Fever Therapy

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Historical background

Fever has always been something special for humans: on the one hand threat of death, on the other hand possibility of new health. Therefore, many cultures have dealt with theories of fever, which often had a religious or philosophical background. When we still speak of the "fever delusion" of a sick person today, we are expressing a primordial idea that was already to be found in early historical times. Religion, magic and medicine formed a unity with the early peoples and in the fever one saw the working of an extrahuman being, a demon, which could be good or bad and which had taken possession of humans. Thus, in the writings of the ancient Assyrians, we find incantations intended to expel evil spirits from the fevered patient.

Hippocrates introduced the idea of boiling into medical history. In the writings of Hippocrates, fever is considered the highest intensifying form of boiling. Hippocrates started from the image of disturbed balance of juices in the body: "The body of man has in it blood, phlegm, yellow and black bile ..., through them he suffers illness. He is really healthy when these are in the right proportion, both in terms of potency and quantity (eucrasia)." In fever, the whole body is subjected to boiling, and its entire surface becomes an excretory organ for the dyscrasia, which is excreted with the sweat. Depending on what kind of dyscrasia is present, the course of boiling will also be. The task of the physician is to measure the fever in the right proportion to the juices. In this show the whole body is worked by the fever in such a way that it can get rid of harmful parts e.g. the pus. Thus the original harmony in the organism is restored. In the Hippocratic picture the whole world (macrocosm) represents a kitchen, and the human being (microcosm) has this kitchen a second time in miniature within himself. In fever, therefore, world forces are active, which individualize themselves in man.

Paracelsus (1493 / 1541) addresses in his "Archeus" an essence of man, which combines in man the 4 elements (water, fire, air and earth) to a qualitatively new, to the fifth element (quinta essentia). The human being is the quintessence of the whole creation. For Paracelsus, fever is a Co KG Löffelstelzer Straße 1-3 | D-97980 Bad Mergentheim | Tel: + 49-7931-536-0 | Fax: +49-7931-536-333 | e-mail: info@hufeland.com | www.hufeland.com Fever Therapy 1. Historical Background: Fever has always been something special for man: on the one hand, a threat of death, on the other hand, the possibility of new health. Therefore, many cultures have dealt with theories of fever, which often had a religious or philosophical background. When we still speak of the "fever delusion" of a sick person today, we are expressing a primordial idea that was already to be found in early historical times. Religion, magic and medicine formed a unity with the early peoples and in the fever one saw the working of an extrahuman being, a demon, which could be good or bad and which had taken possession of humans. Thus, in the writings of the ancient Assyrians we find incantations intended to expel the evil spirits from the fevered patient. Hippocrates introduced the idea of boiling into medical history. In the writings of Hippocrates, fever is considered the highest intensifying form of boiling. Hippocrates started from the image of disturbed balance of juices in the body: "The body of man has in it blood, phlegm, yellow and black bile ..., through them he suffers illness. He is really healthy when these are in the right proportion, both in terms of potency and quantity (eucrasia)." In fever, the whole body is subjected to boiling, and its entire surface becomes an excretory organ for the dyscrasia, which is excreted with the sweat. Depending on what kind of dyscrasia is present, the course of boiling will also be. The task of the physician is to measure the fever in the right proportion to the juices. In this show the whole body is worked by the fever in such a way that it can get rid of harmful parts e.g. the pus. Thus the original harmony in the organism is restored. In the Hippocratic picture the whole world (macrocosm) represents a kitchen, and the human being (microcosm) has this kitchen a second time in miniature within himself. In fever, therefore, world forces are active, which individualize themselves in man. Paracelsus (1493 / 1541) addresses in his "Archeus" an area of being of man, which combines in man the 4 elements (water, fire, air and earth) to a qualitatively new, to the fifth element (quinta essentia). The human being is the quintessence of the whole creation. For Paracelsus, the fever is a purifying force, which the Archeus uses to purify the body.

In the physiology and pathology of van Helmont (1579 / 1644) fever is regarded only as a waste product of the supernatural forces of Archeus, when these accomplish the separation and separation. Cause of the fever is for him the fight of the Archeus against the hostile matter.

Subsequently, the natural sciences made their way into the thinking of physicians, replacing the religiously and philosophically influenced ideas.

