Nasal lavage leukotrienes in infants with RSV bronchiolitis

Respiratory syncytial virus (RSV) bronchiolitis is a very common infection in infants and, after the acute phase, a number of patients develop a reactive airway disease that lasts for years. Although the pathogenesis of the lung damage after RSV bronchiolitis is still largely unknown, previous studies suggest that leukotrienes may play an active part in it. The aim of this study was to measure leukotriene levels in the nasal lavage fluid (NLF) collected in infants during RSV bronchiolitis and 1 month later. Cysteinyl leukotrienes (Cys-LTs) and leukotriene B(4) (LTB(4)) were measured in the NLF of 22 infants with their first episode of RSV bronchiolitis and 16 healthy infants. A second NLF sample was collected to measure leukotriene levels 1 month after the acute disease. NLF Cys-LT levels were significantly higher in infants with RSV bronchiolitis than in healthy controls [950 pg/ml (285.5-2155.9) vs. 110.5 pg/ml (66.5-451.3), p = 0.01], and they remained so a month after the acute infection (p = 0.02). A subanalysis showed no difference in Cys-LTs concentrations, either between bronchiolitis infants with and without a family history of atopy, or between those with and without passive exposure to cigarette smoke. No significant difference was found between the LTB(4) levels measured in the bronchiolitis cases and the control children. Cys-LTs are significantly increased in the NLF of infants with acute RSV bronchiolitis, and remain so at 1-month follow-up, suggesting a possible role of these eicosanoids in the pathogenesis of the disease.     

Bacterial colonization in respiratory secretions from acute and recurrent wheezing infants and children

Lower respiratory tract infection in childhood often results in airway obstruction, characterized by wheezing. However, contribution of bacterial colonization to the wheezy state in children remains unclear. Wheezing and non-wheezing children requiring hospitalization were classified into three groups: (i) wheezing children having a past history of recurrent wheezing; (ii) wheezing children without such history; and (iii) non-wheezing children as control subjects. Respiratory secretions as sputum were analyzed microscopically, and cultured. Cultured pathogenic bacterial species in sputum were categorized into two subgroups according to their amounts, i.e., dominant and non-dominant amounts of colonies. Incidence of bacterial colonization and wheezing were assessed. Hospitalized children were mainly 1- to 2-yr old, and rapidly decreased in number for older ages. Children in the three groups belonged to different clinical entities. Children in the recurrent wheezing group were highly sensitized to mite allergens, and still required hospitalization after 2 yr of age. Incidence of bacterial colonization was similar between the three groups. Dominant and non-dominant amounts of bacterial colonization were 170/997 (17.1%) and 170/997 (17.1%), respectively, in the recurrent wheezing group; 28/146 (19.2%) and 35/146 (24.0%), respectively, in the acute wheezing group; and 15/56 (26.8%) and 7/56 (12.5%), respectively, in the non-wheezing group. Regardless of the presence of wheezing, bacterial colonization commonly occurred at a young age in the three groups. In recurrent wheezing children, boys (122/611, 20.0%) carried non-dominant amounts of bacteria more frequently than girls (48/386, 12.4%) (p < 0.01). Boys showed predominant wheezing and susceptibility to bacterial colonization. Assessment of bacterial colonization allowed us to characterize asthma onset and outgrowth in childhood.     

Allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children

Jartti T, Kuusipalo H, Vuorinen T, Söderlund‐Venermo M, Allander T, Waris M, Hartiala J, Ruuskanen O. Allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children.
Pediatr Allergy Immunol 2010: 21: 1008–1014.
© 2010 John Wiley & Sons A/S Background: Data on the link between atopy and viral wheeze are limited. Aim: To evaluate the association between IgE sensitization and viral infection in wheezing children. Methods: This is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). Eighteen respiratory viral infections were studied using all available methods. A specific immunoglobulin E (IgE) sensitization for common food and aeroallergens and other atopy‐related variables including total IgE, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology. Results: Atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. The number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total IgE level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13). Conclusions: According to our data, allergic sensitization is positively linked to rhinovirus‐, but not other virus‐, associated wheezing and calls attention for studies to test rhinovirus‐associated wheezing as a part of asthma risk indices.     

