Direct and indirect challenges in the clinical assessment of asthma

Objective: To compare direct and indirect bronchoprovocation challenges in the clinical assessment of asthma. Data Sources: PubMed search using the keywords adenosine monophosphate, eucapnic voluntary hyperpnea, exercise, hypertonic saline, mannitol, and methacholine challenges and asthma. Study Selection: Articles were selected based on their relevance to the topic of this review. Results: Methacholine is the most widely used direct challenge. Methacholine is highly sensitive, provided symptoms are clinically current and deep inhalations are avoided during inhalation. There are many causes of a false-positive test result. Specificity is increased if the pretest probability of asthma is greater, if the methacholine responsiveness is moderate or greater, and if the methacholine-induced symptoms mimic the natural symptoms. Indirect challenges are more specific for asthma but are insensitive, particularly for mild and/or well-controlled asthma. The lower sensitivity may relate to the fact that many indirect challenges (eg, exercise, eucapnic voluntary hyperpnea, adenosine monophosphate) are dose limited (ie, the dose of stimulus cannot be increased above a level based on physiology or solubility). Indirect challenges also correlate better with airway inflammation and are more responsive to anti-inflammatory treatments. Conclusions: Direct challenges (ie, methacholine), because of the high sensitivity, function best to exclude clinically current asthma; a positive test result is consistent with but not diagnostic of asthma. By contrast, indirect challenges are superior for confirming asthma and are the challenges of choice when exercise bronchospasm is the question (eg, certification for international athletic competition, armed forces, scuba diving). Indirect challenges would be preferred for monitoring of asthma control and used serially to help diagnose occupational asthma. Ann Allergy Asthma Immunol. 2009; 103:363-370.