Rhinitis & Allergy & Immune Deficiency Flashcards

Question

What is primary atrophic rhinitis? What are the risk factors and possible bacteria etiology 3? What is Fraenkel's triad? What is secondary atrophic rhinitis? What are the common causes - 9

Answer 1

PRIMARY ATROPHIC RHINITIS: Atrophic rhinitis without any defined underlying cause Risk Factors: - Seen commonly in developing countries - Common in children and young adults - Thought to be associated with bacterial infection - MOST COMMON Klebsiella Ozaenae Fraenkel's Triad: 1. Fetor (cacosmia) with foul nasal discharge 2. Crusting 3. Atrophy of nasal structures *Patients themselves may complain of anosmia but the fetor is often so severe that it is perceived by others SECONDARY ATROPHIC RHINITIS: Atrophic rhinitis caused by a secondary reason - Commonly seen in the developed world Symptoms: - Generally less fetor and crusting than in primary atrophic rhinitis Causes: 1. Aggressive sinus surgery (most common) 2. Radiation to the head 3. Leprosy 4. Tuberculosis 5. Syphillis 6. Rhinoscleroma 7. Granulomatous disease 8. GPA 9. Nasal trauma

Answer 2

1. Turbinate atrophy affects normal airflow 2. Loss of nasal airway resistance results in loss of the sense of a satisfying breath (some resistance likely contributes to satisfying feeling of breathing) 3. Less mucosal surface area = less hydration and conditioning of inspired air 4. Loss of sensory and olfactory input affects perception of inspired air 5. Possible variety of central hypersensitivity syndrome

Answer 3

1. Dry nasal airflow results in transformation from pseudostratified ciliated columnar epithelium to keratinizing squamous epithelium which sloughs off. 2. Loss of columnar and goblet cells 3. Increased neutrophils and bacteria

Answer 4

Exam findings: - Clinical diagnosis - Nasal mucosa is paled, shiny, dry - Thinned and cobblestoned nasal mucosa - Once crusting is removed, will see widely patent nasal cavity with loss of normal landmarks Diagnostic Techniques: 1. Complaints of impaired nasal breathing despite a patent nasal cavity on endoscopy (see above) 2. Empty Nose Syndrome 6-item questionnaire score ≥ 11 (max 30) - dryness, sense of diminshed airflow, suffocation, nose feels too open, nasal crusting, nasal burning 3. Positive cotton test - Augment nasal cavity with a cotton ball for an improvement of ≥ 7 points from baseline ENS6Q score Investigations: - CBC - HIV - ACE level, calcium level - sarcoidosis - ANCAs (c-ANCA, p-ANCA) - GPA - CXR - Nasal biopsy if suspect granulomatous cause of secondary AR (e.g. systemic symptoms, pulmonary findings). If septal perforation present, suspect vasculitis and a biopsy should also be taken Treatment: 1. MOISTURE - Saline irrigations at least 2-4 times a day - Non-petroleum nasal lubricant 2. DEBRIDEMENT - 4-6 week intervals initially is ideal - Once better managed, can be debrided less frequently 3. MEDICAL MANAGEMENT - Occasionally, topical antibiotics (gentamycin or mupirocin) can be considered for chronic infection or foul crusts) - Systemic quinolone (Cipro) or tetracycline/IV aminoglycoside if remain refractory to compliant therapy as above (or if Klebsiella Ozaenae positive) - Avoid decongestants and antihistamines as they exacerbate dryness 4. SURGERY - Modified Young's Procedure: Anterior nasal flaps to close off one naris at a time to allow for re-humidification of the nasal mucosa. - Nasal stents: decrease diameter of nares and increase nasal resistance - Surgical Vestibuloplasty: Narrow vestibule to direct air away from the turbinates - Reconstruction of pseudo-turbinate (costal cartilage, medpore implants) Goals of Surgery in atrophic rhinitis: 1. Increase nasal resistance 2. Defect air from operated tissue to non-operated regions (e.g. nasal submucosal implants, inferior turbinate fillers, closing nose) - Can use biomaterial, autologous implants - Complications: extrusion, infection *Surgical options vary at best, should be used only when conservative options are all exhausted*

Answer 5

Pathophysiology: - Thought to be due to more of a hypoactive sympathetic nervous system than a hyperactive parasympathetic system that drives autonomic rhinitis - Classically, will occur in response to physical, emotional, or gustatory stimuli Classic Triggers: 1. Cold air 2. Changes in humidity 3. Exercise 4. Sexual arousal 5. Alcohol 6. Emotional stress 7. Spicy foods 8. Direct manipulation of the nasal mucosa Symptoms: 1. Most common = Water rhinorrhea 2. Nasal congestion can be present but is less of a symptom Treatment: 1. Responds well too Ipratropium (Atrovent) 0.03% nasal spray - 2 sprays 2-4 times daily 2. INCS and intranasal antihistamines have also been found to be effective

Answer 6

GUSTATORY RHINITIS: - Sub-category of vasomotor rhinitis - Food-induced nasal hypersecretion, characterized by acute onset of copious watery or occasionally mucoid rhinorrhea, occurring immediately after the ingestion of certain foods (often hot & spicy) Pathophysiology: (debated) - Overstimulation of parasympathetic nervous system Diagnosis: 1. Clinical history 2. Exclusion of other rhinitis causes Treatment: 1. Conservative: Avoidance of triggers 2. Medical: Anticholinergic nasal sprays (Ipratropium bromide) 3. Topical steroids 4. Surgical: vidian neurectomy - Complications: Dry eye (always, but does get better overtime), numb cheek, SPA bleed - Can also try NSR + inferior turbinate reduction

Answer 7

NARES = Non-allergic rhinitis with eosinophilia syndrome What is it? - Clinical syndrome with features of allergic rhinitis (sneezing, pruritis, watery rhinorrhea) WITHOUT positive allergy testing and WITH marked esoinophilia on nasal smear Epidemiology: - 15-33% of patients with non-allergic rhinitis Pathophysiology: - Unclear, although eosinophils and mast cells clearly play an important role Symptoms: - Symptoms of NARES and allergic rhinitis are essentially the same - only difference is negative vs. positive systemic allergy testing - NARES often have more severe nasal symptoms - Anosmia more common Risk Factors: - Association with AERD, and many patients do develop ASA sensitivity and nasal polyposis in the future - Some reports suggest that NARES is a precursor for AERD (aka. Samsters triad) Diagnosis: 1. Negative allergy test 2. >20% eosinophils to be diagnostic 3. Many have a positive nasal provocation studies (leading to theory of "entopy" vs. atopy, which is a localized allergic reaction) - still a matter of debate Management: 1. INCS is mainstay 2. Oral steroids trial if anosmia 3. ± antihistamines

Answer 8

1. NEUROGENIC - Most common is antihypertensives - Tilt balance between sympathetic and parasympathetic regulation of the nasal mucosa towards parasympathetic through direct or indirect inhibition of norepinephrine - Many antipsychotics and antidepressants similar alter availability of norepinephrine by nEPI and dopa pathways in at the synaptic cleft - Treatment involves identification of offending medication and removal/substitution 2. INFLAMMATORY - ASA, COX-1 inhibiting NSAIDs - Exacerbates excessive production of leukotrienes and prostaglandins due to effect on arachidonic acid pathway - ACEIs --> increases bradykinin, resulting in more vasodilation 3. IDIOPATHIC - Non-benzodiazepine hypnotics (like Zolpidem) - Amiloride Most common classes of medications: 1. Antihypertensives 2. Erectile dysfunction 3. Psychiatric Medications *Note: Many medications list rhinitis in their side effect profile

