Standardized food challenges are subject to variability in interpretation of clinical symptoms.

BACKGROUND: Food challenge tests are the gold standard in diagnosing food allergy. Guidelines provide scoring systems to classify symptoms during challenge and typically recommend that challenges are considered positive when objective symptoms occur. However, currently no standard criteria for the definition of a positive challenge outcome exists and interpretation of food challenges mainly depends on clinical judgment. This study aims to assess inter- and intra-observer variability in outcomes of routinely performed peanut challenges in children. METHODS: All complete food challenge score sheets of double blind placebo controlled peanut challenges performed in 2008-2010 in an academic hospital were included. Score sheets were reassessed independently by three clinical experts including double reassessment in a subset of score sheets. Inter- and intra-observer variability was evaluated using kappa statistics. RESULTS: We included 191 food challenge score sheets. Inter-observer agreement on overall challenge outcome was moderate (κ = 0.59-0.65) and was fair (κ = 0.31-0.46) on challenges with symptoms. Intra-observer agreement on overall challenge outcome was good (κ = 0.63-0.77) but was moderate (κ = 0.50-0.60) on challenges with symptoms. Subjective symptoms (oral symptoms, abdominal complaints, food aversion) were significantly associated with disagreement between observers. CONCLUSIONS: We demonstrate that, despite strict adherence to guidelines, there is a considerable amount of variability in reassessment of symptoms recorded on food challenges sheets between and within well trained clinicians, especially when subjective symptoms occur.

Air pollution, fetal and infant tobacco smoke exposure, and wheezing in preschool children: a population-based prospective birth cohort.

BACKGROUND: Air pollution is associated with asthma exacerbations. We examined the associations of exposure to ambient particulate matter (PM10) and nitrogen dioxide (NO2) with the risk of wheezing in preschool children, and assessed whether these associations were modified by tobacco smoke exposure. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study among 4,634 children. PM10 and NO2 levels were estimated for the home addresses using dispersion modeling. Annual parental reports of wheezing until the age of 3 years and fetal and infant tobacco smoke exposure was obtained by questionnaires. RESULTS: Average annual PM10 or NO2 exposure levels per year were not associated with wheezing in the same year. Longitudinal analyses revealed non-significant tendencies towards positive associations of PM10 or NO2 exposure levels with wheezing during the first 3 years of life (overall odds ratios (95% confidence interval): 1.21 (0.79, 1.87) and 1.06 (0.92, 1.22)) per 10 µg/m3 increase PM10 and NO2, respectively). Stratified analyses showed that the associations were stronger and only significant among children who were exposed to both fetal and infant tobacco smoke (overall odds ratios 4.54 (1.17, 17.65) and 1.85 (1.15, 2.96)) per 10 µg/m3 increase PM10 and NO2, respectively (p-value for interactions <0.05). CONCLUSIONS: Our results suggest that long term exposure to traffic-related air pollutants is associated with increased risks of wheezing in children exposed to tobacco smoke in fetal life and infancy. Smoke exposure in early life might lead to increased vulnerability of the lungs to air pollution.

Early respiratory morbidity in a multicultural birth cohort: the Generation R Study.

Ethnic disparities in the prevalence of asthma symptoms in children have been described. We evaluated to what extent the association between ethnic background and respiratory symptoms during the first 2 years of life could be explained by the mediating effect of risk factors for respiratory morbidity. The Generation R Study is a multiethnic, population-based birth cohort study. Pre and postnatal risk factors for respiratory morbidity were prospectively assessed by questionnaires. Information about ethnicity was available for 5,684 infants. The associations between ethnic background and lower respiratory symptoms at 12 and 24 months were evaluated with log-binomial regression models. Relative risks and 95 % confidence intervals (RR [95 % CI]) were computed for Cape Verdean, Moroccan, Antillean, Surinamese and Turkish ethnicity with Dutch ethnicity as the reference category. We found an increased risk of lower respiratory symptoms at 24 months in Antillean infants (1.32 [95 % CI 1.12-1.57]) that was mediated by early postnatal exposures (pets keeping, siblings, breastfeeding, daycare attendance, smoke exposure). Turkish infants also had an increased risk of lower respiratory symptoms at 12 and 24 months (1.14 [95 % CI 1.02-1.27] and 1.21 [95 % CI 1.07-1.38], respectively), partly explained by previous morbidity (eczema, infections and upper respiratory symptoms). There were no differences for Cape Verdean, Moroccan or Surinamese, as compared to Dutch infants. Hence, ethnic background was associated with respiratory symptoms during the first 2 years of life and this association was largely explained by mediating effects of known pre and postnatal risk factors for respiratory morbidity.

