What is the Jarisch-Herxheimer reaction

1. Definition

• Jarisch-Herxheimer reaction (JHR) → acute, transient inflammatory reaction within 24 h of starting antibiotics for a spirochaetal infection
• Self-limiting → resolves in 12–24 h, often without targeted treatment
• Diagnosis → clinical
• Named after Adolf Jarisch (Austrian dermatologist, late 1800s) and Karl Herxheimer (German dermatologist, early 1900s)
• First seen as worsening of syphilitic skin lesions after mercury treatment

2. Why it is asked in the viva

• Classic oral exam question → "a patient becomes febrile and hypotensive a few hours after the first dose of penicillin"
• Examiner wants the differential diagnosis of sepsis and septic shock
• Second differential → antibiotic allergy (anaphylaxis)
• Reason → severe JHR looks like sepsis or distributive shock, but needs no change of antibiotics
• Model answer:
  1. Name it → Jarisch-Herxheimer reaction
  2. Link it → spirochaetal infection, first antibiotic dose
  3. Time it → onset within hours, gone in 24 h
  4. Separate it → from sepsis and from drug allergy
  5. Manage it → supportive care, continue antibiotics

3. Aetiology

Infections

• Syphilis → most common, and the first in which JHR was described
• Lyme disease
• Leptospirosis
• Relapsing fever → louse-borne and tick-borne
• Also reported → other bacterial, fungal and protozoal infections; babesiosis

Antibiotics

• Most often → penicillins, tetracyclines, erythromycin
• Also → cephalosporins, ciprofloxacin, levofloxacin, clarithromycin, azithromycin, meropenem
• Can follow antibiotics given for another infection (e.g. gonorrhoea) when a spirochaetal infection is undiagnosed

4. Incidence

Syphilis

• Seronegative primary → 55%
• Seropositive primary → 95%
• Secondary → 95%
• Latent → does not occur
• Late → rare, except general paresis of the insane (GPI) → 75%
• Pregnancy → up to 40%

Other spirochaetes

• Lyme disease → 7–30%
• Leptospirosis → about 9%
• Tick-borne relapsing fever → 39%
• Louse-borne relapsing fever → 37–100%, depends on the antibiotic

5. Pathophysiology

1. Antibiotic kills spirochaetes rapidly
2. Lysis releases lipoproteins and endotoxin-like substances
3. Cytokine release → interleukin 6 (IL-6), interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-α)
4. Acute systemic inflammatory response → fever, myalgia, flushing, rash, nausea
5. Onset → within 2 h of the antibiotic
6. Severity → proportional to the spirochaete load

6. Clinical picture

Symptoms

• Fever, chills, rigors
• Headache, malaise, myalgia, weakness
• Nausea, vomiting
• Sore throat → early picture may look viral

Signs

• Tachycardia, hyperventilation, flushing
• Hypotension
• Transient early hypertension
• Worsening of existing skin lesions

Severe form (sepsis mimic)

• Systemic inflammatory response → tachycardia, tachypnoea, hypotension
• Picture of sepsis or distributive shock
• Organ dysfunction → myocardial failure, pulmonary oedema, liver or kidney impairment
• Neurological → meningitis, seizures, cerebral oedema

By stage of syphilis

• Primary → oedema around the chancre, chancre ulceration
• Secondary → more marked rash
• GPI → worse psychosis, seizures, focal deficits
• Tabes dorsalis → more lightning pains, constipation, urinary retention

7. Diagnosis

• Clinical → timing after the first antibiotic dose plus a known or suspected spirochaetal infection

Laboratory

• Lymphopenia
• Polymorphonuclear leucocytosis
• Raised erythrocyte sedimentation rate (ESR)
• Syphilis serology → if risk factors and no known diagnosis
• Unexpected JHR-like reaction after antibiotics → search for a spirochaetal infection, especially syphilis

8. Differential diagnosis

A. Sepsis and septic shock

• Main differential, and the reason JHR is examined
• Both → fever, rigors, tachycardia, tachypnoea, hypotension, organ dysfunction
• Points towards JHR:
  • Starts within hours of the first antibiotic dose
  • Known or suspected spirochaetal infection
  • Settles by itself within 12–24 h
• Points towards sepsis:
  • Worsening despite treatment
  • Persisting or progressing end-organ dysfunction
• Unstable patient or organ dysfunction → assess for bacteraemia and sepsis; never assume JHR

B. Antibiotic hypersensitivity

• Common misdiagnosis → patient wrongly labelled penicillin allergic
• Allergy → generalised urticaria, eosinophilia, anti-penicillin antibodies
• Check the drug history

C. Hoigné syndrome

• Reaction to intramuscular procaine penicillin
• Immediately after injection → acute delirium, fear, perceptual disturbance
• Resolves within 30 min

D. Others

• Progression of the underlying infection
• Viral syndrome
• Viral exanthem, erythema multiforme → rash

9. Treatment

Mild

• Supportive care and observation
• Antipyretics → paracetamol or aspirin
• Continue the antibiotic → mild JHR is not a reason to stop
• Admission → only if risk factors: advanced syphilis, pregnancy

Severe

• Continuous monitoring of observations and end-organ function
• Hypotension → intravenous crystalloids, vasopressors if needed
• Severe leptospirosis → inotropes and temporary dialysis in case reports
• Corticosteroids → adjuvant in neurosyphilis; case reports only, no trial evidence

Prevention

• No reliably effective method
• Anti-TNF-α antibodies before treatment → reduced fever, pulse and blood pressure rise in a randomised trial
• Antipyretics → do not prevent it
• Warn the patient before treating a spirochaetal infection

Pregnancy

• Continuous foetal monitoring → contractions, variable decelerations
• Prefer agents with lower JHR risk where possible

10. Complications

• Most cases → no lasting harm
• Severe → hypotension with end-organ dysfunction or failure
• Neurosyphilis → seizures, focal deficits; transient psychosis in GPI
• Cardiovascular syphilis → heart failure, aortic aneurysm rupture, acute pulmonary hypertension
• Laryngeal gumma → oedema, may need tracheotomy
• Pregnancy → uterine irritability, preterm contractions

11. Prognosis

• Excellent in most → recovery in 12–24 h with supportive care
• Severe cases → depends on organ involvement and comorbidities
• JHR in syphilis → does not predict the response to treatment

Source

• Wood JM, Sbar E. Jarisch-Herxheimer Reaction. [Updated 2025 Jul 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-
• Read the full article → NCBI Bookshelf, NBK557820