Millard, Mark

Abstract Background Anti‐IgE (omalizumab) has been used for the treatment of moderate‐to‐severe asthma that is not controlled by inhaled steroids. Despite its success, it does not always provide patients with significant clinical benefits. Objective To investigate the transcriptional variations between omalizumab responders and non‐responders and to study the mechanisms of action of omalizumab. Methods The whole blood transcriptomes of moderate‐to‐severe adult asthma patients (N = 45:34 responders and 11 non‐responders) were analysed over the course of omalizumab treatment. Non‐asthmatic healthy controls (N = 17) were used as controls. Results Transcriptome variations between responders and non‐responders were identified using the genes significant (FDR < 0.05) in at least one comparison of each patient response status and time point compared with control subjects. Using gene ontology and network analysis, eight clusters of genes were identified. Longitudinal analyses of individual clusters revealed that responders could maintain changes induced with omalizumab treatment and become more similar to the control subjects, while non‐responders tend to remain more similar to their pre‐treatment baseline. Further analysis of an inflammatory gene cluster revealed that genes associated with neutrophil/eosinophil activities were up‐regulated in non‐responders and, more importantly, omalizumab did not significantly alter their expression levels. The application of modular analysis supported our findings and further revealed variations between responders and non‐responders. Conclusion and Clinical Relevance This study provides not only transcriptional variations between omalizumab responders and non‐responders, but also molecular insights for controlling asthma by omalizumab.

AbstractBackgroundIL‐10‐producing regulatory B cells (Bregs) are widely ascribed immune regulatory functions. However, Breg subsets in human asthma have not been fully investigated.ObjectiveWe studied Breg subsets in adult allergic asthma patients by assessing two major parameters, frequency and IL‐10 expression. We then investigated factors that affect these two parameters in patients.MethodsPeripheral blood mononuclear cells (PBMCs) of adult allergic asthma patients (N = 26) and non‐asthmatic controls (N = 28) were used to assess the frequency of five subsets of transitional B cells (TBs), three subsets of CD24highCD27+ B cells and B1 cells. In addition to clinical data, IL‐10 expression by individual Breg subsets was assessed by flow cytometry.ResultsAsthma patients had decreases of CD5+ and CD1d+CD5+, but an increase of CD27+ TBs which was significant in patients with moderate asthma (60 < FEV1 < 80). Regardless of asthma severity, there was no significant alteration in the frequencies of 6 other Breg subsets tested. However, we found that oral corticosteroid (OCS) significantly affected the frequency of Bregs in Breg subset‐specific manners. OCS decreased CD5+ and CD1d+CD5+ TBs, but increased CD27+ TBs and CD10+CD24highCD27+ cells. Furthermore, OCS decreased IL‐10 expression by CD27+ TBs, all 3 CD24highCD27+ B cell subsets (CD5+, CD10+ and CD1d+) and B1 cells. OCS‐mediated inhibition of IL‐10 expression was not observed in the other Breg subsets tested.Conclusion & Clinical RelevanceAlterations in the frequency of Bregs and their ability to express IL‐10 are Breg subset‐specific. OCS treatment significantly affects the frequency as well as their ability to express IL‐10 in Breg subset‐specific manners.

Abstract It is not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.