Murugappan Ramanathan

Allergen-Specific Immunotherapy for Pediatric Asthma and Rhinoconjunctivitis: A Systematic Review

BACKGROUND AND OBJECTIVE: Subcutaneous immunotherapy (SCIT) is approved in the United States for the treatment of pediatric asthma and rhinitis; sublingual immunotherapy (SLIT) does not have regulatory approval but is used in clinical practice. The objective of this study was to systematically review the evidence regarding the efficacy and safety of SCIT and SLIT for the treatment of pediatric asthma and allergic rhinoconjunctivitis. METHODS: Two independent reviewers selected articles for inclusion, extracted data, and graded the strength of evidence for each clinical outcome. All studies were randomized controlled trials of children with allergic asthma or rhinoconjunctivitis treated with SCIT or an aqueous formulation of SLIT. Data sources were Medline, Embase, LILACS, CENTRAL, and the Cochrane Central Register of Controlled Trials through May 2012. RESULTS: In 13 trials, 920 children received SCIT or usual care; in 18 studies, 1583 children received SLIT or usual care. Three studies compared SCIT with SLIT head-to-head in 135 children. The strength of evidence is moderate that SCIT improves asthma and rhinitis symptoms and low that SCIT improves conjunctivitis symptoms and asthma medication scores. Strength of evidence is high that SLIT improves asthma symptoms and moderate that SLIT improves rhinitis and conjunctivitis symptoms and decreases medication usage. The evidence is low to support SCIT over SLIT for improving asthma or rhinitis symptoms or medication usage. Local reactions were frequent with SCIT and SLIT. There was 1 report of anaphylaxis with SCIT. CONCLUSIONS: Evidence supports the efficacy of both SCIT and SLIT for the treatment of asthma and rhinitis in children.

Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33.

Background Abnormalities in host mucosal immunity exist in chronic rhinosinusitis with nasal polyps (CRSwNPs), but it is unclear whether this is a cause or an effect of the eosinophilic inflammation and frequent microbial colonization that characterizes the disease. Sinonasal epithelial cells (SNECs) are critical participants in healthy antimicrobial innate immune defense. They also can promote Th2 inflammation with various mediators, including interleukin (IL)-33, which induces T helper cells to produce Th2 cytokines. Methods CRSwNP SNECs were obtained during sinus surgery and stored. Patients were subsequently classified as either treatment responsive or treatment recalcitrant, based on long-term outcomes of medical and surgical therapy. Epithelial cells from these patients were grown in air–liquid interface (ALI) culture and treated with IL-13, as well as the bacteria-associated molecule, CpG. Expression of IL-33 mRNA was determined by real-time polymerase chain reaction. Results Recalcitrant CRSwNP epithelial cells had increased baseline expression of IL-33 compared with responsive CRSwNPs, which was further increased by 24-hour exposure to CpG. Treatment-responsive epithelial cells were not induced by CpG to express IL-33. Prolonged treatment with IL-13 during differentiation at the ALI diminished the baseline expression of IL-33 and prevented the subsequent induction of IL-33 by CpG. Conclusion Mucosal innate immunity likely plays an important role in CRSwNP pathogenesis. A definitive link between infectious triggers and the development of Th2 inflammation has been elusive. We have found constitutive IL-33 expression by SNECs in recalcitrant CRSwNPs, which can be further induced by a bacteria-associated molecular pattern. Dysregulated epithelial cell immune interactions between host and environment may contribute to Th2 inflammation in CRSwNPs.

Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells

Background Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a disorder characterized by persistent eosinophilic Th2 inflammation and frequent sinonasal microbial colonization. It has been postulated that an abnormal mucosal immune response underlies disease pathogenesis. The relationship between Th2 inflammatory cytokines and the innate immune function of sinonasal epithelial cells (SNECs) has not been explored. Methods Human SNECs (HSNECs) isolated from control subjects and patients with CRS were assessed for expression of antimicrobial innate immune genes and proinflammatory cytokine genes by real-time polymerase chain reaction, ELISA, and flow cytometry. A model of the Th2 inflammatory environment was created by exposure of primary HSNEC to the Th2 cytokine interleukin (IL)-4 or IL-13 for 36 hours, with subsequent assessment of innate immune gene expression. Results HSNEC obtained from CRSwNP patients displayed decreased expression of multiple antimicrobial innate immune markers, including toll-like receptor 9, human beta-defensin 2, and surfactant protein A. Baseline expression of these genes by normal and CRS HSNEC in culture is significantly down-regulated after incubation with IL-4 or IL-13. Conclusion Expression of multiple innate immune genes by HSNEC is reduced in CRSwNP. One mechanism appears to be a direct effect of the leukocyte-derived Th2 cytokines present in the sinonasal mucosa in CRSwNP. Impaired mucosal innate immunity may contribute to microbial colonization and abnormal immune responses associated with CRSwNP.

Innate immunity of the sinonasal cavity and its role in chronic rhinosinusitis

Chronic rhinosinusitis (CRS) is one of the most common health problems in the United States. Medical therapy and surgery are successful in treating the majority of patients with sinusitis; however, CRS patients recalcitrant to traditional therapy are increasingly prevalent. Although traditionally this illness could be explained by sinus ostial obstruction and persistent bacterial infection, the rhinologic literature over the years has suggested a significant underlying inflammatory component. Adaptive immune components, including lymphocytes and their associated cytokines, have been the subject of most research in chronic nasal inflammation. A recent appreciation of the importance of the innate immune system is leading to new areas of investigation regarding the pathogenesis of CRS. This review will outline our current knowledge of sinonasal innate immunity, the role of innate immunity in the pathogenesis of CRS, and potential therapeutic targets in the innate immune system.

Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review.

To systematically review the effectiveness and safety of subcutaneous immunotherapy (SCIT) for treatment of allergic rhinoconjunctivitis and asthma, using formulations currently approved in the United States.

Increased expression of acidic mammalian chitinase in chronic rhinosinusitis with nasal polyps

Background Chitin is an abundant polysaccharide found in fungi, insects, and parasitic nematodes. Innate immune host defense against chitin-containing pathogens include production of chitinases. In human lower airways, acidic mammalian chitinase (AMCase) is produced in epithelial cells via a Th2-specific, IL-13–dependent pathway, and may act as an inflammatory mediator in asthma. The role of AMCase in chronic rhinosinusitis (CRS) has not been studied previously. Methods Eleven controls and 22 subjects with medically recalcitrant CRS were prospectively enrolled before undergoing endoscopic sinus surgery. RNA was extracted from surgically obtained ethmoid mucosa, and real-time PCR was used to determine expression of AMCase, eotaxin, and IL-13. Subjects were followed for at least 6 months postoperatively to assess for polyp recurrence. Based on the presence or absence of polyps, the subjects were classified as either recalcitrant or responsive to therapy. Results AMCase mRNA was detected in the sinus mucosa of 72% of control subjects and in 72% of patients with eosinophilic CRS with nasal polyps (CRSwNP). The expression of AMCase was significantly greater in recalcitrant CRSwNP than it was in treatment-responsive CRSwNP. There was no significant difference in IL-13 expression between these two groups. Conclusion AMCase may be an important mediator in the pathogenesis of Th2 inflammatory diseases of the respiratory tract. Failure of medical and surgical therapy in CRSwNP is associated with significantly increased expression of AMCase, but not the Th2 cytokines IL-13 and eotaxin. Additional studies are needed to determine the potential of AMCase as a therapeutic target in CRSwNP.

Effectiveness of Subcutaneous Versus Sublingual Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and Asthma: A Systematic Review

BACKGROUND Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear. OBJECTIVE We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma. METHODS MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. RESULTS Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. CONCLUSION Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making.

