rhinitis manifested early in life in the majority of the asthmatic children. Persistent nasal symptoms in infancy may point to subsequent development of asthma and possible early intervention.     

口鼻呼出气一氧化氮检测在儿童支气管哮喘控制评估及过敏性鼻炎诊断中的应用

目的 探讨口呼出气一氧化氮(fractional exhaled nitric oxide,FeNO)与鼻呼出气一氧化氮(nasal nitric oxide,nNO)检测值和儿童支气管哮喘(简称哮喘)控制水平的关系,以及对过敏性鼻炎的诊断价值.方法 以上海市儿童医院呼吸科门诊就诊的5～12岁哮喘和/或过敏性鼻炎患儿,...     

The effect of spirometry and exercise on exhaled nitric oxide in asthmatic children.

American Thoracic Society (ATS) guidelines recommend to refrain from spirometry or exercise before measuring fractional exhaled nitric oxide (FENO) because forced breathing maneuvers might influence FENO values. However the few studies already reported in children have given conflicting results. The aim of the study was to observe to what extent spirometry or exercise could affect FENO in asthmatic children. Twenty-four asthmatic children (mean age 12.8 yr) were enrolled. Measurements of FENO were performed before and 5, 15, 30, 45 and 60 min after spirometry or a 6-min walk test, on two separate days in random order. Geometric mean FENO at baseline was 25.6 parts per billion (ppb) before spirometry and 23.5 ppb before exercise. A small drop of FENO to 24.2 and 23.7 ppb was found 5 and 15 min after spirometry (both p = 0.04). After exercise, FENO values showed a larger drop to 18.5 ppb after 5 min and 20.7 ppb after 15 min (p < 0.001; p = 0.004 respectively). Changes in FENO occurred after exercise irrespective of baseline FENO and values returned to baseline within 30 min. We conclude that both spirometry and exercise affect FENO in asthmatic children. As the changes after exercise may lead to erroneous interpretations, children should refrain from physical exercise during at least 30 min before FENO measurements.     

Exhaled nitric oxide fractions are well correlated with clinical control in recurrent infantile wheeze treated with inhaled corticosteroids

Ghdifan S, Verin E, Couderc L, Lubrano M, Michelet I, Marguet C. Exhaled nitric oxide fractions are well correlated with clinical control in recurrent infantile wheeze treated with inhaled corticosteroids.
Pediatr Allergy Immunol 2010: 21: 1015–1020.
© 2010 John Wiley & Sons A/S Fractional exhaled nitric oxide (FeNO) is a non‐invasive marker of bronchial inflammation in asthma. However, the interest of FeNO measurement remained limited in infantile wheeze. The aim of this prospective study was to evaluate the feasibility and reproducibility of FeNO off‐line measurement in very young children with recurrent wheeze and to assess whether clinical control of infantile wheeze correlates with FeNO levels. Two exhalation samples were collected in mylar balloon during quite tidal breathing. FeNO measurements were performed off‐line by a NO analyzer. The participating patients were aged ≤36 months, wheezes had started before the age of 24 months, and they were receiving maintenance treatment with inhaled corticosteroids for at least 3 months duration. The studied population comprised of 40 uncontrolled infants with persistent wheezy respiratory symptoms, median age 14.5 months, and 40 with optimal controlled infantile wheeze, median age 14 months. The reproducibility was excellent (r = 0.95; p < 0.0001). There was a significant difference in FeNO levels between the groups of persistent wheeze and well‐controlled infants: 19.8 (2.5–99.3) ppb vs. 7.7 (0.6–29.5) ppb, p < 0.0001. At a FeNO level >15 ppb, the predictive values for uncontrolled disease were as follows: positive predictive value = 65%, negative predictive value = 90%. FeN0 levels were not increased by atopy or passive tobacco. Off‐line assessment of FeNO is feasible, reproducible, and well accepted in wheezy very young children. Optimal clinical control of infantile wheeze appeared to be associated with the control of bronchial inflammation when evaluated by FeNO measurements.     

