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Thursday, March 13, 2014

Host-microbial interactions in patients with chronic rhinosinusitis

The initiation and perpetuation of chronic rhinosinusitis (CRS) is known to be associated with host-microbial interactions.  Many studies have investigated these interactions with CRS in order to understand the mechanisms of the disease and provide better treatment options.  Dr. Hamilos summarizes the knowledge of host-microbial interactions in regards to normal sinus physiology and pathology, patients with CRS with and without polyps, and allergic fungal rhinosinusitis (AFRS) (J Allergy Clin Immunol 2014; 133(3): 640-653).
Much of the research on the subject of CRS has been on bacterial infection and potential defects in innate immunity that might predispose patients to sinus infections.  Of CRS patients undergoing surgical intervention, more than 50% have bacterial biofilm in their diseased sinus tissues.   Biofilm is an important survival mechanism of bacteria allowing for attachment to surfaces.  The biofilm has been described to have an enhanced resistance to antibiotics and is associated with more severe disease and worse surgical outcomes.  Dr. Hamilos explains that less is known about viral or fungal infection in CRS; in fact it remains unclear if upper respiratory tract viruses contribute causally to CRS analogous to their possible role in asthma.  Other research has ruled out defects, such as defects in mucociliary clearance or toll like receptor function as primary defects in CRS.  A decreased level of the antimicrobial protein lactoferrin has been found in sinus secretions, however other antimicrobial protein levels have been found  to be normal. 

CRS research has focused on patients that have either “refractory” disease which can be defined as no improvement following  surgery  and medical management or “recalcitrant” disease which is defined as the recurrence of nasal polyps after polyp surgery.  Studies suggest that patients with recalcitrant nasal polyps have down regulated innate immunity associated with T helper type 2 (Th2) inflammation, potentially causing persistent infection.   While surgical treatment and use of culture-directed antibiotics remain the best treatment options, Dr. Hamilos is hopeful that further understanding of the underlying genetics of CRS and host-microbial interactions will allow for greater insight and more effective treatment options.

Thursday, March 6, 2014

Genetic analysis of asthma distinguishes subphenotypes

About 50% of asthmatics that are genetically screened have T helper type 2 (Th2)-driven inflammation that is characterized by improved symptoms with inhaled corticosteroid response, higher IgE levels, and higher peripheral blood eosinophils.  While this genetic profiling is highly valuable by elucidating the pathogenesis of asthma and tailoring individual treatment regimens, bronchial airway epithelium brushings are invasive which limits its application to childhood asthma research.  This realization led Poole et al to determine if less invasive nasal airway epithelium brushings can proxy expression changes seen in the bronchial airway transcriptome in children with asthma (J Allergy Clin Immunol 2014, 133(3): 670-678)

In a cohort of Puerto Rican children, the authors used whole transcriptome RNA sequencing (RNA-seq) on nasal airway brushings from 10 controls and 10 subjects with asthma and targeted RNA-seq on 50 asthmatics and 50 controls to profile 105 genes. The results were compared to established bronchial and small airway transcriptomes.  They found 90% overlap in expressed genes between the nasal and bronchial transcriptomes.  Clustering analysis identified Th2-high and Th2-low subjects differentiated by the expression of 70 genes including the Th2 cytokines IL-13 and IL-5 which were activated in Th2-high subjects. Furthermore, Th2-high subjects were more likely to have atopy, atopic asthma, high blood eosinophils, and rhinitis compared to Th2-low subjects.  

Their results indicate that nasal airway gene expression profiles largely recapitulate expression profiles in the lung and can be used to identify the Th2-high subphenotype of children with asthma.  The genetic information in nasal airway brushings can easily and effectively identify individuals with IL-13 driven asthma and a Th2-skewed systemic immune response.  Poole shows that this type of analysis identifies Th2 airway inflammation as part of the mechanistic basis of asthma in atopic individuals and it can be used to identify other genes that are dysregulated in asthma but independent of atopic status.  While larger and more diverse population studies are required, this data is valuable in both research and clinical settings. 

See below for an interview between Dr. Donald Leung, Editor-in-Chief of the Journal, and Dr. Max Seibold, one of the authors of the article: