Anthroposophic Approach to Fever

Introduction

This article helps many hospitals and practices to translate a physiologic approach to fever management (16). There is broad scientific consensus that the potential benefits of the febrile reaction are to be weighed up against the discomfort or exhaustion experienced by a minority (17). Especially in the context of bacterial antibiotic resistance, complementary therapies are gaining ever greater attention, as they can contribute to further reducing unnecessary use of antibiotics and antipyretics (18).

Physiology of fever

Fever is a highly developed evolutionary host response with survival and salutary benefits. Fever is one component of the acute phase response, which is a complex physiological reaction to disease or injury that elicits a cytokine-mediated rise in core temperature, generation of acute phase reactants and activation of a number of physiological, endocrinological and immunological effects (1). Even though increasing the body temperature is energy-costly (10 – 12.5 % increase in metabolic rate per 1 °C increase in body temperature (2)), it is an established mechanism in response to injury and infection in birds and mammals (3). Even fish, amphibians, reptiles and many invertebrates such as insects seek external ways of increasing their body temperature when they are infected and their mortality increases if they are prevented from doing so (4). Studies point to potentially harmful effects of suppressing fever in mammals and humans (5 – 8). The protective effects of fever against invading microorganisms, such as bacteria and viruses, result from a variable combination of direct thermic effects (9) and humoral (10) and cellular (11) defense enhancement. With few exceptions (9), from the point of view of immunity and survival, fever offers the host an adaptive advantage (12). Human studies on malaria (7), chicken pox (6) and induced rhinovirus (13) infections also suggest that fever suppression delays recovery. Fever was associated with decreased mortality in Gram-negative bacteremia (14). Hospitalized elderly patients with community-acquired pneumonia were seven times more likely to die if they did not display fever and leukocytosis (15).

Definition of fever

There is no universally accepted definition of fever. Normal body temperature varies between around 35.7 – 37.3 °C (3rd centile and 97th centile) (19). Therefore, some countries like Japan already speak of fever at temperatures above 37.5 °C. Indeed, in a resting person a temperature above 37.2 °C in the morning and 37.7 °C in the evening is indicative of an infection (20).

The German Society of Pediatricians has defined fever as core temperatures above 38.5 ° C. Temperatures between 37.5 and 38.5 ° C are then called “ sub-febrile ” . Many guidelines also call any temperature above 38.0 ° C “ fever ” (17, 21, 22, 22 – 35).

It is important to know, that in children below the age of three months, the height of the temperature correlates with the severity of the illness (36). Thereafter it does not. On the other hand, in the first few weeks of their life, infants are much less likely to develop fever and may therefore have a severe infection without fever (see below).

Hence, fever in a newborn is a serious sign of illness; however, absence of fever or low fever is not a guarantee that the child does not have a systemic infection.

Measuring fever properly

The gold standard in small children is still rectal measurement with a digital thermometer. Advise using a little cream to facilitate entry. Many children find rectal measurements uncomfortable and in some countries it is felt to be inappropriate. An electronic ear thermometer is a good alternative, but measurements can be inaccurate due to earwax or inappropriate placement. Axillary measurements are reliable enough if done properly. Axillary temperature usually equals rectal temperature minus 1°C (37).

In older children and adolescents, sublingual measurement is a frequently used alternative. Be sure to keep the thermometer under the tongue until measurement is finished.

Deep forehead measurements have been found to be adequate for clinical use (38).

Intense research is being carried out in the area of wearable thermometers and many are getting quite good results, though they are not reliable in all patients under all circumstances (39). If parents or patients use them, it may be advisable for them to double-check the first measurements and the high measurements with a standard thermometer.

Understanding body warmth

We create body warmth in the organs and muscles. It permeates us and is given out, via the body surface, to the environment. The higher the stage of development of an animal, the more it regulates its warmth conditions independently. Humans no longer grow a fur or plumage, but actively regulate their thermal equilibrium: e. g. via changes in blood circulation, sweat and behavior (e. g. choice of clothes). This actively regulated heat flow equilibrium results in a "breathing" stable body temperature: asleep, we "breathe" heat out a little, hands and feet are warm, the body core temperature drops slightly. When we are awake and completely at rest, the warmth is more centered, the body temperature rises slightly. When we are under stress, the body further centralizes warmth, raising core temperature by pulling the warmth out of the periphery. The muscles move quickest at around 39 °C, which is why athletes and musicians warm up. Intensive movement eventually creates more warmth than we need: our periphery warms up, and then we sweat to release heat more quickly. Humans have the most effective and versatile ability to regulate warmth, and fever is generally a very precisely regulated phenomenon.

We feel warmth most consciously at the body surface: We feel chilly when our body needs warmth and is trying to keep the heat to itself (for example when the fever rises) and feel warm and sweat when a lot of heat has to be given off.

Fever is a healthy reaction to stress or microorganisms like viruses and bacteria. Viruses and bacteria are less able to multiply during fever. The body’s defense (immune) system works faster in feverish temperatures. High temperatures can therefore contribute to fighting the microorganisms that led to the disease.

The sensory center for body warmth in the brain (the hypothalamus) regulates heat generation and release according to current body needs. It provides for warm (well-circulated) or cold (less well-circulated) hands and feet, body sweats or chills to achieve an adequate body temperature. In response to neural (including stress) or biochemical stimuli the hypothalamus can increase its so-called set temperature. A feeling of being cold sets in, leading to warmth-seeking behavior and peripheral vasoconstriction (cold extremities, paleness). The muscles will produce heat to the point of shivering.

When should professional support be sought?

All children under the age of 3 months should see a doctor on their first day of fever.

Parents should consult a doctor or health professional if the child

• seems seriously ill, pale or livid,
• does not react normally,
• has a stiff neck,
• has a non-blanching skin rash,
• has strong pain, or cannot be comforted,
• is breathing very quickly and with effort,
• won’t drink anything with dehydration symptoms, especially if the child has diarrhea, is vomiting or is listless,
• has a fever for longer than 3 days (then, at the latest, a urine test should be done).

Babies in the first few weeks of their life are much less likely to develop fever and therefore may have a severe infection without fever. At this age, signs like paleness, lividity, oversensitivity to being touched and refusal to drink are more common. In these cases, a doctor should be consulted even if no fever is found. This also applies to the rare cases in which children have immune deficiencies caused by medicines or an immune defect.

Adults with fever should consult a doctor or responsible health professional if they

• seem seriously ill, pale or livid,
• have a very high fever (above 40 °C),
• have strong pain, or cannot be comforted,
• are breathing very quickly and with effort,
• have diarrhea or vomiting and are listless,
• have a fever for longer than 3 days,
• have come back from overseas.

