Exhaled nitric oxide and exercise-induced bronchoconstriction in young wheezy children – interactions with atopy

The association between exercise-induced bronchoconstriction (EIB) and exhaled nitric oxide (FE_NO) has not been investigated in young children with atopic or non-atopic wheeze, two different phenotypes of asthma in the early childhood. Steroid naïve 3- to 7-yr-old children with recent wheeze (n = 84) and age-matched control subjects without respiratory symptoms (n = 71) underwent exercise challenge test, measurement of FE_NO and skin prick testing (SPT). EIB was assessed by using impulse oscillometry, and FE_NO by standard online technique. Although FE_NO levels were highest in atopic patients with EIB, both atopic and non-atopic wheezy children with EIB showed higher FE_NO than atopic and non-atopic control subjects, respectively. In atopic wheezy children, a significant relationship between FE_NO and the severity of EIB was found ( r  = 0.44, p = 0.0004), and FE_NO was significantly predictive of EIB. No clear association between FE_NO and EIB or predictive value was found in non-atopic wheezy children. Both atopic and non-atopic young wheezy children with EIB show increased FE_NO levels. However, the association between the severity of EIB and FE_NO is present and FE_NO significantly predictive of EIB only in atopic subjects, suggesting different interaction between bronchial responsiveness and airway inflammation in non-atopic wheeze.     

Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants

Background: Inhaled nitric oxide (iNO), commonly used for hypoxic neonates, may react with haemoglobin to form methaemoglobin (MetHb). MetHb monitoring during iNO therapy has been questioned since low doses of iNO are used. Aim: To evaluate the incidence of and identify risk factors associated with elevated MetHb in neonates treated with iNO. Methods: Neonates who were treated with iNO and had at least one MetHb measurement were included. Demographic characteristics and methods of iNO administration (dosage, duration) at the time of each MetHb measurement were analysed. Results: Four hundred and fifty‐two MetHb measurements from 81 premature and 82 term and near‐term infants were analysed. MetHb was above 5% in one‐term infant, and between 2.5–5% in 16 infants. A higher maximum dose of iNO (22.7 vs 17.7 p.p.m.), but not gestational age, was a significant risk factor for elevated MetHb. Significantly higher oxygen levels (75.5% vs 51.7%) were associated with higher MetHb in term infants. Preterm infants had no risk for high MetHb when iNO was kept below 8 p.p.m. These data suggest the possibility of limiting blood withdrawal when low doses iNO are used. Conclusion: High MetHb is exceptional in neonates treated with low dose iNO. Associated risk factors are related to high iNO dose and the simultaneous use of high concentrations of oxygen.     

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 in children with asthma and sinusitis

Exhaled nitric oxide (FE_NO) is a surrogate marker of eosinophilic airway inflammation. The measurement of this gas can be easily performed in children and the result is immediately available. Because of these characteristics, measurement of FE_NO is slowly becoming part of the routine clinical evaluation of an asthmatic patient. FE_NO measurement may have a role both in the diagnosis of asthma and as a guide in therapy algorithms. For example when FE_NO levels are persistently normal and the asthmatic child is asymptomatic, the steroid therapy may be decreased or even stopped. In patients with acute or chronic rhinosinusitis the levels of nasal nitric oxide (nNO) are significantly decreased, while they rise up after a course of antibiotics. The measurement of nasal NO has been proposed as a functional test to evaluate sinus ventilation. Nasal NO is significantly reduced also in primary ciliary dyskinesia and can be used as a screening tool to identify patients affected by this condition.     

一氧化氮对脑室周围白质软化早产儿神经发育的影响

目的探讨一氧化氮(NO)在合并脑室周围白质软化(PVL)的早产儿神经发育中的作用。方法采用随机、对照实验,对合并PVL的106例早产儿,在出生后24h内随机分成吸入NO组(第1天10×10-6,以后改为5×10-6继续用6d)和对照组(吸入氧气7d),在纠正胎龄18个月时采用贝利发育量表评估其神经发育。结果吸入NO组贝利评分明显高于对照组(P<0.05),贝利评分低于70分的发生率明显低于对照组(P<0.05)。结论合并脑室周围白质软化早产儿采用吸入NO治疗,有利于促进其神经发育。     

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.     

