Medical History

THE ROLE OF FEVER IN THE PAST

AND PRESENT

A. SAHIB EL-R
R ADHI*

INTRODUCTION CONCEPTS OF FEVER IN THE HISTORY

Fever is perhaps the most ancient hallmark of dis- The oldest civilizations (Egyptian, Mesopotamian,
ease. It dates back as far as civilization itself. For most Chinese, Indian, and Greek) demonstrated extensive
of the history, fever was feared by ordinary people as a knowledge of fever, but tended to view it as being
manifestation of punishment, induced by evil spirits or a induced by evil spirits. Hence exorcism was used in
marker of death. For medical scholars, however the bio- many ancient cultures (to a lesser extent in Greek medi-
logical role of fever in disease was considered as bene- cine) for the treatment of fever. Many ancient physicians,
ficial, particularly so among Greek scholars (Ancient however, fostered mainly by the Greeks, believed in the
concepts). This concept underwent a radical transforma- beneficial effects of fever. Hippocratic writings, for exam-
tion in the 19th century and scholars began to regard ple, contain evidence that fever was thought to be bene-
fever as harmful. The use of antipyretics was considered ficial to the infected host (1). Rufus of Ephesus in the
beneficial (Changing concepts). With the introduction of second century AD strongly advocated the beneficial role
fever therapy in the 20th century, renewed interest in the of fever. He recommended the use of "fever therapy"
role of fever began (Current concepts). (such as by malaria) to treat various diseases, including
Various forms of antipyretic therapy have been epilepsy (2). Fever therapy was the principal form of
used since ancient times to lower body temperature in treatment, not only for syphilis and gonorrhoea, but also
febrile patients. Nowadays, antipyretics are among the for patients with rheumatoid arthritis and asthma. This
most used drugs worldwide. Despite their widespread belief, held for about 2000 years, should not be ignored.
use and popularity, questions arise as how beneficial Ýis Virtually all cultures use some form of "fever therapy" in
the fever? Do antipyretics prevent fever from climbing the form of "saunas," or "sweat lodges," or "steam baths,"
unabated? What are the arguments in favour and or other ways to raise body temperature artificially. This
against fever in the history, including religious doctrines? probably dates back to the Hippocratic era and is based
Is there any scientific evidence at present in support of on the "humoral" theory of disease, where one of the
the ancient belief about fever? The article summarizes forms of therapy was to "cook" the bad "humour." Events
the knowledge about fever and the changing concepts of in the history are known to repeat themselves, so are
its role in diseases from ancient cultures to our present medical practice and concepts.
time. With the beginning of the Middle Ages (ca. 400-1400
AD), science and medicine became less important than
*From Department of Pediatric, Queen Mary's Hospital, Sidcup, Kent theology and philosophy (3). Galen's writings remained a
DA14 6LT, UK. great influence on medicine during the Middle Ages. He

