Kurzgesagt – In a Nutshell 

We are thankful to the experts for their critical reading and input to the script:

– Dr. Edward Walter
Royal Surrey County Hospital

– Prof. Edward Clint 

Applied Psychology, Oregon Tech

– Prof. Elizabeth A. Repasky
Roswell Park Comprehensive Cancer Center

Sources - Fever

– On earth life is able to thrive between the extremes of -10°C in deep cool pools and 120°C in thermal vents. Step outside this range and die. Every animal or microbe has a temperature range that is ideal and one that is stressful but survivable for a while. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Within the range of approximately -10° to 120°C, no single temperature is universally harmful to all living things. Microbes in the Arctic flourish at subfreezing temperatures, while others at thermal vents replicate above the boiling point.”

#Andrew Clarke. The thermal limits to life on Earth. 2014. 

https://www.cambridge.org/core/journals/international-journal-of-astrobiology/article/thermal-limits-to-life-on-earth/253389B814003A90E62B0E90626B5192

Quote: “At the very highest temperatures only archaea are found with the current high-temperature limit for growth being 122 °C. Bacteria can grow up to 100 °C, but no eukaryote appears to be able to complete its life cycle above ∼60 °C and most not above 40 °C. The lower thermal limit for growth in bacteria, archaea, unicellular eukaryotes where ice is present appears to be set by vitrification of the cell interior, and lies at ∼−20 °C. Lichens appear to be able to grow down to ∼−10 °C. Higher plants and invertebrates living at high latitudes can survive down to ∼−70 °C, but the lower limit for completion of the life cycle in multicellular organisms appears to be ∼−2 °C.”

#Marshall J. Edwards. Review: Hyperthermia and Fever during Pregnancy. 2006.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdra.20277

Quote: “Heat has always been part of the natural environment. It has been a major force in the evolution of existing animals and plants. During their evolution, the more successful species of animals have acquired the capacity to maintain their body temperatures within a relatively narrow range (homeothermy) and at relatively high levels, enhancing metabolic functions and the capacity for physical activity under a wide range of climatic conditions. Normal embryonic development is based on orderly sequences of gene-directed bursts of proliferation, migration, and maturation of cells to form the complex structures that make up the body. Somatic cell proliferation is adapted to, and proceeds optimally at, the normal body temperature range of the species and the deleterious effects of higher levels on meiotic and mitotic cell proliferation and survival are widely recognized. The margin between the

existing mammalian body temperatures and lethal levels is relatively small, which might imply that the evolution of even higher body temperatures might not be possible unless novel genetic mutations overcome this barrier.”

– Humans are warm blooded animals and our bodies expend a lot of energy to keep us around 37°C. 

Obviously there is not a single number, rather a range of temperature as commonly accepted as normal, which is 97.3 °F - 98.2 °F, averaging on 97.9 °F (or 36.3 °C - 36.8 °C, averaging on 36.6 °C) according to the latest studies. We rounded up 36.6 °C to 37 °C for simplicity. 

#Geddes L. The fever paradox. 2020 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195085/

Quote: “Although 37°C is often cited as normal body temperature, it varies throughout the day, with thermometer readings some 0.8°C to 1°C lower first thing in the morning compared with the evening.

Body temperature also tends to be higher in women than in men – and even within women, it is approximately 0.4°C higher during the second half of the menstrual cycle compared with the first. Younger people also tend to have higher body temperatures than older people.”

#Nina Bai. Stanford Medicine. Normal body temperature is personal, Stanford Medicine researchers find. 2023. 

https://med.stanford.edu/news/all-news/2023/09/body-temperature.html

Quote: ““Most people, including many doctors, still think that everyone’s normal temperature is 98.6 F. In fact what’s normal depends on the person and the situation, and it’s rarely as high as 98.6 F,” said Julie Parsonnet, MD, professor of medicine and of epidemiology and population health as well as the George DeForest Barnett Professor in Medicine. She is the senior author of the study that was published Sept. 5 in JAMA Internal Medicine.

[...]

From the remaining data, they found that adults have normal temperatures ranging from 97.3 F to 98.2 F, with an overall average of 97.9 F.”

As a perk of being a mammal, we have to convert most of our food and the heat generated from all reactions in our bodies into keeping a stable internal temperature. A similar sized ectothermal animal would have a lower metabolic rate which might look like an advantage at the first glance. But they are dependent on the environment to reach the temperature that their bodies work properly.

#Popson MS, Dimri M, Borger J. Biochemistry, Heat and Calories. 2023.

https://www.ncbi.nlm.nih.gov/books/NBK538294

 Quote: “Body temperature is tightly regulated by a process called thermoregulation, controlled by a master regulator, the hypothalamus that modulates the heat gain or loss by the body. Up to 60% of the heat generated during metabolic processes is used to maintain body temperature. Accordingly, dysregulation of thermoregulatory mechanisms can result in hypothermia or hyperthermia [8].”

– Which seems wasteful, but this may actually be a defensive adaptation – our temperature makes us almost entirely immune to one of the worst killers and parasites: Fungi. Most colder animals and their insides are infected by them but you are just too hot! 

Out of the about 1.5 million fungal species, only a few hundred are pathogenic for humans, whereas around 270,000 for plants and 50,000 for insects. Our endothermic bodies might be the part of the reason why fungi are not a common malady for humans, and other mammals. 

#Robert and Casadevall. Vertebrate Endothermy Restricts Most Fungi as Potential Pathogens. 2009.

https://academic.oup.com/jid/article/200/10/1623/881601?login=false

Quote: “The paucity of fungal diseases in mammals relative to insects, amphibians, and plants is puzzling. We analyzed the thermal tolerance of 4802 fungal strains from 144 genera and found that most cannot grow at mammalian temperatures. Fungi from insects and mammals had greater thermal tolerances than did isolates from soils and plants. Every 1°C increase in the 30°C–40°C range excluded an additional 6% of fungal isolates, implying that fever could significantly increase the thermal exclusion zone. Mammalian endothermy and homeothermy are potent nonspecific defenses against most fungi that could have provided a strong evolutionary survival advantage against fungal diseases.”

#Arturo Casadevall. Fungi and the Rise of Mammals. 2012

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420938/

Quote: “Primitive mammals like the platypus, with core temperatures near 32°C, are susceptible to Mucor amphibiorum, a fungus with a maximal thermal tolerance of 36°C that would make it avirulent for higher mammals [8]. The resistance of mammals to fungal diseases is in sharp contrast to the vulnerability of other vertebrates, such as amphibians, a group that is currently under severe pressure from a chrytrid [9]. Like mammals, amphibians have adaptive immunity, but unlike mammals, they are ectotherms and lack a thermal environment that is exclusionary to fungi. Hence, their vulnerability to fungal diseases echoes the experimental findings in rabbits whereby high resistance is conferred by a combination of high temperature and vertebrate-level immunity [6]. Amphibians can be cured of chrytridomycosis if placed at 37°C [10].
Another example of the protection provided by the combination of vertebrate-level immunity and endothermy comes from bats. In the summer bats manifest high activity and mammalian temperatures, but during winter hibernation their core temperatures drop as they hibernate and become vulnerable to infection with Geomyces destructans, a fungus that is decimating several North American bat species [11]. Infected bats woken from hibernation made full recovery when provided with supportive care, as higher body temperature inhibited fungal growth [12]. It is noteworthy that birds, which are also endotherms, are susceptible to Aspergillus fumigatus [13], a thermotolerant fungus that can survive up to 55°C [14].”