Immunomodulatory constituents of human milk change in response to infant bronchiolitis

Although epidemiological evidence is generally supportive of a causal association between respiratory syncytial virus (RSV) bronchiolitis during infancy and the development of persistent wheeze/asthma, if not allergy, the mechanism by which this occurs and an explanation for why all children do not succumb remains to be elucidated. Breast feeding has been found to confer a protective effect against respiratory infections such as RSV bronchiolitis and allergy; however, again there is little direct evidence and no clear mechanism. In this study, we examined whether human milk immunomodulatory factors (cells, cytokines) change in response to clinically diagnosed, severe bronchiolitis in the recipient breast-fed infant. We examined milk from 36 breast feeding mothers of infants hospitalized with bronchiolitis and compared them with milk from 63 mothers of postpartum age-matched healthy controls. Milks from mothers of infants hospitalized with bronchiolitis had significantly greater numbers of viable cells when compared with the milks obtained from mothers of healthy infants (1.3 +/- 0.4 vs. 0.3 +/- 0.03 x 10(6) cells/ml, mean +/- s.e.m.; p < or = 0.001). Further, the cells obtained from the mothers of infants hospitalized with bronchiolitis were found to produce a skewed cytokine profile ex vivo in response to stimulation by live RSV but not when cultured with a non-specific mitogen (concanavalin A). This study provides preliminary evidence for an immunological link between mothers and their breast-fed infants during severe respiratory infections as well as a possible contributing factor to the development of persistent wheeze in these infants.     

婴幼儿反复或持续喘息病因谱分析及诊断程序探讨

目的 分析婴幼儿反复或持续喘息的病因分布,并探讨病因诊断程序.方法 对临床以持续喘息≥4周或反复喘息≥3次、年龄≤3岁的185例住院患儿进行病史询间和查体,并进行肺功能、X线胸片、胸部CT或气管三维重建、纤维支气管镜、24 h食管pH值监测等检查,结合治疗效果,最后确定病因诊断.结果 婴幼儿反复或持续喘息病因比例依次为:支气管哮喘123例次(62.12%),气管支气管软化症22例次(11.11%),气管支气管狭窄18例次(9.09%),吸入因素10例次(5.05%,其中异物5例、胃食管反流2例、腭裂2例、气管食管瘘1例),支气管肺发育不良5例次(2.53%),闭塞性毛细支气管炎4例次(2.02%),支气管淋巴结结核4例次(2.02%),先天性心脏病4例次(2.02%),其他病因7例次(3.54%).单一病因171例(92.4%),复合病因14例(7.6%).结论 支气管哮喘是婴幼儿出现反复或持续喘息的首要病因,支气管淋巴结结核、闭塞性毛细支气管炎等与感染相关的喘息性疾病亦不容忽视,6个月以内婴儿最多见的病因为先天性气道发育异常;反复或持续喘息、对常规治疗无效或不敏感者,应作纤维支气管镜、胸部CT三维重建检查,以排除其他原因所致喘息;应根据病因分布和临床特征,制定婴幼儿反复或持续喘息病因诊断程序.     

Eosinophil cationic protein in nasopharyngeal secretions and serum of infants infected with respiratory syncytial virus

Eosinophil cationic protein (ECP) was assayed in nasopharyngeal secretion (NPS) and serum from 42 infants, hospitalized with acute lower respiratory infection, in El Salvador and the results analyzed in relation to etiology of the infection. ECP concentrations were high in NPS, at an average 50 times higher than those found in serum. Exceedingly high levels of ECP (> 1000 μg/L) were found more frequently in wheezing than in non-wheezing children (30% vs 7%) and, accordingly, were more commonly found in children hospitalized with bronchiolitis than in those with pneumonia. Excessive levels were significantly more common in girls than in boys. Of the 42 cases, 28 were found to be caused by respiratory syncytial virus (RSV) subgroup A, and 3 by RSV-B, by means of detection of RSV antigen in nasopharyngeal cells. ECP serum levels were moderately elevated during the acute phase of the respiratory infection and increased slightly but significantly, in cases with RSV antigen-positive bronchiolitis, but not in those with pneumonia. The ECP levels in NPS from patients in Sweden who, by antigen detection in NPS cells, were diagnosed as either RSV or para-influenza 3 infection or none of these, were similar. These results indicate that elevation of ECP in NPS is associated with acute lower respiratory infection in general, but particularly pronounced in cases of bronchiolitis. Elevation of ECP is not an exclusive consequence of RSV infection, but may occur to an equal extent in infections caused by other agents. Girls generally seem to be less prone than boys to developing airway obstruction and may, therefore, acquire severe bronchiolitis only when large amounts of inflammatory mediators, such as ECP, accumulate in the airways.     

