Allergic Rhinitis, Asthma, and Chronic Rhinosinusitis: Commonalit= ies of Etiology and Management April 2012

TITLE: Allergic Rhinitis, Asthma, and Chronic Rhinosinusitis:
Commonalities of Etiology and Management
SOURCE: Grand Rounds Presentation, Department of Otolaryngology
The University of Texas Medical = Branch (UTMB Health)
DATE: April 25, 2012
RESIDENT PHYSICIAN: Joseph L. Russell, MD
FACULTY PHYSICIAN: Farrah Siddiqui, MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, MSICS

"This material was prepared by resident physicians in partial fulfillment of educational requirements established f= or the Postgraduate Training Program of the UTMB Department of Otolaryngology/= Head and Neck Surgery and was not intended for clinical use in its present form.= It was prepared for the purpose of stimulating group discussion in a conferenc= e setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and sho= uld not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." =

Introduction

Allergic rhinitis, asthma, and chronic rhinosinus= itis (CRS) are some of the most common conditions encountered in general otolary= ngology practice. While many otolaryngolo= gists do not directly manage asthma, its frequent coexistence and shared pathogen= esis with allergic rhinitis and CRS make it a worthwhile inclusion in a discussi= on of the others. Indeed, as will be detailed below, some authors consider the three disorders to be different manifestations of the same underlying condition, i.e. pathologic inflammati= on of the airway.

Integrated Airway Hypothesis

Over the last few decades there has been a develo= ping awareness of the interplay and frequent co-existence of allergic rhinitis, asthma, and CRS; this has led to the hypothesis that they are not three separate diseases but rather different manifestations of the same underlying pathogenic process.

There is extensive epidemiologic evidence to support this hypothesis. Asthma occurs in up to 40% of patients = with allergic rhinitis, compared to the general population rate of ~10%. Conversely, allergic rhinitis occurs in 80-90% of patients with asthma, compared to the general population rate of 20%. Allergic rhinitis is present = in 60-80% of patients with CRS, and among asthmatics, 40-60% have abnormal sin= us radiographs, with the magnitude of the sinus abnormalities correlating with= the severity of the patient’s asthma. = Among patients with extensive sinus disease on computed tomography (CT) imaging, = 78% have allergic rhinitis and 71% have asthma. Finally, patients with allergic rhinitis are three times more likely than normal controls to develop asthma later in life.

There is also experimental evidence to support the integrated airway hypothesis. Thic= kening of the bronchial reticular basement membrane, a feature of the airway remodeling seen in asthma, has been observed in patients with allergic rhin= itis who did not have asthma. In two se= parate studies by Braunstahl et al, stimulation of the nasal mucosa of subjects wi= th allergic rhinitis with an allergen to which subjects were sensitized result= ed in increased bronchial symptoms compared to controls and infiltration of eosinophils into bronchial mucosa. When the allergen was introduced via bronchoscopy to the bronchial mucosa, an increase in nasal symptoms compared to controls and infiltration of eosinop= hils into the nasal mucosa were observed.

Several mechanisms have been proposed for interac= tions between the upper and lower airway in the context of an integrated airway: =

·&nb= sp; Asp= iration of nasal secretions

disproven—Bardin= and colleagues instilled radioactive markers in the nasal sinuses of pati= ents with post-nasal drip and found no uptake in the lungs after 24 hours<= /li>

Increased oral breathing

proven—switching= from nose breathing to mouth breathing of cold air produced a significant decrease in FEV1 in asthmatic patients

Nasobronchial reflex

disproven—lidoca= ine instillation in the nasal cavity did not prevent development of bronc= hial 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 èsystemic response è general airway inflammation

current leading theory—local 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 provocati= on

Immunology

One of the basic functions of the immune system i= s to distinguish self from non-self. Th= is is referred to as self tolerance and is essential if the body is to successful= ly ward off invading microorganisms yet leave itself with minimal harm. The molecular basis for self tolerance = is found in the major histocompatibility complex (MHC) located on the short ar= m of chromosome 6. Class I and Class II= MHC molecules are produced from these genes. Class I molecules are present on nearly all nucleated somatic cells = and interact with CD8⁺ (cytotoxic) T cells. Class II molecules are present on antigen-presenting cells (APCs), i.e. macrophages, monocytes, dendritic cel= ls, and B cells, and interact with CD4⁺ (helper) T cells.

The immune system is divided into innate and adap= tive systems. The innate system is non-specific but provides an immediate response to invading microorganisms. The components of = this system include the skin and mucosa, antimicrobial substances such as lysozy= me and lactoferrin, the complement system, and Toll-like receptors (TLRs) on phagocytic cells. The TLRs provide pattern recognition to the phagocytic cells. For example, TLR-2 binds lipoproteins found in the walls of many gram positive and gram negative bacteria, TLR-3 binds double-stranded RNA found = in viruses, TLR-4 binds lipopolysaccharides (LPS) found in gram negative bacte= rial cell walls, and TLR-9 binds cytidine-phosphate-guanosine (CpG) dinucleotide sequences, which are twenty times more likely to be found in bacterial DNA = than in human DNA.

The adaptive immune system is highly specific but provides a slower response to microorganisms compared to the innate immune system. A key aspect of the adapti= ve system is memory, which allows subsequent responses to be faster should a microorganism be encountered again. This system is composed of white blood cells, both of the lymphoid (T, B, and natural killer [NK] ) and the myeloid (monocyte, macrophage, neutrophil, eosinophil, and basophil) cell lines.

T cells

T cells develop in the thymus and comprise 80% of circulating lymphocytes. They are defined by the presence of the surface T-cell receptor (TCR), and are furth= er classified as CD8⁺ and CD4⁺; CD4^-/CD8^=
- T cells do exist and appear to have a regulatory role, but their functions = have not been fully elucidated and will not be discussed here. CD8⁺ cells are the cytotoxic= T cells, are involved in cell-mediated immune responses, and are highly active against virus-infected and tumor cells. CD4⁺ cells are the helper T cells that work to augment humoral (B-cell) and cytotoxic immune responses.

