A. Introduction

1. Extremely common cause of chronic illness and morbidity
2. Uncommon cause of mortality associated with anaphylaxis
3. Most involve immunoglobulin E and/or eosinophils
4. Specific Allergic Diseases
   1. Asthma
   2. Allergic Rhinitis
   3. Anaphylaxis - foods, venoms
   4. Atopic Eczema
   5. Urticaria
   6. Angioedema
   7. Insect Bite/Sting Allergies (see below)
   8. Drug allergies [12]

B. Pathophysiology [17]

1. Overproduction of histamine and other vasoactive substances
   1. Histamine acts mainly through H1 receptors to cause allergic symptoms
   2. Causes smooth muscles contraction in respiratory and GI tracts
   3. Also sneezing and pruritis
   4. Histamine induces nitric oxide in vascular endothelium
   5. Causes vasodilation and fluid extravasation
   6. Also causes flushing, headache, tachycardia, hypotension
   7. H2 receptor activation leads to gastric acid hypersecretion (not allergic symptoms)
2. Key cells include mast cells, basophils, eosinophils
   1. IgE appears to play a key role in many of these patients (Type I Hypersensitivity)
   2. IL4 stimulates IgE production and is a Th2-T helper cell growth factor
   3. IL5 stimulates eosinophils
   4. Leukocyte interactions with vascular endothelium induces allergic effector molecules
3. Overstimulation of IL4 Responses [14]
   1. Gain of function mutation in IL4 receptor (R576 allele) associated with atopy
   2. Relative risk of atopy with this allele is 9.3 fold
   3. This mutation was also found in patients with Hyper-IgE (Job) syndrome
4. Increasing data suggest Th2 bias for T cells [21,30]
   1. Th2 cytokines include IL4, Il5, IL10 which promote IgE and eosinophils
   2. Normal pregnancy has a Th2 bias in maternal circulation
   3. Newborns have some Th2 bias, with some "predisposed" infants having considerable bias
   4. During development, children in low risk allergy areas switch to a Th1 pattern by age 5
   5. Continuation of fetal allergen Th2-type responses during infancy is a risk for atopy
   6. Parasite exposure early in infancy leads to IL10 production and allergy/atopy reduction [31]
   7. IL10 early in life may be a key to switching to Th1 phenotype
   8. Lipopolysaccharide rececptor (CD14) polymorphisms also linked to allergy predisposition
   9. Persistent Th2 patterns in response to allergens associated with reduced IFN gamma
   10. Exposure to early pathogens through day nursery early in life may bias toward Th1 [22]
   11. Likewise, exposure to significant levels of house-dust endotoxin at early age (which stimulates Th1 differentiation) appears to reduce the risk of developing allergies [26]
   12. Infections which induce Th1 such as mumps or hepatitis A associated with reduced rates of asthma and atopy [27]
   13. Exposure to farming early in life associated with reduced rates of asthma, hay fever, and atopic sensitization [32]
5. Early Exposures to Allergens and Pathogens
   1. Exposure of young children to other children (especially daycare) reduces risk of developing asthma by 20-60% [28]
   2. Children entering day nursery >12 months had 2-3X higher risk of atopy than children entering age 6-11 months [22]
   3. Early exposure to house dust mite and cat allergens induces IgE responses in children but does not increase the risk of developing asthma [29]
   4. Exposure to cats or dogs in first year of life reduces risk of subsequent hyperresponsiveness to a variety of allergens [35]
6. T Cell Repertoire Bias
   1. Early infections skewing towards Th1 profile may reduce risk of atopy (Th2 profile)
   2. Likely that microbial burden early in life reduces the risks of atopic diseases [32]
7. Breastfeeding does not affect risk of allergies, atopy, or asthma [36]

C. Symptoms

1. Headache, especially frontal and maxillary sinus headache
2. Nasal congestion, may progress to sinusitis
3. Otitis media
4. Ocular Symptoms
   1. Ophthalmic pruritis
   2. Excessive tearing
   3. Erythema
   4. Conjunctivitis
5. Urticaria
6. Cough (allergic bronchitis)
7. Pulmonary
   1. Dyspnea
   2. Chest tightness
   3. Wheezing (± frank asthma)
8. Fatigue
9. Hypotension
10. Angioedema
11. Anaphylaxis