Christoph Wilhelm Hufeland (1762 / 1836) still sees in fever "an increased activity of the vascular system and accelerated life process with the inseparably associated increased heat generation in the organism." For Hufeland, fever is an expression of a natural force that is supposed to initiate the healing process. Boerhave, who introduced the fever thermometer into clinical routine, also recognized a healing power in fever. In his famous lecture at Leyden, he said, "I would be the greatest physician if I could as easily produce fever as drive it away."

The complete demythologization of fever then occurred in the 19th century, primarily through Virchow and Liebermeister, who blamed the increase in temperature itself for many injuries and disorders. The introduction of salicylic acid into the clinic in 1875 by Buss finally ushered in an antipyretic movement that still dominates the thinking of many physicians today. It culminated in the remarks of Liebermeister, who wrote in 1875: "At the most, there is still talk of a healing effect of fever or in general of a favorable significance of the same for the organism, insofar as one calls such views outdated prejudices of an unscientific period." A positive significance of fever for the organism was thus no longer worthy of discussion for decades to come.(1) This view, long since disproved by modern research, has unfortunately remained with many physicians to this day.

The beginnings of fever therapy

Doctors have always observed that even serious illnesses were favorably influenced by fever, such as asthma, psychoses and even cancer. J. Wagner von Jauregg stated, "If a mental patient is attacked by an infection (abdominal typhus, cholera, changeable fever, erysipelas) in the first six months of his illness, the probability is very great that he will be cured of his psychosis by it." He was one of the pioneers of fever therapy and received the Nobel Prize in Medicine in 1929 for malarial treatment of psychosis and lues. In 1882, Friedrich Fehleisen dared to use erysipelas cocci in cancer patients in Würzburg to set a high-fever infection that often lasted for weeks.

In 1892, William B. Coley used a mixture of Streptococcus and B. prodigiosum, which he killed and used as "Coley's toxin" for the treatment of sarcoma patients with sometimes astonishing success. The literature contains over 700 well-documented cases of spontaneous regression of tumors after high-fever infections.(2) In more recent times, fever therapy has been propagated primarily by Issels, who reports carefully documented cures of incurable cancer patients.

While the fever treatment of psychoses and lues has been rendered obsolete by modern drugs, interest in fever therapy today is focused primarily on the treatment of cancer. It is in this field that a change of opinion has occurred, after the euphoria brought about by the development of modern chemotherapeutic agents had to give way to the sober realization that cure rates for the most common and important cancers have been stagnating for 30 years now, and this despite all the progress made in the fields of surgical and radiation technology and chemotherapy.

For a long time, the role of the immune system in fighting cancer was ignored; indeed, the body's own defenses were denied any importance in this respect. However, this opinion changed in recent years with the development of genetic engineering, which made it possible to produce defined immune-active substances such as interferons, interleukin, TNF, etc. in sufficient quantities for clinical trials. All these messenger substances of the immune system showed a common feature during their clinical trials: they trigger fever. Thus, the old fever therapy has again come into the focus of recent research; among others, a research group of the University of Freiburg (Prof. Engelhardt) on behalf of the Federal Ministry of Education and Research is currently dealing with this form of therapy, which has been disparaged for a long time.

Basic therapeutic idea and method: What do we mean by active fever therapy?

Active fever therapy means raising the body's core temperature by the body's own mechanisms. This is done by administering fever-inducing substances (exogenous pyrogens) that bring about these changes in the organism. In today's established active fever therapy, these exogenous pyrogens are usually components of bacteria such as lipopolysaccharides. Involved in the generation of fever are mainly the temperature control center, which is located in the hypothalamus of our brain. Here, an upward temperature set point adjustment takes place; the body is thus prompted to produce more heat and it does so mainly by muscle tremors (shivering), by an increase in metabolism and by an activation of the circulatory system. Today, we also know that the exogenous pyrogens cannot usually produce the fever themselves, but that it is messenger substances of the immune system (endogenous pyrogens such as interleukins) that are activated and released by the exogenous pyrogens and now in turn induce the temperature increase via the hypothalamus.

This active fever therapy is therefore not to be equated with a passive overheating of the body from the outside, e.g. by means of overheating baths or other more elaborate procedures for overheating the body, which are nowadays frequently introduced in cancer medicine at large clinics under the name "hyperthermia treatment".

At temperatures up to 38° C we speak of subfebrile temperatures; up to 39° C we call moderate fever and from about 39° C we speak of high fever. Based on the empirically achieved successes that have been reported again and again after spontaneous fever, attempts are now being made to produce fever artificially, using exogenously supplied bacterial endotoxins of the Coley toxin type, purified preparations of lipopolysaccharide A3, or even preparations of Corynebact. parvum.

