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Jarisch Herxheimer Reaction

Herxheimer's Reaction

The Jarisch Herxheimer reaction describes flu-like symptoms and is classically associated with penicillin administered for the treatment of syphilis. It may also occur in other combinations of drugs and bacterial diseases.


Presentation

Patients present with symptoms 1 to 12 hours after antibiotic administration and the reaction lasts for a few hours and a day and is not seen on follow-up treatment. Prominent symptoms include fatigue, mild to moderate temperature elevation, flushing caused by vasodilation and an increased heart rate. Laboratory tests may show elevated white blood cell count. New skin lesions may appear in patients and existing lesions can worsen. There is an initial elevation of blood pressure in conjunction with tachycardia and hyperventilation but is usually followed by a drop in blood pressure due to decreased peripheral resistance and vasodilation.

Fever
  • In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations[ncbi.nlm.nih.gov]
  • JHR occurs after the administration of antibiotics in the presence of various infections including syphilis, Q fever, leptospirosis, Lyme disease, tick-borne relapsing fever.[symptoma.com]
Chills
  • The patient described feeling cold with worsening headache and chills approximately one hour after infusion of the first dose of penicillin. On examination, rigors, shallow inspirations, and chills were noted.[ncbi.nlm.nih.gov]
  • Manifestations include fever, chills, headache, myalgias, and exacerbation of cutaneous lesions.[medical-dictionary.thefreedictionary.com]
  • Peripheral vasoconstriction immediately preceded the chill phase and profound vasodilation accompanied the flush phase. 2.[clinsci.org]
Fatigue
  • Patients usually complain of fever, palpitations, flushing and fatigue. In some cases, skin lesions may worsen or new lesions may appear.[symptoma.com]
  • Too strong a reaction may also presuppose fatality through physical and/or emotional fatigue and depression.[mdjunction.com]
  • A primary care doctor had prescribed a couple of weeks of antibiotics for possible Lyme following a tick bite, bull’s-eye rash, pain and fatigue.[lifelovelyme.com]
  • Brain fog, mood & fatigue. Headache, pain, nsaids. Skin issues. Breathing & respiratory. Japanese detox foot pads. Herxheimer reaction probiotics The herxheimer reaction probiotics connection catches many people by surprise.[candidaspecialists.com]
  • In comparison, if a blood pressure medication causes fatigue, and the patient doesn’t even mention it, it is less likely to get reported.[earthmedresearch.org]
Rigor
  • Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P 0.006).[ncbi.nlm.nih.gov]
  • Jarisch-Herxheimer reaction Pathology Type Toxin Cause(s) Death of bacteria due to antibiotics Symptoms Fever, chills, rigor, low blood pressure, headache, tachycardia, hyperventilation, flushing, muscle pain, skin lesions, anxiety.[house.wikia.com]
Constitutional Symptom
  • JHR is common in the treatment of neurosyphilis, but usually produces only transient systemic constitutional symptoms. Neurologic deterioration is rare, but can be dramatic, as in our patient.[ncbi.nlm.nih.gov]
  • There were no fatalities, but constitutional symptoms were severe during J-HR.[jem.rupress.org]
Hypotension
  • Penicillin given on the first day and tetracycline on subsequent days to avoid severe Jarisch-Herxheimer reactions, has the disadvantage of a longer period of spirochetemia and hypotension as compared with tetracycline on the first day.[ncbi.nlm.nih.gov]
  • She became tachycardic and hypotensive after her first dose of antibiotic, and she developed disseminated intravascular coagulation. She was admitted to our hospital for presumed sepsis.[scholars.northwestern.edu]
Tachycardia
  • During pregnancy, it can cause signs and symptoms in both the mother and fetus, including fever, tachycardia, uterine contractions, and fetal heart rate pattern changes.[ncbi.nlm.nih.gov]
  • Jarisch-Herxheimer reaction Pathology Type Toxin Cause(s) Death of bacteria due to antibiotics Symptoms Fever, chills, rigor, low blood pressure, headache, tachycardia, hyperventilation, flushing, muscle pain, skin lesions, anxiety.[house.wikia.com]
  • There is an initial elevation of blood pressure in conjunction with tachycardia and hyperventilation but is usually followed by a drop in blood pressure due to decreased peripheral resistance and vasodilation.[symptoma.com]
Hypertension
  • She developed hypertension, fever, and rigors. Shortly afterward, she became hypotensive and required fluid resuscitation.[ncbi.nlm.nih.gov]
  • Some might also experience hyperventilation, hypertension and then a drop in blood pressure. A secondary rash might occur in those with early syphilis. It is vital to properly identify the reaction.[ic.steadyhealth.com]
  • Hyperventilation and tachycardia are accompanied by hypertension and then by a drop in blood pressure due to vasodilation and declining peripheral resistance.[patient.info]
Auditory Hallucination
  • High dose intravenous penicillin therapy was complicated by a severe Jarisch-Herxheimer reaction (JHR) characterised by fever, obtundation, fluctuating upper motor neuron signs and complex visual and auditory hallucinations.[ncbi.nlm.nih.gov]
Regular Uterine Contractions
  • CONCLUSION: The incidence of Jarisch-Herxheimer reaction in treated syphilitic pregnancies is about 40%; similar proportions of patients develop regular uterine contractions and recurrent variable decelerations.[ncbi.nlm.nih.gov]
  • Thirteen of 31 patients (41.9%) developed regular uterine contractions, median onset, 10 hours. All resolved within 24 hours of treatment. Patients with uterine contractions had a greater mean increase in temperature (1.15F versus 0.68F, P .008).[journals.lww.com]
  • uterine contractions and recurrent variable decelerations. [ 10 ] 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.[patient.info]
  • Incidence in pregnancy amounts to 40% and fetal monitoring is important because of a risk of regular uterine contractions.[symptoma.com]
Headache
  • The patient described feeling cold with worsening headache and chills approximately one hour after infusion of the first dose of penicillin. On examination, rigors, shallow inspirations, and chills were noted.[ncbi.nlm.nih.gov]
  • She presented with a 2 day history of fever, headache, general body malaise and vomiting. She was misdiagnosed as having severe malaria and was treated with quinine. The blood slide showed Borrelia duttoni.[research.vu.nl]
  • Manifestations include fever, chills, headache, myalgias, and exacerbation of cutaneous lesions.[medical-dictionary.thefreedictionary.com]
Confabulation
  • In early 2010, a psychologist noted anxiety and pressured speech but no dementia; however, 2 months later, he was hospitalized for delusions and confabulations.[dx.doi.org]
Babinski Sign
  • He was afebrile with dementia, equal reactive pupils, urinary incontinence, fluctuating mental status, hallucinations, dysequilibrium, hyperreflexia, and Babinski signs. Results from CSF tests were abnormal ( Table ).[dx.doi.org]
Hyperreflexia
  • He was afebrile with dementia, equal reactive pupils, urinary incontinence, fluctuating mental status, hallucinations, dysequilibrium, hyperreflexia, and Babinski signs. Results from CSF tests were abnormal ( Table ).[dx.doi.org]
Focal Seizure
  • The EEG features suggested a focal seizure onset, although the patient's MRI was normal. JHR is common in the treatment of neurosyphilis, but usually produces only transient systemic constitutional symptoms.[ncbi.nlm.nih.gov]

