Jarisch-Herxheimer Research Articles

Changes in intravascular complement, kininogen, and histamine during Jarisch-Herxheimer reaction in secondary syphilis.

Nine patients with secondary syphilis and one control subject were observed for eight hours after the administration of penicillin. Serial clinical observations were made, and blood samples were obtained for the analysis of complement, histamine, and kininogen. Six patients showed Jarisch-Herxheimer reactions, the intensities of which were found to parallel certain changes in activity of complement and concentrations of histamine and kininogen. Results were analysed statistically. Significant falls were seen in: total haemolytic complement (CH50), C1 inhibitor, C3, functional (haemolytic) C4, and to a lesser extent total C4. Split products of C3 were shown in five of the six patients who had a reaction. There was no change in total glycine rich beta-glycoprotein (GBG) or glycine rich gamma-glycoprotein (GGG) or evidence of conversion of GBG to GGG. Plasma kininogen concentrations fell and plasma histamine concentrations rose appreciably before and during the clinical phase of the reaction. These results are discussed in relation to the clinical features and possible pathogenic mechanisms of the Jarisch-Herxheimer reaction.

Glucose and insulin homeostasis during the Jarisch-Herxheimer reaction

Plasma concentrations of glucose and insulin were measured in ten patients during the Jarisch-Herxheimer reaction of tetracycline-treated louse-borne relapsing fever. Plasma glucose fell significantly in eight of the ten patients associated with the peak of the reaction, but plasma insulin remained low. Glucoregulation by insulin was therefore normal. This evidence questions the role of macrophage mediator-induced pancreatic insulin release in causing hypoglycaemia in borreliosis or bacterial endotoxicosis.

Acute Renal Failure Due to Leptospirosis: Clinical Features and Outcome in Six Cases

Six cases of severe leptospiral infection with renal failure are described. Five of the six patients had acute oliguric renal failure requiring dialysis. Renal function recovered over three weeks and by two months all patients had plasma creatinine levels less than 200 mumol/litre. The initial diagnosis of leptospirosis depended on clinical and epidemiological features because serological confirmation was not possible during the first week of the illness. All the patients had either high risk occupations or a history of exposure to external sources of infection. All had fever, myalgia, jaundice and muscle tenderness. Although bilirubin levels were high (greater than 350 mumol/litre in five) the elevations of aspartate transaminase and alkaline phosphatase levels, and prolongations of prothrombin times were relatively slight. Thrombocytopenia occurred in five of the six cases. Leptospira complement fixation tests were weakly positive or negative on admission in five cases but rose to significant levels subsequently. Penicillin treatment resulted in Jarisch-Herxheimer reactions in three cases. The important complications were: upper gastro-intestinal haemorrhage (five cases), thrombocytopenia less than 30 000 platelets/mm3 (four cases), atrial fibrillation (three cases), drowsiness with asterixis (four cases). All six patients were seriously ill and required intensive supportive therapy. All survived.

Antibiotic treatment of louse-borne relapsing fever in Ethiopia: a report of 377 cases.

Single-dose non-random, antibiotic treatment was evaluated in 377 Ethiopians with louse-borne relapsing fever. Oral doses of tetracycline hydrochloride 500 mg, doxycycline 100 mg, erythromycin base 500 mg, chloramphenicol 500 mg, or a single intramuscular injection of 1,200,000 units of penicillin aluminum monostearate (PAM) were equally effective treatments. All drugs induced a Jarisch-Herxheimer reaction, which was clinically less severe in patients given PAM. The duration of spirochetemia after treatment was much longer after PAM treatment, however. Three critically ill patients died shortly after receiving antibiotic treatment, from complications of LBRF that were present on admission to hospital.