The aim and purpose of such a fever therapy is activation of the immune system and vegetative retuning of the organism. Especially in the case of chronic diseases, we frequently observe a disturbed reaction to or regulation of various biological stimuli. The disturbed heat regulation in the chronically ill (5,6) has been well studied and is interestingly related to a disturbed immune regulation. Through thermal measurements it is therefore possible to draw conclusions about the function of the defense system. The author himself has repeatedly observed in his oncological patients that they often do not react adequately to the stimulus set by the injection of the Coley toxin with an increase in temperature and leukocytosis.

Therefore, it can be rightly assumed that a major problem of the chronically ill patient is his disturbed vegetative regulation, which no longer allows him to compensate for disturbances of his organism caused by stimuli.

Possibly this problem is also the key to cancer; for what is cancer but a disturbance of the regulation of the cell, which is no longer able to switch off exposed oncogenes, because presumably the cell's own repair systems fail and, on the other hand, its membrane no longer reacts to the external stimulus of the cell neighbor by inhibiting growth?

But the milieu in which a cell lives is also decisive for its further fate. For example, we now know that malignant cells can be experimentally redifferentiated into normal somatic cells if the environment is changed (7). We also know, for example, that eggs of aquatic turtles differentiate into male or female depending on the ambient temperature. The milieu - in this case the temperature milieu - thus also determines the differentiation or the behavior of the genes. Hypothetically, therefore, it may be put up for discussion whether the milieu change that takes place during fever may not also have a redifferentiating effect on malignant cells.

However, the first goal of fever therapy is to reactivate the blocked vegetative regulation in the sense of a retuning stimulus body therapy, so that the sick organism is given the opportunity to regulate itself and thus to initiate healing processes. We know from well-documented case histories that such spontaneous healing processes are possible even in the case of extensive cancer diseases, and that our organism has the potential for self-healing of large tumors.

As long as we do not succeed in normalizing this regulation, biological therapy methods and also the immunotherapy practiced at our universities today are only successful to a limited extent and usually only temporarily. Since our immune system is much easier to study than vegetative regulatory mechanisms, we have a wealth of work documenting the positive effects of fever on our immune system. Roughly schematized, one can make the following statements regarding the immune modulation by fever therapy:

The bacterial endotoxins cause the fever only indirectly by acting on macrophages and activating them. Activated macrophages can now release various messenger substances of the immune system and thus exert a very broad effect on both the specific and the non-specific immune system, which must be accorded a more important role in the fight against cancer than the specific immune system with the T and B lymphocytes. These released messenger substances, especially interleukin 1 and macrophage inflammatory protein 1, act on the hypothalamus and lead to a setpoint adjustment in the temperature regulation center. This leads to muscle tremors or shivering in the periphery, constriction of the vessels and thus to an increase in the core body temperature.

At the same time, interleukin 1 acts on the complement and properdin system, the nonspecific humoral component of our immune system, which can lead to cytolysis of cancer cells. However, the cellular component with the natural killer cells, the macrophages and microphages, which are of particular importance in cancer therapy, is also activated. Interleukin 1 also activates the T and B lymphocytes. Among other things, plasma cells are formed that can synthesize immunoglobulins and antibodies, and interleukin 2 is now also released, which in turn initiates important immune reactions (production of LAK cells and interferon). Activated macrophages also develop tumoricidal activities and secrete cytolytic substances such as TNF, proteases or H2O2.

Method:

After exclusion of contraindications and careful examination of the patient, fever-producing substances are injected directly intravenously. Usually, after about 45 to 60 minutes, there is shivering and a rise in temperature of varying degrees; temperatures as high as 41.7° C have been reached during the first burst of fever, but are rare; as a rule, the core temperature measured rectally rises between 39° C and 40° C and slowly falls to the initial value after two to three hours, but in some patients it may still be slightly elevated the next day. Symptomatically, additional medications may be administered for nausea, nausea, or headache and pain in the limbs, although we take care to ensure that these medications are not antipyretic. Fever jabs are given one to three times a week. A total of 10 to 15 fever jolts should be administered in a series.

Specific character of fever therapy, differentiation from pure immunotherapy and hyperthermia.