– Which brings us to fever. For any microbe that wants to infect you, your body is a world they want to conquer. Fever is defensive climate change pushing an invader outside its ideal temperature range and making the world horrible. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Elevated temperatures can have many adverse effects on pathogens, including

lesioning of organelles, damage to DNA, spontaneous membrane rupture, loss of

mitochondrial tubules, diminished protein production, and stress-induced apoptosis

(Levy et al. 1969; LeGrand and Alcock 2012; Jego et al. 2013; Blatch 2014). Although, in

many cases, additional research is needed to distinguish between direct and indirect effects of thermal elevation (see, for example, O’Reilly and Zak 1992), nonetheless, the present literature contains numerous in vitro studies documenting deleterious effects of temperature elevation on multiple pathogenic species.”

#Del Bene VE. Temperature. 1990. 

https://www.ncbi.nlm.nih.gov/books/NBK331/

Quote: “For practical clinical purposes, a patient is considered febrile or pyrexial if the oral temperature exceeds 37.5°C (99.5°F) or the rectal temperature exceeds 38°C (100.5°F). Hyperpyrexia is the term applied to the febrile state when the temperature exceeds 41.1°C (or 106°F). Hypothermia is defined by a rectal temperature of 35°C (95°F) or less.”

– It evolved at least 600 million years ago and is widespread: most animals increase their core temperature when they are sick. 

If we broaden the definition of fever beyond the acute increase of temperature in response to pathogens as seen in mammals and birds, then we can also include many poikilothermic animals, arthropods and annelids as they increase their core temperature when infected or injured as well. 

#Evans et al. Fever and the thermal regulation of immunity: the immune system feels the heat. 2015.

https://pubmed.ncbi.nlm.nih.gov/25976513

Quote: “Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. Ectotherms as diverse as reptiles, fish, and insects raise their core temperature during infection through behavioural regulation, which leads to their seeking warmer environments (despite the risk of predation) or, in the case of bees, raising the local temperature of the hive through increased physical activity.2,13–19 Landmark studies published 40 years ago by Kluger’s laboratory showed that survival of the desert iguana Dipsosaurus dorsalis is reduced by 75% if prevented from behaviourally raising its core temperature by approximately 2°C after infection with the Gram-negative bacterium Aeromonas hydrophila.2,13,14 The heat-seeking behaviour of the desert iguana, blue-finned tuna and leech is negated by antipyretic drugs, indicating that common biochemical pathways drive fevers in ectothermic and endothermic animals.14,16,20 ”

#Singh & Hasday. Fever, hyperthermia and the heat shock response. 2013. 

https://www.tandfonline.com/doi/full/10.3109/02656736.2013.808766

Quote: “Fever is a complex physiological response to infection and injury, the key feature of which is a temporary resetting of the body's thermostatic set point resulting in an increase in core temperature. Although fever is recognised as a component of the acute-phase response to infection and perceived to be a response limited to mammals and birds, many poikilothermic animals, including lower vertebrates, arthropods, and annelids, also increase their core temperature in response to infection or injury [1]. The prevalence of fever in such diverse modern animals suggests that it first appeared over 600 million years ago. This evolutionary persistence of fever is even more remarkable when one considers its substantial metabolic cost. In humans, generating fever through thermogenic shivering requires up to a 6-fold increase in metabolic rate [2], and maintaining a physiological core temperature at febrile levels requires an approximately 12% increase in metabolic rate per 1 °C increase in core temperature [3,4]. “

Even though we can not really say the temperature regulation in plants is categorized as fever, some plant species have been shown to react to the pathogenic invasions by increasing their temperature. 

#Evans et al. Fever and the thermal regulation of immunity: the immune system feels the heat. 2015. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786079/

Quote: “Surprisingly, the correlation between infection and increased temperature extends even to plants, which arose 1.5 billion years ago. For example, the temperature of the leaves from the bean plant Phaseolus vulgaris increases by around 2°C following infection with the fungus Collectotrichum lindemuthianum.21 Thermoregulation in plants occurs through mitochondrial respiration22, although it is not known whether these fever-like responses have a direct impact on clearance of infection.”

– Fish swim into warmer waters, lizards bathe in the sun. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “A common lay understanding of “fever” is the metabolic raise in set temperature and human-typical symptoms such as body aches, fatigue, and loss of appetite. This conceptualization is too narrow to afford adequate understanding of how and why organisms increase their temperatures. Pathogen-infected fish swim to warmer waters to elevate their temperature. Poikilothermic reptiles move to a warmer patch of earth. Across species, the manifestation of this phenomenon varies based on the means each organism has for thermoregulation; similarly, species differ as to whether they display associated symptoms typically observed in humans. For these reasons, we refer to protective metazoan fever responses collectively as defensive hyperthermia (DH).”

– Bees heat up the air inside their hive.

#Starks, Blackie, Seeley. Fever in honeybee colonies. 2000.

https://pubmed.ncbi.nlm.nih.gov/10883439/

Quote: “Honeybees, Apis spp., maintain elevated temperatures inside their nests to accelerate brood development and to facilitate defense against predators. We present an additional defensive function of elevating nest temperature: honeybees generate a brood-comb fever in response to colonial infection by the heat-sensitive pathogen Ascosphaera apis. This response occurs before larvae are killed, suggesting that either honeybee workers detect the infection before symptoms are visible, or that larvae communicate the ingestion of the pathogen. This response is a striking example of convergent evolution between this "superorganism" and other fever-producing animals.”

– Fever is part of your first line of defense, triggered by a diverse group of chemicals called “pyrogens”, “The creators of heat”. They float away from the battlefield and pass right into your brain, where specialized receptors pick them up and crank up your internal thermostat.

Pyrogens are substances that cause a fever response. These can be external agents such as the parts of pathogens like bacteria, viruses or toxins. In the most simple terms, in infection, these are recognized by immune cells like macrophages and dendritic cells, which release endogenous pyrogens like cytokines (such as interleukin-1, interleukin-6, tumour necrosis factor). Cytokines then reach the brain region called hypothalamus, which basically keeps the thermostat of our bodies. Here, they trigger another cascade of molecules, like the main pyrogenic mediator prostaglandin E2 (PGE2) which binds to neurons with the corresponding receptor. These neurons then trigger the sympathetic nervous system which in turn triggers responses like activation of muscles for shivering and constriction of blood vessels. However, there are multiple fever-inducing pathways, for example some external pyrogens can directly act on hypothalamus bypassing the cytokines or fever can be induced without any infection as in the case of autoimmune diseases.  

#Evans et al. Fever and the thermal regulation of immunity: the immune system feels the heat. 2015.

https://pubmed.ncbi.nlm.nih.gov/25976513

Quote: (Figure Caption)”The induction of fever during infection

The recognition of damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), by Toll-like receptors (TLRs) and other pattern recognition receptors drives the activation of dendritic cells (DCs) and macrophages. These innate immune cells release prostaglandin E2 (PGE2) as well as pyrogenic cytokines (namely, interleukin-1 (IL-1) IL-6, and tumour necrosis factor (TNF)) that act systemically to induce fever. IL-6 operates downstream of IL-1 in the median preoptic nucleus region within the hypothalamus to induce the synthesis of cyclooxygenase 2 (COX2), the enzyme responsible for production of additional PGE2.64,65 PGE2 is considered the major pyrogenic mediator of fever.31–33 Receptor activator of NF-κB (RANK) expressed by astrocytes also acts via the COX2–PGE2 pathway to induce fever.47 However, it is not known whether this pathway parallels the IL-6 response or if the IL-6 and RANKL pathways converge, potentially via IL-6 regulation of RANKL expression in vascular endothelial cells in the hypothalamus. Neurons expressing PGE2 receptor 3 (EP3) trigger the sympathetic nervous system to trigger norepinephrine release, which elevates body temperature by increasing thermogenesis in brown adipose tissue as well as by inducing vasoconstriction to prevent passive heat loss.2,26,27,42,43 Additionally, acetylcholine contributes to fever by stimulating muscle myocytes to induce shivering.”