Measurement of nasal nitric oxide

Nasal nitric oxide (nNO) is produced in high quantity in the upper airways. It is thought to be involved in host defence functions and regulation of mucociliary function, and to serve as a biochemical airborne transmitter. The measurement of nNO is easy and non-invasive. It has evolved as a screening test to exclude primary ciliary dyskinesia (PCD) in patients with suggestive symptoms, because nNO is extremely low in this condition. Nasal NO is also altered in other nasal, sinus and pulmonary pathologies, but is without diagnostic value outside of PCD.     

Comparability of a hand-held nitric oxide analyser with online and offline chemiluminescence-based nitric oxide measurement

Practicability is crucial for successful implementation of fractional exhaled nitric oxide (FeNO) measurement into asthma management. The study aimed at comparing a conventional chemiluminescence NO analyser (EcoMedics^®) with a hand-held device (NIOX MINO^®) and offline FeNO measurement using a commercially available system in an unselected cohort of children aged 6–16 yr. A secondary objective was to confirm FeNO stability over time in 15 samples from adult volunteers obtained using the offline system. Sixty-six children (mean ± s.d. age 11.8 ± 3.0 yr) underwent single breath FeNO measurement in triplets with each device. Offline collected FeNO was measured after offline breath collection into a Mylar balloon and subsequent analysis using the chemiluminescence NO analyser. Variability and between-method agreement were assessed, and stability over time within the Mylar balloons was tested by repeated hourly measurements. FeNO levels ranged from 2 to 113 p.p.b. Intra-class correlation was excellent (r = 0.98, p <   0.001 for each pair). Bland–Altman plots and back-transformation of logarithmic mean differences revealed fair agreement between methods. Stability over time was confirmed over 10 h both at room temperature and when stored under cooling conditions. FeNO values obtained using the chemiluminescence NO analyser, the portable NIOX MINO^® system and the offline collection technique show between-method agreement within clinically acceptable range.     

Airway nitric oxide in infants with acute wheezy bronchitis

Concentrations of nitric oxide (NO) in exhaled air are increased in children and adults with asthma, and NO measurements are used as a non-invasive marker to monitor airway inflammation in these patients. To define the role of NO in infants with acute wheezy bronchitis, we measured nasal and end-tidal NO concentrations in 17 infants with acute virus-associated wheezy bronchitis, in 22 term infants without respiratory disease, and in nine premature infants. Nasal NO measurements were performed with an olive placed in the infant's nose; end-tidal NO concentrations were assessed during tidal breathing through a snugly fitting face mask. Both end-tidal NO concentrations and nasal NO concentrations were reduced in infants with acute wheezy bronchitis. There were no differences in NO concentrations between term infants and premature infants. Measurements by both techniques were highly reproducible, as assessed by repeated measurements three times daily on three consecutive days in eight premature infants. Reduced airway NO concentrations in infants with virus-associated acute wheezy bronchitis are in contrast to findings in adults where both upper and lower airway NO levels are increased in patients with asthma. Whether this reflects a different inflammatory reaction to upper airway infections in acutely wheezy infants or pathophysiologic differences in airway response remains to be determined.     

Exhaled nitric oxide in childhood asthma

Endogenous synthesis of nitric oxide (NO) and its presence in exhaled air was observed in various species including humans. Particularly high levels were found in adults with bronchial asthma, possibly because of the underlying pulmonary inflammatory activity. We studied oral and nasal exhaled NO by chemiluminescence in 47 children aged between 6 and 10 years. Thirty children had bronchial asthma, 17 were healthy controls. In asthmatic children oral exhaled NO was 13.4±1.4 parts per billion (ppb) (mean±SEM), nasal exhaled NO was 21.7±1.5 ppb. In healthy controls oral exhaled NO was 7.2±1.0 ppb, nasal exhaled NO was 18.2±2.2 ppb. Oral exhaled NO was significantly higher in asthmatic children compared to healthy controls (P=0.0017). Nasal exhaled NO did not differ significantly in the two groups. There was a significant negative correlation between oral exhaled NO and forced expiratory volume in 1 s (FeV₁). No significant correlation between oral or nasal exhaled NO and other markers of obstructive lung function impairment, oral minute ventilation, the body mass index and the presence of upper respiratory tract infection could be found.     