Increased eosinophil cationic protein levels in bronchoalveolar lavage from wheezy infants

Although studies examining the serum suggest a role for eosinophils in wheezing episodes in infants and toddlers, the presence of a chronic eosinophilic inflammation within their airways remains to be demonstrated. In this study we investigated whether eosinophil cationic protein (ECP) levels are increased in BAL fluid (BALF) from infants and toddlers with recurrent wheezing episodes, during an asymptomatic period. The levels of ECP in BALF were quantitated by radioimmunoassay in 61 children (36 with severe recurrent episodes of wheezing and 25 who were non-wheezy), aged 6–36 months, in whom flexible bronchoscopy was clinically indicated. BALF eosinophil counts were ≤ 1% in all patients and did not differ in wheezers, compared to non-wheezers. In contrast, ECP levels in BALF were ≥ 2.2 µg/l in 18 of 36 (50%) wheezy infants but in only three of 25 (12%) control infants (p < 0.01). Neutrophil counts were significantly higher in the wheezer group than in the non-wheezer group (8.1 × 10³ cells/ml vs. 3.0 × 10³ cells/ml). ECP levels in the BALF were not correlated with the absolute number of eosinophils ( r  = 0.03; p = 0.8) but were correlated with the absolute number of neutrophils ( r  = 0.54; p = 0.001). There was no association between high ECP levels in BALF and the atopic status of the wheezers. In conclusion, ECP levels are increased in BALF from young children with recurrent wheezing episodes, even during relatively quiescent periods, suggesting a chronic increased cell activation in the lower airways.     

Increased bronchoalveolar lavage CD8 lymphocyte subset population in wheezy infants

Episodes of wheezing are very common in infancy but, despite their high prevalence, their mechanism is still poorly understood. To better understand the airway inflammation of wheezing infants, we examined cells of the bronchoalveolar lavage (BAL), focusing on the phenotype of lymphocytes and macrophages by using cytofluorimetry. Twenty-one wheezers (mean age 15.4 months) and seven non-wheezers (mean age 24.1 months) were studied. BAL was collected at fiberoptic bronchoscopy. Total and differential cell counts were similar in both populations. Eosinophils were not detected in the BAL fluid. The cell-surface markers CD2, CD3, CD4, CD7, CD8, CD19, and CD45 were studied for the lymphocyte sub-population analysis. The cell-surface markers CD14, CD54, CD62L, and human leucocyte antigen (HLA)-DR were studied for the macrophage sub-population analysis. A significant increase in the CD8⁺ lymphocyte population (p = 0.03) was observed in wheezers (median 43.1%, 25–75% percentile: 30.1–54.9%), as compared to non-wheezers (median 29.3%, 25–75% percentile: 13.5–34.7%). A significantly (p = 0.04) decreased expression of HLA-DR (mean fluorescence intensity [MFI]) was detected in the macrophage population of the wheezers (median MFI, 7,016; range 2135–7986), as compared to non-wheezers (median MFI, 8,369; range: 6478–8860). The results of the present study suggest that viral infection may have induced a CD8⁺ response in BAL cells.     

Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome

AIM: To test the hypothesis that inhaled nitric oxide therapy can decrease the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome; to evaluate the possible predictive factors for the response to inhaled nitric oxide therapy. METHODS: Preterm infants (less than 30 weeks' gestation) were randomized to receive during the first week of life inhaled nitric oxide, or nothing, if they presented severe respiratory distress syndrome. Then, the treated infants were classified as non responders and responders. RESULTS: Twenty infants were enrolled in the inhaled nitric oxide therapy group and 20 in the control group. Bronchopulmonary dysplasia and death were less frequent in the inhaled nitric oxide group than in the control group (50 vs. 90%, p=0.016). Moreover, nitric oxide treatment was found to decrease as independent factor the combined incidence of death and BPD (OR=0.111; 95% C.I. 0.02-0.610). A birth weight lower than 750 grams had a significant predictive value for the failure of responding to inhaled nitric oxide therapy (OR 12; 95% C.I. 1.3-13.3). CONCLUSION: Inhaled nitric oxide decreases the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome. Birth weight may influence the effectiveness of inhaled nitric oxide therapy in promoting oxygenation improvement in preterm infants.     

