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Jarisch-Herxheimer Reaction
Introduction
The Jarisch-Herxheimer reaction (JHR) was first described in the late 1800s by Austrian dermatologist Adolf Jarisch, who observed worsening of syphilitic skin lesions following treatment with a mercurial compound. In the early 1900s, German dermatologist Karl Herxheimer independently reported a comparable clinical phenomenon.
JHR is a transient inflammatory response occurring within 24 hours of initiating antibiotic therapy in patients with spirochetal infections, including syphilis, leptospirosis, Lyme disease, and relapsing fever. This reaction has also been observed in individuals receiving antibiotics for unrelated indications when an underlying spirochetal infection remains undiagnosed. Clinical features commonly include fever, chills, rigors, nausea, vomiting, headache, tachycardia, hypotension, hyperventilation, flushing, myalgia, and exacerbation of preexisting skin lesions.[1][2] JHR is an acute, self-limiting condition that typically resolves without the need for targeted treatment. Accurate recognition is essential to distinguish this condition from potentially life-threatening disorders that may present with overlapping symptoms, such as severe allergic reactions and sepsis.[3][4]
Etiology
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Etiology
Syphilis is the most common spirochetal infection associated with JHR and was the first infection in which the reaction was documented. JHR has also been reported in other infections of bacterial, fungal, and protozoal origin. Strong associations have been established with Lyme disease, louse-borne relapsing fever, leptospirosis, and tick-borne relapsing fever.[5][6] Penicillins, tetracyclines, and erythromycin are the antibiotics most frequently linked to JHR. However, newer antimicrobial agents, including cephalosporins, levofloxacin, ciprofloxacin, clarithromycin, meropenem, and azithromycin, have also been implicated.[7][8]
Epidemiology
Exact frequencies of JHR based on age, sex, and other demographic variables are insufficiently studied. However, disease frequency in the general population has been adequately discussed. Reported occurrences in association with syphilis are: 55% in seronegative primary syphilis, 95% in seropositive primary syphilis, and 95% in secondary syphilis.[9] JHR does not typically occur in latent syphilis and is rare in late syphilis, except among patients with general paresis of the insane (GPI), or paralytic dementia, where it has been documented in 75% of cases.[10] Rising syphilis prevalence in the U.S. and around the world suggests that JHR incidence may also increase.[11]
Incidence in nonsyphilitic infections tends to be lower. In Lyme disease, JHR has been reported in 7% to 30% of patients treated with antibiotics. In leptospirosis, the frequency reaches approximately 9%. Tick-borne relapsing fever is associated with a JHR incidence of 39%, while louse-borne relapsing fever shows a frequency ranging from 37% to 100%, depending on the antibiotic used.[12][13] Recent documentation has also identified JHR in cases of babesiosis.[14]
Pathophysiology
The precise mechanism underlying JHR is incompletely understood, though a multifactorial process is suspected. Spirochetal lysis following antibiotic exposure leads to the release of lipoproteins, endotoxin-like substances, and proinflammatory cytokines, triggering an acute systemic inflammatory response.[14] Cytokines such as interleukins 6 and 8 and tumor necrosis factor α (TNF-α) contribute to the development of symptoms, including fever, myalgia, flushing, rash, nausea, vomiting, and malaise. Onset typically occurs within 2 hours of antibiotic administration, and symptoms resolve within 24 hours.[15][16] Severity generally correlates with spirochete burden.
Histopathology
JHR is a transient clinical phenomenon and typically lacks distinctive histopathologic features. Skin lesion specimens may exhibit acute inflammatory changes, including dilation of small blood vessels and capillaries, dermal edema, perivascular and interstitial infiltration by polymorphonuclear and mononuclear cells, and leukocytic accumulation. These findings often coexist with underlying syphilitic pathology.[17]
History and Physical
JHR is frequently underrecognized and underreported. Fever, chills, myalgia, and rash often precede antibiotic treatment, leading to misattribution of symptom worsening to the underlying infection. Misdiagnosis as an antibiotic allergy is also common. Anticipation of JHR during the treatment of spirochetal infections is essential. Patients typically develop fever, rigors, and rash several hours after antibiotic initiation, with symptoms resolving within 24 hours.[18]
The initial presentation commonly includes fever and flu-like symptoms such as malaise, headache, chills, and pharyngeal discomfort. Exacerbation of preexisting skin lesions may occur. Clinical features may resemble viral illnesses or be mistaken for progression of the underlying infection.