Chronic rhinosinusitis with nasal polyps is associated with decreased expression of mucosal interleukin 22 receptor.

Introduction: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa that is frequently associated with microbial colonization. Innate defense mechanisms at the mucosal surface are critical in protecting the host from airborne environmental pathogens. Recent studies of skin and gastrointestinal tract inflammatory diseases have shown that stimulation of the interleukin‐22 receptor (IL‐22R1) nonspecifically increases innate immune responses. The potential role of IL‐22R1 in the pathogenesis of CRSwNP has never been explored.

The cigarette smoke component acrolein inhibits expression of the innate immune components IL-8 and human beta-defensin 2 by sinonasal epithelial cells

Background Tobacco use is associated with poorer outcomes of medical and surgical therapy for chronic rhinosinusitis (CRS), although the underlying mechanism is unknown. Acrolein (AC) is a major component of cigarette smoke that has been shown to suppress innate immune gene expression by human bronchial epithelial cells and murine macrophages. In this study, we explore whether exposure of human sinonasal epithelial cells (HSNECs) to AC similarly reduces their innate immune gene expression. Methods Primary HSNECs from CRS patients were grown in culture, either differentiated or submerged. HSNECs were treated for 30 minutes with 0–50 μM of AC and were subsequently analyzed by real-time polymerase chain reaction and ELISA to determine IL-8 and human beta-defensin (HBD) 2 expression. Total glutathione was measured to see the oxidative stress within the treatment range. Results In primary HSNEC, IL-8 mRNA levels decreased dose dependently in the range of 10–50 μM of AC with an eightfold decrease at 50 μM. In addition, a 125-fold decrease at 50 μM for IL-8 protein was observed. HBD-2 mRNA decreased twofold and HBD-2 protein decreased fourfold at 50 μM of AC in primary HSNEC. However, differentiated HSNEC showed a marginal decrease in a dose-dependent manner for both IL-8 and HBD-2 within the range of 10–50 μM of AC. There was no oxidative stress observed over this range of AC concentration. Conclusion The tobacco smoke component AC has the capacity to suppress the inflammatory and innate immune function of sinonasal epithelial cells. Whether this effect contributes to the negative clinical impact of smoking on CRS outcomes merits additional investigation.

A comparison of experimental methods in molecular chronic rhinosinusitis research.

Background Research into the molecular pathogenesis of chronic rhinosinusitis (CRS) requires the collection and analysis of sinonasal tissue. Recent gene expression studies have used either surgical tissue specimens or isolated epithelial cell preparations. Here, we compare cultures of nasal epithelial cells, nasal brush biopsy, and whole ethmoid mucosa with respect to expression of innate immune genes. Methods Ethmoid mucosa was collected intraoperatively from 12 CRS and control patients. This tissue either was processed whole for mRNA extraction or was used to generate primary nasal epithelial cell cultures. After 6 weeks, epithelial cells in culture were assessed for multiple innate immune proteins by flow cytometry. In parallel, middle meatal brush biopsy specimens were obtained from the same patients and studied acutely in a similar fashion by flow cytometry. Expression of innate immune genes was determined in whole tissue samples by real-time polymerase chain reaction. Results Flow cytometry revealed that brush biopsy specimens contain 75% epithelial cells, whereas primary nasal epithelial cell cultures were pure. Epithelial cells derived from individual subjects expressed very similar levels of innate immune markers whether studied acutely or after 6 weeks in culture. Whole tissue mRNA levels were variable and not correlated to epithelial expression. Conclusion The choice of experimental methodology can greatly influence the results and interpretation of CRS research. Primary nasal epithelial cells maintain their innate immune receptor expression profile when grown in prolonged culture in vitro. These findings imply that alterations in innate immune gene expression in CRS may be intrinsic to the epithelial cells, even outside of their in vivo microenvironment.