Jarisch-Herxheimer reaction

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Yvonne
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Jarisch-Herxheimer reaction

Post by Yvonne » Mon 25 Feb 2008 20:45

New insights into the pathophysiology of the Jarisch-Herxheimer reaction

The Jarisch-Herxheimer Reaction (J-HR) is a
pathophysiological phenomenon about which
most medical students are taught and unwittingly
probably fail to recognize during clinical
practice. The J-HR is classically a syndrome in
which there is a transient worsening of symptoms
occurring soon after the first adequate
dose of an appropriate antimicrobial drug
used to treat an infectious disease. The reaction
consists of a sudden rise, then more gradual
fall in body temperature; a transient rise
followed by a more profound fall in blood
pressure, and worsening of constitutional
symptoms. The intensity of J-HR varies
between different infections and in its most
severe form is life-threatening. The identity of
systemic mediators causing the reaction has
been sought with little definitive success for
almost a century since the phenomenon was
first documented. However, recent evidence
from clinical experiments on the J-HR of
relapsing fever strongly supports the hypothesis
that cytokines are implicated.
In 1895, Jarisch (an Austrian dermatologistsyphilologist),
described that the spots of
roseola syphilis became more defined and
numerous on treatment with mercury (Jarisch,
1895). Some seven years later, Herxheimer (a
German dermatologist-syphilologist) documented
a systemic reaction consisting of fever,
sweating, and anorexia occurring within 24 h
of the treatment of syphilis using mercury
inunctions (Herxheimer & Krause, 1902). This
transient syndrome now bears the names of
these two dermatologists. It is now recognized
that J-HR occurs on antibiotic treatment of
many bacterial (Bryceson, 1976) and some
protozoal infections, such as African trypanosomiasis
(Whittle & Pope, 1972). However,
studies on the J-HR of two spirochaetal infections,
namely syphilis and louse-born relapsing
fever are now established as paradigms for
clinical investigation of the syndrome.
Physiological changes occurring during the
J-HR asociated with penicillin treatment of
early syphilis have been precisely described
(Warrell et al., 1971) and are experienced by
about 80% of patients (Young et at., 1982).
The principal physiological change is an
increase in body temperature, by more than
0-8°C, peaking 6-8 h after penicillin and often
associated with rigors. In addition, there is
peripheral blood leucocytosis, a fall in lymphocyte
count, and a fall in systemic arterial blood
pressure with an increase in metabolic rate.
Leucocyte pyrogen (endotoxin) was suggested
as a mediator of the observed physiological
changes (Warrell et al., 1971); however, endotoxin
was not detected in the blood of syphilitic
patients experiencing J-HR in response to
penicillin (Young et al., 1082). In addition,
when rabbits infected with Treponema pallidum
were challenged with penicillin, a reaction
resembling J-HR was observed, but endotoxaemia
was not detected. Interestingly, the
rabbits still developed fever when rendered
unresponsive to endotoxin before antibiotic
treatment, thus strengthening the argument
that classical endotoxin may not be involved.
The J-HR associated with antibiotic treatment
of louse-borne relapsing fever is clinically
the most severe form of the reaction.
Relapsing fever, caused by Borrelia recurrentis
which lives in the haemolymph of the human
body louse, is a disease associated with poor
socio-economic conditions and is endemic in
some East African and South American countries,
for example, Ethiopia and Bolivia,
respectively. It is thought that the organism
penetrates the skin after the louse is crushed
and gains access to the systemic circulation.
Patients present with high fever and frequent
chills (Bryceson, 1976) and the diagnosis can
be readily confirmed by the demonstration of
spirochaetes on Wright's stained blood smears.
High concentrations'of spirochaetes, up to 103
organisms per mL, have been recorded in
blood during this condition. In a study of 97
patients in northern Ethiopia, approximately
80% of antibiotic treated patients experienced
J-HR and the mortality was 4% (Zein, 1987).
Physiological changes associated with this condition
have been extensively studied (Parry et
al., 1970; Warrell et al., 1970; Perine et al.,
1971) and consist of a highly predictable syndrome
with around a 1°C rise in body
temperature, with severe rigors, occurring
about 90 min after antibiotic (either penicillin
or tetracycline). Cardiac output initially
increases and then falls, remaining low for
several hours (Warrell et al., 1970). This form
of J-HR lasts about 8 h, but clinically severe
events occur principally in the first 3 h. The
aetiology of such profound physiological
changes has been investigated and in-vivo bioassay
of plasma injected into rabbits caused
fever and hypotension, which not unreasonably,
was thought initially to be due to endotoxin
(Bryceson et al., 1972). Subsequent
studies suggested activation of Hageman factor,
prekallikrein and proteins of the complement
system in B. recurrentis infection and
suggested that endotoxin may play a role in
the evolution of J-HR following antibiotic
treatment (Galloway et al., 1977). However, in
