What is the systematic approach to assessing an allergy?

Systematic Approach to Allergy Assessment

Begin with a detailed clinical history focusing on temporal relationship between exposure and symptoms, as this is the most critical diagnostic step—a positive test without clinical correlation indicates only sensitization, not allergy. 1

Definition

• Allergy: An exaggerated immune system response to external substances that occurs reproducibly on exposure, causing adverse health effects through specific immune mechanisms (primarily IgE-mediated, but also mixed IgE/cell-mediated or non-IgE-mediated) 1, 2

Classification

By Mechanism:

• IgE-mediated: Immediate reactions (minutes to 2 hours); includes anaphylaxis, urticaria, allergic rhinitis, food allergy 1
• Mixed IgE and cell-mediated: Delayed onset; includes eosinophilic esophagitis, atopic dermatitis 1
• Non-IgE-mediated: Cell-mediated reactions; includes food protein-induced enterocolitis syndrome 1

By Allergen Type:

• Inhalants: Pollens (grass, tree), house dust mite, animal dander, molds 1, 2
• Foods: Milk, egg, peanut, tree nuts, shellfish, fish, wheat, soy 1
• Drugs: Penicillins, cephalosporins, NSAIDs 1
• Venoms: Bee, wasp 2
• Contact allergens: Latex, metals, chemicals 2

Differential Diagnosis

Must Exclude:

• Non-allergic adverse reactions: Gastrointestinal symptoms alone (nausea, vomiting, diarrhea without other features), headache, palpitations, blurred vision—these are NOT allergic 1
• Vasovagal reactions: Syncope without other allergic features 1
• Toxic reactions: Dose-dependent, non-immune mediated 3
• Pharmacologic effects: Histamine release from foods (scombroid), caffeine effects 1
• Food intolerance: Lactose intolerance, celiac disease (non-immune or different immune mechanism) 2
• Panic/anxiety disorders: Mimicking anaphylaxis symptoms 1
• Other causes of urticaria: Chronic spontaneous urticaria (not allergic), physical urticarias 1

History Taking

Character of Reactions:

Timing and Onset:

• Immediate reactions (minutes to 2 hours post-exposure): Suggests IgE-mediated allergy 1
• Delayed reactions (hours to days): Consider non-IgE or mixed mechanisms 1
• No temporal association: Rules out allergy; label can be removed 1

Symptom Pattern:

• Cutaneous: Urticaria, angioedema, flushing, pruritus 1
• Respiratory: Dyspnea, wheeze, stridor, throat tightness, rhinorrhea, nasal congestion 1
• Gastrointestinal: Vomiting, cramping, diarrhea (when occurring WITH other organ system involvement) 1
• Cardiovascular: Hypotension, syncope, dizziness, chest pain 1
• Neurologic: Sense of impending doom, confusion (in severe reactions) 1

Reproducibility:

• Reactions must occur consistently with exposure to be considered allergy 1
• Single isolated event: Less likely to represent true allergy 1

Red Flags (Anaphylaxis):

NIAID/FAAN Criteria—Anaphylaxis is highly likely when ANY ONE criterion is met: 1

1. Acute onset (minutes to hours) with skin/mucosal involvement (urticaria, flushing, lip/tongue swelling) PLUS either:

   • Respiratory compromise (dyspnea, wheeze, stridor, hypoxemia)
   • Hypotension or end-organ dysfunction

2. Two or more of the following rapidly after likely allergen exposure:

   • Skin/mucosal involvement
   • Respiratory compromise
   • Hypotension or associated symptoms
   • Gastrointestinal symptoms (cramping, vomiting)

3. Hypotension alone after exposure to known allergen for that patient 1

Additional High-Risk Features:

• Previous severe reactions or anaphylaxis 1
• Asthma (increases risk of severe respiratory reactions) 1
• Cardiovascular disease (increases morbidity/mortality) 1
• Concurrent beta-blocker or ACE inhibitor use (may worsen/prolong reactions) 1

Risk Factors:

For Developing Allergy:

• Atopic predisposition: Personal or family history of atopic dermatitis, asthma, allergic rhinitis 1
• Skin barrier dysfunction: Eczema, particularly in infancy 1
• Delayed food introduction: For peanut and egg specifically 1
• Route of sensitization: Cutaneous exposure may increase risk 1