Peripheral blood eosinophil counts and eosinophil cationic protein content of respiratory secretions in bronchiolitis: relationship to severity of disease

Infants and young children with acute viral respiratory illness were studied to determine the association of peripheral blood eosinophil counts and concentrations of eosinophil cationic protein (ECP) in nasopharyngeal secretions with the development and severity of bronchiolitis. Subjects included those with upper respiratory illness (URI) alone, pneumonia or bronchiolitis. Controls consisted of healthy infants, and those hospitalized with non-respiratory illnesses. While peripheral blood eosinophil counts were suppressed in all infected infants greater than two months of age, eosinophil counts in patients with bronchiolitis were significantly greater than in those with URI alone. ECP concentrations were significantly greater among individuals with bronchiolitis than other infected infants. For bronchiolitis cases with detectable peripheral blood eosinophils, eosinophil counts correlated weakly and inversely with oxygen saturations. In contrast, ECP concentrations were strongly inversely correlated with initial oxygen saturation. ECP concentrations were also significantly correlated with peripheral blood eosinophil counts. Viral infections suppress peripheral blood eosinophil counts in infants greater than two months of age, although the effect is somewhat overcome in patients with bronchiolitis. The form and severity of bronchiolitis is much more strongly related to degranulation of eosinophils in the respiratory tract than to peripheral blood eosinophil counts.     

Adult asthma after non-respiratory syncytial virus bronchiolitis in infancy: Subgroup analysis of the 20-year prospective follow-up study

BACKGROUND: Recent studies have stressed the influence of other viruses than respiratory syncytial virus (RSV) in the development of asthma in later childhood after bronchiolitis in infancy. However, the virus-specific prognosis until adulthood has remained obscure, due to lack of sufficiently long follow-up studies. The aim of the present study was to evaluate adult respiratory morbidity after bronchiolitis in infancy, focused on cases not caused by RSV. METHODS: A total of 54 children hospitalized for bronchiolitis at age <2 years were re-studied at median age 19 years; 22 with RSV bronchiolitis and 22 with non-RSV bronchiolitis outside RSV epidemic were included. RSV etiology was studied by antigen and antibody assays on admission. Adult asthma was defined by two ways, based on written questionnaire, clinical examination and home peak expiratory flow monitoring. Lung function was evaluated by flow-volume spirometry (FVS), bronchial reactivity by methacholine inhalation challenge (MIC), and atopy by skin prick tests (SPT). RESULTS: In the non-RSV group, asthma by two definitions was present in 41-50% (vs 18-27% in RSV group). In logistic regression, adjusted for gender, age on admission, current atopy and smoking, non-RSV etiology of bronchiolitis, compared with RSV etiology, increased asthma risk by both strict (odds ratio [OR], 8.34; 95% confidence interval [CI], 1.18-58.69) and less strict (OR, 7.93; 95% CI, 1.14-55.41) criteria. An abnormal result in FVS was present in 32-41% and in MIC in 48-52% of cases in non-RSV and RSV groups, respectively. CONCLUSIONS: Infants with non-RSV bronchiolitis requiring treatment in hospital are at an increased risk for subsequent asthma in adulthood.     

Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: A longitudinal birth cohort study

Several epidemiological studies have reported recurrent wheezing and asthma in children after respiratory syncytial virus (RSV) bronchiolitis in infancy. The relationship with allergic sensitization is less clear and recent evidence suggests an interaction between atopy and RSV infection in the development of asthma. Data from a large, population-based, birth-cohort (Avon Longitudinal Study of Parents and Children) were used to compare outcomes of children according to whether or not they had been admitted to hospital in the first 12 months with RSV-proven bronchiolitis. Outcomes considered were 12-month prevalence of wheeze at two ages (between 30-42 and 69-81 months), cumulative prevalence of doctor-diagnosed asthma at 91 months and skin prick test defined atopy at 7 yr. Multivariable logistic regression models were used to calculate odds ratios for outcomes adjusted for potential confounders. A total of 150 infants (1.1% of the cohort) were admitted to hospital within 12 months of birth with RSV bronchiolitis. The prevalence of wheezing was 28.1% in the RSV group and 13.1% in controls at 30-42 months and 22.6% vs. 9.6% at 69-81 months. The cumulative prevalence of asthma was 38.4% in the RSV group and 20.1% in controls at 91 months. Atopy was found in 14.6% of the RSV group and in 20.7% of controls at 7 yr. RSV bronchiolitis was associated with subsequent wheezing between 30-42 (Odds ratio [95% CI] 2.3 [1.3, 3.9]) and 69-81 months (OR 3.5 [1.8, 6.6]) and with the cumulative prevalence of asthma at 91 months (OR 2.5 [1.4, 4.3]) but not with atopy (OR 0.7 [0.2, 1.7]). In a population-based birth cohort, RSV bronchiolitis was associated with subsequent wheezing and asthma but not with the development of atopy by age 7 yr.     

Serum eosinophil cationic protein and interleukin-5 in children with bronchial asthma and acute bronchiolitis

The aim of our study was to evaluate the clinical applicability of serum eosinophil cationic protein (ECP), interleukin-5 (IL-5) and total eosinophil counts in childhood asthma and bronchiolitis. These parameters were measured in 44 children aged 12-84 months with moderate and mild asthma during symptomatic and asymptomatic phases of disease. Fifteen of the patients were included at the time of admission to hospital due to an acute asthmatic attack, and ten of these were also examined one month after discharge. None of the patients were treated with glucocorticoids or cromoglycate at any time during the study. Serum ECP was significantly increased in the children with acute asthma compared to children with stable moderate asthma, stable mild asthma, as well as to controls. There was no difference between the groups with stable asthma or between stable asthma and controls, and there was large overlap between all groups of asthmatics and controls. Detectable levels of circulating IL-5 were demonstrated in eight of 15 children with acute asthma, with significantly higher levels in atopic children, whereas all samples from children with stable asthma and controls were negative. The results suggest that even though serum ECP and IL-5 increases during acute asthmatic attacks, these parameters cannot alone be used to discriminate between different groups of young children with stable asthma, nor between asthmatics and healthy controls. In addition, the same parameters of eosinophil inflammation were examined in serum samples from 25 children aged 1-17 months undergoing their first episode of acute bronchiolitis. Children with acute respiratory syncytial virus (RS V) bronchiolitis had significantly higher levels of serum ECP than those with RSV negative disease, whereas the total eosinophil counts were significantly decreased in all patients with acute bronchiolitis. Serum IL-5 was only detected in two children with acute bronchiolitis. The results suggest that the inflammation in RSV bronchiolitis differs from that induced by other viruses.     

Origins of reactive airways disease in early life: do viral infections play a role?

There is mounting evidence suggesting that infection with respiratory syncytial virus (RSV) in early life increases the risk of developing reactive airway disease (RAD) later in childhood. A recent prospective study demonstrated that children hospitalized with RSV bronchiolitis in infancy face a significantly increased risk of recurrent wheezing and allergy at least until the age of 7 y that is independent of hereditary factors. Proposed mechanisms for this link include immune dysregulation, in which RSV-specific IgE or an imbalance between T-lymphocyte-dependent immune pathways may be involved, and abnormal neural control, in which the non-adrenergic, non-cholinergic pathways are altered by RSV infection. More recent studies suggest that immune and neural mechanisms may be linked and that post-RSV airway inflammation may be explained, at least in part, on the basis of these neuroimmune interactions.
Conclusion : Passive immunoprophylaxis may protect against persistent viral-induced inflammation of the respiratory tract, long-term changes in pulmonary function and increased frequency of RAD episodes.     

