Historical background
Fever since time immemorial, fever has been something special for humans: on the one hand, a threat of death, on the other, the possibility of renewed health. This is why many cultures have dealt with fever theories, which often had a religious or philosophical background. Even today, when we talk about the "fever mania" of a sick person, we are expressing a primal idea that was already present in early history. Religion, magic and medicine formed a unity among the early peoples and fever was seen as the work of an extra-human being, a demon, who could be good or evil and who had taken possession of man. In the writings of the ancient Assyrians, we find incantations with which the evil spirits were to be exorcized from the feverish patient.
Hippocrates introduced the idea of boiling into the history of medicine. In the writings of Hippocrates, fever is regarded as the highest form of boiling. Hippocrates based this on the image of a disturbed balance of humors in the body: "The human body contains blood, phlegm, yellow and black bile ... through which it suffers illness. It is truly healthy when these are in the right proportion in terms of both potency and quantity (eucrasia)." In a fever, the whole body is subjected to boiling, and its entire surface becomes an excretory organ for what is separated, which is excreted with the sweat. The course of the boil depends on the type of dyscrasia present. The doctor's task is to measure the fever in the right proportion to the juices. In this view, the whole body is treated by the fever in such a way that it can get rid of harmful parts, e.g. pus. This restores the original harmony in the organism. In the Hippocratic image, the whole world (macrocosm) represents a kitchen, and the human being (microcosm) has this kitchen a second time in miniature within him. Accordingly, world forces are active in the fever, which are individualized in the human being.
In his "Archeus", Paracelsus (1493 / 1541) addresses an area of human essence that combines the four elements (water, fire, air and earth) into a qualitatively new fifth element (quinta essentia). The human being is the quintessence of all 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 humans: on the one hand, a threat of death, on the other hand, an opportunity for new health. For this reason, many cultures have dealt with fever theories, which often had a religious or philosophical background. Even today, when we talk about the "fever mania" of a sick person, we are expressing a primal idea that was already present in early history. Religion, magic and medicine formed a unity among the early peoples and fever was seen as the work of an extra-human being, a demon, who could be good or evil and who had taken possession of man. Thus we find incantations in the writings of the ancient Assyrians with which the evil spirits were to be driven out of the feverish patient. Hippocrates introduced the idea of boiling into the history of medicine. In the writings of Hippocrates, fever is regarded as the highest form of boiling. Hippocrates based this on the image of a disturbed balance of humors in the body: "The human body contains blood, phlegm, yellow and black bile ... through which it suffers illness. It is truly healthy when these are in the right proportion in terms of both potency and quantity (eucrasia)." In a fever, the whole body is subjected to boiling, and its entire surface becomes an excretory organ for what is separated, which is excreted with the sweat. The course of the boil depends on the type of dyscrasia present. The doctor's task is to measure the fever in the right proportion to the juices. In this view, the whole body is treated by the fever in such a way that it can get rid of harmful parts, e.g. pus. This restores the original harmony in the organism. In the Hippocratic image, the whole world (macrocosm) represents a kitchen, and the human being (microcosm) has this kitchen a second time in miniature within him. Accordingly, world forces are active in the fever, which are individualized in the human being. In his "Archeus", Paracelsus (1493 / 1541) refers to a human essence that combines the four elements (water, fire, air and earth) into a qualitatively new fifth element (quinta essentia). The human being is the quintessence of all creation. For Paracelsus, fever is a cleansing force that Archeus uses to purify the body.
In van Helmont's Physiology and Pathology (1579 / 1644), fever is only seen as a waste product of the supernatural powers of Archeus when they carry out the separation and elimination. For him, the cause of fever is Archeus' battle against hostile matter.
In the following period, the natural sciences made their way into the thinking of doctors, replacing religious and philosophical ideas.
Christoph Wilhelm Hufeland (1762 / 1836) still saw fever as "an increased activity of the vascular system and an accelerated life process with the inseparably associated increased heat production 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 clinical thermometer into clinical routine, also recognized a healing power in fever. In his famous lecture in Leyden, he said: "I would be the greatest physician if I could produce fever as easily as I could dispel it."
