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1.  Asthma in preschool children: the next challenge 
Purpose of review
To describe a prospective classification for preschool wheezers according to temporal symptom pattern, and summarise findings relating to the management of viral wheeze and the use of short term therapy for intermittent severe wheeze.
Recent findings
Phenotypes defined from cohort studies should only be applied retrospectively at school-age. A new classification that can be applied prospectively is discussed. The importance of early rhinovirus induced wheezing as a risk factor for asthma has become apparent. However, there is no benefit from short-course oral steroids for acute viral wheeze in the majority of cases. There is conflicting evidence for the role of intermittent montelukast or inhaled steroids in the treatment of acute, intermittent wheeze. A link between reduced vitamin D intake during pregnancy and increased preschool wheeze in offspring has emerged, suggesting a potential role for vitamin D supplementation in primary prevention.
Based on current evidence, a trial of bronchodilators is first line therapy for viral wheeze, and maintenance montelukast or inhaled steroids may be considered in preschool wheezers with persistent symptoms and risk factors for future asthma. No disease modifying therapies are available. New therapeutic options for preschool wheezing disorders are desperately needed.
PMCID: PMC4254141  PMID: 19307884
preschool wheeze; management; diagnosis; phenotypes
2.  Interleukin-33 promotes airway remodelling in paediatric severe steroid resistant asthma 
Th2 cytokines are not responsible for the on-going symptoms and pathology in children with severe therapy resistant asthma (STRA). Interleukin (IL)-33 induces airway hyperresponsiveness (AHR), but its role in airway remodelling and steroid resistance is unknown.
To investigate the relationship between IL-33 and airway remodelling in paediatric STRA.
IL-33 was quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodelling and IL-33 was assessed. HDM induced allergic airways disease (AAD) in neonatal ST2−/− mice lacking the IL-33 receptor was assessed, together with collagen production following IL-33 administration. Impact of steroid therapy on IL-33 levels in neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsies from children with STRA and related to remodelling, and collagen production by paediatric airway fibroblasts stimulated with IL-33 and budesonide quantified.
Blocking IL-13 after AAD was established in neonatal mice did not reduce remodelling or IL-33 levels; AHR was only partially reduced. IL-33 promoted collagen synthesis both from paediatric asthmatic fibroblasts, and following intra-nasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in endobronchial biopsies from children with STRA, whilst remodelling was absent in HDM exposed ST2−/− mice. IL-33 was maintained whilst IL-13 was abrogated by steroid treatment in neonatal HDM exposed mice, and in endobronchial biopsies from children with STRA.
IL-33 is a relatively steroid resistant mediator that promotes airway remodelling in STRA, and is an important therapeutic target.
PMCID: PMC4218948  PMID: 23759184
Asthma; paediatric; airway remodelling; steroid resistance; IL-33; therapy
3.  Viral infections and the development of asthma in children 
Viral aetiology, host susceptibility (in particular allergic predisposition and sensitization), and illness severity, timing and frequency all appear to contribute as synergistic factors to the risk of developing asthma. Experimental models have shown both innate and adaptive immune responses contribute to this risk with lung inflammatory cells showing marked differences in phenotype and function in young compared with older animals, and these differences are further enhanced following virus infection. Findings to date strongly suggest that the impact of infant and preschool viral infections on the maturing immune system and developing lung that subsequently result in an asthma phenotype occur during a critical susceptibility period, and in a genetically susceptible host. There are currently no therapeutic strategies that allow primary or secondary prevention of asthma following early life viral respiratory infections in high-risk children, thus a focus on understanding the mechanisms of progression from viral wheezing in infants and preschool children to asthma development are urgently needed. This review summarizes the data reporting the role of the two most common viruses, that is, respiratory syncytial virus and human rhinovirus, that result in asthma development, comparing risk factors for disease progression, and providing insight into strategies that might be adopted to prevent asthma development.
PMCID: PMC4040725  PMID: 25165549
asthma; preschool wheeze; respiratory syncytial virus; rhinovirus; virus
4.  Management of severe asthma in children 
Lancet  2010;376(9743):814-825.