从美国胸科学会指南看呼出气一氧化氮测定的临床应用

近年来,随着对呼出气一氧化氮研究的增多,学术界对其临床应用价值的认识逐渐清晰。呼出气一氧化氮的测定已经标准化,但在实际临床工作中,如何在不同情况下选择使用此技术和解读其测定结果,很多医师仍感到困惑。美国胸科学会制定的关于呼出气一氧化氮临床应用的指南对有关问题进行了详细阐述,并给出了具体推荐意见。呼出气一氧化氮测定可用于确定嗜酸粒细胞性气道炎症,协助诊断哮喘,预测吸入皮质激素治疗的有效性,监测气道炎症状况。     

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,...     

Neurodevelopmental outcome in high-risk preterm infants treated with inhaled nitric oxide

Inhaled nitric oxide (iNO) is used to treat preterm infants with hypoxaemic respiratory failure. In this study we describe the long-term survival and neurodevelopmental status of high-risk preterm infants enrolled into a randomized controlled trial of iNO therapy. Information regarding long-term outcome was available for all 25 children enrolled in the original trial who survived until discharge from hospital. Formal, blinded, developmental assessment and neurological examinations were performed in 21 out of 22 children still alive at 30 mo of age, corrected for prematurity. No significant differences were found in long-term mortality (12/20 vs 8/22, RR 1.65, 95% CI 0.87-3.3), neurodevelopmental delay (4/7 vs 9/14, RR 0.89, 95% CI 0.37-1.75), severe neurodisability (0/7 vs 5/14, p = 0.12) or cerebral palsy (0/7 vs 2/14, p = 0.53) between iNO-treated and control infants. CONCLUSION: In this study there was no evidence of a significant effect on either survival or long-term neurodevelopmental status in infants treated with iNO.     

Nitric oxide production during the early neonatal period in small-for-gestational-age infants

In a study of endogenous nitric oxide production in growth-retarded, very preterm newborns (<32 wk GA), urinary NOx/creatinine ratio and plasma guanosine 3',5'-cyclic monophosphate levels were determined during the early neonatal period. Newborns were divided into three groups: appropriate-for-gestational-age (AGA, n = 19), moderately small-for-gestational-age (SGA, n = 13) and severely SGA (n = 6) infants. Severely SGA infants showed significant higher values of nitric oxide derivatives during the first 24 h of life compared with the other groups. CONCLUSION: An increased NO production is found in SGA infants during the first 24 h after birth. This may reflect an increased intrauterine nitric oxide production in the feto-placental circulation found in cases with intrauterine growth retardation,     

Endothelial nitric oxide synthase gene polymorphisms are associated with sensitization to seasonal aeroallergens in asthmatic children

Background

Childhood asthma phenotype is the consequence of interaction between environment and genetic factors. Nitric oxide (NO) formation is affected by polymorphisms in nitric oxide synthase (NOS) enzymes, which play a significant role as inflammatory factors in the airways. This study was undertaken to estimate the correlation of -786C>T and 894G>T polymorphisms of the eNOS gene with the sensitization of asthmatic children to common aeroallergens.

Methods

A total of 193 asthmatic children and 96 healthy controls, who were of Mediterranean origin, living in the same geographical area, were enrolled in the study. 894G>T and -786T/C polymorphisms of the eNOS gene were analyzed using a PCR-RFLP method.

Results

The 894GG genotype was more frequent (68.6%) in children with asthma sensitized to Oleaeuropaea than in those with asthma non-sensitized (43.0%) (P=0.004). Likewise, -786TT genotype frequency was higher in children with asthma sensitized to Oleaeuropaea (51.0%) than in those with asthma nonsensitized (31.7%) to this allergen (P=0.035). For the aeroallergens Parietariajudaica and mixed grass, the frequency of -786C allele carriage was associated with protection from sensitization to Parietariajudaica and mixed grass in asthmatic children (P=0.021 and P=0.017, respectively). In the healthy control group, the genotype frequencies for these polymorphisms were similar to genotype frequencies of children with asthma non-sensitized to these three specific aeroallergens.

Conclusion

In children with asthma, 894G>T and -786T/C polymorphisms of the eNOS gene were correlated with sensitization to common seasonal aeroallergens.