Answer 9

Can be caused by overuse of topical decongestants, which results in rapid tolerance and tachyphylaxis with prolonged use (progressive decrease in response to a given dose after repetitive administration of a pharmacologically or physiologically active substance)

Answer 10

Mnemonic: AAA-BB-CDE A: Antihypertensives A: Antipsychotics/antidepressants A: Anti-inflammatories (ASA, NSAIDs) B: BPH medications: alpha-adrenergic blockers, tamsulosin, doxazosin B: Birth control pills C: Cocaine D: Decongestants E: Erectile dysfunction medications (PDE-5 inhibitors like Sildenafil) Medications that contribute to rhinitis: Intranasal Preparations: - Cocaine - Topical nasal decongestants Antihypertensives: - Alpha and beta adrenoceptor antagonists - Reserpine - Hydralazine - Felodipine - ACEI - Beta blockers - Methyldopa - Guanethidine - Phentolamine Agents for Prostatic Hypertrophy - Doxazosin - Tamsulosin Hormones: - Oral contraceptives Antiinflammatory Agents: - NSAIDs - ASA Antiplatelet Agents - Clopidogrel Antidepressants - Selective serotonin Reuptake inhibitors Nonbenzodiazepine Hypnotics - Zolpidem Phosphodiesterase Type 5 inhibitors - Sildenafil - Tadalafil - Vardenafil Psychotropic Agents - Thioridazine - Chlordiazepoxide - Chlorpromazine - Amitriptyline - Perphenazine - Alprazolam

Answer 11

1. Saline irrigations 2. Topical antihistamines 3. Intranasal corticosteroids 4. Ipratropium Bromide Sprays (Atrovent) 5. Systemic antihistamines - can be a consideration if sneezing or pruritis is a major symptom 6. Oral decongestants 7. Capsaicin

Answer 12

1. Azelastine 2. Olopatadine

Answer 13

1. Budesonide (Pulmicort/Rhinocort) - 30% 2. Mometasone (Nasonex) - 0.5% 3. Fluticasone Furuoate (Avamys) - 0.5% 4. Fluticasone Propionate (Flonase) - 0.5% 5. Beclometasone (Beclonase) - 41% 6. Triamcilinone (Nasocort) - 46% 7. Ciclesonide (Omnaris) - < 1% 8. Dymista = combination antihistamine/INCS - 0.8% - Fluticasone Proprionate (flonase) - Azelastine Hydrchloride

Answer 14

Mechanism of Action: 1. Binds to steroid receptor in cytoplasm to allow entry into nucleus 2. Enters the nucleus to bind with the steroid binding receptor on chromatin 3. Downregulates mRNA transcription --> downregulates the manufacturer of inflammatory proteins - Inhibits mast cell degranulation - Inhibits release of cytokines - Decreases mucous production EFFECTS ON NASAL MUCOSA/AR: 1. Decrease arachidonic acid metabolism (PG/LT/TX) 2. Decrease secretion of mediators of inflammatory cell proliferation 3. Decrease influx of eosinophils, basophils, and T-lymphocytes into the nasal epithelium 4. Decrease capillary permeability and promotes vasoconstriction 5. Decrease glandular response to ACTH, decreases mucous production 6. Stabilize lysosomal membranes 7. Decrease migratory inhibitory factor

Answer 15

General: 1. Hypersensitivity Local: 1. Nasal Dryness 2. Recurrent Epistaxis 3. Septal perforation 4. Atrophic rhinitis Systemic: 1. Weight gain 2. Susceptibility to Infection 3. Impaired wound healing 4. Hyperglycemia 5. Systemic fungal infections 6. TB (reactivation) 7. Adrenal suppression Eye: 1. Glaucoma 2. Cataracts 3. Ocular herpes (reactivation) 4. Blindness if injected into inferior turbinate Cardiac: 1. Hypertension 2. Hyperlipidemia Neuro: 1. Sleep disturbances 2. Change in mood GI: 1. Peptic ulcer 2. Pancreatitis Skeletal: 1. Myopathy 2. Osteoporosis 3. Avascular necrosis of the hip Skin: 1. Skin thinning 2. Easy bruising 3. Buffalo hump (suprascapular fossa fat deposition) 4. Moon facies 5. Acne

Answer 16

1. Anti-inflammatory effect by decreasing nitric oxide synthetase (less nitric oxide production --> less congestion) 2. Vasoconstriction

Answer 17

- Positions to improve efficacy of nasal steroid application: 1. Mygind's position (a) - Administration of nasal drops in a head back supine position, followed by a series of head turns 2. Ragan position (b) - Involves the patient lying on one side with the head touching the bed or floor surface, while the drops are instilled in the inferior nostril 3. Moffett position / Mecca (c) - The patient kneels and leeans forward with forehead to the ground and sministers drops in nostrils ## Footnote Vancouver 425

Answer 18

Ipratropium Bromide Sprays (Atrovent) - 0.03% Ipratropium 2 sprays 3-4 times daily - Once therapeutic effect has been achieved, can be decreased to OD or BID dosing

Answer 19

- Adjunct for decongestion of a severely congested nose when starting topical therapy or for temporary systemic relief - Should be limited if hypertension or cardiac history. - Avoid using topical decongestants for more than 72 hours?

Answer 20

Available under the brand "Sinus Buster" Pathophysiology: - Induces rhinorrhea and congestion when ingesting spicy foods - Nasal capsaicin provocation results in rhinorrhea, nasal blockage, and sneezing via stimulation of the unmyelinated sensory C fibers or pain receptors - Repeated intranasal application of capsaicin in some individuals leads to desensitization by prolonged stimulation of the TRPV1 ion channel receptor (Transient Receptor Potential Vanilloid Type 1) Evidence: - One RCT double blind showed effectiveness for relief of IR without side effects or rebound (Stable control for at least 9 months) - Less beneficial in allergic rhinitis Dosage: - No consensus, but most studies show that < 2 weeks of treatment is adequate, and can be repeated if symptoms recur - One study: 1 spray q2-3 days over 2 weeks. Found to be as efficacious as a single day treatment with 1 spray q1h x 5 hours Side effects/Cautions: - Burning sensation with administration, but few other side effects - Caution with concomitant lung disease - cases of fatal asthma attacks with inhalation of capsaicin in larger quantities (pepper spray)

Answer 21

1. Inferior turbinate reduction 2. Vidian Neurectomy 3. Posterior nerve Neurectomy

Answer 22

1. Steroid injection 2. Cryotherapy 3. Electrocautery 4. Coblation 5. Laser reduction 6. Microdebrider-assisted 7. Simple out-fracture Submucosal methods are preferred over extra-mucosal methods. Recent review of techniques: Microdebrider assisted partial turbinoplasty and holmium-YAG laser turbinate reduction demonstrated the most durable improvement in nasal patency lasting for about 3 years

Answer 23

Cut/cauterize the vidian nerve in the PPF (which controls lacrimation and also rhinorrhea). Dry eye is a common side effect.

