Contemporaneous maturation of immunologic and respiratory functions during early childhood: Implications for development of asthma prevention strategies

Holt, Patrick G.; Upham, John W.; Sly, Peter D.

doi:10.1016/j.jaci.2005.04.017

Cited by 201 publications

(185 citation statements)

References 102 publications

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“…In conclusion, this model provides a plausible explanation for epidemiological findings that severe asthma exacerbations triggered by virus infection are much more frequent in atopics than in nonatopics (2,8,9,11,12,38), and that over a longer time scale risk for inflammation-driven progression to persistent asthma is highest in children experiencing these insults in combination (2,56). In relationship to future human research in this area, our findings provide ethical justification for extending these invasive studies to a broader range of relevant clinical phenotypes, in particular to children who experience wheezing attacks in the apparent absence of viral infection.…”

Section: Discussionmentioning

confidence: 78%

Interactions between Innate Antiviral and Atopic Immunoinflammatory Pathways Precipitate and Sustain Asthma Exacerbations in Children

Subrata

Bizzintino

Mamessier

et al. 2009

The Journal of Immunology

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188

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Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated “exhausted” phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcεR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R+ alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-α can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.

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Section: Discussionmentioning

confidence: 78%

Interactions between Innate Antiviral and Atopic Immunoinflammatory Pathways Precipitate and Sustain Asthma Exacerbations in Children

Subrata

Bizzintino

Mamessier

et al. 2009

The Journal of Immunology

Self Cite

188

172

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“…Due to the small calibre of their airways at baseline, these subjects have a tendency to wheeze in response to even relatively mild stimuli that cause only small degrees of airway narrowing [2] and, in community studies, it is difficult to distinguish these subjects from those wheezing as a result of more intense airway inflammation. We have argued previously on the basis of findings from multiple studies that severe airways inflammation during the early postnatal phase of rapid lung growth has potential to disturb underlying tissue differentiation programmes responsible for establishing normal lung function, and, furthermore, that the sequelae of such disturbances can ''track'' over time and manifest in later life as abnormal respiratory functions associated with the asthma phenotype [5,17].…”

Section: Discussionmentioning

confidence: 99%

Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze

Kusel

Kebadze²,

Johnston³

et al. 2011

Eur Respir J

109

145

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Severe viral respiratory illnesses and atopy are risk factors for childhood wheezing and asthma. The aim of this study was to explore associations between severe respiratory infections and atopy in early childhood with wheeze and asthma persisting into later childhood.147 children at high atopic risk were followed from birth to age 10 yrs. Data on all respiratory infections occurring in infancy were collected prospectively and viral aetiology ascertained. Atopy was measured by skin prick tests at 6 months, and 2 and 5 yrs. History of wheeze and doctordiagnosed eczema and asthma was collected regularly until 10 yrs of age.At 10 yrs, 60% of the cohort was atopic, 25.9% had current eczema, 18.4% current asthma and 20.4% persistent wheeze. 35.8% experienced at least one lower respiratory infection (LRI) associated with fever and/or wheeze in first year of life. Children who had wheezy or, in particular, febrile LRI in infancy and were atopic by 2 yrs, were significantly more likely to have persistent wheeze (RR 3.51, 95% CI 1.83-6.70; p,0.001) and current asthma (RR 4.92, 95% CI 2.59-9.36; p,0.001) at 10 yrs.Severe viral respiratory infections in infancy and early atopy are risk factors for persistent wheeze and asthma. The strongest marker of the asthmatogenic potential of early life infections was concurrent fever. The occurrence of fever during respiratory illnesses is an important marker of risk for wheeze and asthma later in childhood, suggesting it should be measured in prospective studies of asthma aetiology.

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“…Not neutrophils but other leukocytes such as lymphocytes and antigen-presenting dendritic cells play a more important role in the defense against most viral infections. Dysregulation of these cells may furthermore contribute to the development of allergy and asthma (5,6). Nicotine, one of the main constituents of cigarette smoke, has a suppressive effect on myeloid dendritic cells (7)(8)(9).…”

mentioning

confidence: 99%

Maternal Tobacco Smoking and Decreased Leukocytes, Including Dendritic Cells, in Neonates

et al. 2007

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Maternal smoking in pregnancy is associated with respiratory diseases in the offspring, possibly due to prenatal influences on the developing immune system. We investigated whether maternal smoking in pregnancy was associated with cord blood leukocyte numbers, including precursor dendritic cells, adjusting for concomitant factors. In a prospective healthy birth cohort study, total leukocyte counts were reduced in neonates of smoking mothers [10.7 (8.4 -13.0 E nvironmental tobacco smoke exposure is associated with an increased risk of infections, impaired lung development, and respiratory morbidity and mortality in children (1). Specifically, smoking during pregnancy has been shown to act as an independent risk factor for wheezing disorders when compared with postnatal exposure to environmental tobacco smoke (2). Whereas inhaled tobacco smoke is known to have an effect on leukocyte numbers in the blood and to induce inflammatory responses in the airways of human adults, the effects of maternal smoking on blood counts and early immune responses of the offspring are poorly understood.Studies showing a decrease in leukocyte counts, especially neutrophilic granulocytes, in cord blood of neonates of smoking mothers have lead to the conclusion that this decrease might contribute to the susceptibility to infections and therefore increased respiratory morbidity in these children (3,4). However, these studies used only univariate statistical methods and were therefore not able to determine whether the decreased leukocyte counts were independently associated with maternal smoking, or whether they could be explained by other factors (e.g. maternal age or perinatal stress) that might be associated with both, maternal smoking and neonatal cell counts.The decrease in the number of neutrophilic granulocytes might contribute to an increased susceptibility to bacterial infections, whereas it is unlikely to be the major cause for the increased susceptibility to viral infections that are associated with symptoms of wheeze. Not neutrophils but other leukocytes such as lymphocytes and antigen-presenting dendritic cells play a more important role in the defense against most viral infections. Dysregulation of these cells may furthermore contribute to the development of allergy and asthma (5,6). Nicotine, one of the main constituents of cigarette smoke, has a suppressive effect on myeloid dendritic cells (7-9). As a consequence, these cells may be particularly affected in children of smoking mothers.The aim of this study was to investigate whether maternal smoking in pregnancy was associated with a decrease of lymphocytes and dendritic precursor cells in the cord blood of the neonates and whether these differences in leukocyte subtypes remained after adjustment for other determinants of neonatal leukocyte counts, such as maternal age, infections, atopic diseases, and perinatal stress. MATERIALS AND METHODSSubjects and protocol. In a prospective birth cohort study, 97 Caucasian infants were prenatally recruited from seven mat...

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Contemporaneous maturation of immunologic and respiratory functions during early childhood: Implications for development of asthma prevention strategies

Cited by 201 publications

References 102 publications

Interactions between Innate Antiviral and Atopic Immunoinflammatory Pathways Precipitate and Sustain Asthma Exacerbations in Children

Interactions between Innate Antiviral and Atopic Immunoinflammatory Pathways Precipitate and Sustain Asthma Exacerbations in Children

Febrile respiratory illnesses in infancy and atopy are risk factors for persistent asthma and wheeze

Maternal Tobacco Smoking and Decreased Leukocytes, Including Dendritic Cells, in Neonates

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