D. Stimuli [15]

1. Pollens
   1. Ragweed
   2. Grasses
   3. Mountain cedar
   4. Parietaria
2. Mold Spores
3. Dust Mites (House)
4. Medications [19]
   1. Most are cutaneous drug reactions
   2. Maculopapular skin eruptions, urticaria, angioedema most common
5. Food Allergies [18]
   1. Mainly glycoproteins (MW 10-60K)
   2. Cow milk caseins
   3. Whey
   4. Chicken egg white
   5. Peanuts
   6. Soybeens
   7. Fish
   8. Shrimp
6. Animal Danders
   1. Dog dander
   2. Cat dander
   3. Exposure to cats or dogs in first year of life reduces risk of subsequent allergies [35]
7. Insects (see below)
8. Workplace Allergens [20]
9. Idiopathic
10. Underlying Disease
    1. Infection
    2. Eosinophilic Syndrome
    3. Congenital Immune System Dysfunction
11. Environmental Triggers
    1. Pollutants
    2. Cigarette (Cigar) Smoke
    3. Viruses
12. "Asian" or "Chinese" Restaurant Syndrome [6]
    1. So-called syndrome thought to be related to reaction to monosodium glutamate (MSG)
    2. Asthma (dyspnea, wheezing), hives, sweating may occur
    3. MSG does not induce bronchoconstriction in patients with reported asthma after ingestion

E. Insect Bite Hypersensitivity [39]

1. Insects of the order Hymenoptera
   1. Includes ants, bees, hornets, wasps, yellow jackets
   2. Deliver 100ng (fire ants) and 50µg (bees) of venom
2. Allergies to insect stings can be fatal
   1. ~40 deaths annually from hymenoptera stings in US
   2. Often persist from childhood to adulthood in many patients
   3. Highly responsive to desensitization therpay during childhood [40]
3. Mechanisms
   1. Nearly all persons develop local reactions may persist for up to 1 week
   2. All stings also contain vasoactive components which cause redness, pain, edema
   3. Prior stings cause production of specific IgE antibodies in sensitive individuals
   4. Sting can then produce anaphylactic or other severe reaction in sensitized persons
   5. These are type 1 hypersensitivity reactions
4. Symptoms in Allergic persons
   1. Swelling in the airway may become life threatening in allergic persons
   2. Pruritus, hives, urticaria, angioedema can occur
   3. Metallic taste, nausea, vomiting, diarrhea, abdominal cramping
   4. Lightheadedness, dizziness
   5. Bronchospasm, hypotension, arrhythmia pose greatest risk
5. Treat any severe allergic / anaphylactic reaction with epinephrine, antihistamines
   1. Glucocorticoids should generally be given to prevent late effects but efficacy unclear
   2. Avoidance and immunotherapy with hymenoptera venom should be considered
   3. Excellent responses to immunotherapy usually seen

F. Identification of Specific Allergens

1. Common allergens include pollen, mold, dust mites, dogs, cats, cockroaches
2. Identification of specific allergens sometimes possible with skin testing or RAST
3. Skin Testing
   1. Subcutaneous administration of low dose allergens
   2. Good positive (PPV) and negative (NPV) predictive values for inhaled allergens
   3. Poor PPV for foods
   4. Good NPV for foods
   5. Low but non-zero risk of anaphylaxis
4. Radioactive Allergen Serum Test (RAST)
   1. Less sensitive than skin testing
   2. Permits testing when patients react severely
   3. Relatively expensive