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THE ROLE OF FEVER IN THE PAST AND PRESENT EL-RADHI

had a philosophy embracing body, mind and soul, which first time, Jesus saw in Peter's house, “his wife's mother
was highly acceptable to the religion of the developing laid and sick of a fever and he touched her hand and the
church (4). The central development of medicine was in fever left her” (Matthew 8: 14-16, Mark 1: 29-34, Luke 4: 38-
anatomy learned mainly from animal dissections but a 41). Elsewhere, Jesus healed the official's son with his
few were performed on humans. Anatomical studies words (John 4: 49- 52), and the apostle Paul prayed to God
began at Bologna (ca.1150 AD) and Padua University and placed his hands on Publius, who was then healed of
(ca.1222 AD). Physiology and pathology were still based fever and a bloody flux, meaning dysentery (Acts 28: 8).
upon the four humours (blood, phlegm, yellow and black Islamic Medicine originated from the time of the
bile). All diseases were characterized as hot, cold, moist Prophet Mohamed (PUH). In Sahih Bukhari narrated by
or dry. 'Hot diseases' were treated by cooling, 'moist dis- Fatima bint Al-Mundhir: Whenever a lady suffering from
eases' by drying. Bloodletting was widely used to treat fever was brought to Asmaa' bint Abu Bakr, she used to
febrile illnesses and practiced by Galen and some other invoke Allah for her and then sprinkle some water on her
ancient physicians. This was based on the notion of body, at the chest and say, "Allah's Apostle used to order
plethora, a theory that attributed disease to congestion of us to abate fever with water." Prophet (PUH) recom-
blood in part of the body. Apart from bloodletting, other mended: barley for fever in a soup form.
methods attempted to cure acute fever included cooling, Islamic teachings encouraged seeking medical
emollients and laxatives. knowledge as it is narrated in different narrations
With the destructive epidemics of the Black Death through Bukhari, Termithi, Ibn Majah and Muslim that the
(Bubonic Plague), which killed as much as one third prophet (PUH) said: "Oh' people seek remedies as Allah
(reportedly twenty-five million) of the European popula- has not created an illness except that He created its
tion in the 14th century (with the peak in 1348), fever cure, however some people would know it while others
became a marker of death. Medicine was not helpful in won’t. Unlike the 'dark period' in European medicine,
preventing or treating the illness. The wrath of fever was Islamic medicine flourished to reach its golden age in the
still attributed to demonic possession and therefore ninth and tenth centuries. The writings of both Hip-
required exorcism to expel it in line with evolving theolog- pocrates and Galen were carefully translated from Greek
ical doctrine. The belief that fever constituted divine pun- into Syriac and Arabic. Two scholars were outstanding in
ishment also prevailed, particularly among the devout. this period. Abu Ali Husayn ibn Abdulla ibn Sina (AD
980-1037), latinized as Avicenna7 was, like Galen, a
CONCEPTS OF FEVER IN RELIGIONS philosopher and physician. His best work, Qanun Fit-
The roots of Hebrew medicine can be traced to the Tibb, or Canon of Medicine was a vast encyclopaedia.
Torah or Old Testament (compiled between 1500 BC and The second great scholar was Abu Bakr Muham-
300 BC) and the Talmud (a book of rules and precepts mad Zakariya Al-Razi (AD 864-923, latinized as Rhazes)
completed between 70 BC and the second century AD) (5). was the first scholar to differentiate measles from small-
Magic, incantation, and mystics appear to be less pox with his original treatise on the two diseases (8). On
significant than in other cultures. Certainly, the Biblical smallpox he wrote: The eruption of the smallpox is pre-
record contains no indication that fever was caused by ceded by a continued fever, pain in the back, itching in
demons or evil spirits. In the Old Testament, fever was the nose and terror in sleep. There is redness in both
part of God's punishment for sins. The Creator of cheeks, both eyes, heaviness of the whole body and dis-
heaven and earth, Yahweh, states “but break my tress and anxiety. Rhazes' best known medical work
covenant, then be sure that this is what I will do: I will "Kitabul-Hawi Fit-Tibb" or Contents of Medicine"
bring upon you sudden terror, wasting disease and appeared in 25 volumes. He noted that for example
recurrent fever” (Leviticus 26: 16; Deuteronomy 28: 22). "exercise excites heat and fuels it like blowing into fire”,
In the New Testament fever is also mentioned on sev- he also reported that fever in tuberculosis is mild and
eral occasions, always without comment on causation. The blun.

