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This systemic reaction, also known as the Herxheimer's reaction, was classically described in the treatment of syphilis. It is believed to be caused by the release of endotoxin-like substances when large numbers of Treponema pallidum are killed by antibiotics. It has been documented in tick-borne diseases like Lyme disease and relapsing fever where the infecting organism is also a spirochete. One study suggested that it was more common in Lyme disease patients treated with cefuroxime. The mechanism may not be straightforward as it is not a feature of neonatal syphilis or non-venereal syphilis in childhood. The reaction can be expected in 50% of primary syphilis, 90% of secondary syphilis, and in 25% of early latent infection, but is very rare in late syphilis. It has been suggested that it is more severe in patients with HIV.
- The reaction starts between 1 and 12 hours after the first injection of antibiotics and lasts for a few hours or up to a day.
- It is not seen with subsequent treatment.
- There is malaise, slight-to-moderate pyrexia, a flush due to vasodilation, tachycardia, and leukocytosis.
- Any existing skin lesions become more prominent.
- Hyperventilation and tachycardia are accompanied by hypertension, and then by a drop in blood pressure due to vasodilation and declining peripheral resistance.
- In some patients with early syphilis, a secondary rash may become visible which was absent before treatment.
- Usually, the reaction resolves over a period of 6 to 12 hours.
It is important to recognise the reaction for what it is and not to ascribe it to a sensitivity to the antibiotic. Rarely, syphilis may be suspected by the appearance of the febrile reaction of the Jarisch-Herxheimer, perhaps with a fleeting rash, when treating another infection such as gonorrhoea. It is important to recognise this and to make the diagnosis and give an adequate course for syphilis.
Usually no investigation is required but if an unexpected reaction to antibiotic treatment occurs, then serological tests for syphilis are required.
Although traditionally associated with syphilis, the reaction is well documented with Lyme Disease and relapsing fever.
For many years there has been a suggestion that mycoplasma may be involved in the aetiology of rheumatoid arthritis and other autoimmune diseases including sarcoidosis. Hence, it may be possible to treat the infection to treat the disease. Minocycline would seem to be the drug of choice and there are reports of it producing improvement but only after a Jarisch-Herxheimer reaction. If this is shown to be the case, it could have massive implications for the management of such diseases.
It is customary to give corticosteroids in late symptomatic syphilis, starting a day before the first penicillin injection and tailing it off the day after the first injection. A dose of around 30 mg prednisolone is typical. This does not prevent the Jarisch-Herxheimer reaction but is said to ameliorate it. The analogous reactions in relapsing fever have been modified by meptazinol or pretreatment with infusions of polyclonal anti-TNF alpha Fab with concomitant reduction in the plasma concentration of interleukin 6 and 8.
In pregnancy, the incidence of the reaction when treating syphilis, is about 40%. Fetal monitoring should be performed as similar proportions of patients develop regular uterine contractions and recurrent variable decelerations.
A review of the literature found conflicting evidence that the reaction is caused by release of endotoxin-like material from the spirochete as well as cytokine elevation in the body. The type of drug and the rate of clearance of the spirochetes have little effect on the incidence of the reaction. Many pretreatment options have been explored with limited efficacy with the exception of anti-tumour necrosis factor antibodies.
In early syphilis the reaction is only a minor nuisance. In late syphilis it can on very rare occasions be more serious. Thus, in neurosyphilis it may lead to epilepsy or a rapid, irreversible progression, and in general paresis it can cause exacerbation amounting to temporary psychosis. Sudden death has been reported in cardiovascular syphilis. In laryngeal gumma, local oedema may necessitate tracheotomy. In the later stages of pregnancy fetal monitoring is advised.
Recovery is usually swift and the course of treatment is completed.
Adolf Jarisch was an Austrian dermatologist who was born in 1850 and died in 1902. Jarisch published his description of the Jarisch-Herxheimer reaction in 1895, seven years before Herxheimer published his own description. As this was many years before the discovery of penicillin, the original description related to the treatment with mercury.
Karl Herxheimer was a German dermatologist who was born in 1861 and died in 1944. Herxheimer published his description of the Jarisch-Herxheimer reaction in 1902. He had already resigned his positions because of his age when the Nazis took power in 1933 but, despite being Jewish, he stubbornly refused to leave his native country. He was imprisoned in the autumn of 1941 and on August 27 1942, aged 81, he died in a concentration camp.
Further reading & references
- Loewen PS, Marra CA, Marra F; Systematic review of the treatment of early Lyme disease.; Drugs. 1999 Feb;57(2):157-73.
- van Voorst Vader PC; Syphilis management and treatment. Dermatol Clin. 1998 Oct;16(4):699-711, xi.
- Marshall TG, Marshall FE; Sarcoidosis succumbs to antibiotics--implications for autoimmune disease.; Autoimmun Rev. 2004 Jun;3(4):295-300.
- Marshall TG, Marshall FE; Antibiotics in Sarcoidosis - Reflections on the First Year; Journal of Independent Medical Research 2003;1(3):2
- Fekade D, Knox K, Hussein K, et al; Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha.; N Engl J Med. 1996 Aug 1;335(5):311-5.
- Myles TD, Elam G, Park-Hwang E, et al; The Jarisch-Herxheimer reaction and fetal monitoring changes in pregnant women treated for syphilis. Obstet Gynecol. 1998 Nov;92(5):859-64.
- Pound MW, May DB; Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions.; J Clin Pharm Ther. 2005 Jun;30(3):291-5.
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Dr Richard Draper
Dr Gurvinder Rull