Jarisch-Herxheimer Reaction in Meningococcal Meningitis

The Jarisch-Herxheimer reaction, characterized by high fever and chills followed by hypotension and sweating, is a recognized complication of treatment of spirochetal infections, such as borreliosis and syphilis, and of bacterial infections, such as brucellosis and tularemia. 1 We report a case of this reaction developing during treatment of meningococcal meningitis. Endotoxin Assay .—Plasma endotoxin levels were determined by the Limulus amebocyte lysate test. 2 Briefly, plasma was incubated with lysate, the protein precipitate was measured by relative light scatter, and this was compared graphically with that produced by endotoxin of Escherichia coli 055:B5. Report of a Case .—A 9-year-old girl was admitted to Baragwanath Hospital, Johannesburg, Republic of South Africa, on Sept 23, 1981, with a history of fever and confusion beginning on the previous day. Examination showed that she had a temperature of 38.2 °C, a pulse rate of 110 beats per minute, and a BP of 120/70

ENDOGENOUS OPIOID WITHDRAWAL IN THE JARISCH-HERXHEIMER REACTION

Meptazinol, a partial opioid agonist, diminishes the Jarisch-Herxheimer reaction in relapsing fever whereas naloxone, a pure opioid antagonist, is virtually inert. Because endogenous opioid activity is probably increased in the acute phase, the efficacy of meptazinol is unlikely to be due to agonist activity. However, it is possible that in such a severe reaction there may be an exhaustion of endogenous opioids, giving rise to a naturally occurring quasi-morphine-withdrawal syndrome which responds to meptazinol.

MEPTAZINOL DIMINISHES THE JARISCH-HERXHEIMER REACTION OF RELAPSING FEVER

Naloxone, an opioid antagonist, and meptazinol, an opioid antagonist with agonist properties, were tested in a double-blind placebocontrolled trial in 24 Ethiopian patients with louse-borne relapsing fever. The potentially fatal Jarisch-Herxheimer reaction (J-HR), which invariably follows tetracycline treatment of the disease, was unaffected by naloxone, 30-40 mg intravenously, but was diminished by meptazinol, 300-500 mg intravenously. Compared with naloxone and placebo, meptazinol reduced the clinical severity of the reaction, significantly delayed and shortened its chill phase, delayed the rise in temperature, and reduced peak temperature and changes in pulse and respiratory rates and leucocyte count. High-dose corticosteroids given before or at the time of tetracycline treatment failed to alter the reaction, which is thought to result from release of endotoxin-like substances. Meptazinol is the first effective treatment for the J-HR of louse-borne relapsing fever. This finding suggests a role for endogenous opioids in the pathogenesis of the J-HR.

Studies on the Pathogenesis of the Jarisch-Herxheimer Reaction: Development of an Animal Model and Evidence Against a Role for Classical Endotoxin

The etiology of the Jarisch-Herxheimer reaction is unknown, but the reaction may result from toxic products of dead or dying treponemes reacting with sensitized syphilitic tissues. Because of similarities of spirochetes with gram-negative bacteria, endotoxin has been proposed as the responsible toxin. In 19 patients with syphilis, a reaction occurred in 15 (79%) during treatment with penicillin. Endotoxemia was not found by the limulus amoebocyte lysate test. All animal model of the Jarisch-Herxheimer reaction was developed in rabbits infected with Treponema pallidum. When treated with penicillin, 18 (78%) of 23 rabbits infected 18-29 days previously developed a reaction that resembled that in humans. Endotoxemia was not detected by the lysate test. After the reaction, rabbits were not refractory to the pyrogenic effects of endotoxin, and syphilitic rabbits rendered tolerant to endotoxin still developed fever when treated with penicillin. These data suggest that classical endotoxin is not the cause of the Jarisch-Herxheimer reaction.

The role of immune complexes in early syphilis and in the Jarisch-Herxheimer reaction

Circulating immune complexes (CIC) were detected in one of 11 patients with primary syphilis and in 5 of 12 patients with secondary syphilis. The level of CIC was significantly increased in patients with secondary syphilis. Four weeks later a significant decline in CIC was found. No relationship was demonstrated between CIC and affection of the skin, lymph nodes, or kidneys. An increased albumin excretion rate was demonstrated before treatment. No differences were found in the excretion rate of beta-2-microglobulin before or after treatment. Nineteen patients had a Jarisch-Herxheimer reaction during treatment. An increase in CIC was found in 5 patients and a decrease in 7 patients. No correlation could be demonstrated between the level of or changes in CIC and the severity of the Jarisch-Herxheimer reaction.

