Jarisch Herxheimer reaction (JHR) was first described in the literature by Adolf Jarisch (Austrian dermatologist) in the late 1800s when he noticed an exacerbation of skin lesions in a syphilis patient after starting treatment with a mercurial compound. In the early 1900s, a similar phenomenon was reported by Karl Herxheimer (German dermatologist).
JHR is a transient clinical phenomenon that occurs in patients infected by spirochetes who undergo antibiotic treatment. More specifically, the reaction occurs within 24 hours of antibiotic therapy for spirochetal infections, including syphilis, leptospirosis, Lyme disease, and relapsing fever. It usually manifests as fever, chills, rigors, nausea and vomiting, headache, tachycardia, hypotension, hyperventilation, flushing, myalgia, and exacerbation of skin lesions. JHR is an acute, self-limiting condition, which is important to identify in patients and to distinguish it from allergic reactions and sepsis.
Syphilis is the leading spirochetal infection associated with JHR. After first described in association with syphilis, the reaction has been noted in other infections of bacterial, fungal, and protozoal origin. Some of the other well-reported infections associated with JHR are Lyme disease, louse-borne relapsing fever, leptospirosis, and tick-borne relapsing fever. Antibiotics that have been most associated with the development of JHR are penicillins, tetracyclines, and erythromycin. Newer antimicrobial agents such as cephalosporins, levofloxacin, ciprofloxacin, clarithromycin, meropenem, and azithromycin can also cause JHR.
The exact frequencies of Jarisch Herxheimer reaction according to age, sex, and other variables are not well studied. However, the disease frequency in the general population as a whole is adequately discussed. The occurrence of JHR in syphilis is as follows: seronegative primary syphilis (55%), seropositive primary syphilis (95%), and secondary syphilis (95%). It is usually not seen in latent syphilis. It is also very rare in late syphilis, with the exception of patients suffering from general paresis of insane (GPI), also called paralytic dementia, where it can occur in 75% of patients. In Lyme disease, the range of JHR frequency is 7 to 30%, a much lower frequency than for syphilis. In leptospirosis patients treated with an antibiotic, the incidence of JHR is around 9%. In patients with tick-borne relapsing fever, the frequency of JHR occurrence is 39% compared to louse-borne relapsing fever in which the occurrence is in a range of 37 to 100% depending upon different antibiotics used.
Despite recent advances in the medical field, the exact mechanism of JHR is still unclear and thought to be multifactorial. The breakdown of the spirochete after the use of antibiotics causes the release of toxins and cytokines. JHR is thought to be caused by an acute inflammatory reaction when cytokines and lipoproteins enter the patient's bloodstream. JHR causes an increase in inflammatory cytokines during the period of exacerbation, including interleukin-6, interleukin-8, and tumor necrosis factor-alpha, which result in the development of body aches, fevers, rashes, nausea and vomiting, and flushing, along with other symptoms. The symptoms usually begin 2 hours from the administration of the antibiotic and resolve within 24 hours.
JHR is a transient clinical reaction and therefore, doesn't have many specific histopathologic findings. Histopathologic findings in skin lesions during JHR show acute inflammatory changes (dilatation of small blood vessels and capillaries, dermal edema, perivascular and interstitial polymorphonuclear round cell and leucocytic infiltration) along with the existing syphilitic pathology.
The Jarisch Herxheimer Reaction is often unrecognized and is underreported. The symptoms of fever, chills, body ache, and skin rash are often present before treatment with an antibiotic, so worsening symptoms after treatment can be overlooked simply as signs of the underlying infection. Another common reason for underdiagnosis is confusing JHR with an allergy to antibiotics. Providers should anticipate JHR while treating spirochetes and be prepared with proper monitoring of vital signs and supportive care. Usually, the clinical scenario is of a patient who presents with fevers, worsening rigors, and rash several hours after starting antibiotics for a spirochetal disease.
JHR is characterized by a triad of transient events:
Fluctuation in body temperature is usually evidenced by cycles of fever (38-41 degrees Celcius), accompanied by flu-like symptoms including malaise, headache and chills, and pharyngitis, followed by sweating and resolution of fever.
In the flare stage, there is an aggravation of symptoms. This can vary in different stages of syphilis. There may be edema and ulcerations around the chancre in primary syphilis. In secondary syphilis, there is prominence in the appearance of the rash. In late syphilis, exacerbation of features related to the different affected organ systems might occur. The JHR in patients with general paresis of insane (GPI) may manifest differently. There can be an aggravation of existing psychoses, convulsions, or focal neurological deficits. Those with tabes dorsalis may complain of intensification of their symptoms, including lightning pains, constipation, and urinary retention. Late syphilitic lesions and organ involvement have been associated with potentially lethal complications during JHR.