– First you begin to shiver. Your skeletal muscles contract really quickly, which generates a lot of heat in your core. At the same time usually the blood vessels near your surfaces contract and prevent heat from escaping through your skin. Your skin cools down while your insides burn.

Hypothalamus triggers peripheral responses like constriction of blood vessels, shivering, burning energy in fat cells to increase the body temperature to its new heightened set point. 

#Geddes L. The fever paradox. 2020 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195085/

Quote: “The most common cause of this is infection. “When immune cells recognise the telltale signs of a germ in the body – and often this can be quite early on in an infection – they release secretions which act on a brain area called the hypothalamus,” says Daniel Davis, an immunologist at the University of Manchester, UK, and author of The Beautiful Cure: Harnessing your body's natural defences. The hypothalamus is responsible, among other things, for controlling body temperature, and it responds to these signals by releasing hormones that cause various heat-boosting responses. Blood vessels in our skin constrict so less heat is lost at the body's surface. Fat cells start burning energy and our muscles rapidly contract, causing shivering – both of which warm us up. As a result, the body's temperature starts to rise.”

The following nicely summarizes the events in the central nervous system that lead to peripheral responses preventing loss of heat and therefore giving rise to fever. 

#El-Radhi AS. Pathogenesis of Fever. Clinical Manual of Fever in Children. 2019 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122269/

Quote: “– Pyrogenic endogenous cytokines (e.g. IL-1, TNF, IL-6 and interferons) are released into the bloodstream in response to exogenous pyrogens (e.g. viruses, bacteria, toxins).

– These endogenous pyrogens act on a specific preoptic area of the anterior hypothalamus, which contains clusters of thermo-sensitive neurons localized within the rostral wall of the third ventricle. The site is called organum vasculosum of the lamina terminalis (OVLT), which has emerged as an interface between circulation and brain. The firing rate of these thermo-sensitive neurons changes according to the temperature of the area’s blood supply and the input from the skin and muscular thermoreceptors. Warm-sensitive neurons have firing rates that increase with warming and decrease with cooling, whereas the firing rates of cold-sensitive neurons increase with cooling or decrease with warming.

– Endogenous pyrogens enter the perivascular space of the OVLT through the fenestrated capillary wall to stimulate cells to produce prostaglandin E2 (PGE2), which diffuses into the adjacent preoptic area to upturn the temperature set point and cause fever.

– Another structure termed circumventricular organs (CVOs), which are situated in the anterior wall of the third ventricle. These organs are characterized by extensive vasculature and lack of blood-brain barrier allowing direct exchange between blood and nervous tissue. When circulating pyrogenic cytokines are detected by the CVOS, PGE2 is induced.

– The ultimate result of these complex mechanisms is an upward shift of the thermostatic set point to a febrile level that signals efferent nerves, especially sympathetic fibres innervating peripheral blood vessels, to initiate heat conservation (vasoconstriction) and heat production (shivering). This is aided by behavioural means aimed also to increase body temperature, such as seeking a warmer environment or covering up with a blanket. The resulting temperature increase continues until body temperature approximates to the temperature of the elevated set point.”

– Fever is a systemic, body wide response that is a serious energy investment for your body. 

There are a wide range of responses across the body during fever. 

#Balli S, Shumway KR, Sharan S. Physiology, Fever. 2023. https://www.ncbi.nlm.nih.gov/books/NBK562334/

Quote: “Metabolic effects associated with a febrile state: 

– Increased oxygen demand

- Increased heart rate

- Increased respiratory rate

– Increased use of body proteins as an energy source

– Metabolism switches from utilizing glucose (an excellent medium for bacterial growth) to utilizing the breakdown products of protein and fat

– Enhanced immune function

- Increase in the motility and activity of white blood cells

- Stimulates interferon production and activation of T cells”

– You burn about 10% more calories to stay alive for every degree centigrade your body temperature rises. 

#Manthous et al. Effect of cooling on oxygen consumption in febrile critically ill patients. 1995. 

https://www.atsjournals.org/doi/abs/10.1164/ajrccm.151.1.7812538

Quote: “Our data also demonstrate that energy expenditure increases by 10%/° C. Thus, the caloric requirements of a patient whose temperature varies between 37 and 40° C vary by nearly 30%. This highlights one of the many difficulties in estimating the daily caloric requirements of critically ill patients and illustrates the potential error in extrapolating 24 h energy expenditure based on a single 15 to 30-min measurement.”

– Fever is also a strong order to lay down and rest, to save energy and give your immune system time to fight. 

Fever is actually part of a more general systemic defense, which is known as the acute phase response.  

#Wrotek et al. Let fever do its job: The meaning of fever in the pandemic era. 2021. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/pdf/eoaa044.pdf

Quote: “In addition to the local inflammatory response to infection, the systemic defensive responses to infection are known as the acute phase response [13, 89]. Besides fever, other components include mobilization of leukocytes; production of a variety of protective proteins (acute phase proteins); reduced blood levels of iron, zinc, and manganese; reduced erythrocyte production (beyond simple iron deficiency); reduced appetite (anorexia); breakdown of muscle protein and fat (cachexia or hypercatabolism); and the uncomfortable, motivation-sapping sickness symptoms and behaviors we associate with infection, including lethargy, depression and aches. The acute phase response is induced and regulated by the infected individual’s own pro-inflammatory cytokines and other mediators acting on specific cell receptors. Because these responses are initiated by the host, not by the pathogen, and because they are evolutionarily conserved—appearing in all vertebrates and many invertebrates [32, 33]—the acute phase response is considered an adaptive non-specific response to infection.

[...]

The most widely-cited explanation for these elements of the acute phase response was proposed by Hart [16] and extended by Straub et al. [92]. This hypothesis centers around the need to conserve resources and to reallocate energy resources towards supporting an effective immune defense. Resources are conserved by restricting less essential activities and not foraging for food. Another hypothesis is that replicating pathogens can be especially vulnerable to many of the harmful components of the acute phase response, so that the harm involved is directed more to pathogens than to the host [18, 49]. In this view, reduced appetite is a nutritional strategy that disproportionately starves pathogens of energy and micronutrients. A recently proposed additional hypothesis views sickness behavior as an evolved defense that primarily benefits close relatives. In this view, termed the ‘inclusive behavioral immune system’, social withdrawal and self-isolation prevent infection from spreading to relatives who share genes with an infected individual [91, 94]”

– Back to the battlefield: When the bacteria entered your body they tried to be stealthy. But now they have switched into high production mode. Their goal is to multiply as fast as possible, which means they need a lot of resources and are highly stressed. Imagine running a marathon while eating a succulent chinese meal and giving birth. The last thing bacteria need right now is more stress.

#LeGrand and Day. Self-harm to preferentially harm the pathogens within: non-specific stressors in innate immunity. 2016.

https://doi.org/10.1098/rspb.2016.0266

Quote: “A universal principle is that growth and replication are more vulnerable to stress than is quiescence. Growth and replication require a gathering and splitting of resources, and the process of synthesis typically involves intermediate stages that are more fragile and vulnerable to stress than either the more stable initial or final stages. A vivid example is that a house may well withstand a hurricane, but actually building a house during a hurricane would be folly. Resources (energy and/or materials) that are devoted to growth and replication are not available for withstanding stress. In other words, these resources could have been used for construction of stress-resistant defences, for repair, or for simply surviving until the stress had passed. As expected, cells are most vulnerable to heat and oxidative stress during replication [11–13]; and mitosis, protein synthesis (particularly folding), and ribosome formation are particularly vulnerable to stress [14,15]. Since pathogens typically rely on growth and replication for their pathogenicity, their vulnerability to stress would be expected to be greater than that of the host's cells and of the host itself.”

– For the bacteria a moment ago the temperature range was pleasant, now the world burns! Heat can cause their organs to break and membranes to rupture, damage their DNA and diminish protein production. They are seriously suffering from the heat.

