Type 3 Hypersensitivity Reaction
Type 3 hypersensitivity is an immune complex-mediated reaction that occurs when antigen-antibody complexes deposit in tissues, triggering complement activation and inflammatory cell recruitment, leading to localized tissue damage.
Mechanism and Pathophysiology
Type 3 hypersensitivity reactions involve the formation of immune complexes (antigen bound to IgG or IgM antibodies) that deposit in blood vessel walls and tissues, activating the complement cascade and recruiting neutrophils that release inflammatory mediators causing tissue injury 1.
Clinical Presentation in Rabies Vaccination Context
In the specific context of rabies vaccination, Type 3 hypersensitivity manifests as a serum sickness-like illness occurring 6-14 days after booster doses of HDCV (human diploid cell vaccine). 2
Key Clinical Features:
- Generalized urticaria is the hallmark presentation, often accompanied by angioedema 2
- Arthralgias and arthritis develop in many affected patients 2
- Systemic symptoms including nausea, vomiting, fever, and malaise are common 2
- Delayed onset occurring 2-21 days after booster administration, with most cases appearing 6-14 days post-vaccination 2
- Leukocytoclastic vasculitis can be demonstrated on skin biopsy specimens 3
Epidemiology and Risk Factors
- Approximately 6% of persons receiving HDCV booster doses develop this Type 3 hypersensitivity reaction 2
- 93% of Type 3 reactions occur following booster vaccination rather than primary vaccination series 2
- The reaction occurs much less frequently among persons receiving primary vaccination 2
- Among all systemic allergic reactions to HDCV, 87 cases of presumed Type III hypersensitivity were reported (9 per 10,000 vaccinees) during CDC surveillance from 1980-1984 2
Underlying Immunologic Mechanism
The reaction is associated with betapropiolactone-altered human serum albumin present in HDCV and the development of IgE antibodies to this allergen. 2
- Patients develop IgE antibodies to vaccine components including fetal calf serum (a trace contaminant), mock vaccine lacking viral antigen, and beta-propiolactone-modified proteins 3
- Increased levels of IgG antibodies to fetal calf serum, mock vaccine, and beta-propiolactone-modified human serum albumin are also found 3
- These humoral responses to vaccine components other than rabies virus are responsible for the hypersensitivity reactions 3
Critical Clinical Management Principles
Rabies prophylaxis must never be interrupted or discontinued because of Type 3 hypersensitivity reactions, as no cases have been life-threatening and rabies is uniformly fatal once symptoms develop. 2
Management Algorithm:
- Continue the vaccination series without interruption regardless of the Type 3 reaction 2
- Manage symptoms with anti-inflammatory and antipyretic agents (such as aspirin, ibuprofen, or acetaminophen) 2
- Administer antihistamines for symptomatic relief of urticaria and pruritus 2
- Have epinephrine readily available and observe patients carefully immediately after subsequent vaccinations 2
- Seek consultation from state health department or CDC for assistance managing serious adverse reactions 2
Important Clinical Distinctions
Type 3 hypersensitivity must be distinguished from Type 1 immediate hypersensitivity (IgE-mediated anaphylaxis), which occurs within 4 hours of vaccination and is potentially life-threatening. 2, 4
- Type 1 reactions occurred in only 1 per 10,000 HDCV vaccinees and all nine cases occurred during primary vaccination 2
- Type 3 reactions have a delayed onset (6-14 days), are not immediately life-threatening, and predominantly occur after booster doses 2