Immediate medical attention is needed if a person

• does not react normally,
• is hallucinating,
• is vomiting profusely,
• has a stiff neck (cannot put their chin on their chest or has pains in the neck when they tilt their heads forward),
• has a non-blanching skin rash,
• has a high resting pulse above 100/minute,
• has convulsions.

Febrile seizures

It is important to differentiate between the three types of febrile seizures:

1. Simple febrile seizure, characterized by a short duration (lasting less than 15 minutes), no focal features and if they occur in series, the total duration is less than 15 minutes (classically a generalized tonic-clonic seizure ). They typically occur between the age of 6 months and 5 years.
2. Complex febrile seizure, in which the seizure lasts longer than 15 minutes or multiple episodes occur within 24 hours and generally does have focal features.
3. Febrile status epilepticus that lasts for longer than 30 minutes.

Febrile seizures occur in less than 5% of children and are partially hereditary.

Three randomized trials and a Cochrane review have come to the conclusion that febrile convulsions cannot be prevented by antipyretics such as paracetamol or ibuprofen (40 – 42). Fortunately, children simple febrile seizures seem to have no negative effect on child development or intelligence.

In rare cases, febrile seizures can be caused by epilepsy – to exclude this, an EEG examination is done in the weeks following a first febrile convulsion in many countries. The EEG should not be performed less than two weeks after the convulsion because during this time, residual effects of the febrile seizure may be falsely interpreted as epilepsy. All children with a first febrile seizure or with any strange event associated with fever should be presented to the pediatric emergency department. Parents whose children frequently have febrile seizures learn how to handle it at home and may not need to bring the child to emergency every time. Warming the child as soon as they appear ill may reduce the rate of seizures (43).

Diagnosis

In about 90 % of the cases, a doctor is able to tell whether fever is related to an ear infection, tonsillitis, bronchitis, pneumonia, intestinal infection or urinary tract infection (the latter generally requires an examination of the urine). Some rashes and symptom constellations are typical for some so-called childhood diseases. In some cases, further examinations such as a blood test or an X-ray may be warranted.

In rare cases, a chronically recurring or long-lasting fever is not caused by an infection. Proper therapy then depends on the correct diagnosis, meaning that a large range of diseases must be systematically excluded. In some cases, no cause is found, and the fever disappears of its own accord. 

Working principles of sustainable integrative therapy

Underlying factors of acute and recurrent infections can be addressed by attending to the following aspects:

• Warmth: During the stage of rising temperature, patients can be helped by being actively warmed. This saves energy, reduces chills and usually increases comfort. Parents can be told that their feverish child is working inwardly and should therefore not be expected to be active outwardly in the sense of playing, socializing or eating. As long as a feverish person has cold hands or feet, or even chills, he or she needs warmth! It is necessary to ensure that the sources of warmth do not cause burns. It is recommendable to avoid stress and suffering by gentle warming during the rise of a fever. Once the person has warm hands and feet, and maybe even sweats, less warming is necessary, but the person should still be kept comfortably warm. To support and balance warmth in the body: Especially when the fever is rising, warm drinks, warming external applications, clothing and avoidance of air conditioning are important. Care for colder body regions!
• Breathing: Good air quality is helpful. The room should be ventilated now and again briefly without causing the patient to get cold; caution with air conditioning.
• Fluids: Consumption of warm fluids in sufficient quantities is essential. Dehydration should be avoided.  But do not force fluid intake. In some countries, enemas are successfully used to prevent dehydration (see chapter “Fluids, Prevention of dehydration” below). [link nach unten]
• Immune supportive nutrition, therapy and microbiota care: During fever, light foods like soups, grated apple, rice water etc. if desired. In convalescence, wholesome nutrition is more important than isolated vitamins and substances. Bitter substances enhance the immune response to acute infections and stimulate digestive processes.
• Exercise, speech and body therapy
• Psychosomatic aspects: Reducing input esp. by screens and media, considering emotional and social conflicts, stress and overload.
• Biographical and social aspects: Considering biographical and social aspects may open a window to change unhealthy behaviors and life circumstances.

Not all these principles will be explained in detail.

Behavior, general recommendations, sick leave

Adult Patients should stop active and passive smoking and reduce screen use, children should avoid all screen use (if they are in need of entertainment, a real person should be with them, telling stories, reading them books, offering drinks, doing manual house work or simply being there). Sick leave should be considered individually, bedrest is recommendable in each case of fever.

Encourage someone familiar to be there for the sick person, especially for children and youth. Days of illness in a person’s life are an opportunity for nurturing relationships and relationship quality is important for health, development and learning.

Each person reacts differently. While some hardly notice much and continue to play/work and eat normally, others may be very tired and just want to sleep. Some may be very grumpy and suffer from not feeling well or from diffuse pains.

If the person is asleep, let him or her sleep. It is unnecessary to measure temperature in a sleeping person. Offer enough to drink, in sips. Eating is less important.

Warmth and external applications

• In the first phase of fever (see above) warm drinks and warm external applications are recommended. In case of high body temperature with severe discomfort, compresses (at body temperature) can help. Do not apply cold.
• Simple household remedies can be used to improve well-being without lowering the fever using medication:
  – Lemon slices on the soles of the feet are recommended to reduce headache, especially when the calves are cold.
  – In high fever with discomfort, warm, thin calf compresses (not cold to avoid a counter-reaction), preferably with a zest of lemon 
     will take the heat off by themselves though evaporation.
  – Compresses on the forehead (with some drops of lemon juice or Arnica essence) may alleviate headache.

For compresses see also:
https://www.kindergesundheit-info.de/themen/krankes-kind/alltagstipps/fieber-co/wickel-umschlaege/ and
http://www.pflege-vademecum.de/anwendungen_bei_fieber.php?locale=de

Fluids, Prevention of dehydration

Herbal teas (for example lime tree blossom tea is warming and helps to dissolve mucus) may be slightly sweetened; light food.

In some countries, enemas are used to prevent dehydration and improve the general condition. This can stabilize the circulation, especially in small children who drink little, as well as gently reduce the temperature. This practice is especially justified where hospitals are far away, dangerous or traumatizing. An approximately 35 – 37 °C enema of an electrolyte solution, such as those offered in pharmacies for children with diarrhea (e. g. Oralpadon® neutral) is used, filled with 50 – 100 ml for infants and up to 200 ml for young children (corresponding enema bulbs are available in the pharmacy or via internet) (44, 45).