—<= span style=3D'font:7.0pt "Times New Roman"'> CD4⁺ T cells are further classified as follows:

· TH1 cells

o Produce IFN-γ essential to macrophage activation

o Involved in intracellular pathogen clearance—viruses, mycobacteria, Listeria

o Key players in delayed-type hypersensitivity

· TH2 cells

o Major role in B cell activation

o Produce IL-4, IL-5, and IL-13—crucial role in allergy

o Involved in extracellular pathogen clearance—parasites, bacteria, allergens

· TH17 cells

o Produce IL-17, a key neutrophil recruiter and eosinophil suppressor

· Treg cells

o These are Foxp3+ cells, which suppress T-cell responses and autoimmunity

o Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)

§&nb= sp; Caused by a loss of function mutation in the Foxp3 gene

§&nb= sp; Spectrum of disease includes type-1 diabetes, autoimmune thyroiditis, eczema, bleedi= ng abnormalities, and chronic wasting

Prior to stimulation, a naïve TH cell has not yet become TH1 or TH2 and is termed TH0. After stimulation occurs, it begins to secrete IL-2 which begins an auto-stimulated process of differentiation. At this point, differentiation becomes dependent on the surrounding environment. If IL-12 produced by macrophages is present, the TH0 cell will be directed down the pathway to become a TH1 cell. Conversely, if = IL-4 produced by mast cells, NK cells, and eosinophils is present, the TH0 cell = will become a TH2 cell.

B cells

B cells develop in the bone marrow and comprise 1= 0% of circulating lymphocytes. They are defined by the presence of surface IgM and IgD receptors which are analogou= s to the TCR for T cells. B cells provi= de humoral immunity via antibody production. Differentiation is promoted by T cells; as B-cells differentiate, th= ey can form germinal centers, become plasma cells that produce large quantitie= s of a specific antibody, or become memory cells that persist indefinitely in the circulation.

B cell activation can occur through both T-cell dependent and independent mechanisms. In T-cell dependent activation, the TCR of the T cell interacts with the MHC C= lass II molecule on the B cell; there is also interaction between the CD40 ligan= d on the T cell and CD40 receptor on the B cell. This process leads to IL-1 and IL-2 secretion by the T cell that fur= ther serves to activate the B cell. T-c= ell independent activation occurs primarily with large carbohydrate antigens wi= th repeating antigenic determinants that cannot be presented on MHC Class II molecules; these antigens are usually components of bacterial capsules and = cell walls. The repeating antigenic determinants crosslink surface immunoglobulins on B cell, resulting in activation. This mechanism results= in IgM class antibody production and is an essential defense against Streptococ= cus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.

Antibodies

There are five classes of immunoglobulin (Ig): G(75%), A(15%), M(10%), D(0.2%), E(0.004%). There are also four IgG subclasses (IgG1-IgG4) and two IgA subclasses (IgA1 and IgA2). Immunoglobulins are composed of two heav= y and two light chains that combine to produce Fab and Fc regions (please see PowerPoint slides for figures). Th= e Fab region binds antigen while the Fc region binds to Fc receptors on various w= hite blood cells. Isotype switching (ch= anging from one Ig class to another) is induced by cytokines. For example, IL-10 promotes switching t= o IgG1 and IgG3 production, IL-4 and IL-13 promote IgE production, TGF-β prom= otes IgA production, and INF-γ promotes IgG2 production. IgM is produced in the primary immune response, declines rapidly, and is replaced by IgG; it is the most efficient complement-fixing antibody due to its pentameric structure. IgG is produced in the late primary and= secondary immune responses. It is the only I= g that crosses the placenta during pregnancy. IgG1, IgG3, and, to some extent, IgG2 fix complement. IgG1 and IgG3 bind protein antigens whe= reas IgG2 binds polysaccharide antigens. IgA is secreted on mucosal surfaces and is found in tears, saliva, and breast m= ilk; it binds microorganisms to prevent them from crossing mucosal barriers. IgE binds to high-affinity Fc receptors= on mast cells and basophils and to low-affinity receptors on neutrophils, eosinophils, macrophages, and platelets. IgD’s only known function is its role as a B-cell receptor.

Natural Kill (NK) Cells

NK cells comprise 10% of circulating lymphocytes = and express CD16 (an Fc receptor) and CD56. Unlike T cells, NK cells are not restricted to interactions with cel= ls bearing MHC molecules, which is essential to their function. Virus-infected and tumor cells frequent= ly down-regulate MHC Class I molecules to avoid T-cell mediated destruction. NK cells solve this problem. When an NK cells encounters a cell in t= he body, it attempts to interact with an MHC Class I molecule; if no MHC Class= I molecule is found, the NK cell will destroy the cell.

Neutrophils

Neutrophils develop in the bone marrow and compri= se 60-65% of circulating leukocytes. = They accumulate at sites of bacterial infection or tissue injury, utilize oxygen radical production and phagocytosis to destroy microorganisms, and produce = many cytokines, including IL-12 and TNF.

Monocytes/Macrophages

These cells comprise 10% of circulating leukocytes. Monocytes mature in th= e bone marrow, then enter tissues from the blood stream to become tissue macrophag= es, dendritic cells, Langerhans cells (epidermis), Kupffer cells (liver), and microglia (CNS). These cells posse= ss both MHC Class I and Class II molecules and function as APCs. They also possess Fc receptors that facilitate phagocytosis of opsonized microorganisms. They produce many cytokines, including = IL-12 and INF-γ.

Eosinophils

Eosinophils comprise 2-5% of circulating leukocyt= es and have a key role in combating parasite infestation. GM-CSF and IL-3 promote eosinophil grow= th and differentiation; IL-5 inhibits apoptosis, thereby maintaining viability. These cells have granules that contain = major basic protein (MBP), eosinophil peroxidase (EPO), eosinophil cationic prote= in (ECP), eosinophil-derived neurotoxin (EDN), and Charcot-Leyden crystal (CLC) protein.

Mast Cells and Basophils

Both of these cells originate from a common proge= nitor cell (CFU-BM); IL-3 and stem cell factor (SCF) are essential for growth and differentiation. Both cell types e= xpress high-affinity receptors (FcεRI) for the IgE Fc region. Crosslinking of these antibody/receptor complexes by antigens leads to degranulation, including histamine release.<= /p>

Hypersensitivity Reactions

Type I (immediat= e)

Mast cell/basop= hil/IgE mediated
Example: anaphy= laxis

Type II (cytotox= ic, antibody-mediated)

Antibodies bind= to antigens on target cells
Example: penicillin-induced autoimmune hemolytic anemia

Type III (immune complex-mediated)

Antigen-antibody complexes deposit in normal tissues
Examples: serum sickness, lupus

Type IV (delayed hypersensitivity, cell mediated)

Antibody indepe= ndent, mediated by T or NK cells
Example: positi= ve PPD test

Allergic Rhinitis

Allergic rhinitis is an IgE-mediated hypersensiti= vity of the nasal mucosa to foreign substances that affects 20% of the United St= ates population. It rarely occurs befor= e 2 years of age and is almost always present in affected individuals by 20 yea= rs of age. There is a male predominan= ce in childhood that equalizes in adulthood. Allergic rhinitis is frequently associat= ed with atopy, which is the genetic predisposition to respond to environmental allergens with the production of specific IgE antibodies to those allergens= .

