Diagnostic Strategies and Classification of Hypersensitivity Reactions
Objective
Apply standardized clinical criteria, biomarkers, and testing modalities to diagnose, grade, and risk‐stratify hypersensitivity reactions, guiding initial management and desensitization planning.
1. Clinical Criteria and Grading Systems
Rapid identification and severity grading of anaphylaxis and related reactions are critical to reduce morbidity and guide the appropriate level of care. Several standardized frameworks exist for diagnosis and classification.
A. NIAID/FAAN Diagnostic Framework
Anaphylaxis is highly likely if any one of the following three clinical scenarios occurs within minutes to hours after exposure to a potential allergen:
- Acute onset of an illness involving the skin, mucosal tissue, or both (e.g., generalized hives, itching or flushing, swollen lips-tongue-uvula) AND either respiratory compromise (e.g., dyspnea, wheeze, stridor) OR a significant drop in blood pressure.
- Two or more of the following that occur rapidly after exposure to a likely allergen: skin/mucosal involvement, respiratory compromise, persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting), or reduced blood pressure.
- Reduced blood pressure after exposure to a known allergen for that patient (systolic blood pressure <90 mm Hg or >30% decrease from baseline).
B. Severity Grading Scales
Once anaphylaxis is diagnosed, severity grading helps with triage and management. The Ring & Messmer and Brown’s scales are commonly used.
| System | Primary Purpose | Key Features & Grades |
|---|---|---|
| NIAID/FAAN | Diagnosis | Three distinct scenario-based criteria designed for high diagnostic sensitivity. |
| Ring & Messmer | Severity Grading | Grades I–IV based on the most severe organ system involved (I: Cutaneous, II: Mild systemic, III: Life-threatening, IV: Arrest). |
| Brown’s | Severity Grading | Grades I–III based on organ involvement (I: Skin only, II: Multi-system without compromise, III: Cardiovascular/respiratory compromise). |
Case Example: Applying the Frameworks
A 62-year-old woman receiving intravenous cefazolin for a skin infection develops generalized urticaria and audible wheezing within 5 minutes of the infusion starting. Her blood pressure is 85/50 mm Hg.
- NIAID/FAAN Diagnosis: Meets scenario 1 (skin involvement + respiratory compromise + hypotension).
- Ring & Messmer Grade: Grade III (life-threatening hypotension and bronchospasm).
- Brown’s Grade: Grade III (cardiovascular and respiratory compromise).
- Action: This is severe anaphylaxis. Immediately administer intramuscular epinephrine and admit to a high-acuity setting like an ICU.
Clinical Pearl: Diagnose, Grade, and Act
Do not delay epinephrine administration while waiting for laboratory confirmation. Use the NIAID/FAAN criteria to make a rapid clinical diagnosis. Concurrently, use the Ring & Messmer or Brown’s scales to grade severity, which helps triage the patient and determine the necessary level of monitoring (e.g., observation unit vs. ICU).
2. Biomarker Evaluation
Biomarkers are essential to confirm mast cell or basophil activation, helping to distinguish IgE-mediated anaphylaxis from other conditions that mimic its symptoms.
A. Serum Tryptase
Tryptase is a protease released from mast cell granules and is the primary biomarker for anaphylaxis.
- Kinetics: Levels begin to rise within 30 minutes of a reaction, peak at 1–2 hours, and typically return to baseline within 6–8 hours.
- Diagnostic Criteria: A clinically significant elevation is defined as an acute (peak) level that is greater than (1.2 × baseline level) + 2 ng/mL.
- Limitations: Tryptase may be normal in some cases, particularly in food-induced anaphylaxis or reactions not mediated by IgE. A normal level does not rule out anaphylaxis if clinical criteria are met.
B. Emerging and Ancillary Biomarkers
- Interleukin-6 (IL-6): Markedly elevated in cytokine release syndrome (CRS) but typically normal or only modestly elevated in anaphylaxis. Useful for differentiating reactions to T-cell engaging therapies.
- Histamine Metabolites: Urinary N-methylhistamine can confirm histamine release, but testing is not standardized or widely available for acute clinical decision-making.
Pitfall: Role of Eosinophil Count
The peripheral eosinophil count is not recommended for the acute diagnosis of immediate hypersensitivity reactions. While eosinophilia can be a feature of chronic allergic conditions or delayed T-cell mediated reactions (e.g., DRESS syndrome), its kinetics are too slow to be useful in the immediate evaluation of anaphylaxis.
Clinical Pearl: The Paired Tryptase Sample
Proper sample timing is critical for interpreting tryptase levels. To definitively confirm mast cell activation, always aim to collect paired samples: one “acute” sample drawn 1–2 hours after the reaction onset, and one “baseline” sample drawn at least 24 hours later or at a follow-up appointment. This allows for proper application of the diagnostic formula and rules out baseline mastocytosis.
3. Confirmatory Skin and In Vitro Testing
After a patient has been stabilized, confirmatory testing is performed to identify the specific causative agent. This is crucial for risk stratification and making decisions about future avoidance or desensitization.