Stabilizing general condition by anthroposophic or homeopathic medicines

Anthroposophic, herbal or homeopathic medicines, such as Belladonna, Aconitum or Ferrum phosphoricum do not primarily reduce fever, but are rather given to stabilize the general condition. It may be appropriate to give:

• Apis/Belladonna Globuli WALA, Erysidoron® 1 drops WELEDA
  Dosage: Apis/Belladonna 5 – 10 pillules up to 2-hrly. Children up to age 2 yrs: 2 – 3 pillules up to 2-hrly. Children up to age 12 yrs: 5 – 8 pillules up to 2-hrly. Erysidoron 1: 6 – 10 gtt. up to 2-hrly. Children aged 2 – 12 yrs: 4 – 8 gtt. up to 2-hrly.
  Is indicated in patients with acute fever, cold hands and feet, sometimes with a reddened face and congestion of the head. Also effective in patients with acute otitis media, catarrhal tonsillitis and acute mastitis.
• Infludo® drops (adult patients), Infludoron® or Kinfludo® pillules (children) WELEDA
  Dosage: Infludo 8 – 10 gtt. up to 2-hrly during the day, with a pause during the night, Infludoron®. Children aged 1 – 5 yrs: 3 – 5 pillules up to 2-hrly. Children aged 6 – 12 yrs: 5 – 10, Adults 15 pillules per dose.
  Indicated especially in the first phase of acute fever with chills; in a reduced dosage (4 – 5 x daily) also appropriate in the second phase until fever disappears. It helps the patient to warm up and keep warm as long as is required to overcome the infection. Cough (an infection of the airways) is a typical symptom, and the medication may prevent infections of the lower airways.  Particularly indicated when a cold climate is an illness trigger.
• Gelsemium comp. WALA
  Dosage: 3 – 5 x daily 5 – 10 pillules
  in patients who develop their fever more slowly, with headache and sore throat. The climate may be comparatively warm in relation to the time of the year.
• Fever and Teething Suppositories WELEDA (also available as Chamomilla comp. suppositories, Fieber- und Zahnungszäpfchen
  Dosage: 1 – 3 x daily
  These Suppositories can be used in infants and little children for treatment of pain and discomfort.

Composition of the medicinal products mentioned:
Erysidoron: Apis/Belladonna: Apis mellifica ex animale toto Gl D4, Atropa belladonna e fructibus D3. Erysidoron 1: Apis mellifica D2, Belladonna D2. Infludo®: Aconitum napellus D3, Bryonia D2, Eucalyptus D2, Eupatorium perfoliatum D2, Phosphorus D4, Sabadilla D3. Infludoron®: Aconitum napellus D1, Bryonia D1, Eucalyptus Ø, Eupatorium perfoliatum D1, Ferrum phosphoricum D6, Sabadilla Ø. Belladonna D3; Chamomilla recutita, Radix D2; Echinacea Φ; Echinacea purpurea, Planta tota Φ; Papaver somniferum, Fructus immat. D3; Argentum metallicum praeparatum D19. Fieber- und Zahnungszäpfchen: Belladonna D3; Chamomilla recutita, Radix D2; Echinacea Φ; Echinacea purpurea, Planta tota Φ; Papaver somniferum, Fructus immat. D3; Argentum metallicum praeparatum D19.

Management of pain and discomfort

In most cases, pain and discomfort management is possible by means of the external and topical applications mentioned above in combination with anthroposophic/phytotherapeutic medicines. Severe pain first requires careful clinical diagnostics.

Paracetamol has analgesic effects and ibuprofen has analgesic and anti-inflammatory effects, but both can cause a wide array of side effects. They may be useful in cases of acute heavy pain without sufficient relief. Fever itself is not an indication for use of paracetamol and ibuprofen (see below).

Advise parents to inform the school or kindergarten. Children should return only when they have been looking and feeling well again and have been fever-free for at least one day without medication.

There is no upper threshold value for the suppression of fever

There is no evidence that children with fever are at increased risk of commonly feared outcomes such as brain damage, epilepsy or death (46, 47) and very low evidence that there is a correlation between height of fever and mortality in adults (48). The correlation may even be negative since in elderly patients with pneumonia mortality was increased in those without fever (15) and there is some evidence that suppression of fever leads to poorer outcomes in serious diseases such as meningitis (49). As well, human studies on malaria (7), chicken pox (6) and induced rhinovirus (13) infections suggest that fever suppression delays recovery and increases shedding time.

Understanding antipyretics

Beyond suppressing the benefits of fever, pharmacological antipyresis has its own risks: a review financed by ibuprofen distributors (50) could not convincingly disprove that ibuprofen may increase the risk of necrotising fasciitis caused by Group A Streptococcus (GAS) secondary to varicella or herpes zoster (51 – 54) while mice inoculated with (GAS) had increased wound area and mortality when receiving ibuprofen (55). There is increasing evidence that ibuprofen in case of respiratory infections or pneumonia may facilitate empyema and complicated pneumonia in children (56 –59) and adults (60), possibly via modification of neutrophil and alveolar macrophage functionality (chemotaxis, adhesion, aggregation, degranulation (61)) and the inhibition of prostaglandin synthesis as well as via cover-up effects on subjective symptoms, thereby delaying diagnosis and treatment. This may explain the correlation between increased sales of ibuprofen for children and complicated pneumonia in France (57), although reverse causation is also possible. Further risks associated with antipyretic use include systemic reactions, asthma (especially for paracetamol (62 –65)), gastrointestinal complications and anorexia (66), low white blood cell count (ibuprofen) (67), hepatic injury (paracetamol) (68), overdose (paracetamol) (68), and, extremely rarely, anaphylaxis (69, 70) (although sometimes the reaction may be due to other substances such as mannitol (71)).

The suppression of the acute phase reaction symptoms and the slightly euphorizing effect of antipyretics is likely to increase interaction with other people and the rate and duration of viral shedding, as has been shown in human volunteers (72) and ferrets (73). Indeed, recent modeling of available data suggests a significant increase in contagion and mortality risk through antipyretics (74). Considering further that accidental acetaminophen overdose has caused over 100 deaths per year in the USA (68), one wonders how many lives may have been saved had scientists popularized their positive attitude towards fever even earlier (adapted from (43)).

Thus, antipyretic drugs such as ibuprofen and paracetamol (acetaminophen) are not necessary even in cases of high fever. Since they interfere with the course of the disease and an overdose is dangerous, they should only be administered when advised that there is a clear need for them and not for the sole purpose of lowering the temperature, for example in cases of pain. Infectious diseases do not heal faster when the fever is lowered (but you may notice them temporarily less).

After an antipyretic, the person sweats temporarily, the body temperature cools down, the person may then feel temporarily less ill than he or she is, and if the cause of the fever persists, after about 6 to 8 hours he or she may have renewed shivering and a worsening general condition. If you prescribe or administer an antipyretic medicine, please reckon with this course and accompany accordingly with appropriate care for warmth (uncover, cover).