Jarisch-Herxheimer reaction in complement-depleted rabbits. Histological and immunofluorescence studies of early cutaneous lesions.

The possible role of complement in the pathogenesis of the Jarisch-Herxheimer reaction was assessed in cutaneous syphilitic lesions in two groups of rabbits treated with penicillin; in one group complement was depleted before penicillin therapy. Serial biopsy specimens were similar histologically in both groups. The activation of the complement pathways did not seem to play a role in the pathogenesis of early cutaneous syphilitic lesions in rabbits during the Jarisch-Herxheimer reaction.

Antitreponemal IgE in early syphilis.

Using a solid-phase radioimmunoassay technique, mean serum IgE concentrations were found to be raised in patients with early syphilis. Antitreponemal specificity of the IgE response was investigated by the fluorescent treponemal antibody absorption test using a fluorescein-isothiocyanate-labelled antiserum against the Fc-fragment of human IgE. Validity of this test procedure was assessed by blocking experiments. The results provide evidence of the antitreponemal specificity of the IgE response in syphilis and indicate a possible role for antitreponemal IgE in the pathogenesis of the Jarisch-Herxheimer reaction and in the immune-complex origin of some of the lesions of secondary syphilis.

The Naeglerial causation of rheumatoid disease and many human cancers. A new concept in medicine

Man and terrestrial animals live in an environment containing free-living amoebae on the surface soil, in pools, fresh water lakes, rivers and streams. They form cysts, which float in the air and which are continually inhaled and found in the nasopharynx and their trophozoites are present in human and animal faeces. Amoebae of the genus, Naegleria, have been demonstrated in all human tissues, both healthy and in larger numbers in those taken from cases of rheumatoid disease, in all human cancers and in the unaffected tissues of cancer patients. They can be killed in vitro by a series of different anti-amoebic substances and treatment of active cases of rheumatoid disease by any of these, either causes cessation of disease activity or a temporary exaggeration of symptoms followed by their lessening or disappearance (Herxheimer reaction), indicating the presence of an amoeba in the affected tissues as the causative organism of the inflammation in this disease in subjects genetically sensitive to the organism. Every internal organ may be involved in the inflammatory response in cases of rheumatoid disease and this also ceases with the above treatments. Many of these internal lesions are premalignant, so that infection with the organism either in sensitive subjects or with pathogenic species, appears to be the primary cause of cancer in many cases. The presence in the body of Naegleria represents the source of the constant antigenic stimulation thought to be responsible both for rheumatoid disease and for the development of lymphomata and myelomatosis.

Lack of proliferation of circulating white blood cells in patients with syphilis before and after a Jarisch-Herxheimer reaction.

The occurrence of lymphoblasts in peripheral blood, measured by incorporating tritiated thymidine ([3H]dThd), was studied before, during, and after a Jarisch-Herxheimer reaction in patients with early syphilis. No difference in [3H]dThd incorporation into peripheral white blood cells was found between five patients with syphilis and 19 healthy controls, whereas in 20 cord blood samples [3H]dThd incorporation was significantly increased.

Brucella canis bacteremia

Naturally acquired Brucella canis infection is believed to be uncommon, but is not readily diagnosed. A 55-year-old woman developed fever, abdominal pain, malaise, weakness, and anorexia eight weeks after her dog delivered stillborn pups. Blood cultures yielded B canis. Specific B canis agglutinins were negative initially and remained negative during convalescence. Therapy with tetracycline and streptomycin was successful but was associated with a probable Jarisch-Herxheimer reaction.

C-reactive protein, C3, C4 and properdin during the Jarisch-Herxheimer reaction in early syphilis.

The occurrence of plasma CRP during the febrile response after the first injection of penicillin was followed in 10 patients with early syphilis. An increase in CRP was noted after 12 hours, with a maximum after 24 hours. The appearance of this acute phase protein could not be correlated to cutaneous reaction, increased body temperature or leukocytosis, nor were baseline values of CRP correlated to clinical or serological activity of the infection. Patients with high levels of CRP prior to treatment suffered the most intense systemic reactions. No activation of the complement system during the Jarisch-Herxheimer reaction was detected from sequential determinations of C3, C4 and properdin.