A. Skin Testing
- Skin Prick Testing (SPT): A small drop of allergen extract is placed on the skin, which is then pricked. It is a highly specific screening test with low risk of inducing a systemic reaction. Sensitivity is moderate (~50%).
- Intradermal Testing (IDT): A small volume of diluted allergen is injected directly into the dermis. IDT is more sensitive (~80%) than SPT but carries a higher risk of causing a systemic reaction and must be performed by trained personnel in a monitored setting.
B. In Vitro Assays
- Specific IgE (sIgE) Assays: These blood tests detect circulating IgE antibodies against a specific drug or allergen (e.g., penicillin). Sensitivity is variable (50–80%), but specificity is high (~90%). Availability is limited for many chemotherapeutics and biologics.
- Basophil Activation Test (BAT): A functional flow cytometry assay that measures the upregulation of activation markers (e.g., CD63) on a patient’s basophils after being exposed to the suspect drug in vitro. It has high specificity and is particularly useful for predicting outcomes of desensitization to platinum-based chemotherapy agents. However, its use is limited by cost, availability, and turnaround time.
Clinical Pearl: When to Use the Basophil Activation Test (BAT)
The BAT is not a first-line test. Reserve its use for high-risk patients where skin testing is contraindicated (e.g., ongoing dermatographism), inconclusive, or when standardized skin test reagents are unavailable for the suspect drug. It is a powerful tool in specialized allergy centers for complex cases.
4. Differential Diagnosis of Acute Reactions
It is crucial to distinguish true hypersensitivity from other clinical syndromes that can present with similar signs, such as hypotension or rash, as the management differs significantly.
Key Distinguishing Features
- Anaphylaxis: Characterized by rapid onset after a trigger, prominent urticaria/angioedema, bronchospasm, and hypotension. It is typically responsive to epinephrine and associated with an elevated serum tryptase.
- Septic Shock: More insidious onset of hypotension, often with fever and a known or suspected source of infection. Key features include elevated lactate and procalcitonin, with a normal tryptase. Urticaria and acute bronchospasm are absent.
- Cytokine Release Syndrome (CRS): Occurs hours to days after administration of T-cell engaging therapies (e.g., CAR-T, BiTEs). Presents with high fever, capillary leak, and hypotension. The key differentiator is a markedly elevated IL-6 with a normal or only modestly elevated tryptase.
- Nonspecific Infusion Reactions: Often characterized by chills, rigors, fever, and myalgias. These symptoms typically resolve by slowing or temporarily stopping the infusion and administering antihistamines or antipyretics. True allergic signs like urticaria and bronchospasm are absent.
Clinical Pearl: Differentiating Reactions to Monoclonal Antibodies
When a patient develops an acute reaction to a monoclonal antibody or other biologic therapy, concurrently measure both serum tryptase and IL-6. A high tryptase points towards true IgE-mediated anaphylaxis, whereas a high IL-6 with normal tryptase is pathognomonic for CRS. This distinction is critical as CRS management involves IL-6 receptor blockade (tocilizumab), not just epinephrine.
5. Integrative Decision-Making and Risk Stratification
A systematic approach that combines clinical grading, biomarker results, and confirmatory testing is essential for streamlining patient care, from initial triage to long-term management planning.
Clinical Pearl: Embed Decision Support
Effective management can be enhanced by embedding decision support directly into the electronic medical record (EMR). For example, an infusion reaction order set can prompt clinicians to grade the reaction using standardized criteria. A Grade III reaction could automatically trigger a recommended order for intramuscular epinephrine and a stat allergy/immunology consultation, ensuring rapid and appropriate care.
References
- Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373–380.
- Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082–1124.
- Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol. 2004;114(2):371–376.
- Joint Council of Allergy, Asthma & Immunology. Drug allergy: A 2022 practice parameter update. Ann Allergy Asthma Immunol. 2023;273:e1.
- Isabwe GAC, Garcia-Neuer M, de las Vecillas Sánchez L, et al. The basophil activation test in the diagnosis of immediate drug hypersensitivity. J Allergy Clin Immunol. 2018;142(1):159–170.
- Giavina-Bianchi P, Galvão VR, Picard M, Caiado J, Castells MC. Tryptase in anaphylaxis: A clinical review. J Allergy Clin Immunol Pract. 2016;5(1):1–9.
- Jakubovic BD, Sanchez-Sanchez S, Hamadi S, Lynch D, Castells M. Basophil activation test for the diagnosis of platinum hypersensitivity in a large cohort of patients. Allergy. 2020;75(8):1943–1951.
- Picard M, Pur L, Caiado J, et al. Risk stratification and skin testing to guide management of hypersensitivity reactions to chemotherapy and monoclonal antibodies. J Allergy Clin Immunol. 2016;137(4):1154–1164.
- de las Vecillas Sánchez L, Alenazy LA, Garcia-Neuer M, Castells MC. Drug Hypersensitivity and Desensitizations: A Review of the Recent Literature. Int J Mol Sci. 2017;18(6):1316.