Workup

No specific diagnostic testing is necessary after the development of the reaction. It is critical, however, to properly identify what is happening and not ascribe the symptoms to antibiotic treatment, so as not to stop the dosage course. In some cases, patients may be diagnosed with another infection than syphilis, and the development of the reaction may prompt physicians to change their working diagnosis. This most commonly occurs when a treatment for gonorrhea is started. In this case, serological testing for syphilis is required with a subsequent adjustment in medication dosage. The development of JHR can also indicate that the treatment is properly working. The Jarisch Herxheimer reaction is not exclusive to syphilis and can occur with various infections including Lyme disease and relapsing fever.

Periodic Lateralized Epileptiform Discharges
Lymphocytic Infiltrate
  • Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate.[ncbi.nlm.nih.gov]

Treatment

The Jarisch Herxheimer reaction does not require any treatment as it is usually self-limiting and resolves on its own within a day. A severe reaction associated with leptospirosis may sometimes require intensive treatment in the form of corticosteroids, fluid injections, vasopressors and transient dialysis [13].

Prognosis

Prognosis is excellent and patients recover quickly without alteration of the treatment course.

Etiology

The disorder is caused by an excessive inflammatory reaction of the human body in response to the release of endotoxins by dead or injured bacteria. JHR occurs after the administration of antibiotics in the presence of various infections including syphilis, Q fever, leptospirosis, Lyme disease, tick-borne relapsing fever. Similar forms of the reaction have been reported in cat-scratch disease, trichinosis, cerebral trypanosomiasis and typhoid fever.

Epidemiology

The Jarisch Herxheimer reaction occurs as frequently in primary syphilis as it does in early secondary syphilis. Nonetheless, the incidence is reported to decrease with the duration of the illness and seronegativity. Studies indicate that 95% of seropositive patients develop an elevation of axillary fever up to 37.6-degree celsius but only 55% of seronegative patients do [4]. Additionally, fever occurs in only 32% of patients with late secondary syphilis and condylomata lata. The incidence of JHR in tertiary syphilis are imprecise, given the scarcity of the condition. However, it is almost certain that it occurs less frequently and less severely than in infectious primary syphilis. Some reports indicate that the reaction can occur in up to 34% of patients with neurosyphilis, including 74% in patients with general paralysis and 23% with tabes dorsalis. Incidence was also closely correlated with elevated cell count and protein concentration in the cerebral spinal fluid [5] [6]. JHR is very rare in the antibiotic treatment of other bacterial infections.

