Foundational Principles of Hypersensitivity Reactions and Desensitization

1. Epidemiology & Patient Populations

The true incidence of hypersensitivity reactions (HSRs) in the ICU is underappreciated due to overlapping clinical syndromes like sepsis. Antibiotics, chemotherapeutics, and contrast agents are the leading triggers. The risk is amplified by chronic diseases, immunosuppression, and social determinants of health.

1.1 Incidence in Critical Care Settings

• While the estimated lifetime HSR prevalence is 1.6–2%, the rate in the ICU is unclear due to significant underreporting and mimicry of other conditions.
• Leading triggers in hospitalized patients include β-lactam antibiotics, platinum-based chemotherapy, taxanes, and radiocontrast media.
• Unrecognized anaphylaxis in the ICU can lead to mortality rates exceeding 5% if not treated promptly.

1.2 Chronic Comorbidities: Asthma & Autoimmune Disorders

• Asthma: An independent risk factor for severe or biphasic anaphylaxis due to underlying airway hyperreactivity.
• Autoimmune Disease: Baseline immunosuppression can mask early signs of an HSR, while patients may experience paradoxical reactions to new immunomodulating agents.
• Polypharmacy: The use of multiple medications and individual pharmacogenomic factors (e.g., specific HLA alleles) can influence IgE cross-reactivity and overall risk.

1.3 Immunocompromised Hosts: Malignancy, Transplant, HIV/AIDS

• Malignancy: Monoclonal antibodies and taxanes can cause HSRs in up to 30% of patients with hematologic malignancies if premedication is not administered.
• Transplant: Immunosuppressants such as calcineurin inhibitors and anti-thymocyte globulin (ATG) are associated with Type II reactions and serum sickness–like reactions.
• HIV/AIDS: Pre-treatment screening for the HLA-B*5701 allele has dramatically reduced the incidence of abacavir hypersensitivity from approximately 8% to less than 1%.

1.4 Social Determinants: Access, Literacy & Disparities

• Limited access to specialty drugs and epinephrine auto-injectors can delay both prophylaxis and rescue treatment.
• Low health literacy may impair a patient’s ability to recognize early signs of a reaction and adhere to avoidance plans.
• Disparities between rural and urban settings highlight the need for solutions like telemedicine and community health worker support to improve outcomes.

2. Immunologic Mechanisms by Gell and Coombs Classification

The Gell and Coombs classification outlines four mechanistic categories that define the timing, mediators, and clinical examples of HSRs. Drug desensitization protocols are primarily applicable to IgE-mediated (Type I) reactions and select non-IgE reactions.

2.1 Type I: Rapid IgE-Mediated Reactions

These reactions are triggered by the crosslinking of drug-specific IgE antibodies on the FcεRI receptors of mast cells and basophils, leading to rapid degranulation and release of inflammatory mediators. Serum tryptase is a key biomarker, peaking 1–2 hours post-reaction and normalizing within 6 hours. Desensitization works by administering incremental doses of the drug in a controlled setting, which induces a state of transient mast cell unresponsiveness. This effect is antigen-specific and requires continuous exposure to be maintained.

2.2 Type II: Antibody-Dependent Cytotoxicity

In this type, a drug adsorbs to a cell surface, creating a neoantigen. IgG or IgM antibodies then bind to this complex, activating the complement cascade and leading to cell lysis. Clinical presentations include drug-induced immune thrombocytopenia (DITP) from agents like heparin or quinine, hemolytic anemia from penicillin, and agranulocytosis from clozapine. Management involves immediate drug cessation and supportive care, with IVIG or plasmapheresis considered in severe cases.

2.3 Type III: Immune Complex–Mediated Reactions

These reactions occur when antigen–antibody complexes form and deposit in small vessel walls or tissues, activating complement and recruiting neutrophils, which causes local inflammation and tissue damage. Classic features include fever, arthralgias, and an urticarial rash appearing approximately 1–3 weeks after drug exposure. Treatment consists of stopping the offending agent and using NSAIDs or corticosteroids for symptom relief.