Hygiene Hypothesis

The hygiene hypothesis states that the decrease in infectious diseases during the past four decades is causally related to the concomitant increase in the incidence of allergic diseases. Several epidemiological observations su= pport this hypothesis: (1) Children raised on a farm are less likely to develop allergic rhinitis than those not raised on a farm. (2) The risk of allergic rhinitis is inversely linked to birth order and family size. (3) Children with older siblings at hom= e and those who attended daycare during the first six months of life have a lower incidence of asthma. Finally, (4) = there is a higher prevalence of atopy and asthma in industrialized countries comp= ared to undeveloped and poorer countries.

The following are some of the proposed mechanisms= of hygiene hypothesis, and are not mutually exclusive:

· TH1= /TH2 regulation

o Cytokines = of one TH cell type down-regulate the activation of the other

o TH1 respon= ses are activated by extracellular pathogens

o TH2-produc= ed cytokines IL-4 and IL-5 promote allergic diseases

· Tre= gs

o Activity of these cells is up-regulated by infections

o These cell= s produce IL-10 and TGF-β, which down-regulate both TH1 and TH2 mediated respons= es

· Tol= l-like receptor interactions

o Activation= of TLRs in dendritic cells promotes TH1 responses critical for cell-mediated immunity, thereby affecting the TH1/TH2 balance in favor of TH1

Pathophysiology of Allergic Rhinitis

The first phase in the pathogenesis of allergic rhinitis is sensitization. APCs in= the nasal mucosa process and present antigen to T cells. Activated TH2 cells secrete IL-4, IL-5,= and IL-13; these cytokines promote isotype switching to IgE and eosinophil recruitment and survival. The IgE produced attaches to high-affinity receptors on the mast cells and basophil= s in the nasal mucosa.

The second phase is marked by the appearance of clinical disease and is divided into early and late responses. The early response occurs within minute= s of antigen exposure. IgE on mast cell= s is crosslinked, leading to degranulation. Both preformed (histamine, kinins, tryptase) and rapidly synthesized= (prostaglandin D2, leukotriene C4, leukotriene B4, major basic protein, and platelet activating factor) mediators are released, leading to the symptoms of sneez= ing, rhinorrhea, and nasal congestion. = There is also a likely neuronal component to this early response, mediated by histamine acting on nasal afferent nerves, as evidenced by unilateral nasal challenge leading to bilateral symptoms and the concomitant ocular symptoms that occur with nasal antigen provocation. The late response occurs hours after exposure, usually peaking at 6 hours post-exposure and resolving by 24 hours post-exposure. The predominant symptom of the late res= ponse is nasal congestion. During this p= eriod, there is an increase in histamine, kinins, and numerous cytokines (IL-5, IL= -6, IL-8, GM-CSF, TNF, and soluble ICAM-1) with a concomitant influx of inflammatory cells. Eosinophils, basophils, and neutrophils increase in nasal secretions while a mononuclear= and mast cell infiltration occurs in the nasal mucosa. Most specifically, the increase in baso= phils correlates with the late rise in histamine, implying that basophil infiltra= tion and subsequent histamine release is a key component of the late response.

Diagnosis of Allergic Rhinitis

·&nb= sp; His= tory

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<= span style=3D'mso-list:Ignore'>—Phy= sical Exam Findings

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—Tes= ting

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>— It affects 10% of ad= ults and 15% of children in the United States; most patients have atopy, which is the major risk factor. There is a = 2:1 male to female ratio in childhood that equalizes in adulthood. The pathogenesis is very similar to all= ergic rhinitis, with a key difference being that capacitance vessels are affected= in allergic rhinitis, leading to rhinorrhea and nasal congestion, whereas in asthma, bronchial smooth muscle is simulated, leading to constriction and airway narrowing.

Pathogenesis of Asthma

Allergens, sensitizers, viruses, and air pollutan= ts lead to lower airway inflammation with a chronic eosinophilic bronchitis. This leads to airway hyperresponsiveness. The hyperresponsiveness combined with triggers leads to symptoms—coughing, wheezing, chest tightness, and dyspnea. Over time airway remodeling occurs, whic= h is characterized by smooth muscle hyperplasia and hypertrophy, fibroblast activation with subsequent collagen deposition, and mucous gland hyperplasi= a.

Triggers

There are numerous triggers for asthma exacerbation. These include indoor allergens such as dust mites, pet dander, and cockroaches and outdoor aller= gens such as trees, grasses, and weeds. Beta-blockers, ACE inhibitors, and aspirin are the most common medication triggers. In women, hor= mone changes can cause premenstrual worsening of asthma symptoms; if severe, treatment with high doses of progesterone can be used. Other triggers include viral infections, exercise, cold air, hot air, fog, and air pollution.

Diagnosis of Asthma

<= span style=3D'mso-list:Ignore'>—His= tory

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—Pul= monary Function Tests (PFTs)

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>— FEV= 1/FVC ratio—normal ratio is between 80-120% of predicted; 70-79%--mild airflow obstruction; 51-69%--moderate airflow obstruction; <50%--severe airflow obstruction

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—

<= span style=3D'mso-list:Ignore'>—Bro= nchial provocation testing

Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a complex group of disorders with inflammation as the major universal finding. It affects approximately 15% of the adu= lt population in the United States. T= he term rhinosinusitis is preferred over the term sinusitis because the nose is almost always involved at the same time as the paranasal sinuses. Several other important definitions are worthwhile to consider. Acute rhinosinusitis occurs with sudden onset and has a duration <4 weeks. Subacute rhinosinusitis has a duration = of 4-12 weeks. Recurrent rhinosinusit= is is defined as >3 episodes of rhinosinusitis in one year. Chronic rhinosinusitis is defined as ha= ving a duration >12 weeks and is further classified as with or without nasal polyposis (CRSwNP and CRSsNP, respectively). Acute exacerbation of chronic rhinosinusitis (AECRS) is used to desc= ribe the acute flares of disease that frequently occur in patients with CRS.

Pathogenic factors in CRS

There are many factors that have been found to pl= ay a role in the development and maintenance of CRS. Bacterial superantigens, such as enterotoxins and toxic shock toxins produced by Staphylococcus aureus, can lead to extensive inflammation due to interaction of the toxins outside= of the normal TCR and MHC Class II molecule binding sites, which results in polycl= onal activation of T-cells.

Biofilms are polymicrobial ecosystems within a polymeric matrix that become irreversibly associated with an inert or living surface; they are much akin to coral reefs. Biofilms are found in up to 80% of patients undergoing surgery for C= RS and are particularly difficult to treat due to the pronounced antibiotic resist= ance provided to the bacteria species living in the biofilm; indeed, antibiotic concentrations greater than 1,000 times therapeutic serum levels can be required to eradicate the bacteria within the biofilm. This high dose requirement usually makes medical therapy impossible, necessitating removal of affected surface, be i= t an inert medical device or living tissue.