Some adults take aspirin when they have fever. Aspirin should not be given to children as it has, in rare cases been associated with Reye’s syndrome.

For the preparation of this expert recommendation the authors have

• collected and analyzed all available official conventional guidelines on the symptomatic management of fever in children from 195 countries and all international health organizations;
• developed a fever Video-Guideline together with the German Professional Association of Pediatric and Adolescent Medicine (see “Brief Summary of Basic Recommendations for parents of a child with fever” and www.feverapp.org);
• analyzed the anthroposophical approach to fever and its scientific validity (43);
• consulted and collaborated with the international, interdisciplinary expert Care II group.

Summary of the comparison of all available guidelines worldwide

The comparison of guidelines of fever management world-wide revealed discrepancies with each other and with scientific literature regarding all aspects covered. A conclusion of the authors from this review of all guidelines is that some recommendations may become part of all guidelines:

• In an otherwise healthy person with a febrile infection, there is no proven temperature threshold above which fever must be suppressed.
• Fever is an immunological resource that should only be suppressed if the febrile person is still significantly distressed after the social and physical environments have been optimized.
• Antipyretics should not be combined, or routinely alternated.
• Antipyretics should not be given with the intention of preventing febrile seizures
• Children with fever should not be underdressed or over-wrapped
• Cold applications (sponging, bathing, compresses) increase discomfort and metabolic strain
• Complementary medicinal products and applications are widely used in many countries and should therefore be mentioned.
• Proctoclysis (enemas) for hydration should be considered in appropriate settings to prevent hospitalization if oral means of preventing dehydration are unsuccessful, especially in young children.

Analysis of the anthroposophic approach to fever and its scientific validity

A narrative review on this subject is freely available on the internet: Martin DD. Fever: Views in Anthroposophic Medicine and their Scientific Validity. Evidence-Based Complementary and Alternative Medicine 2016(1):13 pages. http://dx.doi.org/10.1155/2016/3642659

Scoping the available literature and views within the Anthroposophic Medical Community led to thirteen opinion statements about fever (43):

1. The leading motif in Anthroposophic Medicine is that warmth and, in disease, fever are direct manifestations of the “self” working on the body, making the body more an instrument and expression of the “ego”, the “I” (in German “das Ich”) (75) (76) (77) (78) (79) (80) (81)
2. Fever may allow faster and/or more complete resolution of infections (82) (83) (77) (76) (84) (85) (78) (79) (80) (81)
3. Fever may prevent recurrent infection (76) (78) (79) (80) (81)
4. Fever may assists immune maturation in children (76) (77) (78) (79) (75)(80) (81)
5. Fever may protect against developing allergic diseases (86) (76) (78) (81) (79) (80)
6. Fever may help resolve allergic disease (86) (76) (78) (80) (81) (79)
7. Fever offers a unique opportunity for care-givers to provide loving care (76) (78) (79) (80) (81)
8. Fever may facilitate individual development and creativity (78) (79) (81) (84) (83)
9. Febrile illness may help a developing child take ownership of their body towards a better expression of their unique individuality and to overcome inherited (e.g. genetic and epigenetic) traits (76) (78) (81) (79) (84) (83) (80)
10. Febrile illnesses may be protective against cancer (88) (89) (78) (80) (81) (79)(75)
11. Some febrile illnesses may contribute to curing cancer (78) (79) (75)
12. Febrile reactions to injecting mistletoe products in cancer treatment may improve treatment outcome (88) (79) (89) (78) (79) (80) (81)
13. Antipyretics such as acetaminophen and ibuprofen should be used sparingly: only if other means of relieving discomfort fail or if fever needs to be suppressed for other medical reasons (82) (78) (79) (75) (77) (76) (80) (81)

Many of these views are now well substantiated scientifically and slowly finding their way into the practice of main-stream medicine (16) : Fever is a self-regulated phenomenon and does not, in a normal healthy patient with an acute infection, cause harm of itself. Going through a feverish illness may contribute to individual development and long-term health and should be accompanied in a way that fosters salutogenic competencies. Since it is self-regulated, there is no temperature above which the natural fever of acute infections must be lowered per se in normal children (17) . Antipyretics should be reserved for the cases in which the fever is endangering the patient – such as in brain injury where cooling may be advantageous – or is causing distress and malaise and alternative ways of easing suffering fail or seem inadequate. Be aware of the underlying causes of fever and carefully accompany fever instead of suppressing it. Other views with regards to the long-term benefits of fever still await empirical confirmation, negation or differentiation through further research.

It is important for anthroposophically inclined practitioners, carers and patients to be aware of the fact that the scientific investigation of the effects of febrile infections on short and long-term health and development in humans is only beginning and that many salutogenic effects (86) (82) (6) (7) (13) (90) (91) (92) (15) (93) (94) (95) (96) (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) (112) (113) (114) (115) (89) (116) are emerging. However, fever needs special attention in late gestation (117), infancy (particularly the first three months of life, babies with fever should always be promptly and thoroughly examined by a competent health worker(116)), sedated ventilated septic patients (118) (119), brain injury (120) and in patients with Brugada syndrome (it may be recommendable to perform an ECG during fever if there is a positive family history of sudden death or syncope (121) (122) – bearing in mind that 2 % of the population may have asymptomatic Brugada-ECG signs in febrile conditions).

Appendix: A philosophical perspective on fever

On a physical level it has, for some time been clear, that fever is inherently meaningful: Most viruses and bacteria are less able to thrive in the body at febrile temperatures. On a physiological level it is now very evident that fever enhances the immediate systemic and local immune defenses as well as long-term immune competency. There are conditions in which fever needs to be counteracted – but in an otherwise healthy person with a febrile infection, fever is an important resource to be harnessed and not suppressed.

If we now turn to the levels of cognition, perception, feeling, motivation, self and meaning, a very individualized and multi­-perspective approach is needed, because the “higher” the level, the less we can speak of cause and effect in the way we do on the purely physical level. Yet there are clearly describable phenomena on these levels that can thus be analyzed scientifically. One phenomenon is that a person will be able to cope with a situation much better if he or she understands the situation and can see meaning in it – or feel that the carers do. On a psychological level it can often be the parents of an ill child who, in their whole way of dealing with the child and the illness, communicate “you are meaningful to me, and what you are going through at the moment is meaningful”. The spiritual level is the level at which we actively impart meaning to a situation and develop an inner relationship to it, we make it meaningful in the whole way we deal with it – the candle, the warm tea, the medicines, the external applications, and the feelings, thoughts and attitude we cultivate. Speaking about the spiritual level in our normal language is always paradoxical. It is a level at which nothing exists that we do not create out of ourselves – and yet, by this very act of creation we partake in the deepest fabric of the world and discover that it is perfused with levels upon levels of ever deeper and all-encompassing, active meaning. (Some readers may find it easier to understand the last sentences by replacing the word “meaning” by the word “relationship” – which are two sides of the same coin.)

