Herxhimer Reaction: The Die Off Syndrome

Edited by Michael Biamonte, C.C.N.

This is a phenomenon that results when there is an intensification of the disease symptoms and often an expansion of similar symptoms to other places all of a temporary nature, after which the patient is improved or well. Often it appears to some as if they have the flu, and so is described as “the patient having flu-like symptoms.” “Flu-like symptoms” is an over-simplification of what happens in varying cases and with varying patients. When treating Leishmaniasis, Syphilis or Tuberculosis, the phenomena is called Herxhimer, when treating Leprosy it’s called Lucio’s Phenomena. Other rare tropical diseases also call it the Herxhimer. When treating Candidiasis, patient’s and doctors call it the “die-off effect.”

In all cases of the Herxhimer, there is the appearance of a war or tussle going on inside the body akin to the antigen/antibody warfare, where the body produces fever, sweat, aching and swollen joints, diarrhea, nausea, and so on, in varying proportions with varying degrees depending upon state of metabolism, genetics, source of disturbance and so on.

Die off can also occur perpetually. This occurs due to the patient being on a antifungal regime to destroy Candida or a fungus while being on a high sugar or carbohydrate. This diet will continually feed yeast and fungal organisms allowing them to grow as the continued use of the antifungals then destroys some of them creating the “die-off” reaction. The cycle is then repeated as the patient continues the high sugar and starch diet which allows the Yeast or Fungal organisms to grow again.

Some prescription drugs wrongly are described to be toxic in a certain way because, on observing a Herxhimer reaction in the patient trying the new drug, the drug researchers (and others’ observations during subsequent follow-on research and use of the drug) do not fully understand the Herxhimer and believe the cause is the drug’s “toxicity.” Even with a full understanding of the Herxhimer effect, a pharmaceutical company must follow the “rule of over-caution,” to satisfy FDA requirements for the “health and safety” of us more ignorant citizens. Thus, even with knowledge of the Herxhimer effect, a physician researcher is not necessarily in a position whereby he can, or wants to; discriminate between drug toxicity and the Herxhimer effect.

The Herxhimer Reaction History
by Dr. Paul K. Pybus,
M.A., M.B., B. Chir (Cambridge), M.R.C.S., M.R.C.P. (London), D.R.C.G. (London) F.R.C.S. (England)
BR> “This reaction was first described by an Austrian dermatologist Jarisch Adolf Herxheimer working in Vienna and Innsbruck in 1895 and shortly after this, confirmed by his brother Karl Herxheimer also a dermatologist working in Frankfort. “They were both mainly called upon to treat syphilitic lesions of skin by means of mercury and later arsenical and bismuth preparations. They both noticed that when treating these patients many of them developed signs of high fever, profuse perspiration, night sweats, nausea and vomiting. What was more they also observed that the skin lesions became larger and inflamed before settling down and healing. In addition they found that those cases that responded in this most violent manner healed the best and fastest. The patient was quite ill for 2-3 days after which the syphilitic lesions resolved. Jarisch Herxhimer accounted for this reaction as a toxic manifestation caused by the foreign proteins released from the dying spirochetes. Meanwhile his brother Karl described in detail the Herxhimer fever. There is first a febrile phase with pyrexia, malaise and often a sore throat. The lesions are then aggravated and the ash if present becomes more marked with tension in the regional lymph nodes being more pronounced. In addition the primary ulcer would become edematous and painful (the primary chancre is characterized by its painlessness). [In a letter to The Lancet, p. 340, Feb. 12, 1977, it is suggested that two of the three identifying features of a Herxhimer were known since the end of the 15th century when arsenical ointment was first used to treat the great pox which had just arrived in Europe from the New World: Ed.]

During this reaction many other signs appeared such as histological changes such as transient acute inflammation in the lesion, a leucocytosis and lymphopaenia which was greatest as the pyrexia was at its zenith. It was suggested by another surgeon Heyman that these histological changes indicate that the reaction was hypersensitivity phenomenon of the delayed type similar to the tuberculin hypersensitivity type of reaction.

Theories as to Cause
1. Herxhimer et al. the phenomenon is caused by the release of endotoxin of spirochete breakdown products following treatment. These products are reacting with sensitized syphilitic tissue to produce exacerbation of the lesion.
2. Milian. Suggested it was due to stimulation of the spirochetes and inadequate medication. [Bradford and Allen state that “The purpose of endotoxin to the bacterium that produces it is to act as a semipermeable membrane, limiting and regulating the nature of substances that may enter and provide nutrient for that organism. For this reason endotxoins reside solely on or near the surface (cell wall) and are shed into the surrounding medium only upon the death of the organism. This fact may well be an explanation for what has become known as the Herxhimer reaction in which a patient becomes worse following the administration of antibiotics or other form of treatment that kills the causative organism.] 3. Jadassohn. Suggested that the direct effect of the anti-syphilitic drug on the tissue was an entirely toxic reaction.
4. Fleishman. Suggested this reaction was of a vascular reflex mediated by the autonomic nervous system.
In 1943 Mahoney et al first described Jarisch Herxhimer Reaction in syphilitic patients treated with penicillin and since then it has been observed that other chemotherapeutic agents that are effective with syphilis also produce a Herxhimer reaction.
Moore et al regard the reaction as all or none phenomenon but it was found that if the dose was less than 10 international units per kilogram bodyweight the reaction did not occur. The increase of the dose, however, did not increase the degree of the reaction. It also occurred equally in the seropositive and seronegative patient. Joulia et alreported that during the Jarisch Herxhimer reaction the eosinophils decreased showing it to be an antigen antibody reaction. However, Heyman found that using antihistamines had no effect on the reaction whatsoever.
The Jarisch Herxhimer reaction occurs in other diseases treated with antibiotics. It has been noted in:

1. Yaws treated with penicillin.
2. Vincents Angina treated with metronidazole.
3. Relapsing fever (also a spirochaetal disease) treated with tetracycline.
4. Rat bite fever (also due to a spirillum) treated with penicillin or tetracycline.
5. Leprosy where it is known as the Lucia phenomenon treated with Dapsone.
6. Brucellosis treated with chloramphenicol.
7. Glanders treated with erythromycin.
8. Anthrax treated with Aureomycin.
9. Rheumatoid Disease treated with metronidazole [and other drugs: Ed.] 10. Psoriasis treated with metronidazole [and other drugs: Ed.] 11. [Systemic Lupus Erythematosus and Scleroderma treated with metronidazole and other drugs: Ed.] In 1972 Gudjonsson11 investigated the Herxhimer reaction in adult seropositive and negative syphilitics and found a febrile reaction in 60%. It could be produced with doses above 10 International units per kilogram. However, in 30% of cases no reactions occurred until as much as 600,000 I.U. per kg, were given and so it would appear that the higher doses produced a stronger reaction than the lower ones and this were at variance with the observations of Moore.
He also noted an increase in the neutrophils and a decrease in the lymphocyte count which occurs when the temperature is greatest. The Eosinophil decreased and may be due to the de-granulation of their cells as they phagacytose the breakdown products of the treponemes. This is also an observation in my own series of treated rheumatoid arthritic cases with metronidazole as the eosinophils are completely removed from the blood in most cases with a positive Herxhimer reaction.
Effect of Prednisone on Herxhimer reaction. Here the Prednisone clearly influences the febrile response at a daily dose of 40 mg. The leukocyte changes are not effected and so the Prednisone influences only the febrile component and not the other manifestations of the reaction. Gudjonsson concludes that the reaction is not of an allergic nature, but is caused by some leukocyte pyrogen released by phagocytosis of the treponemes.

If we say that Gudjonsson is correct and that the reaction is due to the release by the leucocytes of a pyrogen when something is phagocytosed, then this further suggests that the Herxhimer reaction seen when treating rheumatoid arthritis with certain drugs, is due to the phagocytosis of an infective agent. Thus, although no one apart from Stamm and Wyburn-Mason has found amoebae for certain, this is strong evidence for an infective cause of the disease. An Herxhimer reaction is the one constant finding in all our search and the strength of the reaction correlates very closely to clinical improvement as shown separately by Prosch, Bingham and Pybus [and now others: Ed.]. Furthermore in my own recent series the correlation is shown to be 100% correct. I have also shown what would occur should these cases that I have done be analyzed on a double-blind study by someone who was not acquainted with the Herxhimer reaction. Herxhimer reaction is becoming the cornerstone of our present research and unless full account is taken of its occurrence any double-blind trial performed will tend to be misleading. The mere fact that it occurs will influence any such trial and would probably be more advantageous if the final assessor could be suitably blinded as to the previous occurrences of the Herxhimer reaction.
“I had sincerely hoped that this was being done at our double-blind studies. I have strongly advocated that it be done.” [The Herxhimer reaction was not taken into account at our double-blind studies at Bowman Gray School of Medicine. This study will be reported separately: Ed.]

The symptoms of the Herxhimer can be most severe. They can discourage not only the patient, but also the doctor and anyone running a trial not knowing of these, will assume they are toxic symptoms and remove the patient from the trial [as occurred at our Bowman Gray School of Medicine study on use of Clotrimazole: Ed.] “This also occurred in the original Guy’s trial when they came to the conclusion that metronidazole had no effect on rheumatoid arthritis and this lack of recognition of the Herxhimer reaction did untold damage to our cause. Not only were the numbers in the trial inadequate, only 20, but other medications were not stopped [Nonsteroidal anti-inflammatories: Ed.] Follow up was only for 6 weeks (they should have waited at least two months), strike dosage was usually inadequate either to produce an Herxhimer or clinical improvement (400 mg b.d.;) and the one case that did produce a reaction was withdrawn because of these ‘side effects.’” [The Herxhimer effect: Ed.]