Fungi can contribute to CRS through non-invasive colonization that leads to obstruction of the sinus ostia or through allerg= ic fungal sinusitis which is an IgE-mediated hypersensitivity.

Allergic rhinitis is present in 40-84% of patient= s with CRS; it is thought to contribute to CRS by inducing mucosal swelling that obstructs the sinus ostia.

Genetic factors can also play a role in CRS. Seven percent of patients with CRS are = cystic fibrosis (CF) carriers, compared to the general population rate of 2%. Furthermore, 36% of CF patients have CR= S, compared to the 15% general population rate.

Immunodeficiency should be considered as a possib= le contributor to CRS when aggressive therapy has failed. In patients with refractory CRS, the ra= tes of immunodeficiency range from 3-10%. The most common disorders seen in this group are selective IgA deficiency, comm= on variable immunodeficiency, and hypogammaglobulinemia.

Finally, environmental irritants such as tobacco = smoke and industrial pollution can contribute to the development and persistence = of CRS.

Diagnosis of CRS

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>— Nasal polyps are present in 19-36% of patients with CRS. Interestingly, eosinophils are abundantly present in 80% of polyps in United States patien= ts, whereas in Asian patients, neutrophils predominant in nasal polyps. The presence of nasal polyps is linked = to CF in children and aspirin sensitivity in young adults. In patients with CF, 37-48% have nasal polyps, which underscores the importance of testing all children with nasal polyps for CF.

The followin= g is a common classification system for nasal polyps:

1.      The antrochoanal polyp, mostly ari= sing from the maxillary sinus and prolapsing into the choana, a commonly large isolated unilateral cyst-like non-eosinophilic formation

2.      Idiopathic unilateral or bilateral, mostly eosinophilic polyps without involvement of the lower airways <= /span>

3.      Bilateral eosinophilic polyposis w= ith concomitant asthma and/or aspirin sensitivity

4.      Polyposis with underlying systemic disease such as cystic fibrosis, primary ciliary dyskinesia, Churg-Strauss syndrome

The following is the endoscopic staging system f= or nasal polyps:<= o:p>

0          No polyps present

1          Polyps confined to the middle me= atus

2          Polyps beyond the middle meatus (reaching the inferior turbinate or medial to the middle turbinate)

3          Polyps almost or completely obstructing the nasal cavity

Samter’s Triad

Samter’s triad is characterized by nasal polyposi= s, asthma, and aspirin sensitivity. In patients with nasal polyps, 15% have aspirin sensitivity and 20-70% have asthma. In patients with aspirin sensitivity, 40-80% have nasal polyps. Symptoms of the triad usually develop following a prolonged upper respiratory infection in the third or fourth decade of life. Initially, the patient suffers from nas= al congestion, rhinorrhea, post-nasal drip, and hyposmia; within a few years, bronchial asthma and nasal polyposis develop. The asthma is usually severe, with 50% of patients requiring chronic burst or daily oral steroid therapy. Asthma and rhinitis attacks are triggered by ingestion of aspirin and non-selective non-steroidal anti-inflammatory drugs (NSAIDs); however, the progression of the disease is not affected by aspirin ingestion.

Pathogenesis of Samter’s Triad

The pathogenesis of Samter’s triad is not complet= ely understood; however, unlike asthma and allergic rhinitis, atopy and IgE do = not appear to play a role. Peripheral = blood and local mucosal eosinophilia are characteristic, as are elevated tissue a= nd urine cysteinyl-leukotrienes (cys-LTs) concentrations, which increase with aspirin exposure. The latter findi= ngs provide a potential mechanism for the disease. Because aspirin inhibits COX 1 and 2 in the arachidonic acid metabol= ism pathway, production equilibrium is shifted toward leukotriene formation. In eosinophils of aspirin sensitive pat= ients, there is a several-fold elevation of LTC4 synthase, which is the terminal enzyme in cys-LT production; therefore, polymorphisms in the LTC4 synthase = gene are suspected to contribute to the development of Samter’s triad.

Diagnosis of Samter’s Triad

No validated laboratory te= sting available

Oral aspirin provocation in a controlled setting is the current gold standard in the U.S.

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>— In 1990, the American College of Rheuma= tology established the follow six diagnostic criteria, at least four of which must= be present:

<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>—<= span style=3D'mso-list:Ignore'>— First, the patient de= velops allergic rhinitis, rhinosinusitis, and asthma of variable severity. Next, blood eosinophilia and eosinophil= ic tissue infiltration occurs. Finall= y, the patient develops life-threatening, multi-organ vasculitis involving the cardiac, pulmonary, gastrointestinal, and central nervous systems.

Diagnosis of Churg-Strauss Syndrome

<= span style=3D'mso-list:Ignore'>—Physical Exam Findings:

<= span style=3D'mso-list:Ignore'>—Nose: nasal polyps, nasal mucosal congestion, rhinorrhea

<= span style=3D'mso-list:Ignore'>—Cardiovascular: heart failure

<= span style=3D'mso-list:Ignore'>—Lungs: wheezes, rhonchi, decreased breath sounds

<= span style=3D'mso-list:Ignore'>—Neurologic: Mononeuritis multiplex—sensory and motor neuropathy in the distribution of = one nerve, polyneuropathy

<= span style=3D'mso-list:Ignore'>—Skin: palpable purpura, papules, ulcers, bullae, and “Churg-Strauss granulomas”—cutaneous extravascular necrotizing granulomas on extensor surf= aces and pressure points (elbow)

=

<= span style=3D'mso-list:Ignore'>—Laboratory:

<= span style=3D'mso-list:Ignore'>—White blood cell

<= span style=3D'mso-list:Ignore'>—Marked eosinophilia (up to 60%)

<= span style=3D'mso-list:Ignore'>—Antineutrophil antibodies (ANCA)—present in 50% of patients

<= span style=3D'mso-list:Ignore'>—Erythrocyte sedimentation rate (ESR)—elevated in most cases

<= span style=3D'mso-list:Ignore'>—Imaging:<= /b>

<= span style=3D'mso-list:Ignore'>—CT thorax—best to demonstrate pulmonary infiltrates

<= span style=3D'mso-list:Ignore'>—Echocardiogram

<= span style=3D'mso-list:Ignore'>—Heart failure

<= span style=3D'mso-list:Ignore'>—Dysfunction from regional fibrosis

=

<= span style=3D'mso-list:Ignore'>—Biopsy Findings:=

<= span style=3D'mso-list:Ignore'>—Skin lesions: extravascular granulomas with eosinophilic infiltrate

<= span style=3D'mso-list:Ignore'>—Lung: massive alveolar and interstitial infiltrates (eosinophilic)