Answer 24

Modification of vidian neurectomy, where sensory and autonomic branches are ligated distal to the pterygoid canal after exiting the sphenopalatine foramen.

Answer 25

What is it? - Chronic granulomatous infectiion by the water parasite Rhinosporidium Seebri - Usually transmitted via traumatic inoculation - Affects the mucosal epithelium Risk factors: - Southern India - Sri Lanka Features: 1. Strawberry Lesions - pink lesions with whitish specks which are the chitinous walls (aminopolysaccharide) of the Rhinosporidium 2. Develops large, hyperplastic bleeding nasal polypoidal masses (looks like a strawberry) 3. Also involves conjunctive, oropharynx, nasopharynx, maxillary antrum, larynx, EAC, and parotid duct Diagnosis: 1. Biopsy showing Sporangia (spores) - Can be seen with typical fungal stains, including (1) Gomori Methenamine silver (GMS) = Grocott, or (2) Periodic Acid-Schiff (PAS) Treatment: 1. Local surgical excision 2. Dapsone cream if recalcitrant (antibiotic, combined with rifampicin and clofazimine to treat leprosy)

Answer 26

INNATE IMMUNITY - Host defense mechanism --> immediate response - Pathogen recognition is through components present on the cell walls via broad receptor recognition Associated cells: - Neutrophils - Eosinophils - Basophils - Dendritic cells (e.g. macrophages) - Mast cells - NK cells Barriers: Skin, mucous membranes, mucous layer, mucociliary transport Molecular barriers: Complementary pathway, cytokines, macrophages, monocytes, NK cells, enzymes, proteins, etc. ADAPTIVE IMMUNITY - Immunologic memory - Pathogen recognition is via antigens that are processed and presented by antigen presenting cells that have MHC receptors - Antigen presenting cells = B cells, macrophages, and dendritic cells Humoral Response = B cells vs. Bacterial pathogens - Immunity is derived from serum antibodies produced by plasma cells Cellular Response = T cells vs. Viral/Fungal pathogens (intracellular) - Cell mediated response = response is carried out by cytotoxic cells OVERALL DIFFERENTATION SUMMARY Response time: - Innate: Fast - minutes or hours - Adaptive: Slow - days Specificity: - Innate: Only specific for molecules and molecular patterns associated with general pathogens or foreign particles overall - Adaptive: Highly specific! Can discriminate between pathogen vs. non-pathogen structures, and miniscule differences in molecular structures Major cell types: - Innate: Macrophages, Neutrophils, NK cells, dendritic cells, basophils, eosinophils - Adaptive: T cells, B cells, and other APCs Key components: - Innate: Antimicrobial peptides and proteins, such as toxic granules - Adaptive: Antibodies Self vs. Non-self discrimination: - Innate: Based on self vs. non-self diiscrimination, so it has to be perfect - Adaptive: Not as good as innate system, but pretty good at determining which is which. Problems in discrimination results in autoimmune diseases

Answer 27

MHC 1 (to CD8) - Found on ALL nucleated cells (so not on RBCs) - Presents endogenous antigens to cytotoxic T-cells (CD8) to determine self vs. non-self for clearance MHC 2 (to CD4) - Found only on antigen presenting cells - APCs: B cells, Dendritic cells, and Macrophages - Present scavenged peptides from sites of inflammation to T-helper cells (CD4) which then activate CD8 cells for clearanage T-helper cells present CD4 on cell surface Cytotoxic T-cells present CD8 on cell surface

Answer 28

- B cell binds pathogen via a surface antibody - B cell (which is an APC) then presents the antigen on a MHCII complex - T helper cell binds MHCII complex and activates cells - They can then differentiate into (1) Effector B cells (aka. Plasma cells) that produce antibodies, or (2) Memory B cells

Answer 29

There is a link between the upper and lower airways, and respiratory diseases can involve both. E.g. Rhinitis can affect asthma by way of the nasobronchial reflex, or cytokine production

Answer 30

Immunoglobulins Structure: 1. 2 light chains (2 types = kappa and lambda) 2. 2 Heavy chains (5 types, determines the class of antibody - GAMED) IgG: 75% of serum Igs - Plays the most prominent role in the memory immune response (chronic/memory) - 4 subtypes - Crosses placenta to protect fetus, can fix complement IgA: 15% of serum Igs - Predominant in body secretions - Primary defense against local mucosal infection - Dimeric with a secretory component bound to it IgM: 10% of serum Igs (acute phase reactant) - Normally exists as a pentamer - Major part of early immune response - Major immunoglobulin expressed on the surface of B cells IgD: 0.2% of serum Igs - Only present in trace amounts, unknown function IgE: 0.004% of serum Igs - Binds with high affinity to mast cells and plays a large role in the allergic response - Binds to basophils, triggers inflammatory mediator release - IgE is produced by B cells after initiation of IL-4 or IL-13 pathways Mneominc: GAMED IgG > IgA > IgM > IgE/D

Answer 31

PRR = Pattern Recognition Receptors - PRRs are part of the innate immune system - Eg. Toll-like receptor (TLR) PAMPs = Pathogen Associaited Molecular Patterns - PRRs recognize highly conservated DNA sequences that are necessary for the survival of many microorganisms (ie. PAMPs) Recognition of PAMPs by PRRs (such as TLRs) induces a cytokine signalling pathway, which can either be: 1. Th1: Produced by Th1 T-helper cells - Major TH1 cytokines are IFN-gamma and TNF-beta - Associated with CRS without NP (CRSsNP) 2. Th2: Produced by Th2 T-helper cells - Major Th2 cytokines are IL-4, IL-5, and IL-13 - IL 4 and 13 pathways then stimulate IgE production - Associated with CRS with NP (CRSwNP) Th1 and Th2 pathways are mutually inhibitory. The mechanism behind selection of a Th1 predominant or Th2 predominant response is complex Th17 cells are associated more with autoimmune diseases and cell-mediated inflammation Treg cells help with immunoregulation and peripheral tolerance (ie. when a cell becomes self-recognizing/reactive, Treg cells help with their destruction) ## Footnote Kevan Page 11

Answer 32

Hypothesis that infections during infancy may protect against atopy by downregulating production of IgE and thus tilt the cytokine response more towards Th1 than Th2

Answer 33

1. Type 1 (IgE Mediated) - IgE binds to mast cells which release inflammatory mediators - Examples: Anaphylaxis, urticaria, angioedema, allergy, allergic rhinitis, asthma - Timing of reaction: Immediate, minutes to hours 2. Type 2 (Cytotoxic - antibody mediated immune reaction) - IgG and IgM mediated - bind to allergy on target cell. - Complement mediated - Examples: Neutropenia, Thrombocytopenia, hemolytic anemia, blood transfusion reactions (from antibodies), Graves' disease, Goodpasture's syndrome - Timing of reaction: Variable 3. Type 3 (Immune Complex - Antigen-Antibody reaction) - Immunoglobulin complexes bind to allergen and then get deposited into tissues - IgG and complement mediated - Examples: Glomerulonephritis (post-strep), SLE, Rheumatoid arthritis, Farmer's Lung (hypersensitivity pneumonitis), serum sickness - Timing: 1-3 weeks post-exposure 4. Type 4 (Delayed hypersensitivity reaction) - T cell mediated to antigens - Th1 cells secrete cytokines, which then activate macrophages and CD8+ cytotoxic T-cells - Examples: Contact dermatitis, Tuberculin Skin test, Hashimoto thyroiditis, Steven-Johnson syndrome - Timing: 48-72 hours "ACID": Allergy, Cytotoxic, Immune complex, Delayed