Severe presentations of JHR may involve a systemic inflammatory response characterized by tachycardia, tachypnea, and hypotension, often mimicking sepsis or other forms of distributive shock. Additional manifestations may include myocardial dysfunction or failure, pulmonary edema, hepatic or renal impairment, meningitis, seizures, and cerebral edema.[19] Transient hypertension may occur early in the course due to inflammatory mediator release.
Symptoms of syphilis may intensify during JHR. In primary syphilis, perilesional edema and chancre ulceration may be observed. In secondary syphilis, rashes may become more pronounced. In late syphilis, exacerbation of organ-specific manifestations may occur. JHR may provoke worsening psychoses, seizures, or focal neurologic deficits among patients with GPI. Individuals with tabes dorsalis may report increased lightning pains, constipation, and urinary retention. Late-stage syphilitic involvement has been linked to potentially life-threatening JHR complications.
Evaluation
JHR is a transient, self-limiting condition that may be diagnosed clinically based on a thorough history and physical examination. Laboratory findings, when assessed, may include lymphopenia, polymorphonuclear leukocytosis, and elevated erythrocyte sedimentation rate. In most cases, additional investigations are unnecessary when clinical suspicion is strong. When JHR occurs in a patient with risk factors for syphilis, serologic testing should be pursued to confirm the diagnosis.
Treatment / Management
Mild JHR episodes are self-limiting and typically resolve within 24 hours without intervention. Symptom management should consist of supportive care and close observation. Patients without risk factors for severe disease, such as individuals who do not have advanced syphilis or are not pregnant, do not require hospital admission. In the absence of contraindications, mild symptoms may be treated with antipyretics such as acetaminophen or aspirin.
Severe presentations warrant continuous monitoring for abnormalities in vital signs and evidence of end-organ dysfunction. Hypotension should be addressed with intravenous crystalloid resuscitation and vasopressors if needed. Reports have documented cases of severe leptospirosis-related JHR requiring intravenous fluids, vasopressors, inotropic support, and temporary dialysis. The use of adjuvant corticosteroids in neurosyphilis has been mentioned in case reports and recommended in some national guidelines, although supporting evidence from controlled trials is lacking.[20][21][22](B3)
No consistently effective strategy has been established for preventing JHR, though empiric corticosteroid use has been proposed. The strongest evidence from randomized controlled trials supports the use of TNF-α antibodies. In a study, premedication with a TNF-α antibody significantly attenuated rises in temperature, blood pressure, and pulse rate, and lowered plasma concentrations of interleukins 6 and 8.[23] Antipyretics have not demonstrated efficacy in preventing the reaction. Clinicians should proactively counsel patients regarding the potential for JHR when initiating antibiotic therapy for spirochetal infections.
Pregnant women undergoing treatment for syphilis face up to a 40% risk of developing JHR. Continuous fetal monitoring is essential, as uterine contractions and recurrent variable decelerations may occur. When feasible, antibiotic selection should favor agents associated with a lower JHR incidence, such as azithromycin in patients with HIV and early syphilis.[24]
Differential Diagnosis
The differential diagnosis for JHR includes antibiotic hypersensitivity reactions, progression of the underlying infection or sepsis, and viral syndromes. A thorough history of prior drug reactions, particularly to penicillin, should be obtained. Patients with penicillin allergy may present with generalized urticaria, eosinophilia, or detectable anti-penicillin antibodies. Rash morphology should be carefully assessed to distinguish JHR from viral exanthems and other acute dermatologic conditions, such as erythema multiforme. In cases with systemic symptoms or hemodynamic instability, evaluation for bacteremia and sepsis is appropriate, especially if end-organ dysfunction is suspected.
Hoigné syndrome, also known as the procaine reaction, may be mistaken for JHR. This reaction presents immediately after intramuscular injection of procaine penicillin and is characterized by acute delirium, psychological shock, and perceptual disturbances. Symptoms typically resolve within 30 minutes of onset.[25] Unrecognized syphilis may be uncovered when a patient develops transient JHR symptoms after receiving antibiotics for an unrelated condition, such as gonorrhea.[26] Any unexpected JHR-like reaction should prompt evaluation for undiagnosed spirochetal infections, particularly syphilis.
