Costs and Perils of Therapeutic Creep

CHILDREN WITH ASTHMA REPORT SYMPTOMS OF GAStroesophageal reflux disease (GERD) more often than children without asthma. Nevertheless, a systematic review of the child health literature, which included studies using pH probes and other objective assessment methods, concluded that the true nature of the association between GERD and asthma, their temporal relation, and the causal direction, remain unknown. Moreover, the potential for antiacid therapy to improve asthma symptoms in children with poorly controlled disease remains largely anecdotal. A small, randomized placebo-controlled trial showed no improvement in asthma status among children treated with omeprazole for 12 weeks. Despite this unimpressive evidence of a consistent role of GER/GERD in asthma morbidity, children with asthma are more likely than those without asthma to be treated with anti-GERD medications. For example, a populationbased study suggested that 13to 14-year-old schoolchildren with asthma were more than 8 times more likely to be treated with anti-GERD therapy than those without asthma. Children with more severe asthma reported much more frequent symptoms consistent with GERD and, thus, were more likely to receive such therapy. It appears that the conclusion based on association studies that poor asthma control could be caused by GER/GERD has contributed to a marked increase in the use of anti-GERD medicines in these patients. The perils and costs of this overuse of anti-GERD therapy are cogently examined by Holbrook and colleagues in this issue of JAMA. Results of this appropriately powered randomized clinical trial show that among children with asthma but without symptoms of GERD whose asthma symptoms were poorly controlled with antiinflammatory therapy, 24 weeks of treatment with the proton pump inhibitor (PPI) lansoprazole had no significant effect on any measure of asthma control, quality of life, lung function, or bronchial responsiveness compared with placebo. In a subset of the population in which the investigators performed 24-hour esophageal pH monitoring studies, 43% showed esophageal acid exposure greater than established thresholds, a striking prevalence in a population with no symptoms of GERD. However, lansoprazole was no more effective in this subgroup than in the entire sample. These results are in concordance with those of a similar study using esomeprazole in adults with poorly controlled asthma and with no or mild GERD symptoms. It could be argued that these studies, by excluding patients with symptomatic GERD, could have missed the patients most likely to respond to PPIs. However, a large study in adults with poorly controlled asthma and moderately severe GERD symptoms showed no effect of esomeprazole on the primary outcome (morning peak flow) or on most other clinical outcomes, with minor improvement in asthma quality of life that were considered of minimal clinical significance by the authors. Holbrook et al also report that several unwanted adverse effects were observed more frequently in the active treatment group than in the placebo group. Treatment with lansoprazole was associated with increased incidence of upper respiratory tract infection, sore throat, and bronchitis. This finding is consistent with reports of increased risk of pneumonia associated with PPI therapy. However, this increased risk of respiratory illnesses, which are a major cause of asthma exacerbations, was not associated with a significantly increased incidence of episodes of poor asthma control in these children. Of much greater concern is the difference in activityrelated bone fractures in children treated with lansoprazole vs placebo (6 vs 1, respectively). This is the first large, blinded, randomized placebo-controlled trial in which this potential complication of PPIs has been studied in children; most available child health studies of PPIs are small, uncontrolled, and of short duration. It is unlikely that the use of inhaled corticosteroids explains this finding because there was no difference in the use of these medicines between the 2 groups of patients. Although the increased fracture risk did not reach formal, 2-sided statistical significance (P=.06), this finding should be considered in the framework of a substantial body of evidence that has prompted the US Food and Drug Administration to issue