What Causes the Jarisch-Herxheimer Reaction
The Jarisch-Herxheimer reaction is caused by the rapid release of endotoxin-like materials (particularly lipoproteins) from dying spirochetes after antibiotic treatment, triggering an acute inflammatory cascade mediated by tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8). 1, 2
Pathophysiologic Mechanism
The reaction follows a specific sequence of events:
- Antibiotic-induced spirochete death releases bacterial components, particularly lipoproteins and other endotoxin-like pyrogens, into the bloodstream within hours of treatment initiation 3, 1
- Accelerated phagocytosis by polymorphonuclear leukocytes (PMNs) removes spirochetes from blood before cytokine elevation, suggesting PMNs provide the early inflammatory signal 1
- Cytokine surge follows, with plasma concentrations of TNF rising sevenfold, IL-6 sixfold, and IL-8 fourfold above baseline, peaking coincidentally with clinical symptoms 2
- This cytokine cascade directly mediates the constitutional symptoms (fever, chills, rigors), leukopenia, and hemodynamic changes characteristic of the reaction 2
Clinical Context and Timing
The reaction occurs exclusively in spirochetal infections:
- Most common in early syphilis, affecting approximately 24% of patients with primary or secondary disease 4
- Also documented in leptospirosis, Lyme disease (15% of early cases), and relapsing fever 5, 1
- Onset within 12 hours of antibiotic administration in most cases, with resolution within 24 hours 5, 4
- The reaction occurs only with the first dose and does not recur with subsequent antibiotic doses 5
Alternative Pathogenic Hypothesis
A competing theory proposes:
- Delayed-type hypersensitivity reaction may contribute, supported by histopathologic findings of lymphocytic spongiotic dermatitis with spirochetes present in areas of inflammation 3
- This mechanism may explain rare delayed-onset cases occurring up to 14 days after treatment initiation 3
Important Clinical Distinction
The reaction represents an immunologic response to microbial death products, not a drug allergy or treatment failure 5, 1. Symptoms lasting beyond 24 hours or recurring with later doses are not JHR and require alternative diagnosis 5.