# Jarisch–Herxheimer reaction
The **Jarisch–Herxheimer reaction** (JHR) is an acute, self-limited inflammatory reaction that begins within hours after the first dose of antibiotics against spirochetal infections, most commonly syphilis, and produces shaking chills, fever, headache, myalgia, and intensification of skin rashes, with symptoms resolving within about a day[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). It is a reaction to treatment, not an allergic reaction to the antibiotic[2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm).
| Key fact | Detail |
|---|---|
| Timing | Begins within a few hours (2–8 h) of the first antibiotic dose and usually resolves within 24 hours, even without intervention[3](https://www.sciencedirect.com/science/article/pii/S1477893913000513) |
| Typical symptoms | Shaking chills, rise in temperature, headache, myalgia, and intensification of skin rashes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) • [2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm) |
| Frequency in syphilis | 55% in seronegative primary syphilis, 95% in seropositive primary syphilis, and 95% in secondary syphilis[4](https://www.ncbi.nlm.nih.gov/books/NBK557820/) |
| Frequency in other infections | Lyme disease 7%–30% of treated patients; tick-borne relapsing fever 39%; louse-borne relapsing fever 37%–100% depending on the antibiotic[4](https://www.ncbi.nlm.nih.gov/books/NBK557820/) |
| Proposed mechanism | Inflammatory response to spirochetal lipoproteins and a nonendotoxin pyrogen, mediated by cytokines including TNF, IL-6, and IL-8[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) |
| Severity | Rarely fatal; no deaths in syphilis or Lyme disease were identified in a review of recent cases[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) |
| Management | Supportive care with antipyretics and fluids; antipyretics relieve symptoms but have not been proven to prevent the reaction[2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm) • [5](https://www.bashh.org/_userfiles/pages/files/syphilis_in_pregnancy_2024.pdf) |
## Clinical picture
Within 24 hours after antibiotic treatment of the spirochetal infections syphilis, [Lyme disease](https://www.edgepedia.org/lyme-disease), leptospirosis, and relapsing fever, patients experience shaking chills, a rise in temperature, and intensification of skin rashes, with symptoms resolving a few hours later[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). The CDC describes the reaction in syphilis as an acute febrile event frequently accompanied by headache, myalgia, and fever within the first 24 hours of any syphilis therapy[2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm).
Case reports show that the reaction can occasionally be more serious, including uterine contractions in pregnancy, worsening liver and renal function, acute respiratory distress syndrome, myocardial injury, hypotension, meningitis, alterations in consciousness, seizures, and strokes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). Rarely fatal, the reaction is nevertheless frightening to patients who have not been warned about it, and on rare occasions it is severe enough that patients stop treatment[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC10343119/).
## Which infections and drugs
Syphilis is the spirochetal infection most commonly associated with the JHR and was the first in which the reaction was documented; strong associations have also been established with Lyme disease, louse-borne relapsing fever, leptospirosis, and tick-borne relapsing fever[4](https://www.ncbi.nlm.nih.gov/books/NBK557820/). The reaction has also been reported in infections of bacterial, fungal, and protozoal origin beyond the spirochetes[4](https://www.ncbi.nlm.nih.gov/books/NBK557820/).
Penicillins, tetracyclines, and erythromycin are the antibiotics most frequently linked to the JHR, but newer agents including cephalosporins, meropenem, ciprofloxacin, levofloxacin, clarithromycin, and azithromycin have also been implicated[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) • [4](https://www.ncbi.nlm.nih.gov/books/NBK557820/). The reaction can even uncover a hidden diagnosis: a woman given penicillin for prophylaxis of *Streptococcus agalactiae* vaginal carriage developed chills and tachycardia and was found after delivery to have syphilis with congenital infection in her baby[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/).
Frequency varies with disease stage and species. In syphilis, occurrence is 55% in seronegative primary disease, 95% in seropositive primary disease, and 95% in secondary disease, presumably because bacterial loads are higher in early stages[2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm) • [4](https://www.ncbi.nlm.nih.gov/books/NBK557820/). In leptospirosis, a systematic review concluded the reaction appears less common and less severe than in other spirochetal diseases, though guidelines still call for systematic monitoring early after antibiotic administration[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC3608636/).
