Eosinophil cationic protein and interleukin-8 levels in bronchial lavage fluid from children with asthma and infantile wheeze

It has been shown previously that airway eosinophils characterize childhood asthma and neutrophils contribute to the pathophysiology of both infantile wheezing and asthma. Therefore, eosinophil cationic protein (ECP) and interleukin‐8 (IL‐8) levels in bronchoalveolar lavage fluid (BALF) from asthmatics (n = 16) and infantile wheezers (n = 30) were analyzed as markers of eosinophil‐ and neutrophil‐mediated inflammation. To aid the interpretation, a control group of children (n = 10) with no lower airway pathology were included. Disease severity was assessed by using a symptom score. Surprisingly, no significant difference was found in IL‐8 or ECP levels among asthma, infantile wheeze, and control groups. Asthma was characterized by: a correlation between ECP levels and eosinophil counts (r = 0.618, p = 0.014); a correlation between neutrophil number and IL‐8 levels (r = 0.747, p = 0.002); and increasing IL‐8 levels with symptom score (p = 0.03). In infantile wheezers, IL‐8 levels were poorly related to neutrophil number but were significantly increased when neutrophils were > 10%. Although detectable levels were found in all but one symptomatic infant, IL‐8 concentrations did not reflect the symptom score in infantile wheeze. ECP was unexpectedly correlated to neutrophil percentages (Rho = 0.832, p = 0.001), and a threshold of ECP > 20 ng/ml was associated with persistent symptoms in these infantile wheezers. Hence, in accordance with BALF cellularity, activation of eosinophils was suggested by raised levels of ECP in childhood asthma, but not in infantile wheeze. Neutrophil‐mediated inflammation appeared to better reflect the severity of asthma than that of infantile wheeze. Although its meaning remains to be elucidated, ECP was suggested to be a helpful indicator of persistent infantile wheeze. However, its utility as a marker predicting ongoing asthma remains to be established.     

Eosinophil cationic protein, myeloperoxidase and tryptase in children with asthma and atopic dermatitis

Serum levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), tryptase, total IgE and differential blood cell counts were studied in atopic children with: 1) moderate to severe asthma using inhaled steroids and symptom-free for the last 3 weeks (n= 13), 2) mild asthma with sporadic symptoms, using only inhaled β₂-agonists < 3 times/week (n= 15), 3) acute asthmatic attacks admitted to hospital (n= 12), 4) mild to moderate atopic dermatitis (n= 14). Fifteen children without any history of atopy served as controls. ECP, MPO, tryptase and IgE were measured in serum by radioimmunoassays (RIA). The symptom-free children with inhaled steroids had similar median ECP and MPO values as the controls, 8.0 and 360 μg/l, vs. 9.0 and 310 μg/l, while both ECP and MPO were significantly (p < 0.001) increased in the symptom-free children without anti-inflammatory treatment, 32 and 887 μg/l and in those with acute asthma, 28 and 860 μg/l. The children with atopic dermatitis had increased ECP but normal MPO levels, 16.0 and 455 μg/l. Tryptase in serum was not measurable in any patient. All groups except the control group had significantly elevated total IgE levels. The results indicate that in atopic children serum ECP is a good marker of ongoing asthma or atopic dermatitis. The normal levels of ECP and MPO in the children with asthma using inhaled steroids seem to reflect successful anti-inflammatory treatment. The increased levels of ECP and MPO in the children with mild asthma and no anti-inflammatory treatment may indirectly reflect airway inflammation.     

