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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4518_Библиотеки_им_академика_М_И_Перельмана
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7 Allergy andImmunology
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Indoor
• Dust
• Mites
• Cockroach
• Molds
• Dander
• Feather
Outdoor
• Tree pollen—spring
• Grass pollen—summer
• Weed pollen—fall
• Molds—(spring/fall)
– Drug
– Insect—sting, bites
– Foods
Allergic Rhinitis
Diagnosis
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• History
– Primary symptoms, duration, frequency, alleviating/exacerbating factors,
associated symptoms or conditions, recent changes in job, environment, diet
– Past medical history: history of asthma, anaphylaxis, eczema, allergen expo-
sure, formula intolerance
– Past surgical history: T+A, BMT, FESS
– Family history: allergic rhinitis, asthma, eczema, angioedema, food intoler-
ance, anaphylaxis
Chance of having atopy with:
• 0 allergic parents: 10–15%
• 1 allergic parent: 30%
• 2 allergic parents: 50%
– Social history: Living accommodations, tobacco exposure, occupation
– Medication use
• Physical
– Eyes: lid edema and erythema, injection of conjunctiva and sclera, chemosis,
itching, watery, photophobia, “allergic shiners,” “Dennies lines”
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A. Del Signore et al.
– Nose: supratip crease, facial grimacing, itching, nasal obstruction, inferior
turbinate hypertrophy, rhinorrhea, increased mucus, sneezing
– Ears: tympanic membrane retraction, Eustachian tube dysfunction, middle
ear effusion
– Oropharynx: “cobblestoning” of posterior pharyngeal wall, hypertrophy of
lateral pharyngeal bands, mouth breathing, angioedema
– Laryngeal: excess secretions, vocal fold edema, laryngeal drying, erythema-
tous arytenoids, viscous mucus
– Possible related systemic ndings:
Skin: eczema, contact dermatitis, urticaria,
Lungs: wheezing, dyspnea, cough
• Differential Diagnosis
– Drug-induced rhinitis
– Rhinitis medicamentosa
– Occupational rhinitis
– Chemical rhinitis
– Infectious rhinitis
– Rhinitis of pregnancy/hormone induced
– Food-/alcohol-induced rhinitis
– Vasomotor rhinitis
– Atrophic rhinitis
– Autoimmune/granulomatous/vasculitic rhinitis
Diagnostic Testing
• In vivo testing
– Although testing is generally safe, necessary medications and airway equip-
ment to treat systemic anaphylaxis must be available.
– Skin testing
Epicutaneously
• Skin prick test.
– Can be tested via individual vs. multiple allergen delivery.
– Useful to direct allergy immunotherapy.
– Allows for the identication of specic sensitivities.
– More specic testing than intradermal (fewer false-positive results).
– Sensitivity and specicity around 80%.
– False negative rate is 5%.
– Various antigens introduced in controlled manner—to determine
reactivity and severity.
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– Few drops of selected antigen are placed on skin surface after small
prick with needle.
– Crosslinks IgE on cutaneous mast cells resulting in release of
mediators.
– Reaction >3mm in diameter is considered positive.
– Contraindications: severe asthma, uncontrolled cardiovascular dis-
ease, inability to refrain from beta-blocker use, pregnancy
Intradermal
• Can be done as a primary testing modality, typically recommended to be
performed after negative prick test, but specic sensitivity is suspected.
• Not appropriate for food allergens due to high risk of false positives and
risk of anaphylaxis.
Small amount of allergen injected subcutaneously.
• More reproducible and sensitive testing than prick testing (fewer false
negatives).
• Can be used to determine starting point of allergy immunotherapy.
Skin end point titration.
– Intradermal injections of allergen at increasing concentrations start-
ing with an anticipated non-reacting dose.
– Wheal which initiates positive reaction is safe starting point for
immunotherapy.
– Vial preparation technique.
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Start with concentrate 1:20 w/v → 1cm3 is mixed with 4cm3 diluent rendering a concentration of 1:100 w/v (#1).
The serial dilution is continued ve additional times until a nal
solution of 1:312,500 w/v (#6).
Final vial dilutions:
• 1:20 w/v (concentrate)
• 1:100 w/v (#1)
• 1:500 w/v (#2)
• 1:2500 w/v (#3)
• 1:12,500 w/v (#4)
• 1:62,500 w/v (#5)
• 1:312,500 w/v (#6)
– Technique
Start with inert diluent injection 0.02mL 4mm wheal, and expand
to 5mm by hydrostatic force measured at 10min → normal.
Testing begins with injection of antigen at the lowest reactive
concentration (#6) followed by sequential increases of concentration (#5) → (#4) → etc. until a wheal enlarges by 2mm which
signies an “endpoint” concentration.