## Pathogenesis
The mechanism is not fully defined, and studies suggest with conflicting evidence that the reaction is caused by release of endotoxin-like material from the spirochete as well as cytokine elevation[8](https://pubmed.ncbi.nlm.nih.gov/15896248/). Clinical observations once suggested a role for endotoxin, but experimental studies showed that spirochetes do not have biologically active endotoxin as defined by the limulus test; the experimental evidence instead points to a nonendotoxin pyrogen and spirochetal lipoproteins[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). In *Treponema pallidum*, lipoproteins stimulate macrophages to produce tumor necrosis factor, and in *Borrelia burgdorferi* the outer surface protein A lipoprotein stimulates cells to produce transcription factors for cytokines[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/).
**Cytokine mediation.** In patients with relapsing fever, plasma concentrations of the pro-inflammatory cytokines TNF, IL-6, and IL-8 rise sharply at 2 to 4 hours after penicillin treatment, while patients are experiencing the reaction, and return toward baseline 12 hours after therapy[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). Antibodies against TNF administered before antibiotics prevented or attenuated the reaction and reduced IL-6 and IL-8 levels[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). The cytokine response to *Borrelia* spirochetes requires recognition by [Toll-like receptor](https://www.edgepedia.org/toll-like-receptor) 2 or TLR1/TLR2 heterodimers on phagocytes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/).
Several older explanations are probably wrong. Lyme disease spirochetes need 48 to 72 hours of antibiotic exposure before they die, ruling out a rapid lethal antibiotic effect, and intact spirochetes have been found in phagocytic vacuoles hours after treatment, which is incompatible with toxin release from destroyed organisms[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). Hypersensitivity is also unlikely based on leukocyte studies and skin injection experiments[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). The earliest event demonstrated to date, in relapsing fever, is the rapid uptake of antibiotic-altered spirochetes by blood polymorphonuclear leukocytes, which removes the organisms from the blood and likely provides an early inflammatory signal[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/).
## Prevention and management
The type of drug and the rate of spirochete clearance appear to have little effect on the incidence of the reaction, and many pretreatment options have been explored with limited efficacy, the exception being anti-tumor necrosis factor antibodies[8](https://pubmed.ncbi.nlm.nih.gov/15896248/). In routine care, antipyretics can be used to manage symptoms but have not been proven to prevent the reaction[2](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm). Supportive treatment with antipyretics and fluids is the general approach, and the reaction is generally self-limiting[5](https://www.bashh.org/_userfiles/pages/files/syphilis_in_pregnancy_2024.pdf).
Physicians are advised to anticipate the reaction when treating spirochetal diseases so they can provide monitoring of vital signs and fluids[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/). In relapsing fever, patients should be monitored closely during therapy, particularly during the first 4 hours after antibiotics are administered[9](https://doh.wa.gov/sites/default/files/2025-08/420-075-Guideline-RelapsingFever.pdf).
## Pregnancy
When syphilis therapy triggers the reaction in a woman in the later half of her pregnancy, premature labor or fetal distress can result, so she should be counseled to contact an obstetrician promptly upon experiencing fever, contractions, or reduced fetal movement.[10](https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm) [Stillbirth](https://www.edgepedia.org/stillbirth) is a rare complication of treatment, but concern for it should not delay necessary therapy[10](https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm). The reaction during pregnancy may also produce preterm contractions and fetal heart rate changes[11](https://www.acog.org/clinical-information/physician-faqs/syphilis-screening-in-pregnancy). No data support that corticosteroid treatment alters the risk of treatment-related complications during pregnancy[10](https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm).
## Diagnosis and differential
No specific tests diagnose the reaction, which is a transient clinical event; reported laboratory findings include polymorphonuclear leucocytosis, lymphopenia, and a raised erythrocyte sedimentation rate[3](https://www.sciencedirect.com/science/article/pii/S1477893913000513). Cytokine assays are not routinely performed and lack diagnostic specificity in patients with fever and active infection, and no universally accepted definition or standardized diagnostic criteria exist[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC12719974/).