     

窒息新生儿肾损害及一氧化氮保护作用

为了解机械通气治疗的窒息新生儿肾损害的发生情况，比较不同窒息程度与肾损害的关系。并探讨一氧化氮（NO）吸入治疗对肾脏的影响。对机械通气治疗的41例窒息新生儿（轻度窒息19例，重度窒息22例），进行回顾性分析，其中13例同时予以NO吸入治疗。结果显示：41中17例（占41．5％），有不同程度的肾损害，重度窒息患儿肾损害发生率明显高于轻度窒息患儿（P＝0．014）。予以NO吸入治疗的窒息患儿肾损害的改善较未予以NO吸入治疗者明显，9例未用NO吸入治疗的肾损害患儿在机械通气治疗后2例肾损害好转，5例无好转，另2例未随访，8例用NO吸入治疗的肾损害患儿在NO吸入治疗后肾损害好转6例，另2例未随访，提示窒息新生儿肾损害的发生率相当高，而NO吸入治疗能较明显的改善窒息后的肾损害。     

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目的通过对哮喘儿童呼出气一氧化氮(FENO)水平的监测,为哮喘的临床诊断治疗及病情评估提供帮助。方法选择2007年10月至2009年8月于首都儿科研究所附属儿童医院门诊确诊的哮喘患儿共358例,根据其哮喘发作与治疗情况分为哮喘发作组与非发作组、治疗组与未治疗组。设计临床观察表记录各组患儿治疗、发作、肺部喘鸣音情况,并进行FENO及1秒用力呼气容积(FEV1)、用力肺活量(FVC)及最大用力呼气中段流量(MMEF)等肺功能指标的测定。结果 358例哮喘患儿的FENO值为28.5(15.5～55.0)×10-9,其中男性为29.0(15.0～49.8.0)×10-9,女性为28.0(16.0～58.6)×10-9,男女相比差别无统计学意义(Z=-1.006,P>0.05)。111例11岁以上哮喘儿童FENO为36.0(20.0～65.0)×10-9,其中男性为30.0(26.0～63.0)×10-9,女性为40.5(17.7～73.8)×10-9,与395例正常儿童相比FENO明显增高,差异具有统计学意义(Z=-11.352,P<0.001)。358例哮喘患儿FENO与年龄呈正相关(r=0.206,P<0.01)...     

一氧化碳和一氧化氮在婴幼儿肺炎致急性肺损伤中的作用

目的：探讨一氧化碳（CO）和一氧化氮（NO）在婴幼儿肺炎致急性肺损伤（ALI）中的作用。方法：用分光光度法检测27例婴幼儿肺炎致ALI患儿血浆CO、NO水平，并与18例不伴ALI的婴幼儿肺炎对照组和20例健康组作比较。结果：ALI急性期血浆CO、NO水平明显高于对照组和健康组（P均＜0．01）；与轻度组比较，重度组（ARDS）血浆CO、NO水平显著增高（P均＜0．01）；患儿血浆CO和NO水平呈正相关（P＜0．01）。结论：内源性CO和NO在ALI的发病过程中具有重要意义。     

Exhaled nitric oxide in asthmatic children and adolescents after nasal allergen challenge

Epidemiological data suggest a comorbidity link between nasal and bronchial allergic disease. Exhaled nitric oxide (FENO) is a sensitive marker of bronchial inflammation and increases after bronchial allergen provocation. We studied FENO in 19 children and adolescents with allergic asthma and 10 controls before and 2, 6 and 24 h after a single nasal allergen challenge. The correlation between FENO and other markers of allergic inflammation, such as eosinophils in blood and eosinophil cationic protein (ECP) in serum and nasal lavage was also assessed. FENO remained unchanged 24 h post-challenge in both steroid and steroid-naive patients. At 6 h post-challenge, FENO decreased in both asthmatics and controls. The asthmatic subjects showed a positive correlation between FENO and blood eosinophils before (r=0.71, p=0.001) and after the challenge, and between FENO and ECP in nasal lavage (r=0.62, p=0.02) 2 h after the challenge. Mean ECP in nasal lavage increased post-challenge but not significantly. We conclude that a single nasal allergen challenge does not augment bronchial inflammation although FENO, is related to blood eosinophil count and to the nasal inflammatory response. Our data do not support the theory of a direct transmission of the nasal inflammation to the lower airways.