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Factors which affect wheal response:
• Recent exposure
• Prior immunotherapy
• Area of body tested—i.e., upper back > lower arm
• Age of patient—pediatric and geriatric tend to have less response
• Medications affecting skin wheal
– Inhibition: antihistamines, tricyclic antidepressants, H2 blockers,
systemic beta agonists, theophylline, vitamin C, anti-IgE monoclonal
antibodies
– Enhancement: histamine control to close to allergen, skin conditions
(dermatographia, urticaria), glycerin sensitivity, beta-blockers
– No effect: systemic steroids, leukotriene modiers, cromolyn,
inhaled beta-2 agonist
• In vitro testing
A. Del Signore et al.
• “endpoint”: concentration that produces positive wheal that is
at least 2mm wider than control
• Considered safe point for starting skin testing
Injection of next stronger concentration that results in further
2mm in growth → “conrmatory” concentration
13mm growth → major reaction, testing stopped
– Serum test
– Detects specic IgE to allergens
Suspected allergen bound to insoluble material → patient serum added
• If IgE present in serum → binding to allergen occurs
• Marker labeled anti-IgE added and attaches to IgE → washed and detection occurs
• Detection of marker
– Radiation: RAST—(Radioallergosorbent test)
– Enzyme linked: ELISA
– Flourescence: Immunocap
• The higher the signal the more IgE in the patient’s serum
Scoring:
• 0–6 based on level of IgE in specimen
– Indications:
Inability to discontinue medications that would interfere with skin testing—i.e., antihistamines, H2 blockers, tricyclic antidepressants, long-term
topical steroids
Severe eczema or psoriasis precluding skin testing
Difcult populations, i.e., children, needle phobia
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Extraordinarily high sensitivity to suspected allergens that may lead to
potentially serious side effects (i.e., anaphylaxis)
Poorly controlled reactive airway disease
– More specic in determining allergen sensitivity, less sensitive than skin tests
Management ofAllergy Symptoms
Nonpharmacologic
• Avoidance
– Goals include:
To remove sources of allergens
To remove accumulated allergens
To prevent allergens from returning
– Outdoor
Pollen
• Types
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– Trees—February through May
– Grass—June through August
– Weeds—August until frost
• Counts highest in morning, hot, dry windy days
• Strategies of avoidance:
– Shift outdoor activities to evening.
– Keep doors and windows closed; utilize AC.
Mold (can be found both outdoor and indoor)
• Present year round
• Strategies of avoidance:
– Minimize wet/damp environments.
– Improve ventilation within house.
– If known source of mold within home, have remediated.
– Indoor
Dust mites
• Keep surfaces clear.
• Remove carpeting.
• HEPA lters
• Wash sheets and pillowcase weekly in hot water >130°C.
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Pet dander
• Avoidance of pet, especially keeping pet out of bed and bedroom.
• Eliminate carpeting.
• Washing pets—only temporary relief.
– Other nonpharmacologic alternatives:
HEPA (high-efciency particulate air) lters
Air puriers
Vacuum cleaners
Dust barriers
A. Del Signore et al.
Pharmacologic Therapy
• Symptomatic relief
• Decongestants
– Reduce blood ow → agonistic action on alpha-1 and alpha-2 adrenergic
receptors
Endothelial cells within nasal vessels
Contraction of sphincters of the venous plexus within turbinate
– Oral agents
Less chance for rebound congestion
Systemic effects include irritability, insomnia, headache, tachycardia,
hypertension, increased intraocular pressure, and urinary retention.
Caution use in patients: hypertension, coronary disease, hyperthyroidism,
glaucoma, urinary retention
For example, pseudoephedrine and phenylephrine
– Topical nasal agents
Rapid onset <5min with duration of 6h
High local potency with fewer systemic effects
Overuse >3–5days leads to lost effectiveness and rebound congestion.
For example, oxymetazoline, neosynephrine, phenylephrine
• Maintenance
• Antihistamines
– Competitively bind to H1 receptors → reduced vascular permeability, smooth
muscle contraction, mucus secretion, vasodilation, pruritis
– Oral
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First generation—available over the counter, cheap
• Limited due to potential for sedative effects → high lipophilicity →
crosses blood brain barrier
• Anticholinergic effects → dry mucus membranes, urinary retention,
constipation, tachycardia, blurred vision: limit use in elderly.
• For example, diphenhydramine, chlorpheniramine, hydroxyzine
Second generation
• Lower CNS penetration and thus less sedating
• Less anticholinergic effects
• Lower interaction with cytochrome P 450
• Better specicity for H1 receptor blockade
• For example, loratadine, cetirizine, fexofenadine
– Topical nasal spray
Advantage of delivering high local concentration
Allows higher anti-inammatory effects, reduction of systemic exposure,
reducing potential for systemic side effects
Typically recommended for patients with seasonal allergic rhinitis
For example, azelastine and olopatadine
• Anti-leukotriene
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– Inferior to intranasal corticosteroids and oral antihistamines; more costly. Not
recommended as monotherapy for AR.Can be considered for patients who
cannot tolerate INCS
– Combined use with antihistamines typically with additive effect
– Synthesis blockade
Blockade of 5-lipoxygenase → prevention of LTA4 synthesis formation
For example, zileuton
– Receptor blockade
Reduces number of peripheral blood eosinophils
For example, montelukast and zarlukast
• Corticosteroids
– Available as systemic, injection, or topical intranasal delivery
Multiple anti-inammatory effects
• Decreased capillary permeability
• Promotes IL-10 production and IL-1 receptor antagonism
• Decreased arachidonic metabolism → decreased prostaglandins, leukotrienes, thromboxane
• Allows inhibition of cytokines and chemokines
• Decreased recruitment and migration of eosinophils
• Decreased activity of basophils and mast cells
• Decreased migration of APC, T cells, B cells
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A. Del Signore et al.