For Severe Reactions:

• Asthma (poorly controlled increases risk) 1
• Previous anaphylaxis 1
• Adolescent/young adult age (higher risk behavior, delayed epinephrine use) 1
• Concurrent medications: Beta-blockers, ACE inhibitors 1
• Exercise (in food-dependent exercise-induced anaphylaxis) 4

For True Allergy (vs. Sensitization):

• Shorter interval between reaction and testing (<1 year) increases likelihood of confirmed allergy 1
• Penicillin allergy: 1.5× higher risk of true allergy compared to other beta-lactams 1
• Cephalosporin allergy label: 3× higher odds of confirmed allergy (OR 2.96) 1

Additional History Elements:

• Subsequent tolerance: If allergen consumed since index reaction without symptoms, allergy label can be removed 1
• Dose-response: Amount of allergen that triggers reaction 4
• Cofactors: Exercise, NSAIDs, alcohol, menstruation 4
• Treatment received: Response to antihistamines vs. requiring epinephrine 1
• Concurrent medications: Antihistamines, corticosteroids may mask symptoms 1
• Environmental exposures: Seasonal patterns for inhalant allergies 1, 5

Physical Examination (Focused)

Head and Neck:

• Nasal examination: Pale, boggy turbinates; clear rhinorrhea; nasal polyps (suggests allergic rhinitis) 1, 6
• Conjunctival injection: Allergic conjunctivitis 6
• Allergic shiners: Dark circles under eyes from venous congestion 6
• Dennie-Morgan lines: Extra fold of skin below lower eyelid 6
• Allergic salute crease: Horizontal nasal crease from chronic rubbing 6
• Oropharynx: Cobblestoning of posterior pharynx, tonsillar hypertrophy 6

Respiratory:

• Auscultation: Wheezing, prolonged expiratory phase (asthma) 1
• Respiratory rate and effort: Increased work of breathing 1

Skin:

• Urticaria: Raised, erythematous, pruritic wheals 1
• Angioedema: Non-pitting swelling of deeper tissues (lips, tongue, face) 1
• Atopic dermatitis: Eczematous changes, lichenification 6
• Dermographism: Wheal formation with stroking (may cause false-positive skin tests) 7

Cardiovascular:

• Blood pressure: Hypotension in anaphylaxis 1
• Heart rate: Tachycardia or bradycardia (in severe anaphylaxis) 1
• Capillary refill: Delayed in shock 1

During Acute Reaction:

• Assess airway patency: Stridor, voice changes, inability to swallow 1
• Respiratory distress: Accessory muscle use, cyanosis 1
• Mental status: Confusion, loss of consciousness 1

Investigations

First-Line Testing:

Skin Prick Testing (SPT):

• Preferred initial test for inhalant and food allergies due to higher sensitivity than serum testing 5, 7
• Technique: Place allergen extract on skin, prick through epidermis 7
• Positive result: Wheal ≥3 mm larger than negative control at 15-20 minutes 1, 7
• Advantages: Rapid results, high sensitivity, cost-effective 5, 7
• Limitations: Affected by antihistamines (discontinue 3-7 days prior), dermographism, cannot use if severe eczema or recent anaphylaxis 7
• Interpretation: Positive test = sensitization only; must correlate with clinical history 1, 3

Serum Specific IgE Testing:

• Alternative when SPT contraindicated (severe eczema, dermographism, inability to stop antihistamines, recent anaphylaxis) 1, 5
• Advantages: Not affected by medications, no risk of systemic reaction, can be done with active skin disease 5
• Limitations: Lower sensitivity than SPT, more expensive, delayed results 5
• Interpretation: Detectable sIgE (≥0.35 kU/L) indicates sensitization, not necessarily clinical allergy 3
• Predictive values: Higher levels increase likelihood of clinical allergy, but thresholds vary by allergen and age 1

When to Perform Allergy Testing:

Indications: 1

• Inadequate response to empiric treatment
• Diagnosis uncertain based on history
• Need to identify specific causative allergen to target therapy (immunotherapy, specific avoidance)