Pertinent Studies and Ongoing Trials
A small study involving adults with active syphilis identified an association between elevated pretreatment levels of apolipoprotein C3 and the absence of JHR following benzathine penicillin administration. The said lipoprotein, known to activate monocytes and contribute to tissue damage, may play a modulatory role in the inflammatory response.[27] Larger, well-powered studies are needed to clarify and confirm this association.[28]
Prognosis
Most patients recover quickly with supportive care and expectant management. Mild cases do not require interruption of the antibiotic regimen. Severe JHR presentations may result in hypotension and subsequent end-organ injury or failure, posing life-threatening risks. Prognosis depends on the extent of organ involvement and the presence of underlying comorbidities. In syphilis, JHR has shown no significant correlation with treatment response.[29]
Complications
Most JHR occurrences are inconsequential, requiring only supportive care and close observation. However, severe cases may progress to hemodynamically significant hypotension accompanied by end-organ dysfunction or outright failure.
Advanced syphilis often presents with more serious complications. In neurosyphilis, JHR can trigger epilepsy or focal neurological deficits. Patients with GPI may experience transient psychosis. In cardiovascular syphilis, JHR can precipitate heart failure or cause rupture of an aortic aneurysm, potentially resulting in sudden death. Some reports also describe episodes of acute pulmonary hypertension. In cases involving laryngeal gumma, local edema may necessitate a tracheotomy.
Uterine irritability and contractions sometimes occur in pregnant women experiencing JHR.[30] During late pregnancy, empirical fetal monitoring is recommended for individuals undergoing antimicrobial treatment for syphilis and for any pregnant patient who develops JHR.[31][32][33]
Deterrence and Patient Education
Patients require appropriate education about JHR, particularly its typically transient and self-limited course. Affected individuals should be advised to seek prompt evaluation if signs of a severe reaction, such as high fever or worsening rash, develop, which may require intervention. This guidance is especially critical for high-risk individuals, including those who have syphilis or are pregnant. Clinicians should actively assess for drug allergies, risk factors for spirochetal infections, and any current symptoms suggestive of such infections.
Enhancing Healthcare Team Outcomes
JHR commonly occurs in patients with spirochete infections receiving antibiotic therapy. Clinicians should maintain a high index of suspicion and distinguish this condition from clinical entities with overlapping features, such as drug hypersensitivity, sepsis, and viral illness. All members of the interprofessional team must be trained to recognize and respond appropriately to JHR.
Awareness should extend beyond infectious disease and sexual health specialists, as patients may present in various settings, including primary care, urgent care, and emergency departments. In some cases, JHR may emerge after treatment for unrelated infections, revealing an unrecognized spirochetal illness. Managing serious cases requires clear communication and coordination across specialties. Although JHR is typically transient and self-limiting, each case warrants careful evaluation due to the risk of severe or life-threatening complications.
References
Aronson IK, Soltani K. The enigma of the pathogenesis of the Jarisch-Herxheimer reaction. The British journal of venereal diseases. 1976 Oct:52(5):313-5 [PubMed PMID: 791455]
Belum GR, Belum VR, Chaitanya Arudra SK, Reddy BS. The Jarisch-Herxheimer reaction: revisited. Travel medicine and infectious disease. 2013 Jul-Aug:11(4):231-7. doi: 10.1016/j.tmaid.2013.04.001. Epub 2013 Apr 28 [PubMed PMID: 23632012]
Pound MW, May DB. Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions. Journal of clinical pharmacy and therapeutics. 2005 Jun:30(3):291-5 [PubMed PMID: 15896248]