Without doubt, fever is one of the ontologically oldest healing reactions of the organism. Obviously, the increased body temperature is not the decisive criterion, rather it is the activation of the immune system, the restoration of a normal reaction state and possibly also the change of the body milieu. Therefore, fever therapy is regulatory and immunotherapy at the same time and stimulates the body's self-healing powers in an excellent way. In contrast to today's common immunotherapy with isolated immunoactive substances - the so-called BMF substances (biological response modifiers) such as TNF, interleukins or interferons, which are administered in non-physiologically high doses, fever therapy induces the immune mechanisms in a physiological way. The entire biological system of our body is not raped, but stimulated in a natural way, so that not only the immune system, but also the higher-level regulatory circuits of the system are positively involved. This explains the success of fever therapy especially in diseases with allergic or autoaggressive components.

But also against the hyperthermia inaugurated by Ardenne in the fight against cancer, which is also intensively researched at our universities today, one must distinguish the fever therapy. The aim of hyperthermia is the thermal damage of the tumor cell. Due to the high convection, it is very difficult to generate the required temperature of 42.5° C and more over a longer period of time in the tumor; as a rule, even this is not sufficient, rather hyperthermia is more effective in combination with radiation or chemotherapy. The thermal damage is merely intended to make the tumor cell more sensitive to the subsequent treatments - chemotherapy and radiotherapy. However, both - chemotherapy and radiotherapy - have exactly the opposite effect of what fever therapy seeks to achieve: they suppress the immune system and block vegetative regulation. On the other hand, it is also known that in the initial phase of hyperthermia - similar to active fever therapy - rather an immunosuppression occurs, which is only later followed by a moderate immune activation. In this phase, however, the immunosuppressive follow-up therapy is usually already effective, if hyperthermia is combined with radiotherapy or chemotherapy. It is therefore important to emphasize that active fever therapy and passive hyperthermia are neither comparable in their objectives nor in their effects.

For the effect of hyperthermia, only the temperature increase that can be achieved in a circumscribed tissue area is decisive; in fever therapy, on the other hand, it is not the level of the fever that is decisive, but the immune modulation that can be achieved through fever induction, the change in the body environment and the restoration of a normal reaction state.

For the effect of hyperthermia, only the temperature increase that can be achieved in a circumscribed tissue area is decisive; in fever therapy, on the other hand, it is not the level of the fever that is decisive, but the immunomodulation that can be achieved through fever induction, the change in the body environment, and the restoration of a normal reaction situation.

Indications and contraindications for active fever therapy

From the previous presentations, it is clear that active remedial fever therapy is particularly indicated for diseases that are associated with a weakness or disorder of the immune system and that have become chronic.

Indications:

• oncological diseases of all kinds (except acute leukemias)

• rheumatic diseases and collagenoses: primary chronic polyarthritis, ankylosing spondylitis, Guillain-Barré polyneuritis

• chronic inflammatory conditions such as: Ulcerative colitis Crohn's disease, Chronic bronchitis Chronic recurrent abscesses or pyoderma.

• Allergic conditions such as chronic urticaria, pollinosis, allergy-related eczema.

contraindications:

• acute microbial infections

• cardiovascular insufficiency - condition after myocardial infarction or pulmonary embolism - cardiac arrhythmia, hypertension

• severe liver parenchyma damage

• adrenal insufficiency

• hemorrhagic diathesis

• ventriculi sive duodeni ulcer

• Pregnancy

What side effects may occur?

Common side effects of a mild nature: headache, backache or pain in the limbs, nausea, vomiting, chills, diarrhea, circulatory problems due to hypotension, lip and acrocyanosis.

Rare side effects requiring immediate treatment:

Severe cardiovascular problems, thrombosis, pulmonary embolism, allergic reactions.

Successes and proof of effectiveness

Fever therapy belongs to the empirically found forms of therapy. Doctors had always observed that after fever attacks serious diseases, often considered incurable, disappeared. Thus, the Greek Parmenides (540 - 480 B.C.) is even credited with saying, "Give me the power to produce fevers, and I will cure any disease." In more recent times, it was Coley (10) and Issels (11) who systematically applied fever therapy, especially to cancer patients, with good, sometimes even spectacular success. Since the early 1980s, controlled studies of fever therapy have also been undertaken on several occasions, using different endotoxins.

As indirect, epidemiological proof of efficacy, several epidemiological studies can be considered, which almost unanimously showed that patients who rarely suffer febrile infections are exposed to a significantly increased risk of cancer. It is therefore fair to say that the evidence for the efficacy of fever therapy is very impressive and is based not only on documented therapeutic successes, but also on clinical observations, animal experimental studies, and epidemiological findings.