Answer 34

Atopy = Genetic tendency to develop allergic diseases Atopic Triad: 1. Allergic rhinitis 2. Asthma 3. Atopic Dermatitis (Eczema) Atopic march: - Patients with atopic dermatitis and food allergies are more prone to then develop asthma and then allergic rhinitis as they grow

Answer 35

Epidemiology: - Second leading cause of chronic disease in the US - Affects ~1/4 households Pathophysiology: Type 1 Hypersensitivity Reaction - Allergen is recognized by an APC and then presented to a T-helper cell (e.g. Th1, Th2) - Th2 responses are predispoed towards allergic inflammation. Th2 cells present the allergen to a B-cell to form an allergic response - B cells then change into an IgE producing plasma cell with the help of allergic cytokines (e.g. IL-4, 13) which are stimulated by Th2 cells - IgE binds to IgE receptors on basophils and mast cells - Mast cells and basophils then release inflammatory markers such as histamine (mast cell degranulation results in early phase inflammation) - Other pro-inflammatory mediators such as IL5 recruit eosinophils and leukotrienes that promote late phase inflammation - SUMMARY OF MEDIATORS: IL 4, 5, 13 Priming: Continued exposure to the allergen results in a threshold shift, where a smaller dose is needed to trigger a response - Many patients have worse symptoms as the allergy season progresses despite unchanged or decreased pollen counts Early phase response (mediated by histamines) - Occurs in sensitized individuals within minutes of exposure (Type 1 immediate hypersensitivity) - Lasts for about 2-3 hours - Mediated by mast cell degranulation as a result of IgE binding, and the release of histamine Late phase response (mediated by eosinophils, leukotrienes) - Occurs 4-6 hours after antigen stimulation - Caused by pro-inflammatory cellular influx including eosinophils and leukotrienes - Mediates by cytokines such as IL-5, which stimulates smooth muscle in the airway and leads to: (1) Proliferation of eosinophils, (2) Tissue edema, (3) Increased and persistent congestion, rhinorrhea, and sneezing

Answer 36

Risk Factors: 1. Family history of atopy (1 parent = 50% risk, 2 parents = 75%) 2. Asthma - always ask about asthma (80% of asthmatics have rhinitis, 10-40% of patients with AR have asthma) 3. Atopic dermatitis (eczema) 4. Maternal Smoking Protective Factors: 1. Living on a farm during early life 2. Having multiple siblings 3. Day care attendance during the first 6 months of life Causes: 1. Hygiene Hypothesis (Controversial) 2. Thought that infections early in life decreases risk of atopy in the future Symptoms/History: - Nasal symptoms: sneezing, itching, congestion, rhinorrhea - Ocular symptoms: watering, redness, itching, swelling - Other atopic features: Atopic dermatitis, Asthma (wheezing) - Onset and duration of symptoms - Episodic vs. Perennial symptoms - Changes in living conditions - Length of time living in local area - Seasonal predilection - Animal exposure (home, work, school) - Medications tried - History of atopy (asthma, eczema, food allergy) - Family history of atopy Physical Exam findings: 1. Allergic shiners (due to periorbital venous stasis from chronic congestion) 2. Debbie-Morgan Lines (low lid lines formed due to edema) 3. Allergic Salute (supratip crease from frequent nose wiping) 4. Features in children with longstanding disease: Dental malocclusion, high arched palate, upper lip elevation 5. Pale nasal mucosa 6. Edematous and boggy turbinates 7. May have polyps 8. Cobblestoning of the posterior pharynx ARIA Classification: 1. Intermittent = < 4 days/week or < 4 weeks duration 2. Persistent = >4 days/week AND > 4 weeks duration 3. Mild = No effects on ADLs, sleep, work, school, leisure 4. Moderate-Severe: Any impairment of the above

Answer 37

1. 60% of asthma have AR 2. 20-30% of AR have asthma

Answer 38

1. Increased ratio of columnar epithelium to goblet cells 2. Increased number of eosinophils (>20% of granulocytes is suggestive of inhalant allergy)

Answer 39

1. POSITIIVE TEST PREVALENCE AND ALLERGY PREVALENCE - Positive allergy test results are more common than clinically bothersome allergic symptoms 2. NEGATIVE ALLERGY TESTS CAN BE SEEN IN PATIENTS WITH ALLERGIES (even anaphylaxis) 4 reasons this happens: a. WINDOW: Some people only test positive during a certain window after exposure b. WORLD: Allergen extract may not match real world allergen c. WRONG (not IgE): Some hypersensitivity reactions are not IgE mediated (e.g. contrast dye anaphylaxis) d. WHERE: Theory of local allergy where immunologic process in the nose does not match mast cells in the skin (entopy vs. atopy) 3. SENSITIVITY AND TOLERANCE - Testing sensitivity and tolerance varies over time 4. VARIABILITY IN ALLERGEN EXTRACT - Creating allergen extracts is an inexact science

Answer 40

1. POLLENS (subdivided into): - Trees - Grasses (more prevalent in the summer) - Weeds (More prevalent in summer/fall) - Ragweed is #1 2. MOLDS 3. EPIDERMALS (e.g. animal dander, cats/dogs) 4. ARTHROPODS - Dust mites are the main one, two most common species are: (1) Dermatophagoides Farinae, (2) Dermatophagoides Pteronyssinus *Pollens tend to have a more seasonal predilection (#1 = Ragweed) * Molds, Epidermals, and arthropods have a more perennial predilection (#1=Dust mites)

Answer 41

1. Dust mite (dermatophagoides) 2. Cockroach 3. Mold - Alternaria (except for when the ground is frozen) 4. Pollen - short ragweed most common 5. Animal dander

Answer 42

No - Allergy skin tests demonstrates presence of allergen-specific IgE - ALONE, this does not DIAGNOSE allergy - Diagnosis requires confirmation that exposure to allergen produces symptoms (history) or demonstration of symptoms (challenge test)

Answer 43

1. Inhalant allergy testing (size < 0.5µm) - Indoor 2-3 years old, outdoor 3-5 years old 2. Food allergy testing - any age

Answer 44

A: Allergy Skin Testing 1. Skin prick testing (SPT) 2. Intradermal Testing (IT) 3. Single Intradermal Testing (SIT) 4. Intradermal Dilutional Testing (IDT) / End-point diluation testing 5. Modified Quantitative Testing (MQT) B: Serum Testing 1. Allergen Specific IgE testing (sIgE) 2. Total IgE testing 3. Nasal Specific IgE (addresses the difference between entopy and atopy, and concept of Local Allergic Rhinitis (LAR)) 4. Serum tryptase (if history of anaphylaxis - enzyme found in mast cells) C: Allergen Challenge Testing