Sex distribution
Age distribution

Pathophysiology

There have been many proposed explanations for the JHR. Herxheimer initially postulated the treponemal products released after the administration of the drug directly target syphilitic tissue, leading to an exacerbation of the lesions. This theory, however, has been abandoned because it has been observed that the reaction is independent of the number of microorganisms at the time of the treatment [7]. Furthermore, the reaction can occur in late syphilis, a stage characterized by a low number of organisms [8]. Other scientists stated that bacterial endotoxins ultimately result in the release of inflammatory molecules and pyrogens [9].

When metal therapy was the treatment of choice, it was thought that JHR is caused by a direct toxic effect of the drug on blood vessels. This theory was later disproved when it was shown that the reaction also occurs with penicillin treatment but not for all diseases [7].

Histamine signaling has been also ruled out as a major cause because the reaction does not respond to antihistamine treatment. Furthermore, there is no concomitant release of kinins with the presence of large quantities of bacterial substances [10].

On the other hand, scientists have observed strong similarities between cell-mediated immune responses and the pathophysiological mechanisms involved in the JHR despite the divergent time courses [7]. It is also established that the cellular immune response plays an important role in the body's response to syphilis, although it is dependent on the stage of the disease. Production of macrophage inhibition factor (MIF) by lymphocytes results in inhibition of migration in the late active syphilis but not in primary syphilis. In contrast, a positive lymphocytic response to Reiter antigen is associated with an absence of MIF production in secondary syphilis [11] [12].

The response of JHR to corticosteroids administration may provide a useful opportunity to investigate the underlying pathophysiological mechanisms. Corticosteroids lead to a significant reduction in febrile reactions but they do not affect other forms of JHR in primary syphilis. In fact, there is evidence that the macular rash observed in JHR can worsen with steroid administration. Furthermore, steroids have no tangible effects on leukocyte patterns. This indicates that their effects in early syphilis are limited to fever reduction. Other evidence nonetheless suggests that steroids have much broader effects on the inflammatory response in late syphilis.

Prevention

The Jarisch Herxheimer reaction can be prevented or contained by following specific measures. An alternative selection of antibodies is recommended in clinical situations, for example, treatment of HIV-positive patients suffering from early syphilis with azithromycin.

The administration of corticosteroids has been also shown to decrease the severity and frequency of the reaction in late symptomatic syphilis. It is advisable to give 30 mg prednisone on the day of antibiotic administration, followed by tapering of the dose in the following day. Administration of TNF-alpha antibody after penicillin treatment can also reduce the incidence of the reaction from 90% to 50%, and result in decreased temperature elevation, cardiac rate, blood pressure and serum levels of interleukin 6 and 8.

Incidence in pregnancy amounts to 40% and fetal monitoring is important because of a risk of regular uterine contractions.

Summary

The Jarisch Herxheimer reaction (JHR) occurs after administration of antibiotics, frequently penicillin in the presence of a syphilis infection. It might also occur in the context of other diseases that are mostly caused by spirochetes such as Lyme disease, leptospirosis, and Q fever [1]. The underlying pathophysiological mechanisms have not been fully understood, but it is thought that injured or dead bacteria release substances that trigger an inflammatory reaction in the human body. It was hypothesized previously that it occurs due to an interaction between bacterial pathogens and syphilitic tissue but this theory has been disproved, as the reaction is independent of the number of organisms and can occur when the number of microorganisms is minimal. The cell-mediated immune response is considered now critical in the pathogenesis, despite the fact that JHR develops very rapidly. The Jarisch Herxheimer reaction is usually more severe in HIV patients and occurs in about 75% of cases of primary and secondary syphilis and is extremely rare in late syphilis [2] [3].

Patients usually present with fever, fatigue, tachycardia and flushing 1 to 12 hours after initiation of antibiotic treatment. An initial rise in blood pressure is followed by hypotension due to vasodilation. In some cases, there is a worsening of already present cutaneous lesions or the appearance of new ones. The reaction is self-limited, resolves in 24 hours and usually requires no intervention. It is not recommended to stop antibiotic treatment in case it occurs. No diagnostic laboratory tests are needed either and the diagnosis can be made clinically. It is important however not to ascribe the symptoms to an allergic reaction to medications so as not to stop the treatment. In selective cases, the development of the reaction to penicillin administration can be a clue to the diagnosis of syphilis and may prompt additional serological testing. Preventive measures that may ameliorate the reaction include corticosteroid treatment on the day of antibiotic administration followed by subsequent tapering. Administration of TNF-alpha antibodies has been also shown to significantly reduce incidence.