哮喘患儿血清IL-5、ECP的测定及相关性研究

为了探讨白介素_5(IL_5)、嗜酸粒细胞阳离子蛋白 (ECP)在儿童支气管哮喘发病机制中的作用 ,并评价其反映哮喘气道炎症的临床价值 ,收集23例哮喘急性发作患儿、22例哮喘缓解期患儿及17例正常儿童的外周血标本 ,用ELISA法测定血清IL_5的水平 ;以PharmaciaCAP系统检测血清中ECP的含量。结果 :哮喘急性发作组血清中IL_5、ECP水平明显高于缓解期组和正常组 ;且IL_5、ECP水平的升高程度与病情严重程度相关 ,两者之间呈正相关 ;而3组EOS计数差异无显著性。提示 :监测血清IL_5、ECP的动态变化 ,可以较好地反映气道嗜酸粒细胞炎症的反应过程 ,具有重要的临床价值     

轻-中度哮喘患儿气道炎症类型与病情、糖皮质激素疗效的关系

目的探讨轻-中度支气管哮喘患儿初始治疗前气道炎症类型与病情及吸入糖皮质激素治疗反应的关系。方法以87例轻-中度哮喘患儿作为研究对象,在糖皮质激素吸入治疗(ICS)前进行痰液诱导及诱导痰细胞学分析,酶联免疫荧光法测定痰液嗜酸粒细胞阳离子蛋白(ECP)、ELISA法检测痰液IL-8、TGF-β1,儿童肺功能仪检测基础肺功能和小气道通气指标、乙酰甲胆碱(Mch)支气管激发试验测定气道高反应性(AHR)。20例健康体检儿童作为对照组,应用SPSS13.0软件进行统计学分析。结果87例轻-中度哮喘患儿根据诱导痰液EOS%分为嗜酸性粒细胞哮喘组(EA)64例,非嗜酸性粒细胞哮喘组(NEA)23例,EA与NEA组ICS治疗前痰液细胞学构成比、诱导痰上清液ECP、IL-8差异有统计学意义(P<0.05);两组间FEV1%预测值(FEV1%pred)、PEF%pred、中-重度AHR%、小气道阻塞(%)、痰液TGF-β1水平等指标差异有统计学意义(P<0.05)。ICS治疗4周后EA组基础肺功能指标、气道高反应性、小气道通气功能明显改善,而NEA组改善不明显。多元逐步回归分析结果表明初治痰液EOS%、FEV1%预测值、痰液TG...     

Evaluation of a clinical algorithm involving serum eosinophil cationic protein for guiding the anti‐inflammatory treatment of bronchial asthma in childhood

A pilot study was performed to investigate a clinical algorithm using serum‐eosinophil cationic protein level (S‐ECP) as an objective parameter for tapering the anti‐inflammatory treatment in chronic childhood asthma. We studied 21 outpatient asthmatic children (6 girls and 15 boys, mean age 9 yr, range 3–12 yr, all with initial S‐ECP ≥ 15 µg/l) over a period of 12 months at monthly intervals. At each visit a short history, clinical examination, blood sample for S‐ECP and eosinophil count, lung function tests and drug compliance were assessed. According to the initial S‐ECP, patients were allocated to two anti‐inflammatory treatment groups: patients with S‐ECP between 15 µg/l and 30 µg/l were treated with Budesonide 200 µg twice daily, while patients with S‐ECP of 30 µg/l and above received Budesonide 400 µg twice daily. After this induction treatment the anti‐inflammatory medication was tapered at monthly intervals according to actually measured S‐ECP: patients with S‐ECP < 15 µg/l received sodium cromoglycate (SCG) 10 mg twice daily per inhalation via spacer, patients with S‐ECP ≥ 15 µg/l and < 30 µg/l received Budesonide 200 µg twice daily via spacer, and patients with S‐ECP ≥ 30 µg/l received Budesonide 400 µg twice daily. Prior to inhalation of topical steroids or SCG all patients had to inhale 500 µg Terbutaline twice daily for optimal bronchodilatation. The use of medication was assessed by weighing the metered dose inhaler containers each month. Our results showed a decrease in symptoms (p = 0.0001) and in S‐ECP (p = 0.02) and MEF50% predicted (p = 0.02) after the initial month of Budesonide treatment. During a total of 246 months of investigation there was no need for emergency room treatment or hospital admission, and no need for oral steroids. During the whole study period there was a tendency for inhaled steroids to be more effective than SCG in reduction of markers of airway inflammation, improvement of symptoms and lung function. Inadequate use of medication was related to an increase in S‐ECP in all treatment groups. From this open pilot study it is concluded that a clinical algorithm including S‐ECP for tapering the anti‐inflammatory treatment may be helpful in childhood asthma. These first observations should be confirmed by a controlled long‐term study.     