Exposure to maternal smoking in the first year of life interferes in breast-feeding protective effect against the onset of respiratory allergy from birth to 5 yr

The aim of this study was to evaluate the interaction between the exclusive breast-feeding protective effect and the exposure to tobacco smoke at domicile in the first year of life, on the onset of respiratory allergy (asthma and rhinitis) in children until 5 yr of age. This is prospective cohort study, observational, institutional based. Three hundred children born in a public hospital of Salvador-Bahia (Brazil) were followed from birth to 5 yr of age. Data from 268 children at 60 months of life were analyzed. Occurrence of allergic symptoms were studied and correlated with gender, allergic relatives in first degree, exclusive breast-feeding duration, smoking mother, and presence of other smoker at home, considering the first year of life. Exclusive breast-feeding for at least 6 months showed a protection effect against the onset of respiratory allergy in children from birth to 5 yr (p < 0.05); odds ratio (OR): 0.33 (95% CI: 0.18–0.59). Breast-fed children for less then 6 months compared with those breast-fed for 6 months or more, presented a higher risk (OR: 2.34–95% CI: 1.4–3.74) for developing allergic respiratory symptoms just to 5 yr. The protective effect of exclusive prolonged breast-feeding on the onset of respiratory allergy in children from birth until 5 yr was lost when their mothers were smokers (OR: 2.50–95% CI 1.19–5.19). Therefore, the protective effect of breast-feeding in the first year of life on the onset of allergic symptoms until the age of 5 yr was confirmed. This study proposes a confounding effect of maternal smoking on this protection, exposed by a higher risk for present allergic symptoms until the age of 5 yr, in children exclusively breast-fed for 6 months or more, when their mothers smoked.     

Cysteinyl-leukotrienes in nasal lavage fluid in children with asthma

The aim of this study was to investigate repeatability of cysteinyl-leukotrienes (cys-LT) measurements in nasal lavage fluid (NLF) and to determine if cys-LT levels in NLF are related to asthma severity in children. As a second outcome, we investigated if cys-LT in NLF reflect lower airway inflammation as assessed by exhaled NO measurement. To assess the repeatability of cys-LT measurements, two NLF samples were obtained from eight healthy controls 24 h apart. Sixty-nine asthmatic children (mean age; range: 12.8; 7.3–17.7 yr), which were grouped according to asthma severity were studied cross-sectionally on one occasion. Cys-LT in NLF were analyzed using a specific enzyme immunoassay, exhaled NO, and pulmonary function parameters were measured. The coefficient of repeatability for the repeated cys-LT measurements was 1.45 pg/ml. Cys-LT levels in NLF differed significantly between asthma severity groups (p < 0.001): mild intermittent: [median (IQR)] 6.88 pg/ml (2.00–27.87); mild persistent: 21.09 pg/ml (4.50–84.67); and moderate persistent asthmatics: 36.41 pg/ml (11.03–118.40). Concentration of cys-LT in NLF and exhaled NO was positively correlated (r = 0.85; p < 0.001). In conclusion, concentration of cys-LT in NLF correlates with asthma severity in children and is related to lower airway inflammation.     

Very high and increasing incidence of type 1 diabetes mellitus in Newfoundland and Labrador, Canada

Objective:  To determine the incidence of type 1 diabetes mellitus (T1DM) among children aged 0–14 yr inclusive in the Canadian province of Newfoundland and Labrador (NL).
Methods:  Prospective and retrospective cohort study of the incidence of T1DM in children aged 0–14 yr from 1987 to 2005. Identified cases during this time period were ascertained from several sources and verified using the capture–recapture technique.
Results:  Over the study period, 732 children aged 0–14 yr were diagnosed with T1DM. The incidence of T1DM in this population over the period 1987–2005 inclusive was 35.08 per 100 000 (95% confidence interval: 32.54, 37.62). The incidence over this period increased linearly at the rate of 0.78 per 100 000 per year. There was a significant difference between the incidence of 31.61 per 100 000 for boys in the 0–4-yr age-group and 19.05 per 100 000 for girls in the 0–4-yr age-group (p = 0.001). The incidence was very high throughout the entire province.
Conclusions/Interpretation:  The province of NL has one of the highest incidences of T1DM reported worldwide. The incidence is increasing over the 19-yr study period.     