Heat can be detrimental to some pathogens. However, this does not seem to apply to all of them, febrile temperatures were shown to have limited destructive power in cultures of some bacterial species. There are two caveats to these results though. First, we don't know how much higher the local temperatures can get at the exact point of inflammation, compared to the core temperature at the febrile state. Second, there could be synergistic effects, like low pH, that can work together with heat inside the body, which would be difficult to replicate in cultured cells. So even though the cases that fever inflicts direct damage on pathogens are not rare, it is more of a secondary effect to its role in elevation of immune response. 

#Hasday, Fairchild and Shanholtz. The role of fever in the infected host. 2000.

https://www.sciencedirect.com/science/article/pii/S128645790001337X

Quote: “4.1. Effects of fever on pathogen viability

While some microbial pathogens are directly sensitive to temperatures in the human febrile range [40, 41], most pathogenic bacteria, including Staphylococcus aureus, E. coli [42], K. pneumoniae [30], Pasteurella multocida [43], and A. hydrophila [3] proliferate equally well at

temperatures in the human basal and febrile ranges. This implies that the improved survival imparted to individuals infected with these pathogens is mediated through enhanced performance of host defenses. In A. hydrophila infected lizards, improved survival in the warmer animals was associated with a greater neutrophil infiltration at the inoculation site [44]. However, the mechanisms through which increasing core temperature improves survival during infection have not been completely elucidated.”

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Thermal Impairment of Microorganisms

Elevated temperatures can have many adverse effects on pathogens, including lesioning of organelles, damage to DNA, spontaneous membrane rupture, loss of mitochondrial tubules, diminished protein production, and stress-induced apoptosis (Levy et al. 1969; LeGrand and Alcock 2012; Jego et al. 2013; Blatch 2014). Although, in many cases, additional research is needed to distinguish between direct and indirect effects of thermal elevation (see, for example, O’Reilly and Zak 1992), nonetheless, the present literature contains numerous in vitro studies documenting deleterious effects of temperature elevation on multiple pathogenic species.”

– Why doesn't this affect your cells? It does! All of this is stressful for your cells too! Virtually every system and organ of your body works worse during fever – except one: Your immune system. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “The febrile response is sometimes dangerous and always costly. It includes anemia (due to iron sequestration), anorexia leading to cachexic malnutrition and, central to the adaptation at issue, high caloric expenditure to maintain an elevated body temperature (Schumacker et al. 1987; Manthous et al. 1995). Locating this trait within a larger category of immune defenses, LeGrand and Alcock (2012) reason that such risky measures could only be adaptive if the cost to the host differs from the cost to the pathogen, with pathogens reliably paying the higher price. In their compelling framework, immune brinksmanship refers to processes whereby the host generates internal conditions that are harmful to itself because the harm inflicted on pathogens is greater than the harm inflicted on the host.”

#LeGrand and Joe Alcock. Turning Up The Heat: Immune Brinksmanship In The Acute-phase Response. 2012.

http://www.jstor.org/stable/10.1086/663946

Quote: “Up to this point, we have discussed the benefits to the host of creating and using nonspecific stressors to preferentially harm the pathogens. As noted in the name of the model we have chosen, “immune brinksmanship,” there are significant risks to this approach, as listed in Table 1, which includes examples of each type of risk. We emphasize that the model supports the common-sense idea that it is better to be relatively unstressed and in good condition before becoming infected.”

The risk of excessive self-harm from an inappropriately exuberant APR suggests the adaptive value of having mechanisms to rapidly reduce self-induced damage. Romanovsky and Sze´kely (1998) noted that cold-seeking behavior/hypothermia is a part of the APR often occurring subsequent to high fever or in sepsis, and they suggested that hypothermia can protect the host from the high energy demands associated with fever. We concur that cold-seeking behavior/ hypothermia should be useful in sepsis, where host defenses are more immediately damaging than pathogen offenses, by serving as a means for the host to rapidly reduce endogenous stress to back away from the brink when needed. Other mechanisms likely exist for allowing rapid modulation of host-induced stressors to the most appropriate level.”

#Hasday, Fairchild and Shanholtz. The role of fever in the infected host. 2000

https://pubmed.ncbi.nlm.nih.gov/11165933

Quote: “A growing list of temperature-dependent immunological responses support the hypothesis that fever provides benefit by enhancing host defenses. However, this literature must be interpreted with caution for several reasons. The temperature ranges studied in experimental models have varied. The temperatures attained in these experimental models have frequently exceeded the febrile range observed during infections. Moreover, many of the in vivo models have used external heat to raise the body temperature of experimental animals. In some models, animals were challenged with high doses of LPS or proinflammatory cytokines which induce responses more closely approximating advanced sepsis, whereas models using challenges with small inocula of viable pathogens more closely resemble less severe disease [45]. These parameters must be considered when extrapolating from the results of such experimental studies to clinical disease. For example, our own laboratory found that increasing core temperature from 37 to 40 °C in mice challenged with an LD75 dose of LPS causes a 13-fold increase in peak plasma tumor necrosis factor-α (TNF-α) levels (figure 1, panel A), fails to improve survival rate, and tends to shorten survival time (panel B) [46, 47], but increasing core temperature to 39.5 °C in mice with experimental K. pneumoniae peritonitis reduces plasma TNF-α levels (panel C) and significantly improves survival rate (panel D) [30].”

– Neutrophils are recruited faster, Macrophages and Dendritic Cells are better at devouring enemies, Killer Cells kill better and so on. 

#Evans et al. Fever and the thermal regulation of immunity: the immune system feels the heat. 2015.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786079/pdf/nihms755275.pdf

Quote: “Thermal stress further increases neutrophil recruitment to local sites of infection and other distant tissues61,79 (FIG. 2a) including tumours77 Neutrophil localization in peripheral tissues is due, at least in part, to heat-induced increases in circulating neutrophils which are dependent upon granulocyte colony-stimulating factor (GCSF).80,81

[...]

The impact of heat on natural killer (NK) cells has been most extensively studied in the context of tumour immunity. It has been shown that NK cell cytotoxic activity and recruitment to tumour sites is increased by fever-range hyperthermia in vivo86–89 (FIG. 2b). 

[...]

Macrophages have served as a major model for the study of febrile-range hyperthermia. Early studies demonstrated that whole-body heating (to ~39.5°C) improves bacterial clearance and also increases serum concentrations of TNF, IL-1, and IL-6 in mice challenged with LPS.59,60,93,94 The source of these cytokines was found to be the macrophages of the liver (that is, Kupffer cells) as well as macrophages in other organs. 

[...]

Several studies demonstrate that elevated temperatures substantially enhance the phagocytic potential of DCs, in addition to augmenting interferon-α (IFNα) production in response to viral infection (FIG. 2c).115–118 Heating of immature DCs also upregulates their expression of TLR2 and TLR4, suggesting a role for thermal signals in enhancing pathogen sensing by innate immune cells.119,120 Febrile temperatures further increase DC expression of MHC class I and class II molecules and co-stimulatory molecules, including CD80 and CD86, and can augment the secretion of the Th1 cell-polarizing cytokines IL-12 and TNF.102,117,119–123.”

Following figure from the same paper summarizes the effects of fever on the innate immune response.

Quote: “Figure 2. Response of innate immune cells to thermal stress

(a) Fever-range temperatures drive several crucial aspects of innate immunity. Fever-range hyperthermia stimulates the release of neutrophils from the bone marrow in a granulocyte–

colony-stimulating factor (G-CSF)-driven manner.80–82 Febrile-range temperatures also

promote neutrophil recruitment to the lungs and other local sites of infection in a CXCchemokine ligand 8 (CXCL8)-dependent fashion that additionally involves decreased barrier function of vessels.61,84,85 Upon arriving in the site of infection, thermal stress further elevates the respiratory burst which increases the bacteriolytic activity of neutrophils.77,78
[...]