Answer 45

SKIN TESTS: A. Advantages: 1. Allows for direct observation of body's reaction to specific antigen 2. Considered more sensitive than blood testing 3. Intradermal can be used when additional sensitivity is required or skin prick negative 4. Less expensive than blood testing B. Disadvantages: 1. Possible systemic allergic reaction (anaphylaxis) 2. May be affected by patient's medications BLOOD/SERUM TESTS: A. Advantages: 1. No risk of anaphylaxis 2. Not affected by patient's medications 3. Can be used for patients with skin conditions such as dermatographism or severe eczema 4. Can be used for patients on beta blockers or with comorbid medical conditions that preclude skin testing B. Disadvantages: 1. Requires reliable laboratory 2. Possible for laboratory errors

Answer 46

Usually the initial test of choice. Technique: - Devices with single or multiple tines that are dipped in allergy used to place the allergen into the epidermis of the skin (forearm or back) - + (histamine) and - (glycerol/saline) control droplets are also placed - Fine needle placed through the droplet into skin - After 15-20 min, results are documented - POSITIVE if 3mm wheal

Answer 47

Most reproducible and more sensitive than skin prick method. - High risk of false positives (therefore usually reserved for patients with negative prick/puncture method) - Not used for food allergy given high sensitivity, but for venom and drug allergy testing Uses a small needle to raise a wheal intradermally, same idea as with TB testing. Patients undergoing testing should be observed for 20-30 minutes for a reaction. During testing, this should always be done with a positive AND negative control: - Positive control = Histamine - Negative control = Dilutent (not just saline) used for the allergen extract (to ensure you don't react with the dilutent) Key Points: 1. Antihistamines, beta-agonists, and TCAs can inhibit skin testing responses and result in a false negative positive-control; so don't take these prior to allergy testing 2. A non-specific reaction to the dilutent or dermatographic can cause a false positive negative-control Technique: - Injection of allergen extract into skin with 27-G needle and raising a bleb - Injection of + and - controls - Positive if wheal > 5mm

Answer 48

Usually done after a negative skin prick test (which confirms the patient is not highly sensitive to allergen) - Interpretation of a positive IT after negative SPT is controversial

Answer 49

- Serially more potent dilutions are adminstered until a positive reaction occurs or no reaction occurs - Had been used in the past to calculate the amount of antigen needed to start immunotherapy - More time consuming, requires multiple dilutions

Answer 50

Starts with a SPT, and depending on how large the response is, may or may not proceed with IDT. Developed to have the same quantitative advantages as IDT without as many skin tests needed. Algorithm: Kevan Page 14

Answer 51

Procedure: 1. Patient serum or plasma is drawn, and exposed to a fixated allergen 2. Patient's IgE binds to the specific allergen if they react 3. Labelled monoclonal IgG is added which binds to the IgE 4. Unbound IgG is washed away and what remains is labelled Types of Labels: 1. RAST = Radioallergosorbent Test (Radioactive marker used to quantify sIgE levels) 2. ELISA = Enzyme Linked Immunosorbent Assay (Immunofluorescence used to quantify sIgE levels) Advantages: 1. Can test for multiple allergens from a single needle stick 2. Not influenced by medications or skin conditions 3. No risk of anaphylaxis Disadvantages: 1. Cost 2. Delay for test results 3. Quality of the antigen used matters UTILITY AND INDICATIONS: - Limited utility clinically in allergic rhinitis. - Better uses options: 1. Food allergy (skin testing not reliable for food allergy) 2. Patients with severe anaphylaxis (skin testing carries unacceptable risk) 3. Dermatologic conditions that preclude skin testing 4. Clarification of bizarre or borderling results from skin testing 5. Pregnancy 6. Patients unable to stop medications (e.g. TCAs, beta-agonists)

Answer 52

- Total IgE normally < 1% of all circulating immunoglobulins (0.004%) - Total IgE is elevated in atopic conditions, but unfortunately there is overlap between atopic and non-atopic IgE levels - sIgE/tIgE ratios can be used to assess the severity of allergic responses (Allergen specific IgE testing)

Answer 53

- Involves locally applying the allergen to the target organ and assessing for a response - e.g. Nasal Provocation testing for allergic rhinitis - Response is measured via subjective symptom scores and objective findings such as acoustic rhinometry, rhinomanometry, or peak inspiratory flow

Answer 54

1. Age 2. Skin reactivity (e.g. dermatographia) 3. Volume injected 4. Increased allergen exposure (see priming) from previous exposures 5. Medications: Antihistamines, TCA antidepressants, Xolair (Omalizumab), Topical steroids at site of testing, Beta-agonists

Answer 55

1. Severe cardiopulmonary disease 2. Asthma 3. History of anaphylaxis 4. Beta Blocker therapy (hold 72 hours prior -- may increase anaphylaxis severity of make anaphylaxis treatment more difficult) 5. Pregnancy 6. Unable to discontinue interfering medications (e.g. antihistamines, etc.) 7. Dermatographia 8. Active dermatitis or cellulitis over area Alternative options: Specific IgE testing should be performed instead (e.g. RAST or ELISA sIgE)

Answer 56

Medications: 1. Antihistamines (~7 days prior; first generation 3 days, second generation 7 days), and intranasal antihistamines 2. TCA antidepressants - interferes testing, but do not stop (per Vancouver notes) 3. Omalizumab (Xolair) = Anti IgE (stop 8 weeks prior) 4. Topical steroids at site of testing 5. H2 antagonists (e.g. Ranitidine) - 2 days Medications not shown to affect skin prick testing: 1. Leukotriene Receptor Antagonists do NOT affect SPT 2. Oral/nasal steroids have not been shown to affect SPT (but Vancouver says stop 3 days)

Answer 57

Thommen's 5 postulates 1. HIGHER: The pollen must be wind borne 2. LARGER: The pollen must be produced in large quantities 3. FARTHER: The pollen must be light/buoyant and small enough to be carried for considerable distances with a diameter between 15-58µm (get past nasal filter) 4. WIDER: The plant must be abundantly distributed, or habitually grown close to human habitation 5. BETTER: The pollen must be allergenic

Answer 58

ENVIRONMENTAL CONTROL 1. Avoidance of allergen if possible 2. High-efficiency particular air (HEPA) filter 3. Hard surface flooring (removal of carpets) 4. Hot water laundry 5. Barrier protection on pillows and mattresses 6. Acaricides (tick and mite killers) 7. Removing allergenic pets if possible PHARMACOTHERAPY A. Antihistamines - First generation are sedating and less effective for nasal congestion. Second generation are preferred (Cetirizine, Loratadine, etc.) - Oral antihistamines vs. Intranasal antihistamines (more effective than PO) B. Intranasal Corticosteroids - Combination of nasal steroid and nasal antihiatmine (e.g. Dymista - Azelastine+Fluticasone 137mcg/50mcg) C. Systemic Steroids - Short course in the context of severe intermittent AR can be considered D. Leukotriene Receptor Antagonists (e.g. Montelukast/Singulair) - Good for patients refractory to glucocorticoids, or concomitant asthma or nasal polyposis E. Nasal Cromolyn Sodium - Mast cell stabilizer - Reduces ability of mast cells to release inflammatory mediators such as histamine - Requires frequent dosing and low efficacy, however has excellent safety profile - One of the few Category B medications in pregnancy along with Rhinocort F. Nasal Decongestants - Should be used intermittently < 72 hours to avoid the risk of rhinitis medicamentosa G. Biologics: (experimental) - Xolair/Omalizumab (Anti-IgE): Monoclonal antibody that blocks action of free IgE, need to have concurrent asthma to qualify - Dupilimab (Anti-IL-4/Anti-IL-13) SURGICAL 1. Inferior turbinate reduction 2. Addressing anatomic nasal obstruction (e.g. nasal valve collapse) IMMUNOTHERAPY aka. Allergy Desensitization 2 most common administration methods are SCIT and SLIT 1. Subcutaneous IT (SCIT) - Injection of allergen into subcutaneous tissues - 2 phases: escalation and maintenance - Start with a dilute dose and then increase - Maintenance therapy usually lasts 3-5 years 2. Sublingual IT (SLIT) - Drops of allergen extract are placed under the tongue

