Exacerbations of asthma requiring unscheduled physician visits, emergency department care, or hospital admission are a major cause of the morbidity and cost of this disease, which affects up to 8% of the population. Extensive evidence suggests that a large proportion of these exacerbations during childhood (after three years of age) and among young adults are triggered by a viral infection, predominantly infections caused by rhinovirus (RV). In addition, a large body of evidence shows that patients who develop an exacerbation with RV are allergic to one or more common inhalant allergens. When patients presenting with acute asthma are studied in an emergency department, they have evidence of inflammation, which is usually interpreted as being part of the response to the virus. However, previous results using the RV challenge model suggest that inflammation, as judged by exhaled nitric oxide (FeNO) or eosinophilia, is as much a risk factor for a pulmonary response to the virus as it is a response that occurs during the viral infection. The mechanistic basis for this synergistic interaction between the viral infection and pre-existing allergy is not known. The clinical trial proposed here (AIM 1) is to treat subjects, who have allergic asthma, for two months with the monoclonal antibody omalizumab (anti-IgE) or placebo, prior to challenging them with the FDA-approved preparation of RV-39. This trial design has been approved by the FDA (FDA-BB-IND #10510) and the University of Virginia IRB. The primary outcome will be cumulative lower respiratory tract symptoms (CLTRS) during the first four days of infection. The patients will also be monitored for a wide range of markers relevant to inflammation of the respiratory tract, as well as for changes in cellular responses occurring during the viral infection. Thus, it will be possible to directly answer whether anti-IgE treatment is effective in reducing both lung symptoms and bronchial hyperreactivity because it decreases IgE and its receptor on relevant cells, or because it decreases inflammation prior to infection. The proposed cellular studies (AIM 2) will investigate whether anti-IgE treatment reduces the induction of allergen-specific or RV-specific CD4+ T cells with a Th2 cytokine signature. The capacity for anti-IgE to down-regulate Th2-promoting pathways in antigen presenting cells (DCs and possibly basophils) will be examined. In complementary T-cell studies, recent advances in the development of novel peptide/MHC II tetramers will be used to identify and enumerate circulating CD4+ T cells specific for allergen (grass and dust mite) and RV in parallel throughout the two-month treatment phase and subsequent RV challenge phase of the trial in order to monitor fluxes in these cells that correspond to migration to the inflamed respiratory tract. In conjunction, the capacity for RV infection to induce a Th2 profile and for anti-IgE treatment to ameliorate this effect will be assessed using in vitro cultures stimulated with allergen or RV. Taken together, these studies are designed to understand the importance of IgE antibodies and to better define the correct targets for the treatment of asthma that is designed to prevent exacerbations.
The object of the proposed clinical trial is to provide information about the ways in which the common cold virus (or rhinovirus) can trigger exacerbations of asthma in patients who are allergic to one or more common allergens. The plan is to use injection of a monoclonal antibody to IgE (the antibodies that cause allergy) for two months before challenging them with a rhinovirus. The studies proposed will provide much clearer information about both the role that allergic inflammation plays in precipitating acute asthma and the mechanisms by which rhinovirus infection can cause acute or severe exacerbations of this extremely common condition.
|Kennedy, Joshua L; Robinson, Derek; Christophel, Jared et al. (2014) Decision-making analysis for allergen immunotherapy versus nasal steroids in the treatment of nasal steroid-responsive allergic rhinitis. Am J Rhinol Allergy 28:59-64|
|Steinke, John W; Negri, Julie; Payne, Spencer C et al. (2014) Biological effects of leukotriene E4 on eosinophils. Prostaglandins Leukot Essent Fatty Acids 91:105-10|
|Steinke, John W; Negri, Julie; Liu, Lixia et al. (2014) Aspirin activation of eosinophils and mast cells: implications in the pathogenesis of aspirin-exacerbated respiratory disease. J Immunol 193:41-7|
|Ma, Larry; Danoff, Theodore M; Borish, Larry (2014) Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol 133:1075-83|
|Kennedy, Joshua L; Shaker, Marcus; McMeen, Victoria et al. (2014) Comparison of viral load in individuals with and without asthma during infections with rhinovirus. Am J Respir Crit Care Med 189:532-9|
|Tripathi, Anubha; Commins, Scott P; Heymann, Peter W et al. (2014) Delayed anaphylaxis to red meat masquerading as idiopathic anaphylaxis. J Allergy Clin Immunol Pract 2:259-65|
|Kennedy, Joshua L; Hubbard, Matthew A; Huyett, Phillip et al. (2013) Sino-nasal outcome test (SNOT-22): a predictor of postsurgical improvement in patients with chronic sinusitis. Ann Allergy Asthma Immunol 111:246-251.e2|
|Settipane, Russell A; Peters, Anju T; Borish, Larry (2013) Chapter 17: Immunomodulation of allergic sinonasal disease. Am J Rhinol Allergy 27 Suppl 1:S59-62|
|Settipane, Russell A; Borish, Larry; Peters, Anju T (2013) Chapter 16: Determining the role of allergy in sinonasal disease. Am J Rhinol Allergy 27 Suppl 1:S56-8|