The reaction is often mistaken for antibiotic allergy, particularly to penicillin; absence of generalized urticaria or wheals, eosinophilia, and specific antibodies to penicillin helps differentiate the two[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/) • [3](https://www.sciencedirect.com/science/article/pii/S1477893913000513). The differential diagnosis also includes progression of the underlying infection or sepsis, viral syndromes, and Hoigné syndrome, a pseudo-anaphylactic procaine reaction that follows intramuscular procaine penicillin injection and features acute delirium and perceptual disturbances resolving within about 30 minutes[3](https://www.sciencedirect.com/science/article/pii/S1477893913000513) • [4](https://ncbi.nlm.nih.gov/books/NBK557820/).
## History
Adolf Jarisch, an Austrian dermatologist, described in 1895 the worsening of syphilitic skin lesions after treatment with a mercurial compound, and Karl Herxheimer, a German dermatologist, independently reported a comparable phenomenon in the early 1900s[4](https://ncbi.nlm.nih.gov/books/NBK557820/). Herxheimer's 1902 description, with K. Krause, is regarded as groundbreaking, and the reaction had been described even earlier by Alfred Buchwald in 1886[13](https://www.altmeyers.org/en/dermatology/herxheimer-karl-127608) • [14](https://jnnp.bmj.com/content/jnnp/57/7/865.full.pdf). After penicillin became the drug of choice for syphilis in the 1940s, the reaction was recognized during the first 24 hours of treatment in primary and secondary disease and in general paresis[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/).
## References
1. [Butler T. The Jarisch–Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. Am J Trop Med Hyg.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5239707/)
2. [CDC. Syphilis – STI Treatment Guidelines.](https://www.cdc.gov/std/treatment-guidelines/syphilis.htm)
3. [Pound MW, May DB. Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions. J Clin Pharm Ther. 2005.](https://pubmed.ncbi.nlm.nih.gov/15896248/)
4. [Jarisch-Herxheimer Reaction. StatPearls, NCBI Bookshelf.](https://www.ncbi.nlm.nih.gov/books/NBK557820/)
5. [BASHH UK guidelines for the management of syphilis in pregnancy and children 2024.](https://www.bashh.org/_userfiles/pages/files/syphilis_in_pregnancy_2024.pdf)
6. [Jarisch‒Herxheimer reaction. Indian J Sex Transm Dis (PMC).](https://pmc.ncbi.nlm.nih.gov/articles/PMC10343119/)
7. [The Jarisch-Herxheimer Reaction in Leptospirosis: A Systematic Review. PLOS ONE (PMC).](https://pmc.ncbi.nlm.nih.gov/articles/PMC3608636/)
8. [The Jarisch–Herxheimer reaction: Revisited. Travel Med Infect Dis (ScienceDirect).](https://www.sciencedirect.com/science/article/pii/S1477893913000513)
9. [Relapsing Fever Reporting and Investigation Guideline, Washington State DOH.](https://doh.wa.gov/sites/default/files/2025-08/420-075-Guideline-RelapsingFever.pdf)
10. [CDC. Syphilis During Pregnancy – STI Treatment Guidelines.](https://www.cdc.gov/std/treatment-guidelines/syphilis-pregnancy.htm)
11. [ACOG. Syphilis Screening in Pregnancy.](https://www.acog.org/clinical-information/physician-faqs/syphilis-screening-in-pregnancy)
12. [Jarisch–Herxheimer reaction following doxycycline therapy in an adolescent with cat scratch disease (PMC).](https://pmc.ncbi.nlm.nih.gov/articles/PMC12719974/)
13. [Herxheimer, Karl. Altmeyers Encyclopedia – Dermatology.](https://www.altmeyers.org/en/dermatology/herxheimer-karl-127608)
14. [J Neurol Neurosurg Psychiatry (BMJ), 1996;57:865.](https://jnnp.bmj.com/content/jnnp/57/7/865.full.pdf)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Anti-infective drugs and resistance › Antibacterial drugs*
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