Answer 59

SCIT: 1. Effectiveness for allergic rhinitis - supported by SR of RCTs 2. Safety profile - 1 per 2.5 million injections 3. Rate of systemic reactions - 0.06% - 0.9% 4. Dosing and administration - Administered in physicians office 5. FDA status - FDA approved 6. Socioeconomic - Covered by most insurance, CPT code exists for SCIT vial preparation and injections SLIT: 1. Effectiveness for allergic rhinitis - supported by SR of RCTs 2. Safety profile - No reported deaths 3. Rate of systemic reactions - 0.056% 4. Dosing and administration - Administered at home, SLIT aqeous dosing not standardized, first tablet should be taken in physician office 5. FDA status - "off-label" use for aqueous; tablets are approved but limited number of allergens available for treatment 6. Socioeconomic - Most not covered by insurance (tablet might be depending on plan)

Answer 60

Mild-Intermittent 1. Oral or intranasal antihistamines; OR 2. LTRA; AND/OR 3. Decongestant PRN Moderate/Severe-Intermittent; OR Mild-Persistent 1. Oral or intranasal antihistamine; OR 2. INCS; OR 3. LTRA; OR 4. Cromolyn; AND/OR 5. Decongestant PRN *Review after 2-4 weeks Moderate/Severe-Persistent 1. INCS preferred 2. Antihistamine or LTRA can also be considered 3. Review after 2-4 weeks - Can increase INCS dose - Can add Atrovent for rhinorrhea - Can consider short course decongestant or oral steroids - If persistent despite this, refer to specialist ## Footnote Kevan Page 16

Answer 61

Indications: Patients must have (1) Symptoms of allergy after natural exposure; and (2) Evidence of clinically relevant specific IgE-mediated disease (skin testing); and (3) One of the following things: 1. Inability to avoid allergen 2. Poor response to avoidance measures 3. Poor response / inadequacy of pharmacotherapy 4. Unacceptable adverse effects of medications 5. Patient wishes to reduce/avoid long-term pharmacotherapy and cost 6. Severe symptomatology, persisting for >1 season 7. Co-existing allergic rhinitis and asthma 8. Possible prevention of asthma in children 9. Motivated patients willing to undergo a program that may last up to 5 years 10. Limited spectrum of allergies (ie. inability to avoid or inadequacy of treatment) 11. Patients who understand risks and limitations of traetment Contraindications: 1. Poorly controlled asthma 2. Pregnancy - not initiated during pregnancy, but maintenance doses can be continued at the same doses during pregnancy 3. Beta-Blocker therapy 4. Medical comorbid that will make patient less likely to survive an anaphylactic reaction (ie. contraindications to epinephrine) 5. Children < 5 years of age or >65yo 6. Severe asthma (FEV1 < 50%) 7. Immunosupression or HIV 8. Non-compliant 9. Unable to understand risks and limitations of treatment; or not able to comply with protocol *Patients should be observed for 30 minutes post-administration

Answer 62

Administration: - Parenteral administration of antigens identified on appropriate in vivo or in vitro tests - First dose in MD office - 30 minutes - Typically, twice a week until a response is noted, then q1week x1 year, q2wks x 2 years, q3wks x 3 years Mechanism of action: - Stimulate formation of allergen-specific IgG4 blocking antibodies which will compete with IgE for binding sites on mast cells or basophils - Decrease IgE and reduces the seasonal rise of IgE - Changes CD4+cells from Th2 to Th1 phenotype

Answer 63

1. Increased IgG 2. Decrease IgE 3. Reduce seasonal rise of IgE 4. Change CD4+ cells from Th2 to Th1 phenotype

Answer 64

1. CRS: Weak evidence to support as adjunctive treatment 2. AERD: Clear seasonal or perennial allergy symptoms - 62% of patients reported no benefit 3. Allergic fungal sinusitis: number of treated patients small - decreased reliance on systemic and topical steroids

Answer 65

2nd generation do not cross the blood brain barrier (highly polarized, larger molescules) and thus are non-sedating. They also have fewer anticholinergic effects Exception: Cetirizine/Reactine (still sedating) FIRST GEN (Sedating): 1. Diphenhydramine/Benadryl 2. Hydroxizine/Atarax 3. Chlorpheneramine/Chlortripolon SECOND GEN (Less sedating) 1. Loratidine/Claritin 2. Desloratidine/Aerius 3. Cetirizine/Reactine 4. Fexofenadine/Allegra - least sedating (doesn't cross BBB) 5. Azelastine (nasal sprays) THIRD GEN (Less/non-sedating, do not cross BBB) 1. Rupatadine (Rupall) - Approved for seasonal and perennial AR, chronic urticaria - Also works on platelet activating receptor (PAR) - antiinflammatory 2. Bilastine (Blexten)

Answer 66

Fexofenadine (Allegra) - shown to have no cognitive effects

Answer 67

H1: Smooth muscle, Endothelial cells, CNS H2: Gastric, mast cells, CNS H3: Presynaptic H4: Hematopoetic cells ## Footnote Kevan Page 16

Answer 68

1. Bronchoconstriction 2. Vasodilation 3. Increases vascular permeability

Answer 69

1. ABCs 2. Cardiac Monitor 3. 1L NS Bolus Medications: 1. 0.3mL (0.3mg) of Epinephrine 1:1000 IM (or 5-15mcg/min IV infusion, especially if in shock) - admiinistered to deltoid or thigh 2. If patient is on beta blockers, use Glucagon 1mg IV/IM instead of epinephrine (may not have an adequate response to epinephrine) 3. Benadryl 50mg IV 4. Ranitidine 50mg IV 5. Methylprednisolone (Solumedrol) 125mg IV *Repeat IM epinephrine if inadequate response at 5 minutes Repeat 1L NS bolus if still hypotensive at 5 minutes Continue with epinephrine infusion if not improving If persistent poor response despite this, call for backup

Answer 70

- No controlled studies examining the role of allergic rhinitis in development of CRSsNP - No evidence treatment of AR alters progression of CRSsNP - No clear association between AR and CRSwNP - Both associated with T-helper 2 - mediated inflammation - Nasal polyps with high levels of tissue eosinophils, mast cells and basophils

