Commonalities of etiology and management

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