Position paper of the European Academy of Allergy and Clinical Immunology

Rhinitis is a common problem in childhood and adolescence and impacts negatively on physical, social and psychological well-being. This position paper, prepared by the European Academy of Allergy and Clinical Immunology Taskforce on Rhinitis in Children, aims to provide evidence-based recommendations for the diagnosis and therapy of paediatric rhinitis. Rhinitis is characterized by at least two nasal symptoms: rhinorrhoea, blockage, sneezing or itching. It is classified as allergic rhinitis, infectious rhinitis and nonallergic, noninfectious rhinitis. Similar symptoms may occur with other conditions such as adenoidal hypertrophy, septal deviation and nasal polyps. Examination by anterior rhinoscopy and allergy tests may help to substantiate a diagnosis of allergic rhinitis. Avoidance of relevant allergens may be helpful for allergic rhinitis (AR). Oral and intranasal antihistamines and nasal corticosteroids are both appropriate for first-line AR treatment although the latter are more effective. Once-daily forms of corticosteroids are preferred given their improved safety profile. Potentially useful add-on therapies for AR include oral leukotriene receptor antagonists, short bursts of a nasal decongestant, saline douches and nasal anticholinergics. Allergen-specific immunotherapy is helpful in IgE-mediated AR and may prevent the progression of allergic disease. There are still a number of areas that need to be clarified in the management of rhinitis in children and adolescents.publishersversionpublishe

Respiratory Syncytial Virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice

<p>Abstract</p> <p>Background</p> <p>Respiratory Syncytial Virus (RSV) infection is usually restricted to the respiratory epithelium. Few studies have documented the presence of RSV in the systemic circulation, however there is no consistent information whether virus detection in the blood correlates with disease severity.</p> <p>Methods</p> <p>Balb/c mice were inoculated with live RSV, heat-inactivated RSV or medium. A subset of RSV-infected mice was treated with anti-RSV antibody 72 h post-inoculation. RSV RNA loads were measured by PCR in peripheral blood from day 1-21 post-inoculation and were correlated with upper and lower respiratory tract viral loads, the systemic cytokine response, lung inflammation and pulmonary function. Immunohistochemical staining was used to define the localization of RSV antigens in the respiratory tract and peripheral blood.</p> <p>Results</p> <p>RSV RNA loads were detected in peripheral blood from day 1 to 14 post-inoculation, peaked on day 5 and significantly correlated with nasal and lung RSV loads, airway obstruction, and blood CCL2 and CXCL1 expression. Treatment with anti-RSV antibody reduced blood RSV RNA loads and improved airway obstruction. Immunostaining identified RSV antigens in alveolar macrophages and peripheral blood monocytes.</p> <p>Conclusions</p> <p>RSV RNA was detected in peripheral blood upon infection with live RSV, followed a time-course parallel to viral loads assessed in the respiratory tract and was significantly correlated with RSV-induced airway disease.</p

Rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells

BACKGROUND: Human rhinoviruses (RV), the most common triggers of acute asthma exacerbations, are considered not cytotoxic to the bronchial epithelium. Recent observations, however, have questioned this knowledge. The aim of this study was to evaluate the ability of RV to induce epithelial cytotoxicity and affect epithelial repair in-vitro. METHODS: Monolayers of BEAS-2B bronchial epithelial cells, seeded at different densities were exposed to RV serotypes 1b, 5, 7, 9, 14, 16. Cytotoxicity was assessed chromatometrically. Epithelial monolayers were mechanically wounded, exposed or not to RV and the repopulation of the damaged area was assessed by image analysis. Finally epithelial cell proliferation was assessed by quantitation of proliferating cell nuclear antigen (PCNA) by flow cytometry. RESULTS: RV1b, RV5, RV7, RV14 and RV16 were able to induce considerable epithelial cytotoxicity, more pronounced in less dense cultures, in a cell-density and dose-dependent manner. RV9 was not cytotoxic. Furthermore, RV infection diminished the self-repair capacity of bronchial epithelial cells and reduced cell proliferation. CONCLUSION: RV-induced epithelial cytotoxicity may become considerable in already compromised epithelium, such as in the case of asthma. The RV-induced impairment on epithelial proliferation and self-repair capacity may contribute to the development of airway remodeling

Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features

BACKGROUND: Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling. METHODS: Levels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations. RESULTS: Rhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations. CONCLUSIONS: Rhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma

Lower Respiratory Tract Infection Induced by a Genetically Modified Picornavirus in Its Natural Murine Host

Infections with the picornavirus, human rhinovirus (HRV), are a major cause of wheezing illnesses and asthma exacerbations. In developing a murine model of picornaviral airway infection, we noted the absence of murine rhinoviruses and that mice are not natural hosts for HRV. The picornavirus, mengovirus, induces lethal systemic infections in its natural murine hosts, but small genetic differences can profoundly affect picornaviral tropism and virulence. We demonstrate that inhalation of a genetically attenuated mengovirus, vMC0, induces lower respiratory tract infections in mice. After intranasal vMC0 inoculation, lung viral titers increased, peaking at 24 h postinoculation with viral shedding persisting for 5 days, whereas HRV-A01a lung viral titers decreased and were undetectable 24 h after intranasal inoculation. Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, induced an acute respiratory illness, with body weight loss and lower airway inflammation, characterized by increased numbers of airway neutrophils and lymphocytes and elevated pulmonary expression of neutrophil chemoattractant CXCR2 ligands (CXCL1, CXCL2, CXCL5) and interleukin-17A. Mice inoculated with vMC0, compared with those inoculated with vehicle or UV-inactivated vMC0, exhibited increased pulmonary expression of interferon (IFN-α, IFN-β, IFN-λ), viral RNA sensors [toll-like receptor (TLR)3, TLR7, nucleotide-binding oligomerization domain containing 2 (NOD2)], and chemokines associated with HRV infection in humans (CXCL10, CCL2). Inhalation of vMC0, but not vehicle or UV-inactivated vMC0, was accompanied by increased airway fluid myeloperoxidase levels, an indicator of neutrophil activation, increased MUC5B gene expression, and lung edema, a sign of infection-related lung injury. Consistent with experimental HRV inoculations of nonallergic, nonasthmatic human subjects, there were no effects on airway hyperresponsiveness after inhalation of vMC0 by healthy mice. This novel murine model of picornaviral airway infection and inflammation should be useful for defining mechanisms of HRV pathogenesis in humans

Elucidation of pathways driving asthma pathogenesis: development of a systems-level analytic strategy.

Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1-6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis

Cellular and animals models for rhinovirus infection in asthma

Human rhinoviruses (RVs) are responsible for the majority of upper respiratory tract infections. Despite the high prevalence, the pathogenesis is incompletely understood. Experimental models would permit study of the immunological response to infections. Animal models have many limitations because of the anatomic and physiological differences between mammalian species. The only nonhuman animals susceptible to RV are chimpanzees and gibbons. Mouse models are not used because of host cell tropism of RV. This problem may have been partially overcome by transfecting mouse cells with viral RNA, by replacing mouse ICAM-1 with the human counterpart and by using a variant virus. It remains to be seen if these advances will translate into establishment of useful mouse models. In the absence of animal models, epithelial cell lines such as BEAS-2B, A549, 16HBE and HEp-2 have been used. Fibroblasts and smooth muscle cells have also been used. Although transformed cell lines have many properties in common with normal epithelial cells, they lose certain differentiated functions. Therefore, primary and recently well-differentiated cultures are used to study the immune response. In addition to a local inflammatory response, a systemic immune response to RV does develop; therefore peripheral blood mononuclear cells and dendritic cells have been infected with RV, shedding additional light on cell-mediated immunity. Cellular models are invaluable investigational tools for understanding mechanisms of RV-induced asthma and evaluating new targets for therapy. Copyright © 2007 S. Karger AG