Research is still needed to be more specific about soul and spiritual aspects of fever. This research needs to be done using both “inner” and “outer” experience. “Outer” research has shown that there is an association between warmth and empathy and generosity (43), and that autistic children seem more socially approachable when they have fever (43). Inner experiences with fever suggest that going through fever in a good way can be a process out of which renewed strength and vigor of body and soul is found (43). One of the aims of Anthroposophic Medicine is to enable just this – and to prevent and treat the weakness, exhaustion and lack of recuperation that can also be the result of a febrile illness.

Viktor Frankl, the founder of Logotherapy, established that one of our deepest needs and quests is for meaning. Indeed, recent research has shown that people in palliative situations or with chronic disabilities and diseases usually have a strong wish that their life is and will have been meaningful to others. Scientific interpretation of the world, of matter, and of disease has tended to be rather reductionist in the last century, leaving little space for meaning beyond a mechanistic “mutate and survive if you are fitter” paradigm. A look at present scientific interpretation of fever indicates that things are changing: fever is gaining meaning.

1. Mackowiak PA. Concepts of fever. Archives of Internal Medicine 1998;158(17):1870–1881.[Crossref]
2. Kluger MJ. Phylogeny of fever. In: Federation Proceedings 1979, p. 30–34. Available at: http://europepmc.org/abstract/med/759235 (15.02.2016).
3. Blatteis CM. Fever: is it beneficial? Yale Journal of Biology and Medicine 1986;59(2):107–116.  
4. Bernheim HA, Kluger MJ. Fever: effect of drug-induced antipyresis on survival. Science 1976;193(4249):237–239.
5. Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analyis. Journal of the Royal Society of Medicine 2010;103(10):403–411.[Crossref]
6. Doran TF, De Angelis C, Baumgardner RA, Mellits ED. Acetaminophen: more harm than good for chickenpox? The Journal of Pediatrics 1989;114(6):1045–1048.
7. Brandts CH, Ndjave M, Graninger W, Kremsner PG. Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria. The Lancet 1997;350(9079):704–709.[Crossref]
8. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, Elhaddad A, Lasko D, Amortegui J, Dy CJ, Dlugasch L, Baracco G, Cohn SM.. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surgical Infections 2005;6(4):369–375.[Crossref]
9. Mackowiak PA. Direct effects of hyperthermia on pathogenic microorganisms: Teleologic implications with regard to fever. Reviews of infectious diseases 1980;3(3):508–520.
10. Mackowiak PA, Marling C. Hyperthermic enhancement of serum antimicrobial activity: mechanism by which fever might exert a beneficial effect on the outcome of gram-negative sepsis. Infect Immunology 1983;39(1):38–42.
11. Appenheimer MM, Chen Q, Girard RA, Wang WC, Evans SS. Impact of fever-range thermal stress on lymphocyte-endothelial adhesion and lymphocyte trafficking. Immunological Investigations 2005;34(3):295–323.
12. Roberts NJ. Temperature and host defense. Microbiological Reviews 1979;43(2):241–259.
13. Plaisance KI, Kudaravalli S, Wasserman SS, Levine MM, Mackowiak PA. Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. Pharmacotherapy 2000;20(12):1417–1422.
14. Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Archives of Internal Medicine 1971;127(1):120–128.
15. Ahkee S, Srinath L, Ramirez J. Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. Southern Medical Journal 1997;90(3):296–298.
16. El-Radhi ASM. Why is the evidence not affecting the practice of fever management? Archives of Disease in Childhood 2008;93(11):918–920.[Crossref]
17. Sullivan JE, Farrar HC, American Academy of Pediatrics, the Section on Clinical Pharmacology and Therapeutics. Clinical report – fever and antipyretic use in children. Pediatrics 2011;127(3):580-587.[Crossref]
18. Emde B, Heine R, Huber B, Martin D, Soldner G, Szöke H, Vagedes H, Winkler H.  Anthroposophic approach to acute and recurrent rhinosinusitis in adults and children. Available at https://www.anthromedics.org/PRA-0685-EN (13.03.2019).
19. Sund‐Levander M, Forsberg C, Wahren LK. Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review. Scandinavian Journal of Caring Sciences 2002;16(2):122–128.
20. Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992;268(12):1578–1580.
21. Ministry of Public Health, General Directorate of Pharmaceutical Affairs. National standard treatment guidelines for the primary level. 2013. Available at http://apps.who.int/medicinedocs/documents/s21744en/s21744en.pdf (13.05.2019).
22. L’association des pédiatres libéraux d’Alger (APLA). Fièvre de l’enfant : que faire? apla. Available at http://www.apla-dz.org/conseils-aux-parents/maladies-infantiles/votre-enfant-a-de-la-fievre/ (23.05.2018).
23. South Australian Child Health Clinical Network. Management of fever without focus in children (excluding neonates), clinical guideline. 2013. Available at  http://www.sahealth.sa.gov.au/wps/wcm/connect/812ad70040d041b4972cbf40b897efc8/Fever+without+Focus_Apr2015.pdf?MOD=AJPERES&CACHEID=812ad70040d041b4972cbf40b897efc8 (13.03.2019).
24. Österreichische Gesellschaft für Kinder- und Jugendheilkunde. Fieber und Schmerzen: Was tun? Available at http://www.paediatrie.at/home/Spezialbereiche/Infektiologie/fieber_und_schmerzen_bei_kindern_was_tun.php (13.05.2019).
25. XI. La fievre chez l’enfant. Available at http://www.pediatrie.be/fr/xi-la-fievre-chez-l_enfant/251/2 (23.05.2018).
26. The College of Family Physicians Canada. Fever in infants and children. 2011. Available at http://www.cfpc.ca/ProjectAssets/Templates/Resource.aspx?id=3596 (23.05.2018).
27. SOCHIPE - Soc. Chilena de Pediatría. Fiebre : Tratamiento Ambulatorio. 2013. Available at http://www.sochipe.cl/v3/presenta_dos.php?id=610 (23.05.2018).