G. Treatment [2]

1. Avoid or Remove offending agents
   1. Pollen count highest in early morning, removed only by heavy rain of long duration
   2. Air conditioning can be very helpful
   3. Advise patients to limit carpeting and upholstered furniture, vacuum often
   4. Linens should be laundered frequently
   5. Pets should not be permitted to sleep in bedroom
   6. Windows should not be left open overnight
   7. Dehumidification may decrease mold growth
   8. Allergen impermeable covers did not reduce asthma or allergic rhinitis in adults, including those with serum IgE to mite antigens [37,38]
2. Overview of Agents
   1. Epinephrine - for anaphylactic reactions
   2. Antihistamines - antagonize histamine H1 receptors
   3. Cromolyn compounds
   4. Glucocorticoids - inhaled (oral, nasal) and/or systemic (for severe disease only)
   5. Immunosuppressive agents for very severe disease
   6. Desensitization (Immunotherapy)
   7. Anti-IgE Antibody (omalizumab, Xolair®)
   8. Anti-Cytokine Therapy (experimental)
3. Epinephrine
   1. Definitive treatment for ANY form of anaphylaxis
   2. 0.01mg/kg body weight to maximum 0.3mg children, 0.5mg adults
   3. Administer to any insect sting patient who has more than a cutaneous reaction [39]
   4. Administer to any patient allergic reaction with breathing difficulty
   5. Failure or delay in administration of epinephrine can lead to coronary vasospasm
   6. Epinephrine autoinjectors should be prescribed for any patient with allergic reactions
4. Oral First Generation Antihistamines [3,4]
   1. Oral agents have rapid onset, but with significant anticholinergic side effects
   2. Very effective for rapid relief of symptoms, particularly useful at night
   3. May cause somnolence, slowed cognition and reaction time, reduced work efficacy [13]
   4. Psychomotor retardation and reduced work productivity may be unnoticed by patient [4]
   5. Also, urinary retention, dry mouth and tachycardia; prolonged QTc very uncommon
   6. Diphenhydramine (Benadryl®): 25-50mg po qd-tid
   7. Chlorpheniramine (Chlor-Trimeton®)
   8. Triprolidine (Actifed®), Hydroxizine (Atarax®, Vistaril®)
   9. For ocular inflammation, levocabastine (Livostin®) may be effective
   10. Many combinations with pseudoephedrine (decongestant) are available
5. Oral Second Generation Antihistamines [3,4,5]
   1. Loratidine and others have little adverse CNS or anticholinergic effects
   2. However, loratidine is given at low doses and is weakest of all antihistamines
   3. Loratadine (Claritin®, Alavert®) - 10mg po qd; onset in 6-12 hours; non-prescription [5]
   4. Desloratidine (Clarinex®) - 5-20mg po qd; no QT prolongation [8]
   5. Fexofenadine (Allegra®) - 60mg po bid; onset <6 hours; no QT prolongation [10]
   6. Cetirizine (Zyrtec®) - 5-10mg po qd; onset 1-2 hours; no QT prolongation; non-prescription [9,42]
   7. Terfenadine (Seldane®) and Astemizole (Hismanal®) prolong QTc interval, off market
   8. Combinations with pseudoephedrine such as Claritin-D® are available
   9. Fexofenadine probably combines the best effectiveness and safey [4,8]
   10. Desloratidine provides no apparent benefit over loratidine [8]
6. Cromolyn Compounds
   1. Cromolyn Sodium (Nasal-Crom®)
   2. Nedocromil (Tilade®)
7. Inhaled Glucocorticoids (Steroids) [7]
   1. For rhinitis and sinusitis (in order of increasing expense)
   2. Beclomethasone (Beconase®, Vancenase®) - 2-4 puffs po bid to qid
   3. Flunisolide (Nasalide®) - 2-4 puffs nasally bid to qid
   4. Budesonide (Rhinocort®) - 2-4 puffs nasally qd to bid
   5. Fluticasone (Flonase®) - 2-4 puffs nasally qd to tid
   6. Triamcinolone (Nasocort®) - 2-3 puffs nasally bid to tid
   7. Mometasone (Nasonex®) - 2 puffs nasally qd
   8. Systemic absorption is minimal in most patients
   9. Nasal steroids are the drugs of choice for perennial and seasonal allergies
8. Systemic Glucocorticoids
   1. Moderate doses are usually required
   2. Recommend prednisone 30-40mg po qd with taper over 10-21 days
   3. Inappropriate to prescibe low, ineffective doses over long periods
9. Ipratropium Bromide (Atrovent®) Nasal Spray
   1. Anti-cholinergic agent with efficacy in allergic rhinitis
   2. Dries nasal mucosa, reduces post-nasal drip and pruritus
10. Omalizumab (Xolair®) [24,33]
    1. Recombinant humanized monoclonal anti-human IgE antibody developed
    2. Recognizes human IgE specifically at the same part of Fc region as the Fc(E) receptor
    3. Reduces serum concentrations of free IgE immediately after one injection
    4. Attenuates early- and late-phase reactions to inhaled allergens
    5. Biweekly IV dosing for 20 weeks in adults with allergic asthma on some form of glucocorticoids led to improved asthma scores and reduced need for glucocorticoids [24]
    6. Some reduction in daily ß-adrenergic agonist use seen in treated patients
    7. Serum IgE levels were reduced >95% with high and low dose anti-IgE treatments
    8. Subcutaneous dosing every 2-4 weeks for 16 weeks in children with allergic asthma reduced inhaled glucocorticoid use and asthma exacerbations [33]
    9. Antibodies to the anti-IgE treatments developed in all patients
    10. Side effects were not different in placebo versus treated patients
    11. Total serum IgE level should be measured in all patients prior to omalizumab
    12. FDA approved for used in persistent asthmatics with elevated serum IgE levels
11. Most therapies for allergies improve only local symptoms
    1. Nasal antihistamine now available
    2. Multiple agents for allergic conjunctivitis [25]