Physiological changes in JHR include vasoconstriction, a rise in blood pressure, and hyperventilation, which occur in the early phase of the reaction. Later, there is hypotension due to vasodilatation and decreased peripheral resistance.
JHR occurs within a few hours of the administration of the first dose of antibiotics and usually resolves within 24 hours without any intervention. The severity of JHR depends upon the organism load in the body. The definition of JHR could be broadened from fever, chills, and intensification of skin rash to include pulmonary failure, meningitis, renal and liver dysfunction, cardiac injury, premature uterine contractions in pregnant women, and worsening cerebral function in some cases.
JHR is a transient and reversible condition that can be clinically diagnosed with proper history and physical examination. However, there are reports of lymphopenia, polymorphonuclear leucocytosis, and raised ESR on laboratory analysis. Usually, no investigation is mandated but if an unexpected reaction to an antibiotic occurs in a patient with risk factors, then a serological test for syphilis is required.
Mild reactions are self-limiting and often resolve spontaneously within 24 hours. The patient should be treated for symptoms and kept under observation. To date, the best evidence from available randomized and controlled trials in the prevention of the JHR has been in support of TNF-alpha antibodies and, in some cases, steroids as well. In one of the studies, there was a significantly lower rise in temperature, blood pressure, and pulse rate when premedicated with TNF-alpha antibody. Additionally, plasma concentrations of interleukin-6 and 8 were significantly decreased. While other premedications such as acetaminophen may mitigate the symptoms or duration of the JHR, the reaction itself is not prevented. The clinician should forewarn the patient about the possibility of a reaction.
Patients must be closely monitored for abnormalities in vital signs, which may indicate intravenous fluids and other support. Treatment of severe leptospirosis-related JHR with crystalloid infusion, corticosteroids, vasopressors, inotropic support, and transient dialysis has been reported.
In pregnant women treated for syphilis, the reaction incidence nears 40%. Fetal monitoring is imperative in these patients as recurrent variable decelerations are often seen. There are, however, various considerations to reduce the risk of reaction and improve outcomes in a patient, such as antibiotic selection (e.g., using azithromycin as a treatment in HIV patients with early syphilis).
When a patient with a history of spirochetal infection and recent antibiotic use presents with fever and rash, nausea/vomiting, chills, headache, tachycardia, and often hypotension, antibiotic allergic reaction, worsening infection/sepsis, and viral syndrome should be considered as important differentials because of similar presentations. Prior drug reaction, especially to penicillin, should be carefully assessed. With penicillin allergy, there are generalized urticaria/wheals and eosinophilia, or there are specific antibodies to penicillin in the serum of patients. Occasionally, underlying syphilis can be discovered when the patient develops transient JHR symptomatology while being treated with antibiotics for another infection such as gonorrhea.
Usually, there is swift recovery and the treatment course can be reinstated. In some instances, Jarisch Herxheimer reaction can be life-threatening if there is a significant drop in blood pressure resulting in acute end-organ injury and failure.
In early syphilis, the reaction is only a minor burden. In late syphilis, it can be more serious requiring hospital-based supportive care. In neurosyphilis, it may lead to the development of epilepsy or a focal neurological deficit. In general paresis of the insane, it can result in temporary psychosis. In cardiovascular syphilis, precipitation of heart failure and rupture of an aortic aneurysm can lead to sudden death. There have been reports of acute pulmonary hypertension following JHR. In laryngeal gumma, local edema may warrant tracheotomy. In the late stages of pregnancy, fetal monitoring is advised.
Patients should receive appropriate education about JHR, including its transient and benign nature in most instances. However, the patient should be properly instructed to seek evaluation as soon as features of JHR such as fever and rash flares are seen, in case emergent measures, including fluid and inotropic support are needed. There should be proper discussions with the patient about any known drug allergies. High-risk patients, such as those suffering from neurosyphilis and pregnant females, should be advised to obtain treatment in an inpatient setting for timely management of potential adverse outcomes.
JHR is a common occurrence among the subgroup of patients undergoing antibiotic treatment for spirochetal infections. The clinician should maintain a high index of suspicion of JHR and effectively differentiate all other similar conditions such as drug allergy, sepsis, and viral infections. All members of the interprofessional team should be aware and trained appropriately to recognize the symptoms of JHR and react accordingly. The management of serious patients mandates proper communication and coordination among multiple specialties. While JHR is usually transient, benign, and self-limiting, every case must be addressed cautiously as there is the potential for severe and even fatal complications.
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