Stanley I Ejiofor, Jan Stolk, Pablo Fernandez, Robert A Stockley

Patients with chronic obstructive pulmonary disease often experience exacerbations. These events are important as they are a major cause of morbidity and mortality. Recently, it has been increasingly recognized that patients may experience symptoms suggestive of an exacerbation but do not seek treatment, which are referred to as unreported or untreated exacerbations. Symptom diaries used in clinical trials have the benefit of identifying both treated and untreated exacerbation events. The Kamada study was a multicenter, double-blind randomized controlled trial of inhaled augmentation therapy in alpha-1 antitrypsin deficiency (AATD). A retrospective review of daily electronic symptom diary cards was undertaken from the two leading centers to identify symptomatic episodes consistent with a definition of an exacerbation. The aims were to explore the relationship between exacerbation events and classical "Anthonisen" symptoms and to characterize treated and untreated episodes. Forty-six AATD patients with airflow obstruction and history of exacerbations were included in the analysis. Two hundred thirty-three exacerbation episodes were identified: 103 untreated and 130 treated. Untreated episodes were significantly shorter (median 6 days; interquartile range [IQR] 3-10 days) than the treated episodes (median 10 days; IQR 5-18.25 days: P<0.001). Using logistic regression analysis, Anthonisen type and length of dyspnea were significant predictors of the treatment of an exacerbation event. Real-time electronic diary cards provide valuable information about the characterization of exacerbations. Untreated episodes are common and are significantly shorter in duration than the treated episodes. Dyspnea is the most important single Anthonisen symptom in the prediction and/or driver of treatment.