<= span style=3D'mso-list:Ignore'>—Blood vessel: necrotizing fibrinoid eosinophilic vasculitis of small to medium-si= zed vessels

=

<= span style=3D'mso-list:Ignore'>—Distinguishing Churg-Straus= s from Asthma:

<= span style=3D'mso-list:Ignore'>—Degree of eosinophilia

<= span style=3D'mso-list:Ignore'>—Churg-Strauss: blood eosinophil counts usually >1500/μL

<= span style=3D'mso-list:Ignore'>—Asthma: blood eosinophil counts usually <1500/μL

<= span style=3D'mso-list:Ignore'>—ESR

<= span style=3D'mso-list:Ignore'>—Positive in Churg-Strauss

<= span style=3D'mso-list:Ignore'>—Negative in asthma

<= span style=3D'mso-list:Ignore'>—ANCA

<= span style=3D'mso-list:Ignore'>—Positive in 50% of patients with Churg-Strauss

<= span style=3D'mso-list:Ignore'>—Negative in patients with “regular” asthma

Therapeutics

Steroids

Steroids (glucocorticoids) are potent anti-inflam= matory and immunosuppressant medications with many formulations—intranasal, inhale= d, oral, intramuscular, and intravenous. These agents are used extensively in the treatment of allergic rhini= tis, asthma, chronic rhinosinusitis, nasal polyposis, Samter’s triad, and Churg-Strauss disease.

A brief review of steroid pharmacology follows. The glucocorticoid receptor (GR) reside= s in the cytoplasm of cells; after binding of a glucocorticoid molecule, the com= plex translocates to the cell nucleus. = Once in the nucleus, GR and other factors modify gene transcription, downregulat= ing some genes while upregulating other genes. The downregulated genes include mediators of inflammation—cyclooxygenase-2, numerous cytokines, and inducible nitric oxi= de synthase. The upregulated genes are metabolic regulators—enzymes involved in gluconeogenesis, amino acid metabolism, etc.

Despite their great usefulness in treating all of= the diseases discussed in this presentation, steroids are not without side effects. The side effects of prolo= nged, systemic, supra-physiologic exposure to glucocorticoids include hyperglycem= ia, hypertension, peptic ulcers, myopathy, behavior changes ranging from nervousness and anxiety to full psychosis, osteoporosis, osteonecrosis, gro= wth retardation in children, and cataracts. The risk for cataract development is dose-dependent; therefore, if a patient is taking prednisone 10-15 mg/day or equivalent on a chronic basis, slit-lamp examination should be performed periodically.

Therapeutic Options for Allergic Rhinitis

The therapeutic options for the treatment of alle= rgic rhinitis include avoidance of the offending allergen(s), intranasal steroid= s, antihistamines, decongestants, anticholinergics, cromolyn, leukotriene modifiers, systemic steroids, and immunotherapy. Each of these is discussed below.

<= span style=3D'mso-list:Ignore'>—Avoidance=

<= span style=3D'mso-list:Ignore'>—Remove offending pet from the home

<= span style=3D'mso-list:Ignore'>—Hypoallergenic mattress covers and pillow cases

<= span style=3D'mso-list:Ignore'>—Washing bedding in hot water

<= span style=3D'mso-list:Ignore'>—In general, hard to accomplish

=

<= span style=3D'mso-list:Ignore'>—Intranasal steroids

<= span style=3D'mso-list:Ignore'>—Reduce number of inflammatory cells and TH2 cytokines in the nasal mucosa

<= span style=3D'mso-list:Ignore'>—Result in significant inhibition of early and late phase reactants

<= span style=3D'mso-list:Ignore'>—Effective in both seasonal and perennial allergic rhinitis

<= span style=3D'mso-list:Ignore'>—Superior efficacy compared to both antihistamines and leukotriene modifiers

<= span style=3D'mso-list:Ignore'>—First-line therapy, except for mildest forms = of allergic rhinitis

<= span style=3D'mso-list:Ignore'>—Continuous use is best; however, as-needed use has been proven superior to placebo

<= span style=3D'mso-list:Ignore'>—Side effects

<= span style=3D'mso-list:Ignore'>—Local irritation (10%)

<= span style=3D'mso-list:Ignore'>—Epistaxis (4-8%)

<= span style=3D'mso-list:Ignore'>—Nasal septal perforation (very rare)

<= span style=3D'mso-list:Ignore'>—Pediatric consideration: regular growth moni= toring every 3-6 months

=

<= span style=3D'mso-list:Ignore'>—Antihistamines

<= span style=3D'mso-list:Ignore'>—H1 blockers

<= span style=3D'mso-list:Ignore'>—First generation (diphenhydramine) more lipophilic, cross CNS, lead to sedation

<= span style=3D'mso-list:Ignore'>—Second generation (cetirizine, loratadine, fexofenadine) are less lipophilic, much less sedating

<= span style=3D'mso-list:Ignore'>—Effective at controlling sneezing, itching, rhinorrhea, and watery eyes; not as effec= tive at controlling nasal congestion

<= span style=3D'mso-list:Ignore'>—Topical preparation available

<= span style=3D'mso-list:Ignore'>—Azelastine

<= span style=3D'mso-list:Ignore'>—Side effects

<= span style=3D'mso-list:Ignore'>—Sedation (20%, first generation)

<= span style=3D'mso-list:Ignore'>—Altered sense of smell immediately after use (azelastine)

=

<= span style=3D'mso-list:Ignore'>—Decongestants

<= span style=3D'mso-list:Ignore'>—Oral

<= span style=3D'mso-list:Ignore'>—Pseudoephedrine

<= span style=3D'mso-list:Ignore'>—Phenylephrine—lack of efficacy compared to placebo

<= span style=3D'mso-list:Ignore'>—Topical

<= span style=3D'mso-list:Ignore'>—More effective than systemic

<= span style=3D'mso-list:Ignore'>—Oxymetazoline (0.05%)

<= span style=3D'mso-list:Ignore'>—Phenylephrine (1%)

<= span style=3D'mso-list:Ignore'>—Mechanism: alpha-agonist mediated vasoconstriction

<= span style=3D'mso-list:Ignore'>—Side effects:

<= span style=3D'mso-list:Ignore'>—Rhinitis medicamentosa (topical)

<= span style=3D'mso-list:Ignore'>—Insomnia, irritability (systemic)

<= span style=3D'mso-list:Ignore'>—HTN (systemic)

<= span style=3D'mso-list:Ignore'>—Seizures in children (systemic)

=

<= span style=3D'mso-list:Ignore'>—Anticholinergics

<= span style=3D'mso-list:Ignore'>—Intranasal ipratropium bromide

<= span style=3D'mso-list:Ignore'>—Useful when rhinorrhea is the predominant symptom