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THE ROLE OF FEVER IN THE PAST AND PRESENT EL-RADHI

One of Rhazes' remarkable observations was his belief that this may prevent complications. Before reach-
differentiation of fever (elevated central thermoregula- ing a conclusion as to whether fever is beneficial, neutral
tory set-point) from heat stroke (normal central ther- or harmful, there are arguments in favor and against
moregulatory set-point): "there is another fever with a fever being harmful which are discussed next.
higher core temperature than the common fever, where
patients are much thirstier and the body feels hot all A. Arguments for fever being harmful
over.9 Rhazes was probably the first scholar to distin- 1. Prevailing concepts among physicians and Par-
guish between the two terms fever and hyperthermia in ents. Fever is a frightening experience for parents who
the form of heat stroke. These two terms are often usually believe that fever is harmful and may bring about
equated even nowadays. discomfort, dehydration, febrile convulsions, brain
damage, and death. Antipyretics are parents' preferred
CHANGING CONCEPTS method of managing fever and there has been an
In the 19th century, fever was still regarded as both: increase in this preference over the past two decades
1) Part of a symptom complex (as it is today) and 2) a from 67% to more than 90% (13).
disease in its own.10 Examples of fever being regarded Most pediatricians agree that treatment of a febrile
as a disease were 'autumnal fever, jail fever, and hospi- child with antipyretics is for the relief of the symptoms of
tal fever'. Fever could also be described in terms of the fever. However, many tend to prescribe antipyretics for a
severity of the disease, for example 'malignant fever' or child with any degree of fever. In a study12 exploring the
'pestilential fever', or even in terms of the supposed beliefs and practices of pediatricians in Massachusetts,
pathology of the fever, 'bilious fever' or 'nervous fever'. USA, the majority (65%) of respondents believed that
The multiplicity of names for fever reflects the lack of a fever itself could be dangerous and can cause seizures,
breakthrough into an understanding of the causes of brain damage and death if the temperature is 40°C or
febrile illnesses. The breakthrough came with the sci- greater.
ence of bacteriology, which was able to reveal the etiol-
ogy of many infectious diseases, such as the 2. The risk of febrile seizures (FS). Fever can cause
identification of the typhoid bacillus in 1880, and the dis- a brief benign convulsion in 3% to 4% of all children. In
covery of the tubercle bacillus in 1882. These discover- a study14 from the USA, 49% of pediatricians consid-
ies related fever to a sign of disease. Great scholars of ered convulsions to be a principal danger of fever and
this period include Claude Bernhard (1813-1878), the 22% believed that brain damage could result from FS
great French physiologist, recognised that body temper- and that antipyretic measures should be administered to
ature was regulated in healthy organisms by the balanc- prevent FS and other complications of fever.
ing of heat production and loss. He demonstrated that
animals died quickly when the body temperature B. Arguments for fever being beneficial
exceeded the normal level by 5-6°C, thus suggesting 1. Fever is self-limiting and well-controlled. With
that fever may be harmful and that antipyretics, which fever, unlike hyperthermia, body temperature is well reg-
were introduced later, may be beneficial (11). William ulated by a hypothalamic set-point that balances heat
Osler declared that 'the humanity has three enemies, production and loss so effectively that the temperature
fever, famine and war, but fever is by far the greatest'. will not climb up relentlessly and does not exceed an
upper limit of 42°C. Within this upper range of 40 to
CURRENT CONCEPTS 42oC, fever is not injurious to tissue. About 20% of chil-
Fever is among the most common complaints and dren seen in the emergency room have temperatures
causes of seeking medical attention. The biological over 40°C and they usually make a full recovery. If there
value of fever (i.e. whether it is beneficial or harmful) is a is morbidity or mortality, it is due to the underlying dis-
matter of dispute and fever is being treated with the ease. The associated fever may well be protective.

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THE ROLE OF FEVER IN THE PAST AND PRESENT EL-RADHI

2. Antipyretics do not prevent FS. There is now cantly greater at temperatures above 40°C (26). Ele-
abundant evidence against the previously assumed risks vated temperatures of 38 and 39°C have a direct posi-
of FS. It is also known that antipyretics are ineffective in tive effect on lymphocyte transformation, the generation
the prevention of FS. Two large population-based stud- of cytolytic cells, B-cell activity, and immunoglobulin syn-
ies15-17 found no deaths or persistent motor deficits thesis. Interleukin-1 is more active at febrile temperature
directly attributed to FS. A temperature >40°C with the (27, 28). Interferon (INF), a potent antiviral agent, has
first seizure was associated with a decreased incidence enhanced antiviral activity above 40°C (29,30).T-cell
of recurrence of FS (18). An evidence-based research proliferative response to interleukin-2 and interleukin-1
(19) concluded that antipyretic drugs are ineffective in was greatly increased at 39°C compared to 37°C.
preventing FS and should not be recommended for pre- Fever may act synergistically with antibiotics. Peni-
venting further FS. cillin was found to have a progressive increase of its
bactericidal activity as the temperature rose from 35° to
3. The effects of fever on microorganisms. Animal 41.5°C (31).
studies have demonstrated that Gram-negative bacteria, There is evidence that elevated body temperatures
such as salmonella typhi, were shown to be increasingly in the range of 41-42°C can effect the growth of certain
susceptible to the antibacterial effects of serum when tumours. Occasional remissions of Hodgkin's disease
cultivated at a temperature >37°C (20). Most viruses occurred after an attack of measles. The metabolism of
ceased to replicate at a temperature between 40°C and many types of cancer cell is selectively damaged at tem-
42°C. The replication rate of poliovirus at 37°C was 250 peratures of 42-43°C (32). Lysosomal enzymes, IL-2
times more than that at 40°C (21). and INF have increased activity at such temperatures,
In human studies fever was the principal form of and may contribute to tumour cell destruction.
treatment for syphilis and gonorrhoea for centuries. 5. The Hygiene Theory: The prevalence of asthma
Insufflation of humidified air at 43°C (three 30-minute and allergic diseases as well as cancer has increased
sessions at 2-3 hourly intervals) into the nasal passages worldwide for many years and the hygiene theory has
of patients suffering from coryza resulted in the suppres- been offered to explain the rise (33,34). The theory pro-
sion of symptoms in 78 per cent of patients (22). Fever poses that early exposure to fevers caused by infections
may also be beneficial in patients with meningitis: the (in particular infection of the upper airways, hepatitis A
presence of fever greater than 40°C did not indicate a and Helicobacter pylori) might protect children against
poor prognosis, but all children presenting with allergic diseases and cancer later in life. It postulates
hypothermia died (23). A study from Japan (24) found that atopy, or allergy, is Th2-driven, which is primarily
that the frequent administration of antipyretics to chil- associated with IL-4, IL-5, IL-10 and IL-13 production,
dren with bacterial diseases led to a worsening of their whereas infection is Th-1-driven, which is dominated by
illness. In another study included 102 children with sal- production of INF-gamma and IL-12. In association with
monella gastroenteritis from Finland (25) there was a reduced exposure to infections, Th-2 immunity domi-
significant negative correlation between the degree of nates through critical childhood periods, resulting in
fever and the duration of excretion of organisms. Subject higher incidence of atopy. In support of this theory are
with fever of greater than 40°C had the shortest duration the following findings:
of bacterial excretion whereas those without fever had - The prevalence of atopy is lower among children
the longest duration. Fever has therefore a favourable of large families or those attending day-care nurseries
prognostic influence on the length of bacterial excretion. than among children of small families or those not at
nurseries.
4. Effects of elevated temperature on defence - Children with older siblings are less likely to
mechanisms: The mobility, phagocytosis and killing of develop allergies than children with younger siblings or
bacteria by polymorphonuclear leukocytes are signifi- none at all.

