To our knowledge, there are no published results of protocols for managing difficult to control asthma (DTCA) or of the spectrum and frequencies of reasons why asthma can be difficult to control (DTC). To assess the usefulness of a systematic management protocol and determine the reason(s) why asthmatics are DTC, we developed a protocol that systematically considered multiple factors that may make asthma worse and prospectively evaluated the outcomes of therapeutic interventions for these factors and of inhaled corticosteroids (ICS) and azathioprine. We studied 42 consecutive and unselected DTCAs (19 men and 23 women) whose age was 48 +/- 15.9 years. They had a diagnosis of asthma for 15.1 +/- 15.8 years, were DTC for 4.8 +/- 7.8 years, and were followed up by us in the study for a total of 3.5 +/- 1.9 years. Initially, the dose of prednisone was 30.2 +/- 22 mg/d. Following utilization of the protocol, 74 percent were no longer DTC. It took 1.8 +/- 1.7 years for them to no longer be DTC; they remained so for 1.8 +/- 1.5 years. In these patients, 2.7 +/- 1.2 factors appeared to be responsible for the DTC state; 80 percent had > or = 2. Improvement was more likely if gastroesophageal reflux (GER) was a factor (p = 0.014); it correlated with the addition of ICS (p = 0.04) and treatment for GER (p = 0.02). Failure to reverse DTCA correlated with the suspicion (p = 0.004) and admission of nonadherence (p = 0.04). In 14 patients given azathioprine, prednisone dose decreased from 45 +/- 25.3 to 13.3 +/- 21.6 mg/d (p = 0.003); 6 of 14 achieved no longer DTC status; and substantial morbidity occurred. The reason(s) for DTCA could be determined in most instances by utilizing a systematic protocol; multiple factors were responsible in the majority of cases; treatment for GER and ICS were the two most helpful interventions; nonadherence was the most likely reason suspected for maintaining DTCA; and azathioprine acted as a corticosteroid-sparing agent that should not be prescribed routinely.