Asthma (With a little SCID to start) Disclosures Outline Starting with the Immune System The Innate Immune System The Adaptive Immune System

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1 Asthma (With a little SCID to start) Lauren Smith, MD CHKD Pediatric Allergy/Immunology Disclosures None Will be discussing some medications that are not yet FDA approved Outline SCID Brief overview Update on newborn screening What to do with positive screens Asthma emerging biologic therapies Starting with the Immune System The Innate Immune System Rapid response, first line defense Uses pattern recognition receptors to recognize components of microbes Elements Skin and mucosal barriers Enzymes Receptors (Toll-like receptors) Complement Phagocytes Natural Killer (NK) cells (comprise part of your lymphocytes) The Adaptive Immune System Changed and adjusted throughout lifetime Extensive repertoire of unique receptors to identify pathogens Immunological memory Components T cells (cellular response cytotoxicity, T helper cells) B cells (humoral response immunoglobulins) The Adaptive Immune System Changed and adjusted throughout lifetime Extensive repertoire of unique receptors to identify pathogens Immunological memory Components T cells (cellular response cytotoxicity, T helper cells) B cells (humoral response immunoglobulins) Overview So what is SCID?? Severe Combined Immunodeficiency (aka Bubble Boy Disease) These patients universally do not produce T cells There are many different genetic causes (genotypes) 1

2 Some patients also do not produce B cells, NK cells, or both Pediatric Medical Emergency! SCID Continued Patients are extremely vulnerable to viral infections Everything from colds, to CMV, EBV, influenza Can get infected from live viral vaccines (rotavirus, MMR, varicella) Once acquired, unable to clear Also vulnerable to fungal and bacterial infections Treatment IVIG Prophylactic antibiotics Avoidance Stem Cell and Gene Therapy Definitive treatment is bone marrow transplant Transplant before 3.5 months of age, 96% survival After 3.5 months: 70% survival* Why am I hearing about this so much now?? Newborn Screening. Initial prevalence thought to be 1/100,000 births, more recent study 1/58,000 In 2010 it was recommended SCID be added to the national newborn screening panel Implemented in VA in June 2015 which is why we are hearing about it now. How does Newborn Screening Work? Uses the same dried blood spot card other newborn screening tests use Screens for TRECs T cell receptor excision circles TRECs are little circles of DNA formed in T cells when they go to school in the thymus High rate of T cell generation early in life VA s testing uses Ct (cycle threshold) counts higher numbers are bad So what if it s abnormal? Three categories: abnormal, critical, or zero TRECs A/I gets called if critical or zero. Abnormal x 2=critical. We have decided to urgently (with a few days) see all these babies We will send confirmatory testing Flow cytometry to Duke or Quest Analyzes the numbers and subtypes of T cells, B cells, and NK cells NICU babies are an exception Why can t we just check a CBC? Absolute lymphocyte count (ALC) is helpful, BUT T cells typically comprise ~70% of your lymphocytes In subtypes that have B cells, can see an increased number giving a falsely reassuring ALC Can also have transplacental transfer of maternal T cells (mature ones that don t help the 2

3 baby), giving a falsely reassuring number Only way is to confirm baby has T cells that just came out of the thymus Switching Gears Segue Severe Asthmatics A small percentage of asthmatics (~5-10%) have severe disease not controlled by inhaled corticosteroids, LABAs, and leukotriene inhibitors For these patients, other therapies are being researched Severe Asthmatics Multiple pathways leading to airway inflammation and injury, smooth muscle dysfunction, mucous production Some mediators may have a more dominant role than others Idea of specific phenotypes and more tailored care Ongoing research to target these specific cells, cytokines, and mediators Biologics in Asthma Underlying immune response to pathophysiologic changes in asthma are complex Epithelial cell disruption/activation by cytokines Denditric cell activation and antigen presentation Activation/expansion of TH2 cells (allergy phenotype) with cytokine secretion Activation of inflammatory and mast cells Recruitment of additional inflammatory cells release mediators Long AA. Monoclonal antibodies and other biologic agents in the treatment of asthma. mabs. 2009;1(3): Omalizumab Humanized monoclonal antibody against IgE Prevents its interaction with high affinity receptor on mast cells, basophils, eosinophils Approved for pts >12 years old with allergic asthma (not adequately controlled), approved for age 6 and over in Europe Risk of anaphylaxis Reduces symptoms, prevents exacerbations, allows for reductions in ICS, but no effect on lung function Reduces IgE levels May have benefit beyond allergen-ige interactions Anti-IL-5 Antibodies IL-5 produced by lymphocytes, mast cells, possibily eosinophils Contributes to eosinophil differentiation, survival, migration, and activation Murine models looked promising 3

4 Mepolizumab, Reslizumab, Benralizumab In trials currently Favorable safety profile, reduce peripheral blood and sputum eosinophils Mepolizumab SIRIUS study 135 patients with severe asthma and peripheral blood eosinophilia On maintenance systemic glucocorticoids Mepolizumab group had reduction in steroid use, decreased exacerbations, improved control of symptoms No significant effect on FEV1 or airway hyperresponsiveness Mepolizumab MENSA trial 576 patients with severe asthma and eosinophilic airway inflammation High dose inhaled corticosteroids Rate of exacerbations decreased by 47% in IV group and 53% subq group compared with placebo Increase in FEV1 from baseline DREAM study 621 patients with severe asthma and eosinophilic airway inflammation Assigned to different IV doses compared with placebo Rate of clinically significant exacerbations decreased in all groups compared with placebo Symptoms and pulmonary function not improved Reslizumab Similar drug to mepolizumab FEV1 and forced vital capacity values improved in study of 106 patients Only trended toward improved asthma control Pts chosen based on high sputum eosinophlia, not just markers of eosinophilic inflammation Previous studies on anti-il-5 antibodies in milder patients without evidence of eosinophilia did not show much benefit Benralizumab Blocks effects of IL-5 on eosinophils, but also results in eosinophil death Dose dependent reduction in blood eosinophils for 8-12 weeks after single dose Has shown reduction in sputum, airway, and blood eosinophil counts Effects on asthma under evaluation IL-4 and IL-13 Push toward Th2 (allergy phenotype) differentiation Increase B cell IgE production and upregulate IgE receptors Inhibit production of Interferon Gamma (Th1 cytokine) Lebrikizumab Anti-IL-13 antibody Compared with placebo in 219 patients not controlled with medium to high dose ICS 4

5 29 30 At 12 weeks study group had significant increase in FEV1, not at 24 weeks Periostin indirect marker of IL-13 activity Subgroup with higher levels had better response Another study of 212 patients on no ICS did not show beneficial effect Others Anti-thymic stromal lymphopoietin monoclonal immunoglobulin Assessed in 31 patients and showed decreased measures of allergic inflammation Gata3-specific DNAzyme Study of 43 patients supported a potential role for disruption of GATA3 in asthma treatment Conclusions Omalizumab has done very well and other biologics show promise and are in trials Will initially likely have limited application to pediatric population initially Further advancements in identifying biomarkers will help to tailor individualized asthma therapies the future of treatment for severe asthmatics 5