Tiotropium vs. Inhaled Corticosteroids in Children With Nonatopic Asthma Pilot Study

Asthma Phenotype Variations Suggest the Need for Improved Tailoring of Treatment Options Asthma is the most common chronic disease among children worldwide. Asthma is characterized by chronic airway inflammation; symptoms vary by intensity and frequency over time. The asthma phenotype (observable characteristics such as symptoms and pulmonary function) may present similarly in children, but differences in the underlying endotypes (pathophysiological and/or molecular mechanisms, e.g.T-helper type 2 cell (Th2)-low and Th2-high asthma) indicate that varying processes are present that can affect treatment response Established guidelines (Global Initiative for Asthma [GINA] and National Heart Lung and Blood Institute [NHLBI]) recommend inhaled corticosteroids (ICS) as first line therapy in all children with persistent asthma to manage the inflammatory process and thus, control symptoms (wheeze, shortness of breath, cough, nocturnal awakenings). Yet, currently, 22%-60% of children with asthma continue to present with symptoms or remain poorly controlled while treated according to the established guidelines, which include ICS. Thus, additional studies are needed in children with phenotypes that are poorly responsive to guideline-based therapy with ICS to identify optimal management.

Because asthma phenotypes present similarly (though differing by severity), ICS continue to be the first line of treatment for patients with persistent asthma despite potential differences in underlying pathophysiology (Th2-low and Th2-high endotype). In a controlled trial in children with mild to moderate persistent asthma, 55% were unresponsive to monotherapy treatment with either ICS or montelukast despite over 90% adherence by dose counting. Response to ICS treatment has been associated with several markers of an allergic phenotype that include higher serum eosinophil cationic protein (or serum eosinophil levels), elevated serum IgE, skin test positivity, and elevated exhaled nitric oxide. Indeed, children with mild asthma treated with ICS over 44 weeks who have a positive allergen skin test are 70% less likely to have an asthma exacerbation when compared with children without positivity.

Poor asthma control associated with inadequate treatment response is associated with more health care provider visits, direct costs, and work absenteeism than those with well-controlled asthma. Biomarker-driven asthma management has been suggested as an emerging strategy to improve asthma control by matching treatment selection to underlying endotype (Th2 low vs. Th2 high asthma) differences in pathophysiology. An understudied population of children with asthma are those who lack an allergic phenotype. Treatment response to ICS is poor in this population, but studies have been limited to subgroup analysis from larger populations of mixed phenotypes. Therefore, those children who lack an allergic phenotype may not be optimally treated with guideline-recommended ICS therapy and require studies focused on this phenotype.

Variability in the Definition of the Nonatopic Asthma Phenotype The nonatopic asthma phenotype has been incompletely described and published studies often report varying characteristics. Typical characteristics include the absence of atopic diseases such as allergic rhinitis, eczema, or food allergies; having normal serum IgE levels; and having normal serum eosinophil levels. The most common factor identifying the child with nonatopic asthma is a negative skin prick test (SPT) to common aeroallergens in combination with physician-diagnosed asthma.

Inhaled Corticosteroid Response in Children with Nonatopic Asthma is Suboptimal, and Treatment Options are not Well Studied.