28. Asociación de Pediatría de El Salvador. Lo que debe saber sobrela fiebre de su hijo. Asopedes 2015. Available at http://asopedes.org/lo-que-debe-saber-sobre-la-fiebre-de-su-hijo/ (23.05.2018).
29. Agence française de sécurité sanitaire des produits de santé (Afssaps). Mise au Point Sur la Prise en Charge de la Fievre Chez l’Enfant. Available at http://ansm.sante.fr/var/ansm_site/storage/original/application/8a3e72e8fec9c0f68797a73832372321.pdf (13.05.2019).
30. Oteman N, Berger MY, Boomsma LJ, Wiersma TJ, Goudswaard AN, Nederlands Huisartsen Genootschap. [Summary of the practice guideline “Children with fever“ (Second Revision) from the Dutch College of General Practitioners]. Nederlands Tijdschrift voor Geneeskunde 2008;152(51–52):2781–2786.
31. Green R, Jeena P, Kotze S, Lewis H, Webb D, Wells M, u. a. Management of acute fever in children: guideline for community healthcare providers and pharmacists. South African Medical Journal 2013;103(12):948–954.[Crossref]
32. Jehangir Apollo hospital. Fever in children. 2013. Available at http://www.jehangirhospital.com/blog/item/2-fever-in-children (13.05.2019).
33. 1177 Vårdguiden. Fever in children/Feber hos barn – engelska – sjukdomar, undersökningar, hitta vård, e-tjänster. Available at https://www.1177.se/Other-languages/Engelska/Barn/Feber--vad-kan-man-gora-sjalv/ (23.05.2018).
34. Swiss Pediatrics Association. When children are ill: some advice for parents. 1995. Available at http://www.swiss-paediatrics.org/sites/default/files/parents/10-16_ans/maladie/pdf/2012.12.31_ryan_kate_e_homepage.pdf (13.05.2019).
35. Association of Ukranian Pediatricians. Fever and hyperperexia in children. Emergency Medicine 2012;44(5):13-16.
36. National Institute for Health and Care Excellence (NICE). Fever in under 5s: assessment and initial management. Guidance and guidelines. NICE 2017. Available at https://www.nice.org.uk/guidance/cg160 (23.05.2018).
37. Shann F, Mackenzie A. Comparison of rectal, axillary, and forehead temperatures. Archives of Pediatrics and Adolescent Medicine 1996;150(1):74–78.
38. Matsukawa T, Sessler DI, Ozaki M, Hanagata K, Iwashita H, Kumazawa T. Comparison of distal oesophageal temperature with “deep” and tracheal temperatures. Canadian Journal of Anesthesia 1997;44(4):433–438.
39. Offringa M, Newton R, Cozijnsen MA, Nevitt SJ. Prophylactic drug management for febrile seizures in children. Cochrane Epilepsy Group (Ed.) Cochrane Database of Systematic Reviews 22 February 2017.[Crossref]
40. Strengell T, Uhari M, Tarkka R, Uusimaa J, Alen R, Lautala P, Rantala H. Antipyretic agents for preventing recurrences of febrile seizures: randomized controlled trial. Archives of Pediatrics and Adolescent Medicine 2009;163(9):799–804.[Crossref]
41. Rosenbloom E, Finkelstein Y, Adams-Webber T, Kozer E. Do antipyretics prevent the recurrence of febrile seizures in children? A systematic review of randomized controlled trials and meta-analysis. European Journal of Paediatric Neurology 2013;17(6):585–588.[Crossref]
42. Martin DD. Fever: Views in Anthroposophic Medicine and their scientific validity. Evidence-Based Complementary and Alternative Medicine 2016(1):13 pages.[Crossref]
43. Rouhani S, Meloney L, Ahn R, Nelson BD, Burke TF. Alternative rehydration methods: A systematic literature review and lessons for resource-limited care. Pediatrics 2011;127(3): e748-757.[Crossref]
44. Nelson BD, Collins LB, Pritchard EWJ. Innovations in low- and middle-income countries for newborn and child health. In: Ahn R, Burke TF, McGahan A (Eds.) Innovating for Healthy Urbanization. Boston: Springer; 2015, p. 19–40. Available at https://link.springer.com/chapter/10.1007/978-1-4899-7597-3_2 (23.05.2018).
45. Richardson M, Purssell E. Who’s afraid of fever? Archives of Disease in Childhood 2015;100(9):818–820.[Crossref]
46. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Archives of Internal Medicine 2000;160(4):449–456.
47. Kiekkas P, Velissaris D, Karanikolas M, Aretha D, Samios A, Skartsani C, Baltopoulos GI, Filos KS. Peak body temperature predicts mortality in critically ill patients without cerebral damage. Heart and Lung 2010;39(3):208–216.[Crossref]
48. Wong VK, Hitchcock W, Mason WH. Meningococcal infections in children: a review of 100 cases. The Pediatric Infectious Disease Journal 1989;8(4):224–227.
49. Southey ER, Soares-Weiser K, Kleijnen J. Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Current Medical Research and Opinion 2009;25(9):2207–2222.[Crossref]
50. Souyri C, Olivier P, Grolleau S, Lapeyre-Mestre M. Severe necrotizing soft-tissue infections and nonsteroidal anti-inflammatory drugs. Clinical and Experimental Dermatology 2008;33(3):249–255.[Crossref]
51. Ford LM, Waksman J. Necrotizing fasciitis during primary varicella. Pediatrics 2000;105(6):1372–1375.
52. Veenstra RP, Manson WE, van der Werf TS, Fijen J, Tulleken JE, Zijlstra JG, Ligtenberg JJM. Fulminant necrotizing fasciitis and nonsteroidal anti-inflammatory drugs. Intensive Care Medicine 2001;27(11):1831–1831.
53. Hidalgo-Carballal A, Suárez-Mier MP. Sudden unexpected death in a child with varicella caused by necrotizing fasciitis and streptococcal toxic shock syndrome. The American Journal of Forensic Medicine and Pathology 2006;27(1):93–96.[Crossref]
54. Weng T-C, Chen C-C, Toh H-S, Tang H-J. Ibuprofen worsens Streptococcus pyogenes soft tissue infections in mice. Journal of Microbiology, Immunology and Infection 2011;44(6):418–423.[Crossref]
55. Byington CL, Spencer LY, Johnson TA, Pavia AT, Allen D, Mason EO, Kaplan S, Carroll KC, Daly JA, Christenson JC, Samore MH. An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations. Clinical Infectious Diseases 2002;34(4):434–440.[Crossref]
56. François P, Desrumaux A, Cans C, Pin I, Pavese P, Labarère J. Prevalence and risk factors of suppurative complications in children with pneumonia. Acta Paediatrica 2010;99(6):861–866.[Crossref]