<= span style=3D'mso-list:Ignore'>—No effect on sneezing or nasal congestion

<= span style=3D'mso-list:Ignore'>—Minimal side effects

<= span style=3D'mso-list:Ignore'>—Cromolyn =

<= span style=3D'mso-list:Ignore'>—Cromolyn sodium intranasal (4%)

<= span style=3D'mso-list:Ignore'>—Mast cell stabilizer

<= span style=3D'mso-list:Ignore'>—Most effective when started prior to onset of symptoms

<= span style=3D'mso-list:Ignore'>—Effective for sneezing, rhinorrhea, and itching

<= span style=3D'mso-list:Ignore'>—Must be dosed 4-6 times per day

<= span style=3D'mso-list:Ignore'>—Useful for known upcoming exposures to allergen and in pregnancy=

<= span style=3D'mso-list:Ignore'>—Minimal side effects

=

<= span style=3D'mso-list:Ignore'>—Leukotriene modifiers<= /o:p>

<= span style=3D'mso-list:Ignore'>—5-lipoxygenase pathway inhibitor (zileuton)

<= span style=3D'mso-list:Ignore'>—Leukotriene receptor antagonists (monteleukast, zafirlukast)

<= span style=3D'mso-list:Ignore'>—Monteleukast

<= span style=3D'mso-list:Ignore'>—Most commonly used in the United States

<= span style=3D'mso-list:Ignore'>—Equal in effectiveness to antihistamines

<= span style=3D'mso-list:Ignore'>—Combination of monteleukast and an antihistamine superior to each agent alone

<= span style=3D'mso-list:Ignore'>—Side effects

<= span style=3D'mso-list:Ignore'>—Headache

<= span style=3D'mso-list:Ignore'>—Dyspepsia

=

<= span style=3D'mso-list:Ignore'>—Systemic corticosteroids

<= span style=3D'mso-list:Ignore'>—Best reserved for patients who present with complete nasal obstruction

<= span style=3D'mso-list:Ignore'>—Uncontrolled allergic rhinitis

<= span style=3D'mso-list:Ignore'>—Rhinitis medicamentosa

=

<= span style=3D'mso-list:Ignore'>—Immunotherapy

<= span style=3D'mso-list:Ignore'>—Reserved for unavoidable allergens and inadequate response to standard therapies

<= span style=3D'mso-list:Ignore'>—Effects

<= span style=3D'mso-list:Ignore'>—Rise in serum-specific IgG

<= span style=3D'mso-list:Ignore'>—Suppression of IgE

<= span style=3D'mso-list:Ignore'>—Shift from TH2 to TH1 profile

<= span style=3D'mso-list:Ignore'>—Reduction of inflammatory cells in the nasal mucosa and secretions<= /p>
<= span style=3D'mso-list:Ignore'>—Onset of action 12 weeks after starting therapy, increases slowly over 1-2 years<= o:p>

<= span style=3D'mso-list:Ignore'>—Subcutaneous (SCIT)

<= span style=3D'mso-list:Ignore'>—Antigen extract is injected into the skin

<= span style=3D'mso-list:Ignore'>—Sublingual (SLIT)

<= span style=3D'mso-list:Ignore'>—Antigen is applied under the tongue

<= span style=3D'mso-list:Ignore'>—Widely used in Europe

<= span style=3D'mso-list:Ignore'>—Not FDA approved, but trials underway

<= span style=3D'mso-list:Ignore'>—Primary benefits are avoiding frequent office visits for therapy and no needles

=

<= span style=3D'mso-list:Ignore'>—General Therapeutic Approac= h for Allergic Rhinitis:

<= span style=3D'mso-list:Ignore'>—For mild disease

<= span style=3D'mso-list:Ignore'>—As-needed intranasal corticosteroid

<= span style=3D'mso-list:Ignore'>—For moderate to severe disease

<= span style=3D'mso-list:Ignore'>—Regular intranasal corticosteroid

<= span style=3D'mso-list:Ignore'>—Reassess two weeks after starting therapy

<= span style=3D'mso-list:Ignore'>—If ocular symptoms persist: intraocular antihistamine

<= span style=3D'mso-list:Ignore'>—If nasal congestion persists: antihistamine/decongestant combination or monteleukast

<= span style=3D'mso-list:Ignore'>—If rhinorrhea persists: ipratropium bromide

<= span style=3D'mso-list:Ignore'>—Perennial disease and inadequate response with maximal medical management—immunothera= py

Therapeutic Options for Asthma

The therapeutic options for the treatment of asth= ma include bronchodilators—short and long-acting β2-agonists and anticholinergics—and controller therapies—inhaled and systemic corticostero= ids, leukotriene modifiers, cromolyn, immunotherapy, and anti-IgE. Each of these is discussed below.

<= span style=3D'mso-list:Ignore'>—β2-agonists

<= span style=3D'mso-list:Ignore'>—Short-acting: albuterol, terbutaline—PRN symptom relief

<= span style=3D'mso-list:Ignore'>—Long-acting: salmeterol, formoterol—steroid-sparing

<= span style=3D'mso-list:Ignore'>—Relax airway smooth muscle

<= span style=3D'mso-list:Ignore'>—Inhibit mast cell degranulation

<= span style=3D'mso-list:Ignore'>—No effect on inflammation or airway hyperreactivity

<= span style=3D'mso-list:Ignore'>—Side effects

<= span style=3D'mso-list:Ignore'>—Palpitations

<= span style=3D'mso-list:Ignore'>—Muscle tremor

=

<= span style=3D'mso-list:Ignore'>—Anticholinergics

<= span style=3D'mso-list:Ignore'>—Ipratropium bromide

<= span style=3D'mso-list:Ignore'>—Inhibit cholinergic-mediated bronchoconstriction and mucus secretion

<= span style=3D'mso-list:Ignore'>—Much less effective than β2-agonists

<= span style=3D'mso-list:Ignore'>—Used only in combination with β2-agonists

<= span style=3D'mso-list:Ignore'>—Side effects:

<= span style=3D'mso-list:Ignore'>—Dry mouth

<= span style=3D'mso-list:Ignore'>—Urinary retention

<= span style=3D'mso-list:Ignore'>—Glaucoma

=

<= span style=3D'mso-list:Ignore'>—Inhaled corticosteroids

<= span style=3D'mso-list:Ignore'>—Most effective anti-inflammatory agents used in asthma

<= span style=3D'mso-list:Ignore'>—Reduce eosinophils in secretions and T cells and mast cells in the mucosa

<= span style=3D'mso-list:Ignore'>—Reduce airway hyperreactivity

<= span style=3D'mso-list:Ignore'>—First-line therapy for pers= istent asthma

<= span style=3D'mso-list:Ignore'>—Side effects:

<= span style=3D'mso-list:Ignore'>—Oral candidiasis (prevent with oral rinse and spacer)

<= span style=3D'mso-list:Ignore'>—Hoarseness

=

<= span style=3D'mso-list:Ignore'>—Systemic corticosteroids

<= span style=3D'mso-list:Ignore'>—Used for acute asthma exacerbations

<= span style=3D'mso-list:Ignore'>—Necessary for maintenance therapy in 1% of patients

<= span style=3D'mso-list:Ignore'>—Side effects

<= span style=3D'mso-list:Ignore'>—See previous section on supra-physiologic effects of steroids

—Leukotriene modifiers<= /o:p>

—Less effective than inhaled corticosteroids

—May be used instead of a long-acting beta agonist (LABA) if an inhaled corticos= teroid does not completely control symptoms

—Cromolyn sodium (and nedocr= omil sodium)

—Safe and effective but limited by minimum 4 times per day dosing that is require= d

—Immunotherapy

—Not recommended in most asthma treatment guidelines due to lack of clinical efficacy in asthma

—However, immunotherapy appears to have a preventative effect against future developm= ent of asthma in patients with allergic rhinitis

—Anti-IgE =

—Omalizumab

—Neutralizes circulating IgE

—Reduces number of exacerbation in patients with severe asthma and improves overall control

—Minimal side effects

—Drawback—very expensive

= ;

A stepwise approach is taken for asthma therapy (= please see PowerPoint slides for figure). For mild intermittent disease, a short-acting β2-agonist alone is used. For mild persistent disease, a low-dose inhaled corticosteroid (ICS) is added. If disease progresses to moderate persistent, a long-acting β2-agonist is added. For seve= re persistent disease, the ICS is increased to high-dose. Finally, for very severe persistent dis= ease, an oral corticosteroid is added.

Medical Therapeutic Options for CRS

The medical therapeutic options for the treatment= of CRS include nasal saline lavage, systemic and topical antibiotics, topical = and systemic antifungals, intranasal and systemic corticosteroids, leukotriene modifiers, decongestants, antihistamines, anti-IgE, and intravenous immunoglobulin (IVIG). Each of the= se is discussed below.

—Nasal saline lavage

—Study results range from showing no benefit at all to more benefit than standard medical therapy

—Cochrane review in 2007 concluded that it does have benefit as an adjunctive treatme= nt in CRS

—Irrigation has shown more benefit than spray

—Oral antibiotics=

—In CRS, no randomized placebo-controlled trial has demonstrated efficacy of sh= ort courses of oral antibiotics

—Long-term macrolide therapy has been shown to be effective in CRS
—Anti-inflammatory mechanism separate from antimicrobial effects

—Possibly decreases biofilm formation and bacterial virulence

—Recommended as part of primary therapy for non-atopic patients with bilateral disease <= o:p>

—Topical antibiotic therapy<= o:p>

—Less need for surgery demonstrated for patients with cystic fibrosis who were treated with tobramycin in saline nasal rinses than in patients with cystic fibrosis who did not undergo any rinses

—However, similar benefited noted in this study and another between antibiotic plus saline and saline alone

—Topical antifungal therapy<= o:p>

—Similar findings as with topical antibiotic therapy—saline alone appears to be equa= lly effective

—Systemic antifungal therapy=

—No strong evidence to date that this is useful in the treatment of CRS

—Intranasal corticosteroids<= o:p>

—Effective in both CRSsNP and CRSwNP

—Systemic corticosteroids

—Effective in CRSsNP

—Strongly effective in CRSwNP

—Particularly useful in short bursts for complete nasal obstruction to increase nasal pat= ency to allow for penetration of nasal corticosteroid sprays

—Leukotriene modifiers<= /o:p>

—Limited studies for use in CRS

—Some benefit has been seen in patients with CRSwNP

—Decongestants

—Best used for short-term relief of nasal congestion (exacerbations)

—Antihistamines

—No controlled studies showing effectiveness in CRS

—Anti-IgE =

—No studies for its use in CRS

—Intravenous immune globulin (IVIG)

—Significant improvement in immunodeficient patients

= ;

Surgical Therapeutic Options for CR= S

The standard surgical option f= or CRS refractory to medical therapy is functional endoscopic sinus surgery (FESS). In the past few years, bal= loon sinuplasty has become a viable alternative for certain subsets of patients. Both of these options are discussed below.

—<= span style=3D'font:7.0pt "Times New Roman"'> Functional endoscopic sinus surgery (FESS)

—<= span style=3D'font:7.0pt "Times New Roman"'> In CRS, inflammation from v= iral, bacterial, and fungal infections and from allergies causes mucosal edema, w= hich leads to obstruction of the natural sinus ostia

—<= span style=3D'font:7.0pt "Times New Roman"'> Anatomic abnormalities—sept= al deviation, concha bullosa, paradoxical middle turbinate, Haller cells, agger nasi cells, and nasal polyps—can obstruct natural sinus ostia

—<= span style=3D'font:7.0pt "Times New Roman"'> Principles of FESS

<= span style=3D'mso-list:Ignore'>—First maximize medical therapy

<= span style=3D'mso-list:Ignore'>—Restore sinus function by re-establishing the physiologic pattern of ventilation and mucociliary clearance

<= span style=3D'mso-list:Ignore'>—Remove diseased mucosa and bone, preserve normal tissue, and widen natural ostia <= o:p>

—<= span style=3D'font:7.0pt "Times New Roman"'> Common steps of the surgery=

—<= span style=3D'font:7.0pt "Times New Roman"'> Resection of the uncinate p= rocess

—<= span style=3D'font:7.0pt "Times New Roman"'> Maxillary antrostomy <= /o:p>

—<= span style=3D'font:7.0pt "Times New Roman"'> Anterior ethmoidectomy

—<= span style=3D'font:7.0pt "Times New Roman"'> Posterior ethmoidectomy

—<= span style=3D'font:7.0pt "Times New Roman"'> Sphenoid sinusotomy

—<= span style=3D'font:7.0pt "Times New Roman"'> Ethmoidectomy completed superiorly

—<= span style=3D'font:7.0pt "Times New Roman"'> Additional steps as needed<= o:p>

—<= span style=3D'font:7.0pt "Times New Roman"'> Frontal sinusotomy

—<= span style=3D'font:7.0pt "Times New Roman"'> Septoplasty

—<= span style=3D'font:7.0pt "Times New Roman"'> Conchal bullosa resection

—<= span style=3D'font:7.0pt "Times New Roman"'> Removal of polyps

—<= span style=3D'font:7.0pt "Times New Roman"'> Marsupialization of mucocel= es

—Balloon Sinuplasty

—Recently developed, with first clinical outcomes published by Bolger in 2007

—Guide catheter positioned near sinus to be dilated under endoscopic guidance=

—Guide wire is passed into sinus cavity

—Position was initially confirmed with fluoroscopy

—A lighted guide wire is now available to confirm position without radiation exposure to the patient