2.4 Type IV: T-Cell–Mediated Delayed Reactions

These are delayed reactions mediated by T-cells. They are further divided into subtypes: IVa (macrophage-driven), IVb (eosinophilic, as in DRESS syndrome), IVc (cytotoxic T-cell driven, as in SJS/TEN), and IVd (neutrophilic). Manifestations range from simple maculopapular exanthems to severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Management requires immediate drug withdrawal and supportive care. Systemic steroids are used in DRESS, but desensitization is absolutely contraindicated in patients with a history of SCARs.

3. Clinical Presentations & Timing

The temporal pattern of a reaction is a crucial clue to its underlying mechanism and helps guide the diagnostic workup. While cutaneous signs are most common, the presence of systemic involvement dictates the urgency of management.

3.1 Immediate vs. Delayed Onset

• Immediate (≤1 hour after exposure): Strongly suggests a Type I (IgE-mediated) mechanism.
• Delayed (>1 hour to days/weeks): Points towards Type II, III, or IV mechanisms (non-IgE, T-cell, or immune complex).

3.2 Cutaneous Manifestations

• Urticaria: Pruritic, raised wheals with central pallor, characteristic of Type I reactions.
• Angioedema: Deeper dermal or mucosal swelling that can compromise the airway.
• Maculopapular Exanthem: A common T-cell mediated rash that can sometimes precede more severe reactions like SCARs.

3.3 Systemic Reactions

• Anaphylaxis: A life-threatening reaction involving respiratory distress, hypotension, and often gastrointestinal symptoms.
• Serum Sickness–Like Reaction: A systemic illness characterized by fever, arthralgias, and lymphadenopathy.
• SJS/TEN: A medical emergency involving widespread epidermal necrosis and severe mucosal involvement, requiring care in a specialized burn unit.

4. Key Clinical Pearls & Pitfalls

Mixed phenotypes and evolving mechanisms can challenge traditional classification systems. A standardized approach to severity grading and multidisciplinary input are crucial for optimizing patient outcomes.

• Mixed Phenotypes: It is common to see overlap, such as in DRESS (Type IVb), which has prominent systemic involvement, or in reactions to monoclonal antibodies, which can exhibit features of both cytokine-release syndrome and classic IgE-mediated anaphylaxis.
• Risk Stratification: Use validated severity grading criteria, such as the Ring & Messmer or NIAID/FAAN systems. Always integrate the patient’s comorbidities and the severity of their initial reaction into the risk assessment.
• Classification Gaps: The classic Gell and Coombs system does not fully account for emerging mechanisms, such as Type V (anti-receptor antibodies) or the cytokine-release syndromes associated with newer biologics like checkpoint inhibitors.

5. Emerging Evidence & Controversies

Advances in biomarkers, recognition of excipient allergens, pharmacogenomics, and personalized protocols promise to improve risk prediction, though many of these tools await full clinical validation.

5.1 Novel Biomarkers

• The basophil activation test (BAT) and analysis of serial tryptase kinetics are useful for the retrospective confirmation of IgE-mediated reactions.
• Elevated IL-6 levels can help distinguish cytokine-release reactions from classic IgE-mediated events, guiding appropriate management.

5.2 Excipients & Cross-Reactivity

• Excipients like polyethylene glycol (PEG) and polysorbate 80 are now recognized as hidden allergens in many biologics, vaccines, and even common medications like laxatives.
• A thorough review of all product components is essential when evaluating reactions, especially in patients reacting to multiple, structurally unrelated agents.

5.3 Personalized Risk Assessment

• HLA genotyping (e.g., for HLA-B*5701 before starting abacavir) is a proven strategy that can reduce HSR risk by over 90%.
• Research is ongoing into the role of polymorphisms in FcεRI and cytokine receptors in predisposing individuals to HSRs.
• Machine-learning models are in development to create individualized risk prediction tools for patients receiving high-risk medications.