The complete demythologization of fever then took place in the 19th century, especially through Virchow and Liebermeister, who blamed the temperature increase itself for many damages and disorders. The introduction of salicylic acid into the clinic in 1875 by Buss finally initiated an antipyretic movement that still determines the thinking of many doctors today. It culminated in Liebermeister's comments, who wrote in 1875: "There is no longer any talk of a healing effect of fever or of its beneficial significance for the organism at all, except to the extent that such views are described as the outdated prejudices of an unscientific period." A positive significance of fever for the organism was thus no longer worth discussing for decades.(1) Unfortunately, this view, which has long since been refuted by modern research, has remained with many doctors 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 mentally ill person is attacked by an infection (abdominal typhus, cholera, intermittent fever, erysipelas) in the first six months of his illness, there is a very high probability that he will be cured of his psychosis as a result." He was one of the pioneers of fever therapy and was awarded the Nobel Prize for Medicine in 1929 for the malaria treatment of psychoses and lues. In 1882 in Würzburg, Friedrich Fehleisen dared to treat cancer patients with erysipelas cocci with a highly febrile infection that often lasted for weeks.
In 1892, William B. Coley used a mixture of Streptococcus and B. prodigiosum, which he killed off and used as "Coley's toxin" to treat sarcoma patients with astonishing success in some cases. The literature contains over 700 well-documented cases of spontaneous regression of tumors after high-fever infections.(2) In more recent times, fever therapy was propagated above all by Issels, who reported carefully documented cures of incurable cancer patients.
While the fever treatment of psychoses and lues has become superfluous due to modern medication, interest in fever therapy today is primarily focused on the treatment of cancer. In this field in particular, there has been a change of opinion after the euphoria caused by the development of modern chemotherapeutic agents gave way to the sober realization that cure rates for the most common and important cancer diseases have been stagnating for 30 years now, 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 the fight against cancer was ignored; indeed, the body's own defenses were denied any significance in this regard. However, this opinion has changed in recent years with the development of genetic engineering, which has made it possible to produce defined immune-active substances such as interferons, interleukin, TNF and others in sufficient quantities for clinical trials. All of these messenger substances of the immune system showed one thing in common during clinical trials: they trigger fever. This brings the old fever therapy back into the focus of more recent research; for example, a research group at the University of Freiburg (Prof. Engelhardt) is currently investigating this long-disparaged form of therapy on behalf of the German Federal Ministry of Education and Research.
Therapeutic basic idea and method: What do we mean by active fever therapy?
Active fever therapy means that the body's core temperature is raised by the body's own mechanisms. This is done by administering fever-inducing substances (exogenous pyrogens), which 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. The temperature regulation center, which is located in the hypothalamus of our brain, is primarily involved in the production of fever. This is where an upward adjustment of the temperature setpoint takes place; the body is prompted to produce more heat and does so primarily through muscle tremors (shivering), by increasing the metabolism and by activating the circulation. Today we also know that the exogenous pyrogens are generally not able to generate 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 the same as passive overheating of the body from the outside, e.g. through overheating baths or other more complex procedures for overheating the body, which are now often introduced in cancer treatment at large clinics under the name "hyperthermia treatment".
At temperatures up to 38° C we speak of subfebrile temperatures; up to 39° C we refer to moderate fever and from around 39° C we speak of high fever. Based on the empirical successes that have repeatedly been reported after spontaneous fever, attempts are now being made to artificially induce fever using exogenously administered bacterial endotoxins in the form of Coley's toxin, purified preparations of lipopolysaccharide A3 or preparations of Corynebact. parvum.
