Described herein are methods for diagnosis and treatment of chronic obstructive pulmonary disease (COPD) exacerbation and/or therapy monitoring based in part on the level of macrophage colony-stimulating factor (M-CSF) expression and/or activity. Methods for diagnosis and treatment of COPD patients using novel molecular signature(s) are also provided. Methods for identifying subjects with COPD exacerbations who are more likely to be responsive to and benefit from a therapy that targets virus-induced exacerbations or non-infective COPD exacerbations are also described herein.