(b) Thermal treatment improves natural killer (NK) cell cytolytic activity through induction of MHC class I polypeptide-related sequence A (MICA) expression on target cells (for example, tumour cells) as well as by inducing the clustering of the MICA counter-receptor NKG2D on the surface of NK cells.90 (c) Temperatures in the febrile range increase the ability of antigen-presenting cells to support the formation of the adaptive immune response. Heat improves the phagocytic potential of macrophages and dendritic cells (DCs) and increases their responsiveness to invading pathogens by upregulating their expression of both Toll-like receptor 2 (TLR2) and TLR4.119,120 Thermal treatment also induces the release of immunomodulatory molecules such as cytokines (for example, TNF), nitric oxide (NO) and heat shock protein 70 (HSP70). Additionally, heat increases expression of MHC class I and II molecules as well as co-stimulatory molecules (CD80 and CD86) by mature DCs and augments their CC-chemokine receptor 7 (CCR7)-dependent migration via the afferent lymphatics that serve as a conduit to draining lymph nodes.117,121–124 DCs exposed to febrile temperatures are also more efficient at cross-presenting antigens and inducing T helper 1 (Th1) cell polarization.121”

– And fever animates your immune cells to gobble up the critical resources your enemies need, like iron, glucose and glutamine, turning the battlefield into a food desert.

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Local inflammation (a) turns a small area into a hostile space by sequestering glucose, iron, and oxygen, and generating concentrations of macrophages, digestive

enzymes, and apoptosis-inducing ligands. Growing cells (b) are more vulnerable to reductions in the availability of materials, such as iron, zinc, and glutamine, and reductions in the availability of energy. When bacterial pathogens change from noninvasive to invasive mode or, in the case of viral pathogens, when infected cells are changed in a manner that upregulates the cell’s stress responses (McInerney et al. 2005; LeGrand and Alcock 2012), (c), these alterations require the production of many new proteins and enzymes; these shifts constitute an extra stressor for the bacterial pathogens or virally infected host cells, stressors not confronted by most host cells.”

#Edmund Kenwood LeGrand and Joe Alcock. Turning Up The Heat: Immune Brinksmanship In The Acute-phase Response. 2014.

http://www.jstor.org/stable/10.1086/663946

Quote: “Neutrophils and macrophages are profligate consumers of glucose and glutamine, resulting in local depletion of these key nutrients. Glucose is primarily utilized by phagocytes through glycolysis (Cramer et al. 2003), which is energetically wasteful and generates lactate, leading to lactic acidosis (another local stressor). Glutamine is an amino acid that has critical functions in synthesis of proteins, nucleic acids, and glutathione; is a ready energy source; and is needed to mount a heat shock response and prevent apoptosis. Glutamine is needed primarily by proliferating and synthesizing cells, including tumor cells, lymphocytes, bacteria, and fungi; although large amounts are also used by macrophages and neutrophils (Curi et al. 2005; Forchhammer 2007; Boer et al. 2010). Neutrophils take up so much glutamine at sites of infection that they have been considered to be glutamine sinks (Mu¨hling et al. 2007).”

– The viruses that infected millions of cells are doing even worse because they are also very sensitive to the heat. For example, the rhinovirus that causes the common cold can only infect your respiratory tract because it is significantly colder than the rest of your body, even without fever. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “The rhinoviruses that cause the common cold specialize in either the upper or lower respiratory tract in part because of the temperature differences between the two; such viruses are unlikely to be able to infect other parts of the interior body because the higher temperature would substantially limit their reproduction, even without fever (Stott and Heath 1970). Indeed, some rhinoviruses specialize in the nasal cavity, a region where temperature is chronically lower than elsewhere in the body (Roth and Braitman 2008); when they do infect the lungs, these viruses may only be able to do so by virtue of the lower temperatures in the large airways of the lung relative to other tissues (reviewed in Foxman et al. 2015).”

– As their internal machinery is breaking and failing they quickly produce billions of heat shock proteins, or HSPs, that start repairs, keeping them alive.

#Singh and Hasday. Fever, hyperthermia and the heat shock response. 2013.

https://www.tandfonline.com/doi/pdf/10.3109/02656736.2013.808766

Quote: “While fever is a systemic response to infection and injury, the HS response acts as a defence mechanism against cellular stress. The HS response, a highly conserved ancient biological process, is essential for survival against a myriad of environmental stresses, including extremes of temperature, chemicals and radiations, each of which can cause denaturation of essential cellular proteins. Also referred to as the ‘cellular stress response’ the HS response is accompanied with reprogramming of the cellular transcriptional and translational machinery to preferentially express a set of stress-inducible proteins namely the heat shock proteins (HSPs). During stress these HSPs act as chaperones and bind to denatured proteins to either preserve them until the stress has abated or to target the denatured proteins for degradation [5–7]. Genes encoding the five families of HSPs are highly conserved. Their presence in all species studied to date including archaebacteria, eubacteria, and eukaryotes, suggests that they first arose at least 2.5 billion years ago. While prokaryotic and eukaryotic HSP genes exhibit striking crossdomain homology, they use different mechanisms of transcriptional regulation.”

– But this is a trap. Even your healthy cells produce HSPs to deal with the heat – but if a cell makes too many of them, this means it is more stressed than it should be. And if it is too stressed, something is wrong and it should be killed. So your Natural Killer Cells and Killer T Cells are activated and attracted by HSPs and start killing infected cells and all the viruses inside them. By trying to protect themselves, infected cells are calling out to be destroyed.

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “From microbes to human cells, all living things can produce heat shock proteins (HSP) (d) in order to prevent protein denaturation during high temperatures (Morimoto 1998; Hasday and Singh 2000). However, the immune system has evolved to use many common HSPs as an activational alarm because infected (or neoplastic) cells are more stressed and therefore more likely to produce them. HSPs can activate natural killer cells, function as antigens, make their source cell a target of cytotoxic T cells, and induce macrophages to produce proinflammatory cytokines (Kol et al. 2000).”

Quote: “Although the active-coping strategy avoids the costs of retreat into inactivity, it entails a formidable liability, namely generating cues that attract and upregulate host defenses. For example, HSP60, a common variant produced by Legionella, Borrelia, Treponema, and Mycobacterium organisms, marks them as targets for cytotoxic T cells, and is also highly antigenic. The leukocyte receptor for HSP60 known as CD14 is the same high-affinity receptor of lipopolysaccharide, suggesting that HSP is a reliable cue of infection exploited by the immune system (Retzlaff et al. 1994; Hasday and Singh 2000; Jiang et al. 2000; Kol et al. 2000). Many heat shock proteins also spur macrophages to release proinflammatory interleukins. Fever thus turns heat shock response, a ubiquitous cellular stress response employed by all living things, into an alarm that activates host immune responses.”

– If your enemies survive fever long enough, natural selection changes them. The individuals that are better suited to deal with heat reproduce more. After a few days, they have adapted. But this becomes a handicap – because the next step is to infect new victims in new bodies, and now healthy humans are now too cold for them! 