Do NOT test: 1

• When diagnosis clear from history and empiric treatment effective
• Screening asymptomatic individuals (high false-positive rate)

Advanced/Specialized Testing:

Component-Resolved Diagnostics (CRD):

• Measures IgE to specific allergen proteins rather than whole allergen extracts 1
• Use: Refine diagnosis when standard testing equivocal, predict severity, assess cross-reactivity 1
• Example: Ara h 2 for peanut allergy (higher specificity for clinical allergy) 1
• Availability: Limited to specialized centers in many regions 1

Basophil Activation Test (BAT):

• Superior specificity and comparable sensitivity to sIgE and SPT 1
• Uses: Monitor resolution, assess immunotherapy response, potentially reduce need for oral food challenges 1
• Limitation: Not widely available, requires specialized laboratory 1

Oral Food Challenge (OFC):

• Gold standard for confirming food allergy diagnosis or resolution 1
• Indications: Discrepancy between history and testing, evaluating tolerance development, before liberalizing diet 1
• Settings: Low-risk challenges in outpatient clinic; high-risk in monitored setting with immediate access to epinephrine 1
• Risk stratification: sIgE >15 kU/L associated with moderate-severe reactions 1
• Contraindications: Recent anaphylaxis, uncontrolled asthma, acute illness 1

Testing NOT Recommended:

• Intradermal testing for food allergy (high false-positive rate, increased systemic reaction risk) 1
• Total serum IgE: Does not diagnose specific allergies 1
• Atopy patch testing: Not standardized, limited evidence 1
• Sinonasal imaging: Not routine for allergic rhinitis diagnosis 1
• Unvalidated tests: IgG testing, applied kinesiology, electrodermal testing, hair analysis, cytotoxic testing 3

Laboratory Findings During Acute Anaphylaxis:

Serum Tryptase:

• Timing: Obtain 30 minutes to 2 hours after symptom onset 1
• Interpretation: Elevated level supports anaphylaxis diagnosis, but normal level does not exclude it (poor sensitivity) 1
• Baseline: Consider baseline tryptase if elevated during reaction (to assess for mastocytosis) 1

Empiric Treatment

Acute Anaphylaxis Management:

Immediate:

• Epinephrine 0.01 mg/kg IM (max 0.5 mg adults, 0.3 mg children) into anterolateral thigh—FIRST-LINE therapy 1
• Repeat every 5-15 minutes as needed for persistent symptoms 1
• Position patient supine with legs elevated (or left lateral decubitus if vomiting/pregnant) 1
• Call emergency services immediately 1

Adjunctive (AFTER epinephrine):

• H1-antihistamine: Diphenhydramine 25-50 mg IV/IM/PO 1
• H2-antihistamine: Ranitidine 50 mg IV or famotidine 20 mg IV 1
• Corticosteroids: Methylprednisolone 1-2 mg/kg IV (may reduce biphasic reactions, though evidence limited) 1
• Bronchodilators: Albuterol for bronchospasm 1
• IV fluids: 1-2 L bolus for hypotension 1
• Oxygen: Maintain saturation >90% 1

Observation:

• Minimum 4-6 hours after symptom resolution (risk of biphasic reaction 1-20%) 1
• Longer observation if severe reaction, delayed epinephrine administration, history of biphasic reactions, or ongoing symptoms 1

Allergic Rhinitis:

First-Line:

• Intranasal corticosteroids: Most effective pharmacotherapy; use daily for best results 1, 5
• Oral antihistamines: Second-generation (cetirizine, loratadine, fexofenadine) preferred over first-generation 1
• Allergen avoidance: For identified clinically relevant allergens 1, 5

Second-Line:

• Intranasal antihistamines: Azelastine 1
• Leukotriene receptor antagonists: Montelukast 1

Refractory Cases:

• Allergen immunotherapy (subcutaneous or sublingual) for inadequate response to pharmacotherapy 1, 5
• Target only allergens correlating with clinical symptoms 5

Food Allergy:

Mainstay:

• Strict avoidance of confirmed food allergens 1
• Epinephrine auto-injector prescription for all with IgE-mediated food allergy (except possibly resolved allergy or very low-risk situations with shared decision-making) 1
• Emergency action plan: Written instructions for recognizing and treating reactions 1