The aim and purpose of this type of fever therapy is to activate the immune system and to rebalance the body's vegetative system. In chronic diseases in particular, we often observe a disturbed reaction to or regulation following various biological stimuli. For example, disturbed thermoregulation in chronically ill patients (5,6) has been well studied and is interestingly related to disturbed immune regulation. Thermal measurements therefore make it possible to draw conclusions about the function of the immune system. The author himself has repeatedly observed in his oncology patients that they often do not react adequately to the stimulus caused by the injection of Coley's toxin with a rise in temperature and leukocytosis.
It can therefore be rightly assumed that a major problem of chronically ill patients is their disturbed vegetative regulation, which no longer allows them to compensate for disturbances in their organism triggered by stimuli.
It is possible that this problem is also the key to cancer; after all, what is cancer other than a disturbance in the regulation of the cell, which is no longer able to switch off exposed oncogenes because the cell's own repair systems presumably fail and its membrane no longer reacts to the external stimulus of the cell's neighbor by inhibiting growth?
But the environment in which a cell lives is also decisive for its future fate. We now know that malignant cells can be experimentally redifferentiated into normal body cells if the environment is changed (7). We also know, for example, that turtle eggs differentiate into male or female depending on the ambient temperature. The environment - in this case the temperature environment - therefore also determines the differentiation or the behavior of the genes. Hypothetically, it can therefore be discussed whether the change in environment that takes place during fever can also have a redifferentiating effect on malignant cells.
The first aim of fever therapy, however, is to restart the blocked vegetative regulation in the sense of a rebalancing stimulus body therapy, so that the sick organism has the opportunity to regulate itself and thus initiate healing processes. We know from well-documented case studies, to which the author can also contribute, that such spontaneous healing processes are possible even in the case of extensive cancer, i.e. that our organism definitely has the power to heal large tumors on its own.
Unless we succeed in normalizing this regulation, biological therapy methods and the immunotherapy practised at our universities today are only successful to a limited extent and usually only temporarily. As our immune system is much easier to study than vegetative regulatory mechanisms, we have a wealth of studies documenting the positive effects of fever on our immune system. Roughly schematized, the following statements can be made regarding immune modulation through fever therapy:
The bacterial endotoxins cause fever only indirectly by acting on macrophages and activating them. Activated macrophages can now release various messenger substances of the immune system and thus have a very broad effect on both the specific and the non-specific immune system, which must be given a more important role in the fight against cancer than the specific immune system with the T and B lymphocytes. It is these released messenger substances, in particular interleukin 1 and macrophage inflammatory protein 1, which 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, vasoconstriction and thus to an increase in core body temperature.
At the same time, interleukin 1 acts on the complement and properdin system, the non-specific humoral component of our immune system, which can lead to the cytolysis of cancer cells. However, the cellular component with the natural killer cells, the macrophages and microphages, which are particularly important in cancer therapy, is also activated. Interleukin 1 also activates the T and B lymphocytes. Among other things, plasma cells are produced that can synthesize immunoglobulins and antibodies and interleukin 2 is now also released, which in turn triggers 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 excluding contraindications and carefully examining the patient, fever-inducing substances are injected directly intravenously. In most cases, chills and a rise in temperature of varying degrees occur after approx. 45 to 60 minutes; temperatures of up to 41.7° C have been reached during the first fever spike, but are rare; the core temperature measured rectally usually rises to between 39° C and 40° C and slowly falls to the initial value after two to three hours, but may still be slightly higher in some patients the next day. Symptomatically, additional medication can be administered for nausea, nausea or headaches and aching limbs, although we make sure that this medication does not have an antipyretic effect. The fever shocks are administered one to three times a week. A total of 10 to 15 fever shocks should be administered in a series.
Specific nature of fever therapy, differentiation from pure immunotherapy and hyperthermia
There is no doubt that fever is one of the ontologically oldest healing reactions of the organism. The increased body temperature is obviously not the decisive criterion, but rather the activation of the immune system, the restoration of a normal reaction and possibly also the change in the body environment. Fever therapy is therefore both regulatory and immunotherapy and is an excellent way of stimulating the body's self-healing powers. In contrast to the immunotherapy commonly used today with isolated immunoactive substances - the so-called BMF substances (biological response modifiers) such as TNF, interleukins or interferons, which are administered in unphysiologically 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 superordinate control circuits of the system are positively involved. This explains the success of fever therapy, especially in diseases with an allergic or auto-aggressive component.