Not impossible to infect, just harder. And the heat resistant microbes now compete with their cousins that like it colder and have an advantage infecting healthy hosts. This creates an evolutionary dilemma without a perfect solution. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “We propose that the key to the durability of DH (defensive hyperthermia) as an effective defense over vast stretches of evolutionary time lies in the manner in which this adaptation exploits natural selection that operates on pathogens at two different stages, namely initial infection and subsequent reproduction. Pathogens must accomplish two goals in order to prosper: replicate in the host, and successfully reach and infect the next host. Selection acts at each of these stages, and many factors influence how these interact in the emergence of new pathogens. Seeking to add to factors recognized to date (see Leggett et al. 2012, 2013), we postulate that DH is part of this complex interaction. Viewed as a source of selection pressure operating on successive generations of a given pathogen with which it has become infected, a host deploying DH effectively changes the environment confronting the pathogen, forcing it to adapt to the presence of higher temperatures if it is to survive and reproduce within the host. However, while evolving to tolerate the elevated temperature makes the pathogen better at accomplishing its first goal, we propose that this necessarily makes the pathogen worse at accomplishing its second goal, for the most basic of Darwinian reasons: we postulate that, all else being equal, the ability to tolerate higher temperatures, via a broadening of the temperature range, or a shifting of the entire range upward, comes at the expense of efficiency in the normaltemperature host. When a fever-tolerant pathogen subsequently reaches a nonfebrile host, it will tend to have its efficacy and virulence impaired. Hence, the more that the pathogen evolves to tolerate fever, the more that it is in danger of being thwarted by host defenses prior to successful replication and transmission.”

– To circumvent this, serious pathogens like measles use hit and run tactics. The measles virus is the most infectious right before your fever hits with full force. It is brutally beaten back once your full immune response shows up. But by then the damage is done.

#Hilleman et al. Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections. 2004.

https://pubmed.ncbi.nlm.nih.gov/15297608/

Quote: “Two different strategies for survival are assumed by viruses. One is hit and run infection whereby there is successive propagation in a series of hosts. The other is hit and stay with viral persistence in the same host. Hit and run viruses are mainly cytolytic and destroy the cells of the host in which they multiply. They are highly infective, readily transmit to susceptible new hosts, and include viruses such as influenza, rhinoviruses of the common cold, and measles. The most common resolution of viral infection is by an effective cell-mediated immune response, requiring the virus to escape to new hosts before immunological resolution or before death of the host itself.”

#European Centre for Disease Prevention and Control. Factsheet about measles. Retrieved March 2024. 

https://www.ecdc.europa.eu/en/measles/facts

Quote: “The prodrome starts after a 10–12-day incubation period and is characterised by fever, conjunctivitis, coryza, cough and bronchiolitis. Nearly all infected susceptible individuals develop clinical disease.

Koplik’s spots, the enanthema believed to be pathognomic for measles, appear on the buccal mucosa 1–2 days before the onset of rash.

The measles rash, an erythematous maculopapular exanthema, develops 2–4 days after the onset of fever and spreads from the head to the body over the next 3–4 days.

The rash, which blanches on pressure early in the course, fades in the order of appearance during the next 3–4 days and assumes a nonblanching appearance.”

#NSW Health. Measles fact sheet. Retrieved March 2024. 

https://www.health.nsw.gov.au/Infectious/factsheets/Pages/measles_factsheet.aspx

Quote: “People with measles are usually infectious from just before the symptoms begin until four days after the rash appears.”

#Griffin. Measles immunity and immunosuppression. 2021. 

https://www.sciencedirect.com/science/article/pii/S1879625720300699

Quote: “MeV infection is clinically inapparent during the incubation period when virus is actively replicating in lymphoid tissue and spreading systemically. Innate responses are not well defined with evidence primarily of inflammasome (IL-1b, IL-18) and NF-kB (IL-6), rather than type I IFN pathway activation, but these responses do not prevent virus replication and dissemination [11,41]. Clearance is dependent on the adaptive immune response. The maculopapular rash that appears 10–14 days after infection is a manifestation of the cellular

immune response to infection with lymphocyte infiltration into sites of virus replication in skin epithelial cells [42]. MeV-specific IFN-g-producing T cells and IgM antibodies are detectable in blood as the rash is fading and infectious virus is cleared within a week after appearance of the rash. MeV-specific IgM antibodies provide the primary diagnostic test for confirmation of a diagnosis of measles. Although antibody is likely to contribute, MeVspecific T cell responses are required for virus clearance [43,44].”

#Griffin. The Immune Response in Measles: Virus Control, Clearance and Protective Immunity. 2016. 

https://www.mdpi.com/1999-4915/8/10/282

– If you are sick, you are supposed to feel a reasonable amount of pain so you lie down and save energy. This is not a bug but a feature of your immune system. But pain and fever are closely connected and over the counter pain medication like Ibuprofen and Paracetamol also work against fever. 

It is important to note that not all painkilling substances, called analgesics, are working against fever. There are a plethora of molecules which act through different mechanisms. The ones involving paracetamol, or medications like aspirin, ibuprofen which are collectively grouped under nonsteroidal anti-inflammatory drugs (NSAIDs) are available over the counter or as prescription drugs in many countries and work against fever. Another group analgesics, opioids including substances like morphine for example have no effect against fever. 

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Over-the-counter medications may exacerbate the harm to public health caused by interfering with DH. Even an informed consumer who understands that DH is important may inadvertently take an antipyretic because all over-the-counter products designed to relieve cold or flu symptoms, including all pain relievers (aspirin and all other salicylates, and the class of drugs that includes ibuprofen and acetaminophen), are also antipyretics. There are presently no pain relievers available in the drugstore that do not reduce fever because the regulatory pathways for fever, inflammation, and pain sensitivity are closely connected.”

#Wrotek et al. Let fever do its job: The meaning of fever in the pandemic era. 2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/#eoaa044-B93

Quote: “Because of the ubiquity of prescribed and over-the-counter NSAIDs and acetaminophen, these drugs may be assumed to be benign. In many cases, blocking fever and sickness symptoms is inconsequential because most infections are self-limiting, as is typical for the common cold. For potentially lethal infections like COVID-19, interfering with evolved defenses may be more problematic.”

#NHS. Common questions about paracetamol for adults. 2022.

https://www.nhs.uk/medicines/paracetamol-for-adults/common-questions-about-paracetamol-for-adults/

Quote: “How does paracetamol work?

Paracetamol seems to work by blocking the chemical messengers in the brain that tell your body that you have pain. It also reduces a high temperature by affecting the chemical messengers in an area of the brain that regulates body temperature.”

#Jiyun Choi, Seyun Chang & Jong Gyun Ahn. Comparison of Fever-reducing Effects in Self-reported Data from the Mobile App: Antipyretic Drugs in Pediatric Patients. 2020. 

https://www.nature.com/articles/s41598-020-60193-1

Quote: “IBU, discovered in the 1960s, is a propionic acid derivative and a member of the antipyretic class of nonsteroidal anti-inflammatory drugs (NSAID)11. IBU is also effective for pain relief and is often used when pain accompanies inflammation12. The optimal dose of IBU is 8–10 mg/kg, which should be administered every 6 hours. The antipyretic effect of IBU commences between 30 minutes and 60 minutes after administration and its main adverse effects are gastrointestinal disorders; allergic reactions affecting the face, tongue, neck, and lips; dyspnea; and urticaria13.”

– Especially in children, fever is often suppressed by worried parents or doctors – sometimes because they think fever itself is the disease or they are worried that it can do long term harm.

#Wrotek et al. Let fever do its job: The meaning of fever in the pandemic era. 2020

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/#eoaa044-B93

Quote: “Antipyretics are taken by some people in order to treat sickness symptoms, such as headache, malaise and muscle aches. Others take antipyretics out of concern that the high temperature itself is harmful. Patients can misunderstand the source of fever, believing that it is caused directly by the infection, instead of the body’s response to infection. Some patients and medical professionals consider fever to be dangerous and take or prescribe antipyretics to return the body temperature to normal. The excessive fear of fever has been termed fever phobia [41, 42]. Parents in particular are often anxious that their children’s high temperature will cause a seizure. Febrile seizures are frightening events that occur mostly in children younger than 6 years of age. Fortunately, most common febrile seizures are harmless and leave no neurological sequelae [43, 44]. In addition, there is no evidence that taking an antipyretic will prevent the occurrence of a febrile seizure [43].”