Miller WM, Gorini F, Botelho G, Moreira C, Barbosa AP, Pinto AR, Dias MF, Souza LM, Asensi MD, da Costa Nery JA. Jarisch-Herxheimer reaction among syphilis patients in Rio de Janeiro, Brazil. International journal of STD & AIDS. 2010 Dec:21(12):806-9. doi: 10.1258/ijsa.2010.010281. Epub [PubMed PMID: 21297087]
Maloy AL, Black RD, Segurola RJ Jr. Lyme disease complicated by the Jarisch-Herxheimer reaction. The Journal of emergency medicine. 1998 May-Jun:16(3):437-8 [PubMed PMID: 9610974]
Level 3 (low-level) evidenceWebster G, Schiffman JD, Dosanjh AS, Amieva MR, Gans HA, Sectish TC. Jarisch-Herxheimer reaction associated with ciprofloxacin administration for tick-borne relapsing fever. The Pediatric infectious disease journal. 2002 Jun:21(6):571-3 [PubMed PMID: 12182387]
Level 3 (low-level) evidenceNizič T, Velikanje E, Ružić-Sabljić E, Arnež M. Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin. Wiener klinische Wochenschrift. 2012 Jul:124(13-14):427-33 [PubMed PMID: 22760494]
Level 1 (high-level) evidenceTsai MS, Yang CJ, Lee NY, Hsieh SM, Lin YH, Sun HY, Sheng WH, Lee KY, Yang SP, Liu WC, Wu PY, Ko WC, Hung CC. Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy. Journal of the International AIDS Society. 2014:17(1):18993. doi: 10.7448/IAS.17.1.18993doi: 18993. Epub 2014 Aug 28 [PubMed PMID: 25174641]
Level 2 (mid-level) evidenceLi J, Wang LN, Zheng HY. Jarisch-Herxheimer reaction among syphilis patients in China. Journal of the European Academy of Dermatology and Venereology : JEADV. 2013 Oct:27(10):1304-7. doi: 10.1111/j.1468-3083.2012.04544.x. Epub 2012 May 21 [PubMed PMID: 22607395]
Level 2 (mid-level) evidenceBryceson AD. Clinical pathology of the Jarisch-Herxheimer reaction. The Journal of infectious diseases. 1976 Jun:133(6):696-704 [PubMed PMID: 932495]
Level 3 (low-level) evidenceKojima N, Klausner JD. An Update on the Global Epidemiology of Syphilis. Current epidemiology reports. 2018 Mar:5(1):24-38. doi: 10.1007/s40471-018-0138-z. Epub 2018 Feb 19 [PubMed PMID: 30116697]
Lopez JE, Krishnavahjala A, Garcia MN, Bermudez S. Tick-Borne Relapsing Fever Spirochetes in the Americas. Veterinary sciences. 2016:3(3):. pii: 16. doi: 10.3390/vetsci3030016. Epub 2016 Aug 15 [PubMed PMID: 28959690]
Guerrier G, D'Ortenzio E. The Jarisch-Herxheimer reaction in leptospirosis: a systematic review. PloS one. 2013:8(3):e59266. doi: 10.1371/journal.pone.0059266. Epub 2013 Mar 26 [PubMed PMID: 23555644]
Level 1 (high-level) evidenceKarim M, Sapadin AN. A case of Lyme disease complicated by the Jarisch-Herxheimer reaction and coinfection with Babesia. JAAD case reports. 2023 Feb:32():68-70. doi: 10.1016/j.jdcr.2022.11.023. Epub 2022 Dec 1 [PubMed PMID: 36654768]
Level 3 (low-level) evidenceVidal V, Scragg IG, Cutler SJ, Rockett KA, Fekade D, Warrell DA, Wright DJ, Kwiatkowski D. Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nature medicine. 1998 Dec:4(12):1416-20 [PubMed PMID: 9846580]
Level 3 (low-level) evidenceKaplanski G, Granel B, Vaz T, Durand JM. Jarisch-Herxheimer reaction complicating the treatment of chronic Q fever endocarditis: elevated TNFalpha and IL-6 serum levels. The Journal of infection. 1998 Jul:37(1):83-4 [PubMed PMID: 9733392]
Level 3 (low-level) evidenceSingh G, Jalpota YP. Jarisch-Herxheimer reaction in early syphilis. Indian journal of dermatology, venereology and leprology. 1995 Nov-Dec:61(6):386 [PubMed PMID: 20953041]
Level 3 (low-level) evidenceDionne JA, Zhu C, Mejia-Galvis J, Workowski K, Batteiger TA, Dombrowski JC, Mayer KH, McNeil CJ, Seña AC, Taylor S, Wiesenfeld HC, Hamill MM, Perlowski C, Hook EW 3rd. Jarisch-Herxheimer Reaction After Benzathine Penicillin G Treatment in Adults With Early Syphilis: Secondary Analysis of a Randomized Clinical Trial. JAMA network open. 2025 Feb 3:8(2):e2459490. doi: 10.1001/jamanetworkopen.2024.59490. Epub 2025 Feb 3 [PubMed PMID: 39946129]