the latter study preparations of borrelia organisms
produced negative Limulus lysate tests
for- endotoxin, and it was concluded that if
endotoxin was aetiological there was the possibility
possibility
that it had leaked into the circulation
from intestinal Gram-negative organisms.
A major recent advance in the study of hostmicrobial
interactions has been the discovery
that cytokines mediate many of the systemic
effects of infection such as fever, anorexia, and
the synthesis of acute phase proteins
(Friedland & Griffin, 1991). Cytokines are
polypeptide hormones released principally
from macrophages but also from other cells,
for example endothelial cells, in response to a
variety of infectious stimuli. Lipopolysaccharide
is known to be a potent soluble
stimulus of cytokine release, and in addition,
phagocytosis of pathogens, such as
Mycobacterium tuberculosis by macrophages,
is also a strong signal for cytokine production.
An important cytokine known to mediate
some of the host response to infection is
Tumor Necrosis Factor (TNF), and a
sequence of other Interleukins (IL) (1 to 10)
have now been described. Discrete physiological
functions of individual cytokines arc
now becoming apparent; for example, IL-6
(previously known as Interferon /J2) stimulates
proliferation of B cells and causes hepatocytes
to secrete acute phase proteins (Gauldie et al.,
1987). IL-8 has been shown to be the most
powerful chemoattractant yet discovered
1989). Considerable knowledge about the
pathophysiological roles of cytokines has been
gained from the use of animal models of infection.
This is particularly exemplified by TNF
which has been shown to be pivotal in mediation
of Gram-negative lipopolysaccharide
induced injury in animals, and has been
detected in the circulation of man and primates
during bacteraemia (Hesse et al., 1988)
and in human volunteers receiving endotoxin
(Michie et al., 1988). The pathophysiological
significance of TNF was demonstrated by the
discovery that in animal models of bacteraemia
monoclonal antibodies directed against
this cytokine prevent death (Tracey et al.,
1987) and reduce the appearance in the circulation
of other cytokines, namely IL-1/? and IL-6
(Fong et al., 1989).
Thus, immunological, physiological, and
metabolic effects of infection appear to be
mediated by the orchestrated release of a
network of cytokines. Extrapolation of data
derived from cell and animal experiments to
the situation of human infection has proved
complicated, and it is now clear that the
response to bacteraemia in man involves a
complex pattern of cytokines (Waage et al.,
1989). It is thought that large differences of
TNF plasma levels which have been detected
between individual bacteraemic patients may
represent variability of infectious stimuli, and
more importantly that patients with serious
infection commonly present clinically at
unpredictable times in the infectious process
when early events, such as initial pulsatile
release of cytokincs, have occurred (Friedland
& Griffin, 1991). This is particularly true for
TNF, which in all situations investigated, in
vitro or in vivo, is released in short pulsatile
bursts lasting 2-3 h.
Since many of the features of J-HR resemble
those caused by administration of TNF to
humans, it was thought reasonable to hypothesize
that this cytokine might play an important
role in the pathophysiology of that condition.
In addition, since J-HR of relapsing fever is
clinically the most severe form of the phenomenon,
it has been used as a model to correlate
observed physiological changes with
plasma cytokine levels. A major advantage of
the J-HR in kinetic studies, such as these, is
that its predictable time course allows well
defined studies to be carried out. The clinical
experiments were carried out in Addis Ababa,
Ethiopia, on 17 patients with proven
B. recurrentis infection (Remick et al., 1991).
Eighty-three per cent of patients experienced
a classical J-HR on penicillin treatment with a
1-2°C rise of temperature with rigors at
90 ± 15 min after intramuscular penicillin. The
peak of J-HR was strongly associated with
high plasma levels of TNF (up to 469 ng/L)
occurring in a single peak coincidental with the
severity of symptoms. In addition, single pulsatile
peaks of IL-6 (up to 28,467 ng/L) and
IL-8 (up to 12,000 ng/L) occurred just after
that of TNF. In a previous study of meningococcal
septicaemia, TNF plasma levels of
140 ng/L were closely associated with
mortality (Waage et al., 1989), but in this
study no deaths occurred during the J-HR.
Raised plasma cytokine levels were not
detected in the three (17%) patients not experiencing
J-HR.
Thus, it appears very likely that J-HR of
louse-borne relapsing fever is mediated by the
action of cytokincs relased into the circulation.
The highly predictable nature of the J-HR
makes this clinical phenomenon an elegant
model of cytokine release and immunopathology
in man. Studies of cytokine profiles in
plasma in other forms of J-HR are currently
being carried out. It is attractive to postulate
that the principal mediation of cytokine release
we have demonstrated is through rapid phagocytic
removal from the circulation of Borrelia
spp. In addition, since therapeutic amelioration
of J-HR has at the best only been
partially successful (Teklu et al., 1983), the
rational use of therapeutic agents directed
against the cytokine cascade is attractive.