Inflammation markers and symptom activity in children with bronchial asthma. Influence of atopy and eczema

Background. Eosinophil cationic protein (ECP) has been reported to reflect the eosinophil inflammatory activity in asthma. However, the relative impact of asthma symptoms and atopic eczema upon serum (s)-ECP in asthmatic children has not been established.
Objectives. To examine s-ECP levels and s-myeloperoxidase (MPO) in relation to asthma symptoms and atopic eczema in asthmatic children.
Methods. S-ECP and s-MPO were assessed in relation to symptom activity, lung function, exercise induced bronchoconstriction and bronchial responsiveness in 101 children; median age 9 years, range 1-16 years; with moderate to severe asthma, admitted to Voksentoppen Center.
Result. S-ECP was significantly higher in children with persistent compared to episodic or no asthma symptoms in the past four weeks, S-ECP was also higher in children with atopic compared to non-atopic asthma, as well as in those with active compared to past history of no history of atopic eczema. SMPO was higher in children with persistent asthma symptoms, but did not differ in relation to atopy of eczema state. Persistent asthma symptoms had the greatest impact upon s-ECP levels, followed by atopy and active eczema.
Conclusion. S-ECP may be used in assessing symptom activity in asthmatic children, but with the realisation that active eczema and the presence of atopy may also influence levels.     

诱导痰液与哮喘患儿气道炎症的关系探讨

目的探讨简便有效的诱导痰液及细胞分析方法,了解儿童哮喘发作期气道炎症的特点。方法运用高渗盐水雾化吸入诱导痰液的方法,收集３７例哮喘发作期患儿、４８例正常儿童（对照组）痰液。一部分痰液经二硫苏糖醇（ＤＴＴ）液化后,在血球计数板上行细胞总计数;另一部分痰液涂片经瑞氏、甲苯胺蓝染色行细胞分类计数。结果哮喘组８４％取痰成功,诱导过程中呼气峰流速（ＰＥＦ）未见下降（Ｐ＞００５）。痰液细胞总计数哮喘组为（１１２±８９）×１０９／Ｌ,对照组为（７１±６２）×１０９／Ｌ（Ｐ＜００５）。嗜酸性粒细胞、肥大细胞在哮喘发作期气道中明显升高（Ｐ＜００１）。结论诱导痰液分析、评判哮喘患儿气道炎症是一种安全、可靠的新研究方法;嗜酸性细胞、肥大细胞为哮喘发作的主要效应细胞。     

Carbohydrate, lipid and glucocorticoid metabolism in children with asthma following treatment with high-dose steroid aerosol

In 16 asthmatic children 5–16 years old (mean 11.4 yr) treated with inhaled beclomethasone dipropionate or budesonide, serum lipids and serum lipoproteins, serum C-peptide and serum insulin and urinary cortisol excretion were measured. The dose of inhaled corticosteroid was unchanged for 5 to 12 months prior to investigation. The doses ranged from 800 to 4000 μg (mean 1465 μg) per day. Serum lipids and serum lipoproteins were within the normal range in all patients. One patient treated with an extremely high dose of inhaled steroid showed a high level of serum C-peptide and serum insulin and a very low level of urinary cortisol excretion. The results of the other 15 patients were within the normal range.     

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.     