Level 1 (high-level) evidenceButler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. The American journal of tropical medicine and hygiene. 2017 Jan 11:96(1):46-52. doi: 10.4269/ajtmh.16-0434. Epub 2016 Oct 24 [PubMed PMID: 28077740]
Level 3 (low-level) evidenceKomamura H, Nakamura T, Kobayashi J, Harada R, Endo K, Ogura M, Higuchi J. Early neurosyphilis presenting with multiple cranial nerve palsies: A case report of management by combined penicillin-corticosteroid treatment. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2019 May:25(5):362-364. doi: 10.1016/j.jiac.2018.11.007. Epub 2018 Dec 8 [PubMed PMID: 30538059]
Level 3 (low-level) evidenceZhang SQ, Wan B, Ma XL, Zheng HM. Worsened MRI findings during the early period of treatment with penicillin in a patient with general paresis. Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2008 Oct:18(4):360-3. doi: 10.1111/j.1552-6569.2007.00199.x. Epub 2008 Nov 6 [PubMed PMID: 18302644]
Kingston M, Apea V, Evans C, Fifer H, Foster K, Patrick P, Grant A, Manns V, Ramsden S, Sinka K, Sukthankar A, Sullivan A, Tyler S. BASHH UK guidelines for the management of syphilis 2024. International journal of STD & AIDS. 2024 Dec:35(14):1142-1160. doi: 10.1177/09564624241280406. Epub 2024 Sep 13 [PubMed PMID: 39270129]
Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, Warrell DA. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. The New England journal of medicine. 1996 Aug 1:335(5):311-5 [PubMed PMID: 8663853]
De Santis M, De Luca C, Mappa I, Spagnuolo T, Licameli A, Straface G, Scambia G. Syphilis Infection during pregnancy: fetal risks and clinical management. Infectious diseases in obstetrics and gynecology. 2012:2012():430585. doi: 10.1155/2012/430585. Epub 2012 Jul 4 [PubMed PMID: 22829747]
Ilechukwu ST. Acute psychotic reactions and stress response syndromes following intramuscular aqueous procaine penicillin. The British journal of psychiatry : the journal of mental science. 1990 Apr:156():554-9 [PubMed PMID: 2386866]
Chan DJ, Michelmore HM, Gold J. A diagnosis unmasked by an unusual reaction to ceftriaxone therapy for gonorrhoeal infection. The Medical journal of Australia. 2003 Apr 21:178(8):404-5 [PubMed PMID: 12697015]
Level 3 (low-level) evidenceWang M. ApoC3 fires up monocytes to promote tissue damage. Nature reviews. Nephrology. 2020 Mar:16(3):131. doi: 10.1038/s41581-019-0246-0. Epub [PubMed PMID: 31853009]
Tsai HC, Chou PY, Chang HM, Lee SS, Chen YS. Increased serum APOC3 in patients with syphilis can predict the absence of Jarisch-Herxheimer reaction after benzathine penicillin treatment. Journal of the Chinese Medical Association : JCMA. 2025 Jun 1:88(6):461-468. doi: 10.1097/JCMA.0000000000001238. Epub 2025 Apr 17 [PubMed PMID: 40241422]
Seña AC, Wolff M, Martin DH, Behets F, Van Damme K, Leone P, Langley C, McNeil L, Hook EW. Predictors of serological cure and Serofast State after treatment in HIV-negative persons with early syphilis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Dec:53(11):1092-9. doi: 10.1093/cid/cir671. Epub 2011 Oct 12 [PubMed PMID: 21998287]
Mori H, Shibata E, Kondo E, Sasaki N, Sawada Y, Yoshino K. The incidence of Jarisch-Herxheimer reactions and associated risk factors in pregnant women and nonpregnant women: A retrospective chart review at a university hospital in Japan. The journal of obstetrics and gynaecology research. 2023 May:49(5):1435-1442. doi: 10.1111/jog.15583. Epub 2023 Feb 28 [PubMed PMID: 36854284]
Level 2 (mid-level) evidenceHughes GR. Jarisch-Herxheimer reaction and syphilitic aortitis. British medical journal. 1968 Feb 10:1(5588):360 [PubMed PMID: 5638263]
Zifko U, Lindner K, Wimberger D, Volc B, Grisold W. Jarisch-Herxheimer reaction in a patient with neurosyphilis. Journal of neurology, neurosurgery, and psychiatry. 1994 Jul:57(7):865-7 [PubMed PMID: 8021683]
Level 3 (low-level) evidenceTunbridge AJ, Dockrell DH, Channer KS, McKendrick MW. A breathless triathlete. Lancet (London, England). 2002 Jan 12:359(9301):130 [PubMed PMID: 11809256]
Level 3 (low-level) evidence