H. Desensitization (Immuno-) Therapy [2,15,23]

1. When particular allergens are identified, consider desensitization therapy
2. Desensitization therapy is effective for 50-70% patients
   1. May improve systemic as well as local symptoms
   2. Effective for allergic rhinitis symptoms but less so for asthma symptoms
   3. Clear improvement in patients desensitized to grass-pollen antigens [23]
   4. After ~3 years, need for continued immunotherapy is questionable [23]
   5. No improvement in asthma observed in allergic children treated with immunotherapy [11]
   6. Densitization of children to insect stings is highly effective, even into adulthood [39,40]
3. Desensitization is time-consuming and somewhat expensive
4. Classical densitization involves subcutaneous injections of allergens
   1. Initially, skin tests are performed with very low levels of allergens
   2. Positive skin tests may mean that patient is allergic to substance
   3. Classical densitization uses subcutaneous injections of increasing doses of allergens
   4. Goal is to reduce IgE responses, usually converting them to IgG responses
   5. Desensitization early in evolution of allergic responses may be beneficial [23]
5. Mechanism of Action [2]
   1. Complex and multiple mechanisms
   2. IgG "blocking" Abs induced by subcutaneous injections of allergens
   3. These blocking Abs may also prevent aggregation of IgE complexes and IgE receptor
   4. Also appear to interfere with antigen trapping by IgE bound to antigen presenting cells
   5. Immunotherapy induces shift from Th2 type cytokines to Th1 type cytokines
   6. These T cell changes probably drive inhibition of late-phase reactions
6. Sublingual/oral immunotherapy with mite allergens reduces symptoms [16]
   1. Also reduces ICAM-1 expression on conjunctival epithelium
   2. Serum levels of eosinophil cationic protein also decreased with immunotherapy
7. Cat Allergies [34]
   1. Feline d1 allergen (Fel d1) is target in many people with cat allergies
   2. T cell peptides derived from Fel d1 can induce T cell tolerance to Fel d1
   3. Fel d1 peptides administered to cat-allergic persons can be beneficial
8. Immunotherapy with Ragweek-TLR-9 Agonist Vaccine [41]
   1. Toll-like receptor 9 (TLR-9) stimulates Th1 cytokines
   2. Amb a 1, ragweek-pollen allergen, conjugated to a TLR-9 stimulator
   3. Six weekly injections of conjugate vaccine versus placebo
   4. Vaccine reduced peak-seaon rhinitis scores and daily nasal symptoms
   5. Vaccine also prevented usual seasonal increase in ragweed specific IgE response
   6. Generally well tolerated
9. Sublingual immunotherapy with grass pollen (Grazax®) is approved outside of USA [43]

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