Methodological aspects of exhaled nitric oxide measurements in infants

Guidelines for the measurement of fractional exhaled nitric oxide (FE(NO)) recommend refraining from lung function tests (LFT) and certain foods and beverages before performing FE(NO) measurements, as they may lead to transiently altered FE(NO) levels. Little is known of such factors in infants. The aim of the present study was to evaluate whether forced expiratory maneuvers, sedation, nasal contamination, and breastfeeding affect FE(NO) values in infants. FE(NO) was measured off-line during tidal breathing by means of a facemask covering nose and mouth. FE(NO) measurements were performed in 45 sedated infants (mean age 12.1 months) who underwent LFT because of airway diseases and in 83 unsedated healthy infants (mean age 4.3 months). In infants with airway diseases, no difference was found in FE(NO) values before and 5 min after LFT (n = 19 infants, p = 0.7) and FE(NO) values before sedation did not differ from FE(NO) values during sedation (n = 10 infants, p = 0.2).Oral FE(NO) values were significantly lower than mixed (nasal + oral) FE(NO) (n = 42 infants, p < 0.001). FE(NO) values before and 5 min after breastfeeding were not different (n = 11 healthy infants, p = 0.57). The short-term reproducibility in healthy infants (n = 54) was satisfactory (intraclass correlation coefficient = 0.94). We conclude that, in infants with airway diseases, LFT prior to FE(NO) measurement did not influence FE(NO) values and FE(NO) values did not change after sedation. Oral FE(NO) values were significantly lower than mixed (oral + nasal) FE(NO), and breastfeeding did not influence FE(NO). Short-term reproducibility in awake healthy infants was good.     

Improved glycemic control and lower frequency of severe hypoglycemia with insulin detemir; long-term experience in 105 children and adolescents with type 1 diabetes

Objective:  To assess the effect of the insulin analog detemir on glycemic control and severe hypoglycemia in children and adolescents with type 1 diabetes.
Research design and methods:  A retrospective chart analysis was performed in 105 patients with type 1 diabetes after switching to insulin detemir between 2004 and 2007. In children below 12 yr of age (n = 53), evening neutral protomin hagedorn (NPH) insulin was replaced by insulin detemir if therapeutic goals were not reached and blood glucose levels were unpredictable or hardly controllable. In adolescents above 12 yr of age (n = 52), insulin detemir was started when changing to intensified insulin therapy.
Results:  In children below 12 yr of age, hemoglobin A1c (HbA1c) at start was 8.3 ± 0.8% and after 12 months of treatment with insulin detemir significantly lowered (7.6 ± 0.6%, p < 0.001). In the age-group above 12 yr of age at the start of the study, the improvement of HbA1c after 12 months of treatment was less pronounced (8.0 ± 1.2 vs. 7.6 ± 1.0%) but still significant (p < 0.01). The risk for severe hypoglycemia was significantly decreased compared with patients attending the outpatient clinic between 1995 and 2003 (4.8/100 patient years vs. 7.6/100 patient years, p = 0.003). From the beginning to the end of the follow-up period, body mass index dropped significantly in children below 12 yr of age but no effect was observed in adolescents.
Conclusions:  Use of insulin detemir allows a safe nocturnal glycemic control in children and adolescents with type 1 diabetes and is associated with significantly improved HbA1c levels and fewer severe hypoglycemic events. This makes insulin detemir a most valuable new tool for the treatment of children and adolescents with type 1 diabetes.     

Exhaled nitric oxide differentiates airway diseases in the first two years of life

Fractional exhaled nitric oxide (FE(NO)) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FE(NO) measurements could distinguish between children below the age of 2 with different airway diseases. FE(NO) measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FE(NO) was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FE(NO) values were 10.4 (9.1-12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6-22.2) ppb in wheezy infants, 11.7 (8.2-16.8) ppb in BPD infants and 5.9 (3.4-10.1) ppb in CF infants. FE(NO) in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FE(NO) than nonatopic wheezers (p = 0.04). CF infants had lower FE(NO) than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FE(NO) values in BPD and control infants were not different. We conclude that FE(NO) is helpful to differentiate various airway diseases already in the first 2 y of life.