Children who are referred to specialist care with asthma that does not respond to treatment (problematic severe asthma) are a heterogeneous group, with substantial morbidity. The evidence base for management is sparse, and is mostly based on data from studies in children with mild and moderate asthma and on extrapolation of data from studies in adults with severe asthma. In many children with severe asthma, the diagnosis is wrong or adherence to treatment is poor. The first step is a detailed diagnostic assessment to exclude an alternative diagnosis (“not asthma at all”), followed by a multidisciplinary approach to exclude comorbidities (“asthma plus”) and to assess whether the child has difficult asthma (improves when the basic management needs, such as adherence and inhaler technique, are corrected) or true, therapy-resistant asthma (still symptomatic even when the basic management needs are resolved). In particular, environmental causes of secondary steroid resistance should be identified. An individualised treatment plan should be devised depending on the clinical and pathophysiological characterisation. Licensed therapeutic approaches include high-dose inhaled steroids, the Symbicort maintenance and reliever (SMART) regimen (with budesonide and formoterol fumarate), and anti-IgE therapy. Unlicensed treatments include methotrexate, azathioprine, ciclosporin, and subcutaneous terbutaline infusions. Paediatric data are needed on cytokine-specific monoclonal antibody therapies and bronchial thermoplasty. However, despite the interest in innovative approaches, getting the basics right in children with apparently severe asthma will remain the foundation of management for the foreseeable future.
PMCID: PMC3471126  PMID: 20816548
5.  Relationship between Serum Vitamin D, Disease Severity, and Airway Remodeling in Children with Asthma 
Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).
Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA.
Serum 25-hydroxyvitamin D [25(OH)D3] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D3, the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling.
Measurements and Main Results
25(OH)D3 levels (median [IQR]) were significantly lower in STRA (28 [22–38] nmol/L) than in MA (42.5 [29–63] nmol/L) and control subjects (56.5 [45–67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D3 levels and percent predicted FEV1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D3 levels (r=−0.6, P = 0.008). There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001).
Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA.
PMCID: PMC3471128  PMID: 21908411
vitamin D; asthma; remodeling; airway smooth muscle; pediatrics
6.  1α,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells 
Thorax  2012;67(7):574-581.
CD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R. This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable. Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated.
CD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1α,25-dihydroxyvitamin D3 (1α,25VitD3) exposure in vitro and in peripheral T cells following 1α,25VitD3 oral ingestion in vivo. The effect of 1α25VitD3 was also assessed in human airway-resident cells.
1α25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals. CD200R expression was not modulated in any cells studied. CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium. T cells isolated from the human airway also responded strongly to 1α25VitD3 to upregulate CD200.
The capacity of 1α,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health.
PMCID: PMC3471129  PMID: 22334534
7.  Development of the bronchial epithelial reticular basement membrane: relationship to epithelial height and age 
Thorax  2011;66(4):280-285.
The bronchial epithelium and underlying reticular basement membrane (RBM) have a close spatial and functional inter-relationship and are considered an epithelial–mesenchymal trophic unit (EMTU). An understanding of RBM development is critical to understanding the extent and time of appearance of its abnormal thickening that is characteristic of asthma.
RBM thickness and epithelial height were determined in histological sections of cartilaginous bronchi obtained postmortem from 47 preterm babies and infants (median age 40 weeks gestation (22 weeks gestation–8 months)), 40 children (2 years (1 month–17 years)) and 23 adults (44 (17–90) years) who had died from non-respiratory causes, and had no history of asthma.
The RBM was visible by light microscopy at 30 weeks gestation. RBM thickness increased in successive age groups in childhood; in infants (r=0.63, p<0.001) and in children between 1 month and 17 years (r=0.82, p<0.001). After 18 years, RBM thickness decreased with increasing age (r=−0.42, p<0.05). Epithelial height showed a similar relationship with age, a positive relationship from preterm to 17 years (r = 0.50, p<0.001) and a negative relationship in adulthood (r=−0.84, p<0.0001). There was a direct relationship between epithelial height and RBM thickness (r=0.6, p<0.001).
The RBM in these subjects was microscopically identifiable by 30 weeks gestation. It thickened during childhood and adolescence. In adults, there was either no relationship with age, or a slow reduction in thickness in older age. Developmental changes of RBM thickness were accompanied by similar changes in epithelial height, supporting the close relationship between RBM and epithelium within the EMTU.