http://jac.oxfordjournals.org/cgi/reprint/29/6/613.pdf
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Thu 8 Jul 2010 8:42

J Clin Pharm Ther. 2005 Jun;30(3):291-5.

Proposed mechanisms and preventative options of Jarisch-Herxheimer reactions.

Pound MW, May DB.

Department of Pharmacy Practice, Campbell University School of Pharmacy, Buies Creek, NC 27506, USA. mpound@capefearvalley.com

OBJECTIVE: To review the aetiologies and preventative methods associated with Jarisch-Herxheimer reactions (JHR).

DATA SOURCES: Ovid Medline (1966-June Week 1 2004) was utilized to assess biomedical literature; a review of the bibliographies of articles was also performed.

DATA SYNTHESIS: JHR often occurs with the treatment of spirochete infections. However, the mechanism by which the reaction takes place is not clearly defined.

CONCLUSION: Studies suggest with conflicting evidence that the JHR is caused by release of endotoxin-like material from the spirochete as well as cytokine elevation in the body.
It appears the type of drug and the rate of spirochete clearance from the body 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.

PMID: 15896248
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Thu 8 Jul 2010 8:43

http://www.ncbi.nlm.nih.gov/pubmed/9610974

Lyme Disease Complicated by the Jarisch-Herxheimer Reaction
A 31-year-old wo man diagnosed with Lyme disease was treated with amoxicillin. One hour after the first antibiotic dose, the patient became acutely ill. She developed hypertension, fever, and rigors. Shortly afterward, she became hypotensive and required fluid resuscitation. This systemic illness, the Jarisch-Herxheimer reaction, was first noted in association with antibiotic therapy for neurosyphilis. Thus, the institution of antibiotic therapy may be complicated by the Jarisch-Herxheimer reaction.
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Thu 8 Jul 2010 8:44

Cutis. 1987 May;39(5):397-8.

Jarisch-Herxheimer reaction in Lyme disease.

Moore JA.

Abstract
The Jarisch-Herxheimer reaction includes the accentuation of symptoms during antibiotic therapy. More commonly associated with the treatment of syphilis, it can also occur in patients treated for Lyme disease caused by the spirochete Borrelia burgdorferi.

PMID: 3581911
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Thu 8 Jul 2010 8:44

J Neuroophthalmol. 1994 Jun;14(2):77-80.

Transient worsening of optic neuropathy as a sequela of the Jarisch-Herxheimer reaction in the treatment of Lyme disease.

Strominger MB, Slamovits TL, Herskovitz S, Lipton RB.

Department of Ophthalmology, Montefiore Medical Center, Bronx, NY 10467.