12 Medical Journal of Islamic World Academy of Sciences 19:1, 9-14, 2011

THE ROLE OF FEVER IN THE PAST AND PRESENT EL-RADHI

- Children who experienced several febrile CONCLUSION

episodes during the first year of life have lower incidence Over the past 40-50 years, intensive research has
of allergies than those with only one or no febrile illness. been carried out to investigate the role of fever. Although
- Children exposed to high levels of endotoxin (a there is still debate whether fever is beneficial or harm-
major product from gram-negative bacteria) show ful. There is evidence now indicates that the effects of
reduced prevalence of atopy. fever are complex but overall beneficial. Accumulated
- The use of antibiotics during the first year of life is data from extensive research suggest that fever has a
associated with increased incidence of asthma, hay protective role in promoting host defence against infec-
fever and eczema later in life. Antibiotics could destroy tion, rather than being a passive by-product. There is
the beneficial bacteria (probiotics) in the digestive tract. evidence that fever exerts an overall adverse effect on
- Atopic diseases are rare in countries with parasitic the growth of bacteria and some tumours, as well as on
infestation. replication of viruses. It also enhances immunological
- A study from Switzerland (35) demonstrated a sig- processes.
nificant association between febrile infections during Although scientific evidence does not support this
childhood and the risk of developing cancer in adult- practice, antipyretics are often prescribed automatically
hood. for children with fever whether the child is playful or
apears toxic with significant discomfort due to fever. This
Thus, we conclude from these intriguing data that current practice is widely accepted although gives the
exposure to infectious diseases in early childhood, par- wrong impression to patients, parents and other health
ticularly those that may be associated with modest professionals that fever per-se is harmful and that
fevers, may protect the child against a wide array of antipyretics are needed. It is the underlying disease
future diseases. which we should be concerned about and not the fever
per se. The presence of fever could be beneficial to the
6. Side-effects and fatalities from using antipyretics: infected host.
It is well-established that reducing the fever with As clinicians, we need to educate our patients and
antipyretics does not usually have a positive role on other health professionals about this fact and that
the underlying disease, nor does it reduce the time of antipyretics should be used sparingly in our clinical
infection. practice.
Antipyretics are known to cause adverse reactions, We should recognize that the issue as to whether
such as gastrointestinal bleeding and renal failure, and fever is beneficial or not is still controversial and more
some fatalities (37), In the UK, 10% of inquiries to the efforts should be exerted to determine this function in
National Poisons Information Services and up to 43% of every febrile disease. In particular, we need to know which
all hospital admissions for self-poisoning are due to diseases are likely to benefit from the presence of fever,
paracetamol ingestion. in another study,, paracetamol so that minimal interference during their courses may be
has been one of the most popular choices for suicide considered and in which diseases fever may be harmful
attempts in adolescents and adults, causing 100-150 and need to be treated. It is also important to determine
deaths in the UK annually. In the USA, paracetamol- what degree of fever is dangerous and measures must be
associated overdoses account for 56,000 emergency taken to reduce it. Until these types of studies are con-
visits, 26,000 hospitalizations, with approximately 450 ducted for a wide assortment of infections, the question of
deaths each year. About 100 of these deaths are unin- whether most fevers should be left alone or treated in the
tentional (36). pediatric or adult patient will remain unanswered.

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THE ROLE OF FEVER IN THE PAST AND PRESENT EL-RADHI

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