Patient Information

The Jarisch Herxheimer reaction describes a reaction of the human body to antibiotic treatment of certain bacterial infections, frequently penicillin treatment in the presence of a syphilis infection. This is a normal reaction and can indicate that the body is responding well to the treatment. JHR can be known by several names, including Herx reaction, Herxheimer effect, Herx or Herks. It is thought to be caused by the release of substances from dead and injured bacteria that subsequently trigger inflammatory reactions in the human body. The major issue associated with JHR is not the reaction itself but the fact that many patients stop taking the medication after they develop symptoms. This can lead to a worsening of the infection and a deterioration in their condition.

JHR usually develops very rapidly after intake of antibiotics, in around 1 to 12 hours. It is self-limiting and resolves by itself in less than a day. Patients usually complain of fever, palpitations, flushing and fatigue. In some cases, skin lesions may worsen or new lesions may appear. JHR requires no treatment and diagnosis is established by the physician clinically, with no need for any laboratory tests. Sometimes the presence of the reaction can tell the physician what the likely infection is and may prompt him or her to test for syphilis. However, it is very important not to confuse JHR with an allergic reaction to the medication. Otherwise, the treatment course may be stopped or dosage reduced, leading to an exacerbation of the infection.

JHR does not occur with the same frequency in all disease stages of syphilis. It is usually more common in the early phases and becomes very rare in the more developed stages. It can also be associated with diseases other than syphilis. These are usually caused by similar but not identical bacteria and include Q fever, leptospirosis, and Lyme disease.

Some medications can be useful to lessen the symptoms or reduce the incidence. For example, a course of prednisone at the day of antibiotic treatment can ameliorate many of the bothering symptoms. Novel medications such as antibodies to an inflammatory mediator called TNF-alpha can also reduce incidence.

Mild reaction with no significant discomfort may require only limited action described below and the treatment should be continued. If the reaction is very severe, reducing the dosage or stopping treatment for a day or two may be appropriate, but with the condition of later continuing the recommended dosage. Other steps that can help in the prevention or amelioration of the symptoms include a decrease in exercise level, drinking a lot of water, following a light diet that does not load the body with toxins and foreign chemicals and making sure to get adequate sunlight.

References

Article

  1. Loewen PS, Marra CA, Marra F. Systematic review of the treatment of early Lyme disease. Drugs. 1999 Feb;57(2):157-73.
  2. Tsai MS, Yang CJ, Lee NY, et al. Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy. J Int AIDS Soc. 2014 Aug 28;17:18993.
  3. Li J, Wang LN, Zheng HY. Jarisch-Herxheimer reaction among syphilis patients in China. J Eur Acad Dermatol Venereol. 2013 Oct;27(10):1304-7.
  4. Putkonen T, Salo OP, Mustakallio KK. Febrile Herxheimer reaction in different phases of primary and secondary syphilis. Br J Vener Dis. 1966 Sep;42(3):181-4.
  5. Hoekenga MT, Farmer TW. Jarisch-Herxheimer reaction in neurosyphilis treated with penicillin. Arch Intern Med 1948;82:61 1-22.
  6. Putkonen T, Rehtijarvi K. Febrile Herxheimer reaction in neurosyphilis. Acta Derm Venereol Suppl (Stockh). 1950 Sep 4-10;31(Suppl. 24):120-31.
  7. Sheldom WH, Heyman A. Morphologic changes in syphilitic lesions during the Jarisch-Herxheimer reaction. Am J Syph Gonorrhea Vener Dis. 1949 May;33(3):213-24.
  8. Skog E, Gudjónsson H. On the allergic origin of the Jarisch-Herxheimer reaction. Acta Derm Venereol. 1966;46(2):136-43.
  9. Schofield TP, Talbot JM, Bryceson AD, Parry EH. Leucopenia and fever in the "Jarisch-Herxheimer" reaction of louse-borne relapsing fever. Lancet. 1968 Jan 13;1(7533):58-62.
  10. Heyman A, Sheldon WH, Evans LD. Pathogenesis of the Jarisch-Herxheimer reaction; a review of clinical and experimental observations. Br J Vener Dis. 1952 Jun;28(2):50-60.
  11. Levene GM, Turk JL, Wright DJ, Grimble AG. Reduced lymphocyte transformation due to a plasma factor in patients with active syphilis. Lancet. 1969 Aug 2;2(7614):246-7.
  12. Smith EB, Bartruff JK, Blanchard V. Skin biopsy in cases of secondary syphilis. Br J Vener Dis. 1970 Oct;46(5):426.
  13. Guerrier G, D'Ortenzio E. The Jarisch-Herxheimer reaction in leptospirosis: a systematic review. PLoS One. 2013;8(3):e59266.

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Last updated: 2019-07-11 20:20