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Challenges in Treating Pediatric Asthma in Developing Countries.

Asthma is the most common chronic disease in children in many low- and middle-income countries. In these settings, the burden of childhood asthma is increasing and is associated with severe disease. There are a number of challenges to providing optimal management of childhood asthma in such settings.

These include under-diagnosis of childhood asthma, access to care, ability of healthcare workers to manage asthma, availability and affordability of inhaled therapy, environmental control of potential triggers, education of healthcare providers and of the public, and cultural or language issues. International and national guidelines for childhood asthma have been produced, but implementation remains a real challenge. Access to and affordability of essential inhaled asthma drugs, especially low-dose inhaled corticosteroids and short-acting bronchodilators, are major challenges to effective asthma control in many countries. A low-cost spacer made from a plastic bottle is effective for use with a metered-dose inhaler, but use must be included in asthma educational initiatives. Educational programs for healthcare personnel and for the public that are culturally and language appropriate are needed for effective implementation of asthma guidelines.

Socioeconomic and structural barriers to care within health services remain obstacles to achieving optimal treatment of asthma for many children.

Emerging airway smooth muscle targets to treat asthma.

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Asthma is characterized in part by variable airflow obstruction and non-specific hyperresponsiveness to a variety of bronchoconstrictors, both of which are mediated by the airway smooth muscle (ASM). The ASM is also involved in the airway inflammation and airway wall remodeling observed in asthma. For all these reasons, the ASM provides an important target for the treatment of asthma. Several classes of drugs were developed decades ago which targeted the ASM - including β-agonists, anti-cholinergics, anti-histamines and anti-leukotrienes - but no substantially new class of drug has appeared recently. In this review, we summarize the on-going work of several laboratories aimed at producing novel targets and/or tools for the treatment of asthma.

These range from receptors and ion channels on the ASM plasmalemma, to intracellular effectors (particularly those related to cyclic nucleotide signaling, calcium-homeostasis and phosphorylation cascades), to anti-IgE therapy and outright destruction of the ASM itself.

Development of asthma is determined by the age-dependent host response to respiratory virus infection: therapeutic implications.

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Lower respiratory tract virus infections are the major cause of asthma exacerbations. Severity of infection and age at initial encounter with virus appear to be major determinants of the risk for allergic asthma later in life. In animal models, reinfection of mice initially infected as neonates leads to markedly enhanced alterations in airway function and inflammation, unlike reinfection of older mice. Both innate and adaptive immune responses contribute to this susceptibility with lung dendritic cells showing marked differences in phenotype and function in young compared to older mice, and these differences are further enhanced following virus infection.

These findings have implications for therapeutic targeting, for example, of RSV G and F surface proteins at different stages of the response to infection.

Deficient antiviral immune responses in childhood: Distinct roles of atopy and asthma.

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Impaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation.

OBJECTIVE: We sought to investigate airway interferon production in response to rhinovirus infection in children who are asthmatic, atopic, or both and its correlation with the airway inflammatory profile.

METHODS: Bronchial biopsy specimens and epithelial cells were obtained from 47 children (mean age, 5 ± 0.5 years) undergoing bronchoscopy. The study population included asthmatic children who were either atopic or nonatopic, atopic children without asthma, and children without atopy or asthma. Rhinovirus type 16 induction of IFN-λ and IFN-β mRNA and protein levels was assessed in bronchial epithelial cell cultures. The immunoinflammatory profile was evaluated by means of immunohistochemistry in bronchial biopsy specimens.

RESULTS: Rhinovirus type 16-induced interferon production was significantly reduced in atopic asthmatic, nonatopic asthmatic, and atopic nonasthmatic children compared with that seen in nonatopic nonasthmatic children (all P < .05). Increased rhinovirus viral RNA levels paralleled this deficient interferon induction. Additionally, IFN-λ and IFN-β induction correlated inversely with the airway T(H)2 immunopathologic profile (eosinophilia and IL-4 positivity: P < .05 and r = -0.38 and P < .05 and r = -0.58, respectively) and with epithelial damage (P < .05 and r = -0.55). Furthermore, total serum IgE levels correlated negatively with rhinovirus-induced IFN-λ mRNA levels (P < .05 and r = -0.41) and positively with rhinovirus viral RNA levels (P < .05 and r = 0.44).

CONCLUSIONS: Deficient interferon responses to rhinovirus infection are present in childhood in asthmatic subjects irrespective of their atopic status and in atopic patients without asthma. These findings suggest that deficient immune responses to viral infections are not limited to patients with atopic asthma but are present in those with other T(H)2-oriented conditions.

Sputum cell counts and methacholine hyperresponsiveness as asthma outcomes

The National Institutes of Health and the Agency for Healthcare Research and Quality are to be commended for convening a workshop to make recommendations for inclusion of core and optional measurements as baseline and outcome variables for clinical trials to evaluate various interventions in asthmatic patients. However, we would like to point out 2 misinterpretations related to the use of sputum cell counts and methacholine hyperresponsiveness, both of which are considered supplemental and not core measurements.

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