Risk of respiratory syncytial virus in survivors with severe congenital diaphragmatic hernia

Background: During the follow-up period in surviving patients with severe congenital diaphragmatic hernia (CDH), respiratory complications, such as recurrence of CDH or chronic lung disease, have been reported to occur as a late complication. Although some risk factors for deterioration of respiratory condition have been reported in CDH, the risk of respiratory syncytial virus (RSV) in postoperative CDH patients has not as yet been reported upon.
Methods: In 21 survivors with severe CDH, which had been detected antenatally, and whose lung:thoracic ratio was <0.2, the risk of RSV infection in those patients was investigated.
Results: Five survivors with severe CDH had RSV infection and three patients needed hospitalization due to bronchiolitis during the follow-up period. In two patients the recurrence of CDH after the infection resulted in the need to perform a re-operation for CDH. All patients often suffered from chronic wheezing requiring medication after the first RSV infection.
Conclusion: RSV infection is a risk for deterioration of postoperative respiratory condition in severe CDH survivors. Considering the presence of pulmonary hypoplasia in severe CDH, the routine use of monoclonal antibody for RSV (palivizumab) might be effective for patients with severe CDH in the high season of RSV, similar to the patients with chronic lung disease, although further large multicenter studies are needed to clarify this hypothesis.     

辅助性T细胞17及白介素-17在呼吸道合胞病毒毛细支气管炎的表达及作用

目的探讨呼吸道合胞病毒（RSV）毛细支气管炎（毛支）患儿急性期外周血辅助性T细胞17（Th17）和白介素17（IL-17）水平的变化及作用。方法选取RSV毛支急性期患儿（n=28,其中轻度组16例、重度组12例）为毛支组,以哮喘急性发作儿童（n=12）为哮喘组,近期无感染的小儿外科术前患儿（n=10）为对照组。以流式细胞术检测外周血Th17表达,ELISA方法检测外周血IL-17;分析RSV毛支患儿急性期外周血Th17细胞和IL-17表达与病情严重程度的关系。结果毛支重度组外周血Th17细胞比例和IL-17水平分别高于轻度组和对照组,差异均有统计学意义(P＜0.05);但与哮喘组比较,差异无统计学意义(P＞0.05)。结论 RSV毛细支气管炎患儿急性期外周血Th17细胞和IL-17表达水平增加,Th17细胞和IL-17可能参与RSV毛细支气管炎的发病机制。     

Viral Findings in Children under the Age of Two Years with Expiratory Difficulties

ABSTRACT. Viral findings were prospectively studied in lower respiratory tract infections in small children with and without expiratory difficulties. On first admission, a viral aetiology was found in 71 of 127 children (56%). On re-admission, a viral etiology was found in only two of 31 cases (6%). Respiratory syncytial viruses (RSV) were responsible for 71% of the cases with viral diagnoses. A recently-developed method for the direct detection of viral antigens in nasopharyngeal specimens by radio-immunoassay was more sensitive than complement fixation serology, especially in patients aged less than six months. Viral diagnosis was reached using this new method alone in 43% of infections caused by RSV and in 27% of infections caused by other viruses. In children under six months, RSV were found in 89% by direct antigen detection and in 22% by serology. We suggest that direct antigen detection should be used as the primary virological method in small children with lower respiratory tract infections. The aetiological agents were the same in cases with and without expiratory difficulties, RSV being found in about 40% of children in both instances. It is concluded that host factors are critical to the development of expiratory difficulties.     

嗜酸性粒细胞趋化因子在呼吸道合胞病毒性毛细支气管炎中的作用和意义

目的探讨呼吸道合胞病毒(RSV)毛细支气管炎(毛支)患儿血、痰中嗜酸性粒细胞趋化因子(Eotaxin)的临床意义。方法对象为轻、中度毛支患儿22例和重度毛支患儿11例,选择无喘息病毒性肺炎12例作为对照组。采用双抗体夹心酶联免疫吸附试验(ELISA)测定各组患儿血清和痰中Eotaxin水平,并进行比较。结果急性期轻、中度毛支组和重度毛支组血清、痰Eotaxin水平高于对照组(P<0.01)。恢复期轻、中度毛支组和重度毛支组血清Eotaxin水平高于对照组。轻、中度毛支组和重度毛支组比较差异无统计学意义。结论 RSV毛支患儿血和痰液中Eotaxin增高,Eotaxin在毛支的发病机制中起重要作用。