Hyperthermia must also be distinguished from the hyperthermia inaugurated by Ardenne in the fight against cancer, which is also the subject of intensive research at our universities today. The aim of hyperthermia is to thermally damage the tumor cell. Due to the high convection, it is very difficult to generate the required temperature of 42.5° C and more in the tumor over a longer period of time; as a rule, even this is not sufficient; rather, hyperthermia is more effective in combination with radiotherapy 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 to that which 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 - immunosuppression tends to occur, which is only later followed by 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.
The only decisive factor for the effect of hyperthermia is the temperature increase that can be achieved in a circumscribed tissue area; in fever therapy, on the other hand, it is not the level of 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.
The only decisive factor for the effect of hyperthermia is the temperature increase that can be achieved in a circumscribed tissue area; in fever therapy, on the other hand, it is not the level of 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 descriptions, it is clear that active fever therapy is particularly indicated for diseases that are associated with a weakness or disorder of the immune system and that are chronic.
Indications:
Oncological diseases of all kinds (except acute leukemias)
Diseases from the rheumatic group and collagenoses: primary chronic polyarthritis M. Bechterew Polyneuritis Guillain-Barré
Chronic inflammatory conditions such as: Ulcerative colitis M. Crohn's disease, chronic bronchitis Chronic recurrent abscesses or pyoderma
allergic diseases such as chronic urticaria, pollinosis, allergic eczema
Contraindications:
Acute microbial infections
Heart and circulatory insufficiency - Condition following a heart attack or pulmonary embolism - Cardiac arrhythmia, hypertension
severe liver parenchymal damage
adrenal insufficiency
haemorrhagic diathesis
ventricular ulcer sive duodeni
pregnancy
What side effects can occur?
Mild side effects: headache, back pain or aching 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 efficacy
Fever therapy is one of the empirically discovered forms of therapy. Doctors had always observed that serious illnesses, often considered incurable, disappeared after fever attacks. The Greek Parmenides (540 - 480 BC) is even credited with saying: "Give me the power to produce fever and I will cure any disease." In more recent times, it was Coley (10) and Issels (11) who systematically applied fever therapy to cancer patients with good, sometimes even spectacular success. Since the beginning of the 1980s, controlled studies on fever therapy have also been carried out several times, using different endotoxins.
A number of epidemiological studies can be regarded as indirect, epidemiological proof of efficacy, 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 studies and epidemiological findings.
The activation of the immune system after fever therapy can be measured directly in various ways. For example, the increased serum levels of interleukin 1 and 2 can be measured directly, as can the increase in leukocytes, B and T lymphocytes, NK cells and LAK cells.
Before activation, however, there is initially a suppression in the initial phase, recognizable by a significant drop in the leukocyte count in the first few hours after injection of the endotoxin. It can therefore not be disputed that fever therapy triggers clear immunological effects in vivo, which provide an explanation for the clinically observed effects.
Widespread use of fever therapy
Therapy with active fever is particularly widespread in German-speaking countries. It is carried out in some specialized clinics under inpatient conditions and on an outpatient basis by general practitioners and even by some alternative practitioners. However, fever therapy has also been used experimentally in the USA, for example at the Memorial Sloan Kettering Cancer Center in New York, and in Japan.
Scientific studies on the effectiveness of fever therapy
Koch, R., Petruschky, J.:
Observations on erysipelas vaccinations in humans. Z. Hyg. 23, 477-489, (1896)
Wagner-Jauregg, J., von: On the effect of malaria on progressive paralysis. 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.: Tumor carriers rarely have a history of infections. 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, p. 177 / 188. N. York 1980
Eggers, H. J.: Significance of fever and hyperthermia for the course of viral infections. In: Z. pyhs. Med. 2, 69 / 77 (1971)
This list does not claim to be exhaustive.