57. Elemraid MA, Thomas MF, Blain AP, Rushton SP, Spencer DA, Gennery AR, Clark JE5; North East of England Pediatric Respiratory Infection Study Group Newcastle upon Tyne, UK. Risk factors for the development of pleural empyema in children. Pediatric Pulmonology 2015;50(7):721–726.[Crossref]
58. Le Bourgeois M, Ferroni A, Leruez-Ville M, Varon E, Thumerelle C, Brémont F, Fayon MJ6, Delacourt C7, Ligier C8, Watier L8, Guillemot D9; Children, Antibiotics, Nonsteroidal Anti-inflammatory Drugs and Childhood Empyema (ChANCE) Study Group. Nonsteroidal anti-inflammatory drug without antibiotics for acute viral infection increases the empyema risk in children: A matched case-control study. Journal of Pediatrics 2016;175:47–53.[Crossref]
59. Voiriot G, Dury S, Parrot A, Mayaud C, Fartoukh M. Nonsteroidal antiinflammatory drugs may affect the presentation and course of community-acquired pneumonia. CHEST Journal 2011;139(2):387–394.[Crossref]
60. Mikaeloff Y, Kezouh A, Suissa S. Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease. British Journal of Clinical Pharmacology 2008;65(2):203–209.[Crossref]
61. Beasley R, Clayton T, Crane J, von Mutius E, Lai CK, Montefort S, Stewart A; ISAAC Phase Three Study Group. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme. The Lancet 2008;372(9643):1039–1048.[Crossref]
62. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, FitzGerald JM. Acetaminophen use and the risk of asthma in children and adults. CHEST Journal 2009;136(5):1316.[Crossref]
63. Perzanowski MS, Miller RL, Tang D, Ali D, Garfinkel RS, Chew GL, Goldstein IF, Perera FP, Barr RG. Prenatal acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort. Thorax 2010;65(2):118.[Crossref]
64. Kanabar D, Dale S, Rawat M. A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms. Clinical Therapeutics 2007;29(12):2716–2723.[Crossref]
65. Ludvigsson JF. Epidemiological study of constipation and other gastrointestinal symptoms in 8000 children. Acta Paediatrica 2006;95(5):573–580.
66. Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. Jama 1995;273(12):929–933.
67. Nourjah P, Ahmad SR, Karwoski C, Willy M. Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States. Pharmacoepidemiology and Drug Safety 2006;15(6):398–405.[Crossref]
68. Kang LW, Kidon MI, Chin CW, Hoon LS, Hwee CY, Chong NK. Severe anaphylactic reaction to ibuprofen in a child with recurrent urticaria. Pediatrics 2007;120(3):e742–e744.[Crossref]
69. Bachmeyer C, Vermeulen C, Habki R, Blay F, Leynadier F. Acetaminophen (paracetamol)-induced anaphylactic shock. Southern Medical Journal 2002;95(7):759–761.
70. Jain SS, Green S, Rose M. Anaphylaxis following intravenous paracetamol: the problem is the solution. Anaesthesia and Intensive Care 2015;43(6).[Crossref]
71. Graham NM, Burrell CJ, Douglas RM, Debelle P, Davies L. Adverse effects of aspirin, acetaminophen, and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. The Journal of Infectious Diseases 1990;162(6):1277–1282.
72. Husseini RH, Sweet C, Collie MH, Smith H. Elevation of nasal viral levels by suppression of fever in ferrets infected with influenza viruses of differing virulence. The Journal of Infectious Diseases 1982;145(4):520–524.
73. Earn DJ, Andrews PW, Bolker BM. Population-level effects of suppressing fever. Proceedings of the Royal Society B: Biological Sciences 2014;281(1778):20132570.[Crossref]
74. Husemann F. Scharlach und eitrige Angina in zehn Jahren Praxis. Der Merkurstab 1998;51(1):16–24.
75. Soldner G, Stellmann HM. Krankheitsbekämpfung und Gesundheitsentwicklung: Therapiemöglichkeiten der Pneumonie im Kindesalter. Der Merkurstab. 2002;55:43–59.
76. Harmsen IA, Ruiter RAC, Paulussen TGW, Mollema L, Kok G, de Melker HE. Factors that influence vaccination decision-making by parents who visit an anthroposophical child welfare center: A focus group study. Advances in Preventive Medicine 2012;175694.[Crossref]
77. Soldner G, Stellmann HM. Individual Paediatrics: Physical, Emotional and Spiritual Aspects of Diagnosis and Counseling - Anthroposophic-homeopathic Therapy. 4th. ed. Boca Raton: CRC Press; 2014.
78. Girke M. Innere Medizin. Grundlagen und therapeutische Konzepte der Anthroposophischen. 2nd ed. Berlin: Salumed; 2012.
79. Vagedes J, Soldner G. Das Kinder-Gesundheitsbuch. München: Gräfe und Unzer; 2008.
80. Glöckler M, Goebel W. A Guide to Child Health: A Holistic Approach to Raising Healthy Children. Edinburgh: Floris Books; 2013.
81. Hamre HJ, Glockmann A, Schwarz R, Riley DS, Baars EW, Kiene H, Kienle GS. Antibiotic use in children with acute respiratory or ear infections: prospective observational comparison of anthroposophic and conventional treatment under routine primary care conditions. Evidence-Based Complementary and Alternative Medicine 2014; Article ID 243801.[Crossref]
82. Kummer KR. 1001 mal Masern – prospektive Untersuchung von 886 und retrospektive von 115 Verläufen in der Praxis. Der Merkurstab 1999;52:369–375.
83. Fintelmann V, Hopferwieser M, Kennyeres B, Görnitz S. Die Masernepidemie in Salzburg, Ostern 2008. Der Merkurstab 2011;64:128–142.
84. Busche P. Masern im Erwachsenenalter – eine Kasuistik. Der Merkurstab 2015;68(6):455–458.
85. Alm JS, Swartz J, Lilja G, Scheynius A, Pershagen G. Atopy in children of families with an anthroposophic lifestyle. The Lancet 1999;353(9163):1485–1488.[Crossref]
86. Alm JS, Swartz J, Lilja G, Scheynius A, Pershagen G. Atopy in children of families with an anthroposophic lifestyle. Lancet. 1. Mai 1999;353(9163):1485–1488.[Crossref]
87. von Schoen-Angerer T, Wilkens J, Kienle GS, Kiene H, Vagedes J. High-dose viscum album extract treatment in the prevention of recurrent bladder cancer: A retrospective case series. The Permanente Journal 2015;19(4):76–83.[Crossref]
88. Albonico HU, Bräker HU, Hüsler J. Febrile infectious childhood diseases in the history of cancer patients and matched controls. Medicinal Hypotheses 1998;51(4):315–320.
89. Sutton LP, Dodge KG. The treatment of chorea by induced fever. Journal of Pediatrics 1933;3(6):813–826.
