Limitations of short-term studies in predicting long-term adverse effects of inhaled corticosteroids

Abstract

This paper examines the value of short-term studies in predicting long-term, clinically relevant adverse effects of inhaled corticosteroids (ICS) in children with asthma. Increasing use of ICS in younger and less severely affected children with asthma justifies concern about long-term adverse effects. For each system potentially affected by ICS, short-term and sensitive studies have limited value in predicting clinically relevant effects, even when correlations are highly statistically significant. This is due to inherent limitations of the short-term tests utilized and normal physiologic variations in systems being studied. Specific limitations include: 1) poor distinction between systemic presence of ICS and adverse systemic effects (e.g., integrated plasma cortisol) 2) lack of data validating the connection between test results and the end point in question (bone markers to predict growth and fracture risk) 3) sensitivity confounded by normal physiologic variation (knemometry to predict long-term growth). Consequently, predicting clinically relevant long-term effects from short-term studies detecting physiologic perturbations remains a challenge. Positive predictive value is improved by well-designed intermediate-term (>12 months) studies utilizing dynamic hypothalamic-pituitary-adrenal (HPA) axis testing, dual x-ray absorptiometry (DXA) scanning, or precise stadiometry. Ultimately, however, long-term studies are required to assess long-term risks, and the reliability of short-term assessments in predicting them.