#MyHealth.Alberta.ca. Fever or Chills, Age 11 and Younger. 2022.

https://myhealth.alberta.ca/Health/Pages/conditions.aspx?hwid=fevr3

Quote: “Children tend to run higher fevers than adults. The degree of fever may not show how serious your child's illness is. With a minor illness, such as a cold, a child may have an oral temperature of 40°C (104°F). But a very serious infection may not cause a fever or may cause only a mild fever. With many illnesses, a fever temperature can go up and down very quickly and often. So be sure to look for other symptoms along with the fever.”

#Plaisance KI, Mackowiak PA. Antipyretic Therapy: Physiologic Rationale, Diagnostic Implications, and Clinical Consequences. 2000.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415390

Quote: “Nevertheless, many clinicians believe that even the relatively modest increases in core temperature encountered during fever are deleterious to certain patients and should therefore be suppressed.

Children, primarily between ages 3 months and 5 years, are 1 such category of patients. In these children, seizures have occurred during episodes of fever at a frequency of from 2% to 5% in the United States and Western Europe18,19 to as high as 14% in other selected countries.20 Although most children have temperatures of 39.0°C or lower at the time of their seizure,21 many tolerate higher fevers at later dates without convulsing.22 Unfortunately, antipyretic therapy has not been shown to protect against recurrences of febrile seizure in the few controlled trials conducted thus far.23”

#Seattle Children’s Hospital. Retrieved March 2024. 

https://www.seattlechildrens.org/conditions/a-z/fever-myths-versus-facts/

Quote: “MYTH. All fevers are bad for children.

FACT. Fevers turn on the body's immune system. They help the body fight infection. Normal fevers between 100° and 104° F (37.8° - 40° C) are good for sick children.

MYTH. Fevers above 104° F (40° C) are dangerous. They can cause brain damage.

FACT. Fevers with infections don't cause brain damage. Only temperatures above 108° F (42° C) can cause brain damage. It's very rare for the body temperature to climb this high. It only happens if the air temperature is very high. An example is a child left in a closed car during hot weather.

MYTH. Anyone can have a seizure triggered by fever.

FACT. Only 4% of children can have a seizure with fever.

MYTH. Seizures with fever are harmful.

FACT. These seizures are scary to watch, but they stop within 5 minutes. They don't cause any permanent harm. They don't increase the risk for speech delays, learning problems, or seizures without fever.

MYTH. All fevers need to be treated with fever medicine.

FACT. Fevers only need to be treated if they cause discomfort (makes your child feel bad). Most fevers don't cause discomfort until they go above 102° or 103° F (39° or 39.5° C).

MYTH. Without treatment, fevers will keep going higher.

FACT. Wrong, because the brain knows when the body is too hot. Most fevers from infection don't go above 103° or 104° F (39.5°- 40° C). They rarely go to 105° or 106° F (40.6° or 41.1° C). While these are "high" fevers, they also are harmless ones.”

#Stanford Medicine Children’s Health. Not All Fevers Need Treatment. 2019. 

https://www.stanfordchildrens.org/en/topic/default?id=not-all-fevers-need-treatment-88-p11048

Quote: “If you’re like most parents, your anxiety level rises along with your child’s temperature. Fever is a warning sign that your child may have an illness that needs attention. But the American Academy of Pediatrics (AAP) stresses that fever itself is usually not a problem. In fact, it can be helpful. 

[...]

It’s best to take the temperature rectally for children ages 3 and younger. A rectal temperature more than 100.4°F (38°C) is considered a fever. When taken orally, a temperature higher than 99.5°F (37.5°C) is diagnosed as a fever.    

A child who is eating and sleeping well and having playful moments often doesn’t need any fever-lowering treatment. But call your child’s healthcare provider in these cases:

Age 3 months or younger: Rectal temperature of 100.4°F (38°C) or higher

Younger than age 2: Fever lasts more than 24 hours

Ages 2 and older: Fever lasts more than 72 hours

Any age: Fever repeatedly goes higher than 104°F (40°C) or is accompanied by other symptoms, such as having a seizure, severe sore throat, severe ear pain or headache, unexplained rash, repeated vomiting or diarrhea, unusual sleepiness, or very fussy behavior.”

#The Royal Children’s Hospital Melbourne. Fever in children. 2021. 

https://www.rch.org.au/kidsinfo/fact_sheets/fever_in_children/

Quote: “Key points to remember

A fever is when a child’s temperature is 38°C or higher

Fevers are common in children

A fever itself rarely causes harm and can help fight an infection

If your child seems otherwise well and comfortable, there is no need to treat a fever.

If your child is under three months and has a fever above 38°C, take them to the doctor, even if they have no other symptoms.

Take your child to the doctor if they seem to be getting worse or have a prolonged fever.” 

#Boston Children’s Hospital. About Fevers. Retrieved April 2024.

https://www.childrenshospital.org/conditions/fever

Quote: “When should a fever be treated?

If your child is very uncomfortable, treatment may be necessary. Treating your child’s fever will not help her body get rid of the infection any quicker, but it will relieve discomfort associated with it.

Rarely, children between the ages of 6 months and 5 years can develop seizures from high fever (called febrile seizures). If your child does have a febrile seizure, there is a chance that the seizure may occur again, but, usually, children outgrow the febrile seizures. A febrile seizure does not mean your child has epilepsy.”

– In general it is fair to say that for temperatures below 40°C or 104 °F, fever is not dangerous and doesn’t need to be treated.

There are contradicting views regarding whether to treat fever or not, in which cases it should be treated, or when and how to treat it. The controversy is mostly coming from the lack of studies or the varying results from the existing ones. Some experts think that fever should be suppressed because its metabolic costs are higher than its potential physiologic benefit whereas others think that fever is protective and should be allowed to ride its course under most circumstances.
Also, it is important to note that fever by nature is stressful for the body. Even middle grade fever can do a bit of damage but in some cases, like infection, the benefit might outweigh the risks. However, fevers not due to infection, like heatstroke, inflict more harm than benefit. 

So it is very difficult to get a general rule covering all these questions or give a single temperature below which fever is always ok and can be safely left untreated. Other accompanying symptoms and duration of fever are important determinants in treatment as well. We arrived at this sentence through discussions with our experts, but one has to be cautious and the decision whether it is to be treated or not must be taken by a physician.

We are listing a few relevant articles below:

#Plaisance KI, Mackowiak PA. Antipyretic Therapy: Physiologic Rationale, Diagnostic Implications, and Clinical Consequences. 2000.

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415390

Quote: “Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the other, that suppressing fever will reduce if not eliminate fever's noxious effects. Neither assumption has been validated experimentally. In fact, there is considerable evidence that fever is an important defense mechanism that contributes to the host's ability to resist infection.15,16 Moreover, it has never been shown in humans that increases in core temperature encountered during fever, which rarely exceed 41°C (105.8°F), are harmful per se.17 Nevertheless, many clinicians believe that even the relatively modest increases in core temperature encountered during fever are deleterious to certain patients and should therefore be suppressed.”

#Belon L, Skidmore P, Mehra R, Walter E. Effect of a fever in viral infections — the ‘Goldilocks’ phenomenon? World J Clin Cases 2021. 

https://www.wjgnet.com/2307-8960/full/v9/i2/296.htm

Quote: “Current epidemiological and biological evidence suggests that viral replication is reduced and that human host defence mechanisms are enhanced at degrees of mild fever, compared with normothermia. However, at higher degrees of fever, (around 39-40 °C), mortality again increases, suggesting that any benefit at mildly elevated temperatures is outweighed by the damage the fever causes on the host. This ‘U’-shaped curve, demonstrating improved outcomes at mild febrile temperatures, does not appear to be replicated in non-pathogenic states, suggesting that the damage that the fever exerts on the host is not matched by any perceived benefit, and that this permissive pyrexia may only be true with an infective aetiology.”