PMCID: PMC3471130  PMID: 21233480
8.  The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells 
European journal of immunology  2012;42(10):2697-2708.
1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4+ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3− T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.
PMCID: PMC3471131  PMID: 22903229
1α,25-Dihydroxyvitamin D3; Asthma; Immune regulation; Regulatory T cells
10.  Innate helper cells: a novel cell type essential in the initiation of asthma? 
Thorax  2011;66(9):834-835.
The role of the innate immune system in asthma initiation is being increasingly recognised, and several innate epithelial cytokines, such as interleukin 33 (IL-33), IL-25 and thymic stromal lymphopoietin, have been described as important in asthma pathogenesis. However, until now, the mechanism by which these cytokines initiate Th2 responses and form a link with the adaptive immune system was undetermined. The recent discovery of a new group of non-T, non-B innate helper cells, which are induced by epithelial innate cytokines and secrete the Th2 cytokines IL-4 and IL-13, may provide a mechanism by which the innate and adaptive immune systems become activated in asthma.
PMCID: PMC3466786  PMID: 21680565
11.  Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines 
The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood.
We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the TH2 cytokines IL-4, IL-5, and IL-13.
Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen TH2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation.
Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5+ and IL-13+ cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid TH2 cytokines had significantly lower lung function than those with undetectable BAL fluid TH2 cytokines.
STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the TH2 mediators that are thought to drive allergic asthma were mostly absent.
PMCID: PMC3381727  PMID: 22385633
Pediatric asthma; eosinophilia; remodeling; severe therapy-resistant asthma; mediators
12.  Asthma and allergy: The emerging epithelium 
Nature medicine  2010;16(3):273-274.
Thinking about how asthma and allergic diseases arise is undergoing several shifts. In ‘Bedside to Bench’, Clare M. Lloyd and Sejal Saglani examine how recent human studies are putting the focus on the epithelium as a major contributor to asthma. The findings shift the emphasis away from the T helper type 2 immune response, and call into question the utility of current animal models of the disease. Although asthma and other allergic disorders are known to have origins in infancy, some researchers are looking even earlier, to effects in utero and before conception. In ‘Bench to Bedside’, Catherine Hawrylowicz and Kimuli Ryanna highlight animal studies that outline some of the effects of the maternal environment, and they examine the potential implications for prevention of disease.
PMCID: PMC3380503  PMID: 20208514
13.  Pathophysiological Features of Asthma Develop in Parallel in House Dust Mite–Exposed Neonatal Mice 
Asthma frequently commences in early life during airway and immune development and exposure to new environmental challenges. Endobronchial biopsies from children with asthma are abnormal, and lung function is maximally reduced by 6 years of age. As longitudinal biopsy studies are unethical in children, the relationship between development of pathology and reduced lung function is unknown. We aimed to establish a novel neonatal mouse model of allergic airways disease to investigate the developmental sequence of the pathophysiologic features of asthma. Neonatal Balb/c mice were challenged three times weekly from Day 3 of life using intranasal house dust mite (HDM) or saline for up to 12 weeks. Weekly assessments of airway inflammation and remodeling were made. Airway hyperresponsiveness (AHR) to methacholine was assessed from Week 2 onward. Total and eosinophilic inflammation was significantly increased in the lungs of HDM-exposed neonates from Week 2 onwards, and a peak was seen at 3 weeks. Goblet cells and peribronchiolar reticulin deposition were significantly increased in HDM-exposed neonates from Week 3, and peribronchiolar collagen was significantly greater from Week 4. HDM-exposed neonates had increased AHR from Week 2 onward. Although inflammation and AHR had subsided after 4 weeks without allergen challenge, the increased reticulin and collagen deposition persisted in HDM-exposed mice. Neonatal mice exposed to intranasal HDM developed eosinophilic inflammation, airway remodeling, and AHR as reported in pediatric asthma. Importantly, all abnormalities developed in parallel, not sequentially, between 2 and 3 weeks of age.
PMCID: PMC3380517  PMID: 19151316
pediatric; remodeling; asthma pathophysiology; mouse model; allergic airways disease

Results 1-13 (13)