90. Sutton LP, Dodge KG. Fever therapy in chorea and in rheumatic carditis with and without chorea. Journal of Laboratory and Clinical Medicine 1936;21(6):619–628.
91. Baize S, Marianneau P, Loth P, Reynard S, Journeaux A, Chevallier M, Tordo N, Deubel V, Contamin H. Early and strong immune responses are associated with control of viral replication and recovery in Lassa virus-infected cynomolgus monkeys. Journal of Virology 2009;83(11):5890–5903.[Crossref]
92. Baudouin SV, Saunders D, Tiangyou W, Elson JL, Poynter J, Pyle A, Keers S, Turnbull DM, Howell N, Chinnery PF. Mitochondrial DNA and survival after sepsis: a prospective study. The Lancet 2005;366(9503):2118–2121.[Crossref]
93. Young P, Saxena M, Bellomo R, Freebairn R, Hammond N, van Haren F, Holliday M, Henderson S, Mackle D, McArthur C, McGuinness S, Myburgh J for the HEAT Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. New England Journal of Medicine 2015;373(23):2215–2224.[Crossref]
94. Williams LK, Peterson EL, Ownby DR, Johnson CC. The relationship between early fever and allergic sensitization at age 6 to 7 years. Journal of Allergy and Clinical Immunology 2004;113(2):291–296.[Crossref]
95. Williams LK, Peterson EL, Pladevall M, Tunceli K, Ownby DR, Johnson CC. Timing and intensity of early fevers and the development of allergies and asthma. Journal of Allergy and Clinical Immunology 2005;116(1):102–108.[Crossref]
96. von Mutius E, Illi S, Hirsch T, Leupold W, Keil U, Weiland S. Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children. European Respiratory Journal 1999;14(1):4–11.
97. Matricardi PM, Franzinelli F, Franco A, Caprio G, Murru F, Cioffi D, Ferrigno L, Palermo A, Ciccarelli N, Rosmini F. Sibship size, birth order, and atopy in 11,371 Italian young men. Journal of Allergy and Clinical Immunology 1998;101(4):439–444.
98. Curran LK, Newschaffer CJ, Lee L-C, Crawford SO, Johnston MV, Zimmerman AW. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics 2007;120(6):e1386–1392.[Crossref]
99. Mehler MF, Purpura DP. Autism, fever, epigenetics and the locus coeruleus. Brain Research Reviews 2009;59(2):388–392.[Crossref]
100. Grossarth-Maticek R, Frentzel-Beyme R, Kanazir D, Jankovic M, Vetter H. Reported herpes-virus-infection, fever and cancer incidence in a prospective study. Journal of Chronic Diseases 1987;40(10):967–976.
101. Wrotek S, Kamecki K, Kwiatkowski S, Kozak W. Cancer patients report a history of fewer fevers during infections than healthy controls. Journal of Pre-Clinical and Clinical Research 2009;3(1):31–35.  
102. Kölmel KF, Pfahlberg A, Mastrangelo G, Niin M, Botev I, Seebacher C, Schneider D, Lambert D, Shafir R, Kokoschka EM, Kleeberg UR, Henz BM, Gefeller O. Infections and melanoma risk: results of a multicentre EORTC case-control study. Melanoma Research 1999;9(5):511-519.
103. Krone B, Kölmel K, Grange J, Mastrangelo G, Henz B, Botev I, Niin M, Seebacher C, Lambert D, Shafir R, Kokoschka EM, Kleeberg UR, Gefeller O, Pfahlberg A. Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study. European Journal of Cancer 2003;39(16):2372–2378.
104. Kokolus KM, Capitano ML, Lee C-T, Eng JW-L, Waight JD, Hylander BL, Sexton S, Hong CC, Gordon CJ, Abrams SI, Repasky EA. Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature. Proceedings of the National Academy of Sciences 2013;110(50):20176–20181.[Crossref]
105. Coley WB. The treatment of sarcoma of the long bones. Annals of Surgery 1933;97(3):434–460.
106. Kienle GS. Fever in cancer treatment: Coley’s therapy and epidemiologic observations. Global Advances in Health and Medicine. 2012;1(1):92–100.[Crossref]
107. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420(6917):860–867.[Crossref]
108. Hobohm U. Fever and cancer in perspective. Cancer Immunology, Immunotherapy 2001;50(8):391–396.
109. Kleef R, Jonas WB, Knogler W, Stenzinger W. Fever, cancer incidence and spontaneous remissions. Neuroimmunomodulation 2001;9(2):55–64.[Crossref]
110. Hobohm U. Fever therapy revisited. British Journal of Cancer. 2005;92(3):421–425.[Crossref]
111. Levin JS. Spontaneous remission: An annotated bibliography. JSTOR 1995.
112. Hager ED. Fever, Pyrogens and Cancer. Eurekah Bioscience 2005;1(8):680–710.
113. Abdelrazeq AS. Spontaneous regression of colorectal cancer: a review of cases from 1900 to 2005. International Journal of Colorectal Disease 2007;22(7):727–736.[Crossref]
114. Madeleyn R, Soldner G, Tautz C, von Laue B. Hirntumore bei Kindern: Therapieverläufe (Teil II). Der Merkurstab 2002;55(1):36-47.
115. Richardson M, Purssell E. Who’s afraid of fever? Archives of Disease in Childhood 2015;100(9):818–820.[Crossref]
116. Mouihate A, Harré E-M, Martin S, Pittman QJ. Suppression of the febrile response in late gestation: evidence, mechanisms and outcomes. Journal of Neuroendocrinology April 2008;20(4):508–514.[Crossref]
117. Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, Dellamonica J, Bouadma L, Cook F, Beji O, Brun-Buisson C, Lemaire F, Brochard L. Fever control using external cooling in septic shock: a randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2012;185(10):1088–1095.[Crossref]
118. Shime N, Hosokawa K, MacLaren G. Does cooling really improve outcomes in patients with septic shock? American Journal of Respiratory and Critical Care Medicine 2013;187(11):1274–1275.[Crossref]
119. Thoresen M. Who should we cool after perinatal asphyxia? Seminars in Fetal and Neonatal Medicine 2015;20(2):66-71.[Crossref]
120. Ghandi Y, Chaichi PY, Sharifi M, Bolandnazar N. The Brugada syndrome unmasked by fever in a two-year-old child: case report. Journal of Comprehensive Pediatrics 2016;7(1).[Crossref]
121. Probst V, Denjoy I, Meregalli PG, Amirault J-C, Sacher F, Mansourati J, Babuty D, Villain E, Victor J, Schott JJ, Lupoglazoff JM, Mabo P, Veltmann C, Jesel L, Chevalier P, Clur SA, Haissaguerre M, Wolpert C, Le Marec H, Wilde AA. Clinical aspects and prognosis of Brugada syndrome in children. Circulation 2007;115(15):2042–2048.[Crossref]