Answer 71

Eosinophilic Granulomatosis with Polyantigis aka. Churg-Strauss Disease DIAGNOSTIC CRITERIA (High Yield) - 2 Airway related: (1) Asthma, (2) Non-fixed pulmonary infiltrates - 2 Related to Eosinophils: (1) Serum eosinophilia > 10%, (2) Perivascular eosinophils on biopsy - 2 Other: (1) polyneuropathy, (2) Nasal polyposis - ≥4/6 required for diagnosis - Sensitivity of 85%, specficity of 99.7% - Also associated with positive p-ANCA STAGES (Lanham et al.) 1. Prodromal Phase - Asthma, atopic disease, or other allergic symptoms only - Can often be mistaken for recurrent pneumonia or bacterial infections 2. Eosinophilic Phase - Peripheral eosinophilia, Pulmonary disease, ± gastroenteritis 3. Vasculitis Phase - Constitutional and systemic vasculitic manifestations (e.g. myocarditis, polyneuritis, arthralgias) BIOPSY FINDINGS: 1. Necrotizing extravascular granulomas + Langhans giant cells 2. Vasculitis 3. Extravascular eosinophils TREATMENT: - Induction followed by maintenace immunosuppressive therapy - Induction therapy typically involves treatment with oral or IV steroids - Rheumatology involvement - Generally will not require surgery if systemic disease is well controlled - Mepolizumab = Nucala --> Anti-IL5, recently approved by FDA for eGPA as targeted therapy

Answer 72

1. Fever 2. Headache 3. Halitosis 4. Dental pain 5. Fatigue 6. Cough 7. Ear pain/pressure/fullness

Answer 73

Risks: 1. Rhinitis medicamentosa 2. Hypertension 3. Insomnia 4. Palpitations 5. Anxiety (most common) 6. Headaches 7. Decreased urinary flow Contraindiations: 1. Coronary artery disease 2. Concurrent MAOi use (antidepressant - monoamine oxidase) 3. Poorly controlled hypertension 4. Thyroid disease 5. BPH 6. Pregnancy

Answer 74

Decongestants = alpha and beta-adrenergic stimulation to the sympathetic nervous system - Alpha receptor stimulation leads to vasoconstriction - Beta adrenergic stimulation contributes to vasodilation - Prolonged use results in rapid tolerance = tachyphylaxis Multiple Theories: 1. Exhaustion of pre-synaptic norepinephrine - Due to prolonged stmiulation 2. Decreased sensitivity and number of alpha-1 receptors - Post-synaptic alpha-1 receptors decrease due to the inhibitory effects of the alpha-2 receptor 3. Prolonged beta-adrenergic vasodilation outlasts alpha-vasoconstriction - Prolonged beta-adrenergic vasodilation outlasts the alpha-adrenergic effects of the decongestant 4. Prolonged vasoconstriction --> hypoxia --> rebound vasodilation - Rebound vasodilation due to vascular fatigue or due to the need to resupply nutrients 5. Increased compensatory parasympathetic tone --> increased vascular permeability --> edema ## Footnote https://www.ncbi.nlm.nih.gov/books/NBK538318/

Answer 75

1. Cessation of offending agents (can be staged; e.g. stop one side, then the other) 2. Identify possible causes of underlying rhinitis 3. Short course of oral steroids 4. Nasal saline rinses 5. Intranasal corticosteroids 6. Emotional support

Answer 76

B-CELL DISORDERS 1. Common Variable immunodeficiency (SECOND MOST COMMON) 2. X-linked Agammaglobulinemia of Bruton 3. Selective Immunoglobulin deficiency (MOST COMMON) - such as IgA, IgG below 4. Selective IgA deficiency (most common immunoglobulin deficiency) 5. Selective IgG Hypogammaglobulinemia T-CELL DISORDERS 1. DiGeorge Syndrome (Thymic Aplasia) 2. Chronic Mucocutaneous Candidiasis 3. HIV/AIDS (see infectious disease card related to HIV) COMBINED B- AND T-CELL DISORDERS 1. Severe Combined Immunodeficiency (SCID) 2. Wiskott-Aldrich Syndrome: 3. Ataxia-Telangiectasia OTHER CONGENITAL IMMUNE DEFICIENCY 1. C3 deficiency 2. C5-C9 deficiency 3. Hyper IgM syndrome 4. Hyper IgE/Job syndrome

Answer 77

B-CELL DISORDERS: - Signs/Symptoms: Recurrent upper airway infections (sinonasal, otitis media, pulmonary), conjunctivitis, dermatitis, malabsorption, and pyogenic bacterial infections - Diagnosis: Quantitative immunoglobulins and subclasses, Schick test (diphtheria immunity), serum protein, immunoelectrophoresis, in vitro specific antibody responses - Treatment: Antibiotics, IVIg (IV immunoglobulin) 1. Common Variable Immunodeficiency Syndrome (CVIDS) - Most common form of hypogammaglobulinemia - Failure of B-cell maturation, characterizede by decrease in at least 2 immunoglobulins AND defective antibody production - Usually acquired, associated with T-cell deficiencies and other autoimmune disorders - Manifests in early adulthood - Other hallmark infection/signs: Encapsulated organisms, poor vaccination responses, increased risk of bronchiectasis of diagnosis 2. X-Linked Agammaglobulinemia of Bruton - X-linked recessive, BTK gene defect, causes defect in tyrosine kinase and causes failure of B-lymphocyte maturation to B-cells - Decreased immunoglobulins and specific antibody production - Commonly seen in boys age 6-12 months after losing maternal immunity (maternal IgG declines and this then shows up), but can survive up to adulthood - Hallmark infection/signs: Encapsulated organisms, Giardia lambia, and enterovirus infections; increased risk of leukemia and lymphoma 3. Selective IgA Deficiency (most common selective immunoglobulin deficiency) - Most common inherited B-cell defect - Selective IgA B-Cells do not mature to plasma cells - Clinical presentation: Often asymptomatic, associated with allergies, transfusion anaphylaxis, autoimmune disorders, and associated with IgG subclass deficiency - Management: Keep IgA content of blood produts low (as this may cause anaphylaxis) 4. Selective IgG Hypogammaglobulinemia: may affect one or more subtype of IgG (G1-G4) - IgG1: Rare, IgG1 composes majority of total serum IgG - IgG2: Most common hypogammaglobulin deficiency in CHILDREN, inability to mount an antibody response to polysaccharides (encapsulated bacteria) - IgG3: Most common hypogammaglobulin deficiency in ADULTS, reduced ability to generate an antibody response to viral infections, M. catarrhalis, and S. pyogenes - IgG4: Common, usually asymptomatic (unclear clinical significance)

Answer 78

T-CELL DISORDERS: - Signs/symptoms: Increased viral, fungal, protozoal, and bacterial infections; - Atrophic lymphoid tissue - Diagnosis: Total lymphocyte count, T-cell count, skin tests (candidal, mumps controls, PPD), functional tests (proliferation to mitogens, alloantigen helper/suppressor function) 1. DiGeorge Syndrome (Thymic Aplasia) - Disorder of third and fourth branchial pouch development, thymic hypoplasia - Also associated with hypoplastic parathyroids (hypocalcemia, tetany), aortic arch and facial abnormalities - 90% due to chromosome 22q11 deletion 2. Chronic Mucocutaneous Candidiasis - T-cell dysfunction resulting in skin and mucous membrane candidal infections - Onset usually in childhood - Treatment: antifungals 3. HIV/AIDS - See separate card on HIV in Infectious disease section under General