Abstract
A 58-year-old woman developed neurologic and neuroophthalmologic manifestations of Lyme disease, including a radiculomyelitis, cranial neuritis and mild right optic neuropathy. Upon treatment with intravenous ceftriaxone a Jarisch-Herxheimer reaction occurred with encephalopathy, mild fever, worsening radiculomyelitis, and deterioration of her visual acuity. Intravenous methylprednisolone was given, and the visual acuity recovered over 72 hours. This case suggests that transient worsening of optic neuropathy can develop as a sequela of the Jarisch-Herxheimer reaction in the treatment of Lyme disease.

PMID: 7951931
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Thu 8 Jul 2010 8:46

Duodecim. 1997;113(9):845-7.

Jarish-Herxheimer reaction during the treatment of Lyme disease caused episcleritis

[Article in Finnish]

Mikkilä H.

Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.

PMID: 11466905

Episcleritis = http://emedicine.medscape.com/article/1228246-overview
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Dr Googlittle
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Re: Jarisch-Herxheimer reaction

Post by Dr Googlittle » Thu 8 Jul 2010 17:47

Hi Yvonne,

It's good that you publish these descriptions of classical J-HR's, since in my opinion this word is rather often being mis-used, among patients with Lyme, to describe any form of ailments or pains which can, and oftentimes will occur during an antibiotics treatment.

Unfortunately, J-HR is even used to rationalise the neurlogic pain associated with taking certain drugs, which are slightly neurotoxic and therefore can elicit adverse effects signifying polyneuropathy in some patients. However, those who use J-HR in the wider sense tend to interpret and rationalise e.g. burning foot soles or needleprick and tingling sensations in hands/feet as evidence that "the drug is working on the bacteria".

I have suffered a classical J-RH as a consequence of i.v. Ceftriaxone once and it was one of the most harrowing, painful and fewerish things I've ever experienced, not to mention the spells of hypotension. But the worst thing was actually that the condition as such, including the remedial actions, was completely unknown to the infection specialists who were treating me.
Best regards,
DrG
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Fri 9 Jul 2010 16:03

Hi Dr. Googlittle
It's good that you publish these descriptions of classical J-HR's, since in my opinion this word is rather often being mis-used, among patients with Lyme, to describe any form of ailments or pains which can, and oftentimes will occur during an antibiotics treatment.
Yes, I also think that is often being mis-used.
In the beginning I did that too. On the forums were told that worsening of symptoms was a good sign that the ABX would be successful and that it was a Herx. Now I don' t think that any more, not everything is a Herx

I have suffered a classical J-RH as a consequence of i.v. Ceftriaxone once and it was one of the most harrowing, painful and fewerish things I've ever experienced, not to mention the spells of hypotension. But the worst thing was actually that the condition as such, including the remedial actions, was completely unknown to the infection specialists who were treating me.
Sorry to hear that. Did you had to stop with the treatment or just go through ?

I had in the beginning of all ABX slight fever. First I thought that might have been Herx reactions.
But when I got Amoxicillin/Clavulanic acid last week for an infection of a cat bite I got fever too.
In the accompanying letter from the pharmacy was that you could get fever by substances released from dead bacteria

Yvonne
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Dr Googlittle
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Re: Jarisch-Herxheimer reaction

Post by Dr Googlittle » Sun 11 Jul 2010 8:43

Hi Yvonne,

I used every pain-killer I could think of in an as high dose that I dared and the pains/fever subsided within three days. Since the doctors didn't know what it was they allowed me to compelte the treatment.

In retrospect the nature of the pain was interesting since the headache also included the spinal canal all the way down to the lumbal vertebarae. It felt like both the spine and the head would explode due to an increased internal pressure. However, at two separate instances the headache was suddenly reduced 25-50% following a wierd feeling of "passing liquid" within my head, but it would subsequently slowly and steadily increase to unbearable again :?
Best regards,
DrG
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Yvonne
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Re: Jarisch-Herxheimer reaction

Post by Yvonne » Sat 7 Aug 2010 20:16

Treating the Jarisch-Herxheimer(JH) Flare Reaction

by Stuart L. Weg, M.D.( is certified by the American Board of Anesthesiology with added qualifications in pain management ):



http://www.roadback.org/index.cfm?fusea ... lay_id=124
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