Effects of montelukast on symptoms and eNO in children with mild to moderate asthma

BACKGROUND: Asthma is a chronic inflammatory airway disease. Exhaled nitric oxide (eNO) is a marker reflecting airway inflammation. This study was conducted to investigate whether montelukast, a leukotriene receptor antagonist, could be used for the management of asthma and how fast the montelukast sodium decreased airway inflammation as demonstrated by eNO levels. METHODS: Twenty children aged 6-14 years (mean age: 9.2 +/- 2.4 years; mean weight 30 +/- 4.6 kg) with mild to moderate asthma were recruited for the study. They received montelukast plus an inhaled short-acting beta2 agonist as open and uncontrolled therapy. Asthma score (AS) and peak expiratory flow rate (PEFR) and eNO concentrations were measured at pretreatment (0 week) and post-treatment (1 and 2 weeks) as well as 2 weeks after withdrawal of therapy. RESULTS: In one week, the eNO levels (33.3 +/- 15.5 p.p.b. vs 14.8 +/- 8.6 p.p.b.; P < 0.05), and AS (4.2 +/- 1.3 vs 1.8 +/- 1.3; P < 0.05) decreased rapidly, and PEFR (206.9 +/- 69.7 L/min vs 236.2 +/- 69.8 L/min; P < 0.05) increased. Concurrent beta2 agonist use decreased from a mean +/- SD of 2.2 +/- 0.4-1.3 +/- 0.3 puffs per weeks (P < 0.05). After the withdrawal of treatment for 2 weeks, the eNO levels (29.2 +/- 16.1 p.p.b) rebounded again, although the improvements in AS (1.1 +/- 1.3) and PEFR (245.0 +/- 91.3 L/min) persisted. CONCLUSION: Oral montelukast sodium treatment of these children with mild to moderate asthma effectively improved asthmatic symptoms and suppressed airway inflammation in 1 week, suggesting that this leukotriene antagonist combined with short-acting beta2 agonists may provide effective treatment option in mild to moderate childhood asthma. Larger, controlled, and double-blinded studies are needed to confirm these preliminary open uncontrolled observations.     

Eosinophil granule proteins in the assessment of airway inflammation in pediatric bronchial asthma

Eosinophil granule proteins such as eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and eosinophil protein X (EPX) in serum and urine are indirect measures of eosinophil activity. The measures have been evaluated for prediction, diagnosis and monitoring of anti-inflammatory treatment modalities in children with asthma. Assessments in serum and urine are highly dependent on sampling procedures and must be performed under strictly controlled conditions using standardized sampling and laboratory procedures. The measures are influenced by circadian and seasonal variations. Measurement of the eosinophil granule proteins does not improve the predictive value of a family history of atopy. Due to insufficient sensitivity and specificity, the measures are not useful in the diagnosis of asthma in children, and the clinical use of eosinophil proteins in the individual child for assessment of asthma severity has not been sufficiently validated. Serum and urine eosinophil granule proteins, however, may be useful in extending our knowledge of suppressive effects on eosinophil activity of various doses, devices and administration regimens of inhaled glucocorticoids in children. Such evaluations may be performed in randomized, double-blind trials of well-defined age groups and they should include measures of compliance. One important aspect to look at would be the distinction between suppressive effects on eosinophil activity and clinically important anti-inflammatory effects. Considering the complexity of airway inflammation and the heterogeneity of childhood asthma, however, it may be too simplistic to look for a single measure of the inflammatory processes. In the future, perhaps, a combination of products of inflammatory cells may give more clinically relevant information with respect to prediction, diagnosis, monitoring and outcome of childhood asthma.     

