Commonalities of etiology and management

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  • Commonalities of etiology and management

    Joseph L. Russell, MD Farrah Siddiqui, MD

    Department of Otolaryngology University of Texas Medical Branch (UTMB Health)

    Grand Rounds Presentation April 25, 2012

  • Overview Integrated airway hypothesis

    Review of immunology as it relates to allergy

    Allergic rhinitis

    Asthma

    Chronic rhinosinusitis

    Nasal polyposis

    Samters triad

    Churg-Strauss syndrome

  • Overview Therapeutics

    Steroids

    Medical therapy for allergic rhinitis

    Medical therapy for asthma

    Medical therapy for chronic rhinosinusitis

    Surgical therapy for chronic rhinosinusitis

    Functional endoscopic sinus surgery (FESS)

    Balloon Sinuplasty

    Therapy for Samters triad

    Therapy for Churg-Strauss syndrome

  • Epidemiologic Evidence Extensive overlap among the diseases:

    Asthma occurs in up to 40% of patients with allergic rhinitis (general population rate: 10%)

    Allergic rhinitis occurs in 80-90% of patients with asthma (general population rate: 20%)

    Allergic rhinitis is present in 60-80% of patients with chronic rhinosinusitis

    Among asthmatics, 40-60% have abnormal sinus radiographs; magnitude of sinus abnormalities correlates with the severity of the patients asthma

    Among patients with extensive sinus disease on CT imaging, there was associated allergic rhinitis in 78% of patients and asthma in 71% of patients

    Patients with allergic rhinitis are three times more likely than normal controls to develop asthma later in life

  • Experimental Evidence Thickening of the bronchial basement membrane has

    been demonstrated in patients with allergic rhinitis who did not have asthma.

    Nasal provocation with grass allergen in allergic rhinitis patients increased bronchial symptoms and bronchial mucosa eosinophils, ICAM-1, E-selectin, and VCAM-1

    Selective bronchial provocation with grass allergen in allergic rhinitis patients was shown to cause increased nasal symptoms and eosinophil infiltration of the nasal mucosa

  • Proposed Mechanisms of Interaction in the Integrated Airway

    Aspiration of nasal secretions disprovenBardin and colleagues instilled radioactive markers in the

    nasal sinuses of patients with post-nasal drip and found no uptake in the lungs after 24 hours

    Increased oral breathing provenswitching from nose breathing to mouth breathing of cold air

    produced a significant decrease in FEV1 in asthmatic patients

    Nasobronchial reflex disprovenlidocaine instillation in the nasal cavity did not prevent

    development of bronchial symptoms with a nasal allergen challenge; however, phenylephrine instillation did prevent bronchial symptoms, suggesting that local vasoconstriction prevents systemic access to allergen and allergen-stimulated local mediators

    Local response systemic response general airway inflammation current leading theorylocal provocation leads to systemic

    inflammation response, with release of eosinophil upregulator IL-5; eosinophils then concentrate in both the upper and lower airways, regardless of the site of provocation

  • Basic foundations Self versus non-self

    Self tolerance

    Major histocompatibility complex (MHC) Located on the short arm of chromosome 6

    Class I molecules Present on nearly all nucleated somatic cells

    Interact with CD8+ (cytotoxic) T cells

    Class II molecules Present on antigen-presenting cells (APCs)macrophages,

    monocytes, dendritic cells, and B cells

    Interact with CD4+ (helper) T cells

  • Innate Immunity Immediate response

    Non-specific

    Components:

    Skin, mucosa

    Antimicrobial substances, e.g. lysozyme

    Complement system

    Toll-like receptors (TLRs)pattern recognition

    TLR-2: lipoproteins

    TLR-3: double-stranded RNA

    TLR-4: lipopolysaccharides (LPS)

    TLR-9: cytidine-phosphate-guanosine (CpG) dinucleotide sequence

  • Adaptive Immunity

    Slow response

    Highly specific

    Memory

    Lymphoid cells

    Myeloid cells

    Role of cytokines in differentiation

    Photo source: Cummings Otolaryngology: Head & Neck Surgery

  • T cells Develop in the thymus

    Comprise 80% of circulating lymphocytes

    Defined by the presence of surface T-cell receptor (TCR)

    Further classified by:

    CD8+: cytotoxic, cell-mediated immunity, highly active against virus-infected and tumor cells

    CD4+: helper cells, augment humoral (B-cell) and cytotoxic responses

  • CD4+ T cells TH1

    Produce IFN-macrophage activation Intracellular pathogen clearanceviruses, mycobacteria, Listeria Delayed-type hypersensitivity

    TH2 B cell activation Produce IL-4, IL-5, and IL-13crucial role in allergy Extracellular pathogen clearanceparasites, bacteria, allergens