– Topical intranasal delivery
Recommended for persistent nasal congestion
Systemic effects a theoretical concern and not supported by the literature
• Inhibition of growth in children, metabolic disturbances, glaucoma,
cataract formation, immunosuppression, skin thinning
Effectiveness
• Effective for all symptoms of SAR and PAR
• Appropriate for mixed rhinitis
• Clinical response equivocal for all available steroids
Topical side effects include local burning, stinging, irritation, and dryness.
For example, beclomethasone, budesonide, unisolide, triamcinolone,
uticasone, mometasone
• Mast cell stabilizers
– Inhibit Ca2+-dependent mast cell degranulation
– Inhibit migration and survival of macrophages, eosinophils, and monocytes
– When used prophylactically, they can prevent and treat symptoms, although
they commonly need to be used as adjunct and not rst-line therapy.
– Side effects include nasal burning, stinging, and sneezing.
– For example, cromolyn
• Anticholinergic agents
– Muscarinic receptor blockade → inhibits rhinorrhea, congestion, and sneezing
– Side effects can include dry mouth, dizziness, blurred vision, conjunctivitis,
and hoarseness.
– Typically suggested for treatment of rhinorrhea
– Caution in use with elderly with glaucoma and urinary retention
– For example, ipratropium
• Immunomodulation
• Allergen immunotherapy (AIT)
– Differs from pharmacotherapy because it reverses the underlying pathophysi-
ology of allergy, not just symptom control or cell stabilization. Evidenced by
reduction in new sensitizations
– Treats IgE-mediated allergy → regular and progressive doses of appropriate
allergen → downregulation of immune response and control of symptoms
– Benets include:
Improvement in quality of life
Reduction of symptoms
Decrease reliance on medications
Long-term benet after stopping treatment if they complete 3–5 years
of therapy
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Decrease risk of developing asthma
Prevent new sensitizations
– Indications for therapy
Demonstration of IgE-mediated disease correlates with symptoms
Insufcient response to avoidance and pharmacotherapy
Signicant side effects with medical therapy
Unable to comply with medical therapy and avoidance of allergens
Moderate-to-severe symptoms which last for a majority of a year or spanning across two or more seasons
– Effective to following antigens:
Grass
Tree
Pollen
Animal dander
Insect venom
House dust mites
Mold
– Relative contraindications
Concomitant therapy with beta-blocker
Contraindication to administration of epinephrine
Noncompliance of patient
Autoimmune disease
Pregnancy
Uncontrolled asthma
HIV or other immunodeciency
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– Mechanism of action
With initial treatments → 2–3months of increased antigen specic IgE
followed by gradual decline over 2years
• Decline does not correlate to clinical improvement
With decline in IgE → rise in IgG1 and IgG4
• Mediated by T
• Increase in IgG4 correlates with symptom relief
Increase in antigen specic suppressor T cells
Shift TH2 cells to TH1 via increased IFN-gamma and IL-12
Decline in levels of pro-allergenic cytokines
Reduced basophil, mast cell, and lymphocyte reactivity
Blunting of post-seasonal rise in specic IgE antibody
Gradual decrease in symptoms with repeated exposure to same allergen level
production of IL-10 and TGF-β
reg
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– Schedule of treatment
Total treatment period is 3–5years
Escalation phase → rst year
• Rush versus standard schedules
– Allows for the attainment of maintenance doses in as low as 6days
through the use of increased frequency dosing (q 3–4 h) versus
3–6months with standard schedules
– Rush schedules typically necessitate hospitalization during the esca-
lation period
Maintenance phase → up to 5years
• Weekly for rst year, every 2weeks for second year, every 3weeks for
third year
– Allergy extracts
Ideally, extracts are highly immunogenic without elevated risk of IgE
release.
Traditional extracts—allergenic component extracted from raw material
(plant, animal, mold source)
Modied extracts—modied raw extracts that allow augmented immunogenicity while decreasing adverse events
A. Del Signore et al.
– Modes of delivery
Subcutaneous immunotherapy (SCIT)
• Time-tested and effective for treatment of AR
• Wide variability in form of administration (single allergen vs. multiple
allergens, formulation)
• Diluents
– 50% glycerin—effective for maintaining extract potency, but painful
upon injection
– Phenol-saline extract containing 0.3% albumin maintains potency for
non-proteolytic allergens. Less painful
• Regimen begins at a dilution of nal dose for safety and is escalated
weekly/monthly to a maintenance schedule.
• Must be delivered at a medical facility where adverse events are
promptly recognized and mitigated
• Discuss with patients the short-term increased cost and inconvenience
compared to long-term pharmacologic need.
Sublingual immunotherapy (SLIT)
• Supported by many high-quality studies approaching the volume
of SCIT.
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