Eosinophil activation in preterm infants with lung disease

AIM: We investigated the role of eosinophils in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Fifteen preterm infants with BPD were compared to 13 preterms with respiratory distress syndrome (RDS) and to 16 healthy preterms. We assessed total eosinophil and neutrophil counts in venous blood samples and the levels of the eosinophilic activity markers eosinophilic cationic protein (ECP) and the cellular surface antigen (CD9). RESULTS: The eosinophil count was greater in BPD compared with RDS and healthy infants (1414 vs. 797 and 471 cells per microlitre, respectively, p = 0.03). ECP levels were elevated (34 vs. 12.8 and 9.8 microg/L, respectively, p = 0.002) and CD9 levels reduced (75 vs. 94 and 86 mean fluorescence intensity units, respectively, p = 0.01) in BPD compared with RDS and healthy infants, suggesting eosinophilic activation in BPD. These findings were not solely explained by differences between gestational age or birth weight of the different groups. ECP levels were positively correlated with the duration of oxygen supplementation in the BPD group. The eosinophil count fell promptly after steroid treatment was commenced in the BPD group. CONCLUSION: The findings suggest that BPD is linked to eosinophil activation, which might contribute to the pathogenesis.     

Co-administration of salbutamol and fluticasone for emergency treatment of children with moderate acute asthma.

This study aimed to compare the efficacy of nebulized therapy with salbutamol alone or in combination with fluticasone. In a randomized, double-blind clinical trial, 150 children with moderate acute asthma were randomly assigned to receive by nebulizations either (i) three doses of salbutamol 30 microl/kg per dose, each dose administered every 15 min, (ii) three doses of salbutamol plus two doses of fluticasone 500 microg/dose at 15 and 30 min after first dose of salbutamol, or (iii) three doses of salbutamol/fluticasone 500 microg/dose, each combined dose administered every 15 min. Pulse oxymetry (SaO2), peak expiratory flow (PEF) and Wood et al. (Am J Dis Child, 123, 1972, 123) clinical scale were evaluated at baseline, 15, 30, 45, 60, 90 and 120 min after the first nebulization. Patients in the three groups significantly improved since 15 min after the first nebulization. We did not observe differences in the recovery of SaO2 and PEF among the three groups of treatment (p > 0.10). In group 3, children showed better clinical response at 120 min than the other two groups (p < 0.05). No significant adverse effects were observed with any treatment. To summarize, in children with acute moderate asthma, nebulized salbutamol at an accumulated dose of 90 mul/kg plus fluticasone at an accumulated dose of 1500 microg produced better clinical relief after 2 h. However, similar PEF and SaO2 responses were observed with salbutamol alone or in combination with different doses of fluticasone.     

急性哮喘发作患儿诱导痰液炎性细胞、白细胞介素-6、-8变化的意义

目的 了解儿童哮喘急性发作时气道炎性特征及临床意义 方法 对34例急性发作期、24例稳定期哮喘患儿和15例正常儿童的诱导痰液进行炎性细胞计数和分类,并测定其中白细胞介素-6(IL-6)、IL-8水平,分析炎性细胞与上述细胞因子及最大呼气流速(PEF)的关系 结果 哮喘急性发作组总细胞数较正常对照组明显增高,急性发作组嗜酸性粒细胞(EOS)、中性粒细胞及单核细胞比例均高于正常对照组,淋巴细胞比例明显低于正常对照组,稳定组EOS比例明显高于正常对照组 EOS比例与PEF呈显著负相关,IL-8水平与中性粒细胞呈显著正相关,急性发作期IL-6水平与EOS呈显著正相关 结论 急性哮喘发作患儿气道炎症是由EOS、中性粒细胞及单核细胞参与的炎症,IL-6、IL-8可能是参与此过程的重要细胞因子 痰液EOS数与病情严重程度相关,可作为监测病情及疗效的指标之一 针对这些细胞因子的治疗具有潜在价值     