    TH17 Produce IL-17, a key neutrophil recruiter IL-17 reduces pulmonary eosinophil recruitment

    Treg Foxp3+ cells, suppress T-cell responses and autoimmunity Immunodysregulation, polyendocrinopathy, enteropathy, X-linked

    syndrome (IPEX) Loss of function mutation in Foxp3 gene Spectrum of disease includes type-1 diabetes, autoimmune thyroiditis, eczema,

    bleeding abnormalities, and chronic wasting

  • TH cell Interactions

    TH cell after stimulation produces IL-2, begins to differentiate, initially termed TH0

    From there, differentiation to TH1 or TH2 depends on environment

    IL-12 from macrophages leads to TH1 cells

    IL-4 from mast cells, NK cells , or eosinophils leads to TH2 cells

    Photo source: Cummings Otolaryngology: Head & Neck Surgery

  • B cells Develop in the bone marrow

    Comprise 10% of circulating lymphocytes

    Defined by presence of surface IgM and IgD receptors (analogous to TCR)

    Provide humoral immunity via antibody production

    Differentiation promoted by T cells

    Germinal center formation

    Plasma cells

    Memory B cells

  • B cells T-cell dependent activation

    TCR:MHC class 2 interaction CD40:CD40 ligand interaction T-cell produced IL-1 and IL-2 Cytokine mediated isotype switching

    T-cell independent activation Occurs with large carbohydrate antigens that cannot be

    presented on MHC class 2 molecules (capsule, cell wall) Repeating antigenic determinate cross-links surface

    immunoglobulins, resulting in B cell activation Primarily results in IgM antibody production Essential defense against Streptococcus pneumoniae,

    Haemophilus influenzae, and Neisseria meningitidis

  • Antibodies Five classes: G(75%), A(15%), M(10%), D(0.2%), E(0.004%)

    Four IgG subclasses (IgG1-IgG4)

    Two IgA subclasses (IgA1 and IgA2)

    Heavy and light chains

    Fab and Fc regions

    Isotype switching induced by cytokines:

    IL-10: IgG1 and IgG3

    IL-4 and IL-13: IgE

    TGF-: IgA

    INF-: IgG2

  • IgM: primary immune response, declines rapidly, replaced with IgG; most efficient complement-fixing antibody

    IgG: secondary immune response and later primary response, IgG1&3, and to some extent, IgG2, fix complement; only Ig to cross placenta; IgG1&3protein antigens; IgG2polysaccharide antigens

    IgA: secretory, prevents microbes from crossing mucosal barriers

    IgD: only functions as B-cell receptor

    IgE: High-affinity receptors on mast cells and basophils; low-

    affinity receptors on neutrophils, eosinophils, macrophages, and platelets

    Photo source: Middletons Allergy: Principles and Practice

  • Natural Killer (NK) Cells Comprise 10% of circulating lympocytes

    Unlike T cells, NK cells are not MHC restricted

    Express CD16 (Fc receptor) and CD56

    Virus-infected and tumor cells frequently down-regulate class I MHC molecules to avoid T-cell mediated destruction

    NK cells are the solution to this: Interact with class I MHC on cells encountered

    If no class I MHC molecules present, the cell is destroyed

  • Neutrophils Comprise 60-65% of circulating leukocytes

    Develop in the bone marrow

    Accumulate at sites of bacterial infection or tissue injury

    Utilize oxygen radicle production and phagocytosis

    Produce cytokines, including IL-12 and TNF

  • Monocytes/Macrophages Comprise 10% of circulating leukocytes

    Monocytes mature in the bone marrow

    Enter tissues from the blood stream to become macrophages, dendritic cells, Langerhans cells (epidermis), Kupffer cells (liver), microglia (CNS)

    Possess both class I and class II MHC molecules

    Function as APCs

    Fc receptor facilitates phagocytosis of opsonized microbes

    Produce many cytokines, including IL-12 and INF-

  • Eosinophils Comprise 2-5% of circulating leukocytes

    Combat parasite infestation

    GM-CSF and IL-3 promote growth and differentiation

    IL-5 inhibits apoptosis, maintaining viability

    Granule contents: Major basic protein (MBP)

    Eosinophil peroxidase (EPO)

    Eosinophil cationic protein (ECP)

    Eosinophil-derived neurotoxin (EDN)

    Charcot-Leyden crystal (CLC) protein

  • Mast Cells and Basophils Both originate from a common progenitor cell (CFU-

    BM)

    IL-3 and stem cell factor (SCF) are essential for growth and differentiation

    Both cell types express high-affinity receptors (FcRI) for IgE

    Crosslinking by antigens leads to degranulation, including his