Emerging:

• Oral immunotherapy: Under investigation; not standard of care 1
• Early introduction: Peanut and egg introduction at 4-6 months reduces allergy development 1

Drug Allergy:

Immediate:

• Discontinue suspected drug 1
• Treat reaction as per severity (antihistamines for mild, epinephrine for anaphylaxis) 1

Future Management:

• Avoid drug class if confirmed allergy 1
• Consider alternatives: Different drug class or desensitization if no alternatives 1
• Remove label if low-risk features present (see History section) 1

Indications to Refer to Allergist

Mandatory Referral:

• All patients after anaphylaxis: For education, epinephrine auto-injector training, identification of trigger, and long-term management plan 1
• Inadequate response to empiric treatment for allergic rhinitis after appropriate trial 1
• Uncertain diagnosis requiring specialized testing 1
• Need for allergen immunotherapy: Requires specialist administration and monitoring 1, 5

Consider Referral:

• Multiple food allergies: Complex dietary management 1
• Occupational allergies: Workplace modifications needed 1
• Severe or poorly controlled asthma with allergic triggers 1
• Need for oral food challenge: To confirm diagnosis or assess tolerance 1
• Drug allergy requiring desensitization: No alternative medications available 1
• Pediatric food allergy: Early intervention and monitoring for resolution 1

Critical Pitfalls

Diagnostic Errors:

• Equating positive test with clinical allergy: Up to 54% of general population has positive skin tests without symptoms; sensitization ≠ allergy 1, 3
• Testing without clinical correlation: Leads to unnecessary avoidance, anxiety, and cost 1, 3
• Over-reliance on self-reported allergy: Overestimates prevalence 4-fold (12% self-report vs. 3% confirmed) 1
• Using unvalidated tests: IgG testing, applied kinesiology, electrodermal testing have no evidence base and cause harm through misdiagnosis 3
• Failing to distinguish food allergy from intolerance: Different mechanisms and management 2
• Accepting allergy label without verification: >90% of penicillin allergy labels can be removed after proper assessment 1

Management Errors:

• Delaying epinephrine in anaphylaxis: Antihistamines and corticosteroids are NOT first-line; epinephrine is the only life-saving treatment 1
• Discharging too early: Minimum 4-6 hour observation required due to biphasic reaction risk 1
• Not prescribing epinephrine auto-injector: All patients with IgE-mediated food allergy or history of anaphylaxis require prescription and training 1
• Failing to provide emergency action plan: Written instructions critical for patient/caregiver recognition and treatment 1
• Not referring after anaphylaxis: Specialist evaluation mandatory for all anaphylaxis patients 1
• Unnecessary strict avoidance: Most patients are not "highly allergic"; consider individualized approach for low-dose tolerant patients with shared decision-making 4

Testing Pitfalls:

• Performing skin tests on antihistamines: False negatives; discontinue 3-7 days prior 7
• Intradermal testing for food allergy: High false-positive rate and systemic reaction risk 1
• Testing during acute reaction: Wait 4-6 weeks for IgE levels to stabilize 1
• Not obtaining baseline tryptase: If elevated during reaction, baseline needed to assess for mastocytosis 1
• Ordering imaging for allergic rhinitis: Not indicated as routine diagnostic test 1

Treatment Pitfalls:

• Using expired epinephrine: Check expiration dates regularly 1
• Wrong epinephrine route: Must be intramuscular (IM) into thigh, not subcutaneous or IV (unless by trained personnel in monitored setting) 1
• Relying on antihistamines alone for anaphylaxis: Delays definitive treatment and increases mortality 1
• Starting immunotherapy without proper evaluation: Must confirm clinically relevant allergens first 1, 5
• Implementing environmental controls without testing: Expensive and often ineffective if allergens not identified 1

Documentation Pitfalls:

• Incomplete allergy label information: Must document specific symptoms, timing, dose, route, treatment, and outcome 1
• Not updating allergy status: Remove labels when criteria for low/no risk met 1
• Failing to document subsequent tolerance: If allergen consumed without reaction, allergy label should be removed 1