Answer 79

1. Severe Combined Immunodeficiency (SCID) - Multiple genetic forms resulting in lack of T- and B-cell immunity - Severe infections (pneumonia, diarrhea, thrush) - early onset bacterial, fungal, and viral infections (bubble boy) - Higher risk of malignancy - Variant associated with adenosine deaminase (ADA) deficiency (accumulation of deoxyadenosine, toxic to lymphocytes) - Presents within first few months of life, fatal if untreated - Treatment: Bone marrow transplant, gene therapy is experimental 2. Wiskott-Aldrich Syndrome - X-linked inheritance, WASP gene defect associated with IgM deficiency - Triad: Thrombocytopenia (bleeding), eczema, and recurrent infections due to poor functional antibody response to polysaccharides (otitis media, pneumonia, and pyogenic organisms) - Associated autoimmune diseases and increased risk of malignancy (Non-hodgkin lymphoma) - Treatment: Bone marrow transplant, splenectomy, IVIg, antibiotic prophylaxis, gene therapy is experimental 3. Ataxia-Telangiectasia Syndrome / Louis Bar Syndrome - Cerebello-oculocutaneous telangiectasias - Defect in DNA repair, IgA deficiency - Hallmark signs: Cerebellar ataxia, telangiectasias - Mean survival 25 years - Treatment: antibiotics, possibly IVIg

Answer 80

1. C3 Deficiency - Defect: Lack of bacterial opsonization - Encapsulated organisms 2. C5-C9 Deficiency - Defect: Terminal complement deficiency - Nisseriae Meningitis common 3. Hyper IgM syndrome - Decreased IgG and normal or elevated IgM 4. Hyper IgE/Job syndrome - Triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections

Answer 81

Selective IgA deficiency - 1:200-500 - Usually of no consequence and found incidentally - If relevant, will present with chronic diarrhea and sinus problems Treatment: - Prophylactic antibiotics - May go on to develop IgA antibodies, therefore at risk of transfucion reactions

Answer 82

Common Variable Immunodeficiency - 1:25000 - Bimodal age presentation: 1-5 and again 18-25 - Delayed recognition is common

Answer 83

1. Viral (HIV, Hep C, EBV, etc.) 2. Chemotherapy 3. Post-transplant 4. Diabetes 5. Lymphoma/leukemia 6. Drug-induced 7. Steroids

Answer 84

Workup should be considered with ≥2 of these signs 10 WARNING SIGNS IN CHILDREN: 1. 4+ ear infections in 1 year 2. 2+ severe sinus infections in 1 year 3. 2+ months on antibiotics without improvement 4. 2+ pneumonia in 1 year 5. Failure to thrive 6. Recurrent deep skin or organ abscesses 7. Persistent thrush or fungal infection on skin 8. Need for IV antibiotics to clear infection 9. 2 or more deep-seated infections (including septicemia) 10. Family history of immunodeficiency 10 WARNING SIGNS IN ADULTS: 1. 2+ ear infections in 1 year 2. 2+ sinus infections in 1 year (in absence of allergy) 3. 1+ pneumonia a year for >1 year 4. Chronic diarrhea and weight loss 5. Recurrent viral infections (colds, herpes, condylomae) 6. Recurrent need for IV antibiotics to clear infection 7. Recurrent deep skin or organ abscesses 8. Persistent thrush or fungal infection on skin 9. Infection with normally harmless TB-like bacteria 10. Family history of immunodeficiency Common Features between Children/Adults: 1. Multiple ear infections: - 4+ in 1 year in children < 18 - 2+ in 1 year in adults 2. Multiple episodes of sinusitis - 2+ in 1 year in children - 2+ in 1 year in adults (in absence of allergy) 3. Recurrent pneumonia - 2+ in 1 year in children - 1+ in >1 year in adults 4. Weight loss - FTT in children - Chronic diarrhea and weight loss in adults 5. Recurrent deep skin or organ abscesses 6. Need for IV antibiotics to clear infection 7. Persistent thrush or fungal infection of skin 8. Family history of immunodeficiency

Answer 85

4 STAGES STAGE 1: - History and physical examination, height, weight - CBC and differential - Quantitative immunoglobulin levels (IgG, IgM, IgA) - related to age STAGE 2: - Specific antibody responses (tetanus, diptheria) - Response to pneumococcal vaccine (pre-post); check antibody levels (for ages >3) - IgG subclass analysis STAGE 3: - Candida and Tetanus T-cell stimulation skin tests - Lymphocyte surface markers: CD3/4/8/19/16/56 - Mononuclear lymphocyte proliferation studies (using mitogen and antigen stimulation) - Neutrophil oxidation burst (if indicated) STAGE 4: - Complement screening: CH50, C3, C4 - Enzyme measurements (adenosine deaminase, purine nucleoside phosphorylase) - Phacocyte studies (surface glycoproteins, mobility, phagocytosis) - NK Cytotoxicity studies - Further complement studies AH50 - Neo-antigen to test antibody production - Other surface/cytoplasmic molecules - Cytokine receptor studies - Family/genetic studies - Secondary screening: HIV and DM screen

Answer 86

Consistently low total immunoglobulins

Answer 87

1. B cells (humoral immunity) 2. T cells (Cellular immunity) 3. Phagocytes (innate immunity) 4. Complement system (innate immunity) 5. Antibody deficiency (humoral immunity) - most common

Answer 88

CRITERIA: 1. History of recurrent infections 2. Impaired antibody production with low IgG concentration 3. Absent or highly impaired antibody response to vaccine or infectious agents 4. Poor antibody response measured to protein or polysaccharide antigens TREATMENT: 1. IVIg or SC Ig - Starting dose 400-600mg/kg (ideal body weight) - q4 weeks, or every week (for SCIg) - Titrate to trough of > 7 or 8 (most patients feel better > 8 or 9) - Maximum 600mg/kg q2weeks - If known bronchiectasis, start at higher dosing - If trough not met, investigate if losing protein or underlying infection Indications for Immunoglobulin replacement: - CVID - Agammaglobulinemia - IgG subclass deficiency with poor vaccine response - Hyper IgE syndrome - SCID

Answer 89

Recurrent CRS: - Not controlled by conservative management for 4 months - IgG, IgA, or IgM deficiencies in 13% of patients with recurrent disease - Difficult to treat CRS: Surgery or conservative management for 1 year (23% of patients with difficult to treat disease have some form of immunodeficiency)

Answer 90

1. IgG subclasses 2. IgM 3. IgA 4. IgE 5. Ability to respond to polysaccharide antigens of S. Pneumo and H. flu

Answer 91

1. Personal and family history 2. CRP + ESR 3. ANCA (antineutrophil cytoplasmic antibodies) 4. Rheumatoid factor 5. Biopsy of sinus and nasal structures (absence of granulomas does not rule out disease)

Answer 92

1. Vaccination: low levels of specific antibodies against pneumococcal subtypes - Do not respond normally to polysaccharide vaccine, conjugated pneumococcal antigen vaccine (because this is T-cell dependent) 2. Early treatment with antibiotics 3. Prophylactic antibiotics 4. Immunoglobulin replacement (CVID, SAD, not IgA deficiency) 5. Endoscopic sinus surgery