Exhaled nitric oxide measurements in the first 2 years of life: methodological issues, clinical and epidemiological applications.

Fractional exhaled nitric oxide (FeNO) is a useful tool to diagnose and monitor eosinophilic bronchial inflammation in asthmatic children and adults. In children younger than 2 years of age FeNO has been successfully measured both with the tidal breathing and with the single breath techniques. However, there are a number of methodological issues that need to be addressed in order to increase the reproducibility of the FeNO measurements within and between infants. Indeed, a standardized method to measure FeNO in the first 2 years of life would be extremely useful in order to meaningfully interpret FeNO values in this age group. Several factors related to the measurement conditions have been found to influence FeNO, such as expiratory flow, ambient NO and nasal contamination. Furthermore, the exposure to pre- and postnatal risk factors for respiratory morbidity has been shown to influence FeNO values. Therefore, these factors should always be assessed and their association with FeNO values in the specific study population should be evaluated and, eventually, controlled for.There is evidence consistently suggesting that FeNO is increased in infants with family history of atopy/atopic diseases and in infants with recurrent wheezing. These findings could support the hypothesis that eosinophilic bronchial inflammation is present at an early stage in those infants at increased risk of developing persistent respiratory symptoms and asthma. Furthermore, it has been shown that FeNO measurements could represent a useful tool to assess bronchial inflammation in other airways diseases, such as primary ciliary dyskinesia, bronchopulmonary dysplasia and cystic fibrosis. Further studies are needed in order to improve the reproducibility of the measurements, and large prospective studies are warranted in order to evaluate whether FeNO values measured in the first years of life can predict the future development of asthma or other respiratory diseases.

Fractional exhaled nitric oxide in infants during cow's milk food challenge.

Cow's milk allergy (CMA) is the most common food allergy in early childhood. The golden standard for the diagnosis of CMA is a food challenge after a period of elimination. Increased levels of fractional exhaled nitric oxide (FE(NO)) have been shown after bronchial allergen provocation. We evaluated whether FE(NO) may also be a predictor of a positive reaction during cow's milk challenge in infants. Forty-four infants [mean age (range): 4.2 (3.7-4.6) months] suspected of CMA underwent an open food challenge with cow's milk formula administered in ascending quantities, starting with 2 ml and then 6, 20, 60 and 200 ml until a clinical reaction occurred. Off-line FE(NO) samples were obtained during tidal breathing by means of a facemask covering infants' nose and mouth. FE(NO) was measured twice before the challenge (baseline), immediately before each new dose of milk and after a positive reaction or after the last dose of milk. Eleven children showed immediate positive clinical responses to cow's milk, whereas 13 infants presented only a late-type reaction. FE(NO) values before or after a positive reaction (either immediate or late) were not different from FE(NO) values at baseline. Baseline FE(NO) in infants with a positive reaction did not differ from FE(NO) in infants without a reaction at any time point. We conclude that FE(NO) values are not predictive and not related to the occurrence of a positive reaction during a cow's milk challenge in infants, suggesting that a positive reaction may not result from eosinophilic activation.

Exhaled nitric oxide in infants--what is a nice test like FENO doing in a place like this?

In adults and older children the measurement of fractional exhaled nitric oxide (FENO) has been shown to be useful as a tool to diagnose and monitor eosinophilic airway inflammation. However, the recommended method to measure FENO in school-age children is not suited for use in preschool children and infants. This article reviews the data on FENO measurements in infants. In the first year of life, measurement of FENO can be done during tidal breathing or during a single forced passive expiration. Several technical factors, including contamination with nasal and ambient NO, and the influence of expiratory flow influence FENO levels in infants. Because asthma is uncommon in infants and wheezing is often related to viral infections, considerable differences in clinical utility of FENO between older children and infants could be expected. From the available data FENO could potentially be useful to identify early-onset asthma, to diagnose primary ciliary dyskinesia (PCD), and to monitor the effect of various treatments. In conclusion, there is still much uncertainty about the potential clinical utility of FENO in infants. There is a need for clinical studies showing the merits and limitations of different methodologies, to standardize FENO measurements in infants, and to obtain normal reference values for this age group.

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.

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.

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.