Louse-borne relapsing fever: II. Combined penicillin and tetracycline therapy in 160 Sudanese patients

One hundred and sixty patients with louse-borne relapsing fever were treated with a combination therapy of procaine penicillin and tetracycline. Fortified procaine penicillin B.P. was given as 400,000 units in the first day. This was followed the next day by 2 g tetracycline orally in divided doses for seven days. A mild rise in temperature was observed in 22 (13·7%) patients within four hours of administering penicillin. Rigors and hypotension occurred in one patient. Relapse occurred in two patients, of whom one had concomitant typhoid and one visceral leishmaniasis. The combined therapy has been found to be effective and safe. It lacks the disadvantages of penicillin (relapses) and tetracycline (severe reaction), when each drug is used alone. The use of the arsenicals ( Wolff et al., 1946 ; Garnham et al., 1947 ), penicillin ( Taft & Pike, 1945 ; Ingraham & Lepenta, 1946 ; Harrison & Whittington, 1951 ; Knaack et al., 1972 ) and tetracycline ( Bryceson et al., 1970 ; Knaack et al., 1972 ) in louse-borne relapsing fever has resulted in a dramatic reduction of the mortality rate from more than 40% in untreated cases ( Garnham et al., 1947 ) to less than 5%. However, each of these drugs suffers from one drawback or another. The arsenicals are toxic ( Wolff et al., 1946 ). Penicillin is slow in clearing the spirochaetaemia, has a higher rate of relapse and does not clear residual infection in the brain ( Harrison & Whittington, 1951 ). Tetracycline almost invariably induces a distressing Jarisch-Herxheimer reaction ( Bryceson et al., 1970 ; Knaack et al., 1972 ; Perine et al., 1974 ). The combined use of penicillin (to reduce reaction) and tetracycline (to prevent relapses) can be a safe and effective alternative in the treatment of this disease. This paper describes the treatment of 160 Sudanese patients with louse-borne relapsing fever, using combined penicillin and tetracycline.

Jarisch-herxheimer reaction case report

The Jarisch-Herxheimer reaction is a response to the treatment of syphilis. The most common findings are fever, malaise, headache, and exacerbation of cutaneous lesions. The reaction is thought to be due to the effects of treponema breakdown products, and it should not be confused with an allergic reaction to the antibiotic employed. Thus, further therapy must not be withheld. Treatment is symptomatic.

The enigma of the pathogenesis of the Jarisch-Herxheimer reaction.

The enigma of the pathogenesis of the Jarisch-Herxheimer reaction.

Clinical pathology of the Jarisch-Herxheimer reaction.

The Jarisch-Herxheimer reaction is a complication that can follow treatment of several infectious diseases. Its most severe form is in louse-borne relapsing fever; in this syndrome the reaction can cause death. Information from studies in Ethiopia during the past eight years is presented, and clinical, physiological, pathological, and immunological features of the reaction are described. Possible causative mechanisms of the reaction are discussed, especially in relation to the role of endotoxin, and an attempt is made to consider this reaction in relation to other endotoxin-associated states.

SINGLE-DOSE DOXYCYCLINE TREATMENT OF LOUSE-BORNE RELAPSING FEVER AND EPIDEMIC TYPHUS

26 patients with louse-borne relapsing fever (L.B.R.F.) and 10 others with serologically proven epidemic typhus were treated with a single oral dose of 100 mg. of doxycycline. All patients were cured and no relapses of L.B.R.F. or typhus occurred during the 2-week period of posttreatment observation. Each of the L.B.R.F. patients experienced a Jarisch-Herxheimer reaction following treatment, which was complicated by hypotension and/or cardiac failure in 5 patients. This was successfully treated with intravenous digoxin. The difficulty of diagnosing typhus and differentiating it from enteric fevers may restrict the use of single-dose doxycycline to epidemics or to mass-treatment campaigns directed at eradicating the human reservoirs of these infections.