The majority of asthmatics can be well controlled with reasonable doses of inhaled corticosteroids and/or long-acting β2-agonists. However, a subset of patients called « refractory asthmatics » remained uncontrolled despite high doses of inhaled and sometimes also oral corticosteroids. Although mild-to-moderate asthma is known to be Th2 driven, we need a better understanding of the immunological mechanisms leading to refractory asthma.
In the first part of this work, we have assessed cytokine production (IL-4, IL-6, IL-10, IFN-γ and TNF-α) from sputum and blood cell culture in refractory asthmatics defined according to the ATS criteria and compared them with mild untreated and moderate treated asthmatics and non-atopic healthy subjects. The majority of refractory asthmatics still exhibited intense eosinophilic airway inflammation despite heavy treatment with corticosteroids. We found that moderate and refractory asthmatics were characterized by a lower IL-6 production from sputum cells. At the systemic level, the three groups of asthmatics exhibited raised IL-4 production from peripheral blood leucocytes when compared to healthy subjects. Moreover, moderate asthmatics displayed raised IL-10 production when compared to healthy subjects and refractory asthmatics.
In the second part, we compared the stimulated cytokine production from peripheral blood leucocytes in allergic asthmatics classified according to their level of asthma control (ACQ 7 Juniper). We showed that both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously produced more IL-4 than healthy subjects. IL-4 release induced by LPS was greater in both asthma groups compared to atopic non-asthmatics and non-atopic healthy subjects. By contrast, IFN-γ release induced by LPS was lower in uncontrolled asthmatics than in controlled asthmatics and non-atopic healthy subjects.
Finally, we have assessed sputum total IgE and cytokines (IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IFN-γ and TNF-α) in a large group of asthmatics classified according to disease severity, sputum cellular phenotype and atopy. Total IgE (tIgE) were detectable in sputum supernatant from the majority of subjects. We found a strong correlation between total sputum and serum IgE. The three groups of asthmatics exhibited higher tIgE levels than healthy subjects without any significant difference between the groups of asthmatics. By contrast, when classifying the patients according to cellular phenotype, eosinophilic asthmatics were characterized by raised sputum IgE, IL-5 and IL-13 compared to healthy subjects and pauci-granulocytic asthmatics. Atopic asthmatics also distinguished from non-atopic asthmatics and healthy subjects by raised sputum tIgE levels without any significant difference regarding sputum cytokine levels.
Refractory asthmatics keep, for the majority of them, the eosinophilic asthma phenotype with persistence of raised IL-4 production at systemic level. While the increased production of IL-4 in response to LPS distinguishes asthma from atopy, a diminished release of interferon-γ in response to LPS seems to be a feature that distinguishes refractory asthma from milder forms of the disease. Finally, sputum IgE which was raised in all groups of asthmatics irrespective of disease severity, is strongly associated with sputum eosinophilia and a Th2 cytokine pattern.