The activation of the immune system after fever therapy can be directly measured in several ways. For example, increased serum levels of interleukin 1 and 2 can be measured directly, as can increases in leukocytes, B and T lymphocytes, NK cells, and LAK cells.

However, prior to activation, suppression initially occurs in the initial phase, recognizable by a marked decrease in the leukocyte count in the first hours after injection of the endotoxin. Thus, it cannot be denied that fever therapy induces distinct immunologic effects in vivo that provide an explanation for the clinically observed effects.

Distribution of fever therapy

Active fever therapy is especially widespread in German-speaking countries. It is carried out in some specialized clinics under in-patient conditions and on an out-patient basis by physicians in private practice, and even by some alternative practitioners. But also in the USA, e.g. in the Memorial Sloan Kettering Cancer Center in New York and in Japan, fever therapy was and is used experimentally.

Scientific work on the effectiveness of fever therapy

Koch, R., Petruschky, J.:
Beobachtungen über Erysipel-Impfungen am Menschen. Z. Hyg. 23, 477-489, (1896)

Wagner-Jauregg, J., von: Über die Einwirkung der Malaria auf die progressive Paralyse. Psychiatr.-Neurol. Wschr. 20, 132, (1918)

Coley W.B.: The treatment of inoperable sarcoma by bacterial toxins (of the Streptococcus of erysipela and the Bacillus prodigiosus). Proc. Royal Soc. Med. Surg. Sect. 3, (1909 / 1910), 1-48.

Coley, W. B.: The treatment of malignant tumors by repeated inoculations of erysipelas; with a report of original cases. Amer. J. Med. Sc. 105, 487-511 (1893)

Fowler, G. A.: Beneficial Effects of Acute Bacterial Infections or Bacterial Toxin Therapy on Cancer of the Colon or Rectum. Cancer Research Institute, N. Y. Monograph # 10, (1969 a)

Kempin, S., Cirrincione, C:, Straus, D. L. et al: Improved remission rate and duration in nodular non-Hodgkin‘s lymphoma (NHL) with the use of mixed bacterial vaccines (MBV). Proc. Amer. Soc. Clin. Oncol. 22, 514 (1981)

Nauts, H. C.: Pyrogen Therapy of Cancer: An Historical Overview and Current Activities. Trans. International Symposium on Cancer Therapy by Hyperthermia and Radiation, Washington, D. C., Apil, (1975 a)

Nauts, H. C.: Bacterial vaccine therapy of cancer. In „Proc. Symp. on Biological Preparations in the Treatment of Cancer, London, April 13 – 15, (1977)“. Developments in Biological Standardization 38, 487 / 494 (1978) S. Karger, Basel

Katano, M. , Torisu, M.: New approach to managemant of malignant ascites with a streptococcal preparation OK-432. II. Intraperitoneal inflammatory cell-mediated tumor cell destruction. Surgery, 93, 365 / 373 (1983).

Schlesinger, D.: Endogenous mediators in host response to bacterial endotoxin. Microbiology - 1980. Am. Soc. Microbiol. (1980) 2 / 167

Westphal, O., Lüderitz, O.,Galanos, C., Mayer, H., Rietschel, E. Th.: The story of bacterial endotoxin. In: Chedid, L., Hadden, J. KW., Ipreafico, F., Ducor, P., Willogby, D., (eds) Adv. Immunopharmacol. 3, (1986), 13 / 34, Pergamon Press.

Remy, W., Hammerschmidt, K., Zänker, K. S., Ulm, K., Theisinger, W., Lange, J., Trappe, A., Maubach, P., Rastetter, J.: Tumorträger haben selten Infekte in der Anamnese. Med. Klin. 78, 95?98 (1983) Schulz, G.: Verhütet Fieber Karzinome – Münch. Med. Wschr. 111, 1051 / 1052 (1969)

Vosika, G. J., Barr, Chr., Gilbertson, D.: Phase-I-study of intravenous modified lipid A. Cancer immunol. Immunother. 18, 107 / 112 (1984)

Blatteis, C. M.: Ontogenetic development of fever mechanisms. In: J. M. Lipton (ed): Fever, S. 177 / 188. N. York 1980

Eggers, H. J.: Bedeutung von Fieber und Hyperthermie für den Verlauf von Virusinfektionen. In: Z. pyhs. Med. 2, 69 / 77 (1971)

This list does not claim to be exhaustive.