Persistent cough in children and the overuse of medications

OBJECTIVE: Children referred for persistent cough were evaluated for the referring and final diagnosis, and the extent of the use of medications prior to referral and the side effects encountered. METHODS: Data on children seen by respiratory paediatricians for persistent cough (> or =4 weeks) in a tertiary respiratory setting were collected prospectively over 12 months. RESULTS: Of the 49 children, 61.2% were diagnosed with asthma at referral, with similar referral rates from general practitioners and paediatricians. Children with isolated cough were just as likely to have been diagnosed with asthma as children with cough and wheeze. Medication use (asthma, gastro-oesophageal reflux and antibiotics) prior to referral was high, asthma medications were most common, and of these 12.9% had significant steroid side effects. The most common abnormality found (46.9%) was a bronchoscopically defined airway lesion, and in 56.5% of these children, another diagnosis (aspiration, achalasia, gastro-oesophageal reflux) existed. No children had a sole final diagnosis of asthma and pre-referral medications were weaned in all children. CONCLUSION: Over diagnosis of asthma and the overuse of asthma treatments with significant side effects is common in children with persistent cough referred to a tertiary respiratory clinic. Children with persistent cough deserve careful evaluation to minimize the use of unnecessary medications and, if medications are used, assessment of response to treatment is important.     

The effect of nebulized budesonide treatment in children with mild to moderate exacerbations of asthma

Background: The role of inhaled corticosteroids in the treatment of acute asthma remains a controversial subject. Objective and methods: A randomized, double-blind, placebo-controlled parallel-group clinical trial on the effect of a 5-d course of nebulized budesonide treatment in children with mild to moderate exacerbation of asthma was performed. The need for systemic corticosteroid intervention was evaluated as the primary outcome measure. Results: Sixty-seven children aged 6 to 15 y were enrolled. During the emergency department phase, they received three nebulizations of either budesonide(1 mg/dose) or placebo, and then in the home phase of the study, they continued their study medications twice a day for another 4 d. Though the level of improvement in the emergency department phase was similar between the groups given either budesonide or placebo treatments (6.8±1.9% vs 4.0±1.5%, p=0.30, respectively), nebulized budesonide caused a trend towards a benefit in terms of the need for systemic corticosteroid intervention (2/33 vs 7/34, p=0.07), but not in secondary outcome measures.

Conclusion: Though we show a tendency towards a benefit with nebulized budesonide in children with mild to moderate exacerbations in terms of prevention of progression of the illness, the documented benefit is small and includes, at least, consideration for clinical significance, cost-effectiveness, impracticality and safety.     

儿童支气管哮喘的心理治疗

支气管哮喘是儿童期较常见的一种变态反应性疾病。是一种以嗜酸粒细胞、肥大细胞和T淋巴细胞反应为主的气道变应性炎症和气道高反应性为特征的疾病。临床表现为反复发作伴有哮鸣音的呼气性呼吸困难。是儿童期常见的慢性疾病,严重威胁儿童健康。近几年其发病率和死亡率均呈上升趋势。许多研究已证实儿童哮喘与心理因素存在一定关系,社会心理因素对患儿的哮喘促发起直接或间接作用。免疫学研究也发现支气管哮喘变态反应的启动与心理因素有很大关系。1心理因素与哮喘发作的关系随着医学模式的转变,有关行为、精神及心理因素与哮喘的关系逐渐受…     

Reduced levels of IgG subclasses and IgA in young children with asthma

Serum immunoglobulins including IgG subclasses were measured in 73 unselected children with asthma. The results showed that 22 (30%) had partial IgA and/or IgG₄ subclass deficiency. Clinical assessment showed that 21 children were infection-prone, and 52 were not. Further analysis showed that infection-prone children were significantly different from non-infection-prone children with regard to familial history of allergy (29% vs 60%, p = 0.015), elevated IgE (62% vs 33%, p = 0.021), IgA deficiency (38% vs 15%, p = 0.38) and IgG subclass deficiency (24% vs 4%, p = 0.018). These results suggest that there may be subgroups of children with asthma who are also immunodeficient.     

Preventing asthma deaths in young people

Children die from asthma. When this happens, in almost all cases, there are avoidable and modifiable risk factors. Healthcare professionals can take simple steps, when we see children with asthma, that may prevent a death. These include identifying risk from a good history, ensuring children have the right treatment (and that they know how to take it), seeing hospitalisation as a trigger to educate children and families, and addressing wider determinants of health.