—Balloon passed over guide wire and inflated while within the sinus ostium

—Used for maxillary, frontal, and sphenoid sinus

—Initially confined to the operating room, now also being performed in the clinic sett= ing

—Results from Bolger’s initial study of 115 patients and follow up:

—Patency at 6 months and 1 year were >80% by endoscopy

—18% indeterminate

—1% non-patency rate

—Revision rate of 1%, 2%, and 3.6% at 6 months, 1 year, and 2 years, respectively

—Caveats

—Original study by Bolger excluded patient with nasal polyposis

—If balloon sinuplasty is performed instead of FESS, diseased tissue is not rem= oved

—Balanced view of balloon sinuplasty—a goo= d tool when used in appropriately selected patient populations

General Approach to Therapy for CRS=

·&nb= sp;        CRSsNP

—Mild symptoms

—Intranasal corticosteroids and nasal saline lavage

—Reassess after three months

<= span style=3D'mso-list:Ignore'>—If no improvement, culture and start long-term macrolide

<= span style=3D'mso-list:Ignore'>—Consider CT scan

—Reassess after another three months

<= span style=3D'mso-list:Ignore'>—If no improvement, CT scan and consider sinus surgery

—Moderate/severe symptoms

—Start with intranasal steroids, nasal saline lavage, culture, and macrolide; if no response in three months, CT scan and consider sinus surgery

—CRSwNP

—Similar approach to CRSsNP, except antibiotics are not recommended

—Mild/moderate symptoms

—Intranasal corticosteroid and nasal saline lavage

—Reassess in three months

—If no improvement, oral corticosteroids for one month

—If symptoms persist, CT scan and consider sinus surgery

—Severe symptoms

—Start with both intranasal corticosteroids and one month of oral steroids

—Reassess in three months

—If no improvement, CT scan and consider sinus surgery

Therapeutic Options for Samter’s Tr= iad

—Medical Therapy<= /span>

—Avoidance of aspirin and non-specific NSAIDs

—Acetaminophen and celecoxib are tolerated in most patients

—Treatment of asthma symptoms as per asthma guidelines

—Leukotriene modifiers

—Somewhat effective, though no more so than in regular asthma

—Aspirin desensitization

·         Sur= gical Therapy

o   FESS necessary in some patients due to burden of nasal polyps and inadequate response to medical treatment

Therapeutic Options for Churg-Strauss Syndrome

—Oral corticosteroids

— = ;

—————————Bro= nchodilators—as needed for bronchial hyperreactivity

Summary

The integrated airway hypothesis highlights the similarities and interplay among allergic rhinitis, asthma, and CRS. In these three diseases there is an inc= iting event that stimulates the immune system, leading to inflammation that is predominantly TH2 and IgE mediated and eosinophilic in nature. Atopy is therefore a major risk factor = for the development of these diseases. Given that inflammation is central to each of these diseases, it is not surprising that corticosteroids constitute the most effective medical therapy for each one. Continued research for better= , more lasting solutions to these diseases has led to the development of sublingual immunotherapy and balloon sinuplasty, two treatment modalities that are poi= sed to become convenient, less painful alternatives to current therapy for pati= ents with allergic rhinitis and CRS, respectively.

References

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= 2.      Braunstahl GJ. United airwa= ys concept: what does it teach us about systemic inflammation in airways disea= se? Proc Am Thorac Soc 2009; 6(8): 652-4.

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= 6.      Holgate ST, Lemanske RF, O’= Byrne PM, et al. Chapter 51: Asthma Pathogenesis. Middleton’s Allergy: Princip= les and Practice. 7^th ed. Ed. Adkinson, NF, et al. Mosby Elsevie= r, 2008. Electronic resource. Accessed April 23, 2012.

= 7.      Winn RA, Chan ED, McKinley = S, et al. Chapter 4: Laboratory Evaluation. Current Diagnosis and Treatment in Pulmonary Medicine. Ed. Hanley ME and Welsh CH. McGraw-Hill, 2003. Electronic resource. Accessed April 23, 2012.

= 8. Benninger MS. Chapter 47: T= he pathogenesis of rhinosinusitis. Cummings Otolaryngology: Head & Neck Surgery. 5^th ed. Ed. Flint PW, et al. China: Mosby Elsevier, 2010. Print.

= 9. Manning SC. Chapter 50: Med= ical management of nasosinus infectious and inflammatory disease. Cummings Otolaryngology: Head & = Neck Surgery. 5^th ed. Ed. Flint PW, et al. China: Mosby Else= vier, 2010. 728-738. Print.

10.&= nbsp; Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis. Ot= olaryngol Head Neck Surg 2007. 137(3 Suppl): S1-31.

= 11. Bachert C, Gevaert P, van Cauwenberge P. Chapter 56: Nasal p= olyps and rhinosinusitis. Middleton’s Allergy: Principles and Practice. 7<= sup>th ed. Ed. Adkinson, NF, et al. Mosby Elsevier, 2008. Electronic resource. Accessed April 24, 2012.

= 12. Weller PF. Chapter 49: Eosinophilia and eosinophil-related disorders. Middleton’s Allergy: Principles and Practice. 7^th ed. Ed. Adkinson, NF, et al. Mo= sby Elsevier, 2008. Electronic resource. Accessed April 24, 2012.=

= 13. Seo PS, Stone JH. Chapter 3= 5: Churg-Strauss syndrome. Current Rheumatology Diagnosis & Treatment.<= /i> 2^nd ed. Ed. Imboden JB,= et al. McGraw-Hill, 2007. Electronic resource. Accessed April 24, 2012.=

= 14. Schimmer BP, Funder JW. Chapter 42: ACTH, adrenal steroids, and pharmacology of the adrenal cortex. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12^th ed. Ed. Brunton = LL, et al. McGraw-Hill, 2011. Electronic resource. Accessed April 24, 2012.

= 15. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical management. J Allergy Clin Immu= nol. 2011. 128(4): 693-707.<= /span>

= 16. Lal D, Stankiewicz JA. Chap= ter 51: Primary Sinus Surgery. Cummings Otolaryngology: Head & Neck Surg= ery. 5^th ed. Ed. Flint P= W, et al. China: Mosby Elsevier, 2010. 7= 39-758. Print.

= 17. Kim E, Cutler JL. Balloon dilatation of the paranasal sinuses: a tool in sinus surgery. Otolaryngol Clin North Am. 2009. 42(5):847-56, x.

= ///