Corticosteroid withdrawal-induced loss of control in mild to moderate asthma is independent of classic granulocyte activation

Abstract Background Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. Yet, whether eosinophils, or indeed the also present neutrophils, actively contribute to the accompanying inflammation has not been investigated extensively. Methods 23 patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study, 22 of whom lost asthma control. We assessed various immune, inflammatory and oxidative stress parameters as well as markers of eosinophil and neutrophil activity in exhaled breath condensate, plasma and sputum collected at three phases: baseline, during loss of control and after recovery. Results Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses, nor for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H3, suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in forced expiratory volume in 1 second % predicted upon ICS withdrawal (both rs=0.46, p=0.03). Conclusions The clinical effect in mild to moderate asthma upon interruption of ICS is not related to the classic inflammatory activation of eosinophils and neutrophils, but may reflect another pathway underlying the onset of loss of disease control and asthma exacerbations.