#Juliet J. Ray and Carl I. Schulman. Fever: suppress or let it ride? 2015.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703655/

Quote: “Despite this evidence, treatment of fever is common in the ICU setting and likely related to standard dogma rather than evidence-based practice. In this prospective controlled trial by Young et al. published in the NEJM on December 3, 2015, 700 ICU patients with fever of known or suspected infectious etiology were randomized to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death (20). The patients in the treatment group did have a statistically, but likely not clinically, relevant lower mean daily average temperature (absolute difference −0.28 °C, P<0.001). Sustained resolution of fever was also significantly higher in the treatment versus placebo group (22.8% vs. 16.9%, P=0.05). The main outcome was ICU-free days until day 28, which was not shown to be decreased in the treatment arm. Secondary outcomes, including 28 and 90-day mortality and ICU and hospital length of stay, were also not significantly different between groups. However, acetaminophen was associated with a shorter ICU stay than placebo among survivors and a longer stay in non-survivors. In terms of adverse events, there was no difference between groups in discontinuation of the drug due to liver dysfunction, and one patient in the placebo group suffered from markedly elevated temperature associated with death. It should be noted that the study population was predominantly non-surgical and that the treatment period was relatively short. More and more high-level randomized controlled trials are supporting the “let it ride” philosophy compared to the original prospective observational studies, which seem to support the opposite.

[...]

Is fever good or bad? Scientifically, we just do not know. However, if we take the evolutionary perspective, then blunting of the adaptive febrile response must be maladaptive.”

#Samer Singh, Dhiraj Kishore, Rakesh K. Singh. Potential for Further Mismanagement of Fever During COVID-19 Pandemic: Possible Causes and Impacts. 2022.

https://www.frontiersin.org/articles/10.3389/fmed.2022.751929/full#B123

Quote: “It may be opportune to upwardly revise the temperature range for antipyresis consideration. Soon after the publication of the first guideline by the WHO in 2000 (132), a meta-analysis published in the bulletin of the WHO (70) identified 41°C as “normal febrile range,” highlighted the continued practice of antipyresis as “parents and health professionals routinely treat fever in young children” despite the clear-cut realizations of “fever helps survival during infection, and that antipyresis increases mortality” in many diseases and the “potential for hepatotoxicity” and “overdosage” (70, 89–92). Moreover, it indicates “the WHO recommendations for the management of fever in children include the use of paracetamol for children with fever of ≥39°C” despite “insufficient data, however, support this recommendation” and suggest “We recommend that health professionals should not be encouraged to give antipyretics routinely to febrile children. Treatment should only be given to those children in obvious discomfort or those with known painful conditions” (70). The revised fever reduction guidelines were published by the WHO in 2013 to increase awareness among healthcare providers and parents, and to improve the adherence to appropriate practices (32) (as shown in Table 2A).”

Important things to keep in mind that there might be different ranges for grades of fever depending on which reference is used and the body temperature varies depending on where it is measured. Therefore if an article says “a low grade fever is not dangerous” without any further specifications, it might be referring to different temperatures. 

#Osilla EV, Marsidi JL, Shumway KR, et al. Physiology, Temperature Regulation. 2023.

https://www.ncbi.nlm.nih.gov/books/NBK507838/

Quote: “Fever is an elevation in body temperature due to changes in the hypothalamic set-point. 

Below is a summary of the categorization of fever. Based on the source, these figures may have slight variations.[4]

Low grade: 37.3 to 38.0°C (99.1 to 100.4°F)

Moderate grade: 38.1 to 39.0°C (100.6 to 102.2°F)

High grade: 39.1 to 41°C (102.4 to 105.8°F)

Hyperthermia: Greater than 41 C (105.8°F)”

#Swetha Balli; Karlie R. Shumway; Shweta Sharan. Physiology, Fever. 2023

https://www.ncbi.nlm.nih.gov/books/NBK562334/

Quote: ”An issue of concern that should be addressed when discussing the concept of fever is understanding that the site of measurement influences body temperature readings. The average axillary temperature reading is 35.97 degrees C (96.75 degrees F), oral is 36.57 degrees C (97.83 degrees F), urine is 36.61 degrees C (97.90 degrees C), tympanic is 36.64 degrees C (97.95 degrees F), and rectal is 37.04 degrees C (98.67 degrees F).[3]

It is also important to consider the patient's normal baseline body temperature. If a patient typically runs "cold" or "hot," then their baseline body temperature may be decreased or elevated above what is considered "normal" and does not necessarily indicate a fever or febrile illness.”

Generally medical institutions advise to call your doctor even though there is some variation.

#Howard E. LeWine. Harvard Health Publishing. Fever in adults: When to worry. 2023. 

https://www.health.harvard.edu/diseases-and-conditions/treating-fever-in-adults

Quote: “When to worry about fever

If you have a fever over 104°F (40°C), you should call your doctor.

Seek medical help right away if you have a fever along with any of these symptoms:

seizure

loss of consciousness

confusion

stiff neck

trouble breathing

severe pain anywhere in the body

swelling or inflammation of any part of the body

vaginal discharge that is discolored or smells bad

pain when urinating or urine that smells bad.”

– Of course there are also patients that should not have fever – like pregnant women, seniors and seriously weakened patients. For them the extra stress may be dangerous.

#Clint and Fessler. Insurmountable Heat: The Evolution And Persistence Of Defensive Hyperthermia. 2016. 

https://www.journals.uchicago.edu/doi/abs/10.1086/685302

Quote: “Some of the individuals most vulnerable to infection—pregnant women and the elderly—are least capable of benefitting from fever because elevated temperature during pregnancy can cause birth defects, while senescence reduces the ability to bear the burden of maintaining an elevated temperature (Gomolin et al. 2005).”

Elevated temperatures can constitute a risk factor in different stages of pregnancy and have serious consequences from birth defects to embryonic death.

#Marshall J. Edwards. Review: Hyperthermia and Fever during Pregnancy. 2006.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdra.20277

Quote: “An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life.”

There are conflicting findings on this though since it is not an easy topic to study clinically. The following study could not find any relation on the other hand with fever in the first 16 weeks of pregnancy and fetal death. 

#Andersen et al. Fever in pregnancy and risk of fetal death: a cohort study. 2002 https://pubmed.ncbi.nlm.nih.gov/12443593/

Quote: “Findings: 1145 pregnancies resulted in a miscarriage or stillbirth (4.8%). During the first 16 pregnancy weeks 18.5% of the women experienced at least one episode of fever. However, we found no association between fever in pregnancy and fetal death before or after adjustment for known risk factors of fetal death (relative risk 0.95 [95% CI 0.80-1.13]). This finding was consistent irrespective of measured maximum temperature, duration and number of fever incidents, or the gestational time of the fever incident, and was observed for fetal death in all three trimesters of pregnancy.

Interpretation: We found no evidence that fever in the first 16 weeks of pregnancy is associated with the risk of fetal death in clinically recognised pregnancies.”

– Fever over 40°C is dangerous to anybody because it is most likely caused by your internal heat monitor failing. 

Even though under 40 °C, the body is still relatively in control and knows what it is doing. It dispatches the mechanism causing fever because it needs to. However, overshooting 40 °C is likely to mean that those mechanisms are not functioning properly anymore. It is important to note that fever by its nature is harmful and it can get dangerous very quickly. However, the problem with these higher temperatures is that the control system is not getting the correct information or is not responding properly to its inputs. 

Following lists some of the dangerous effects of continuing high fever. 

#Balli S, Shumway KR, Sharan S. Physiology, Fever. 2023. https://www.ncbi.nlm.nih.gov/books/NBK562334/

Quote: “A sustained, severely elevated fever can lead to lethal effects within multiple organ systems:

Brain

– Acute neurologic and cognitive function may occur after an episode of hyperthermia, with approximately 50% of heatstroke survivors experiencing chronic neurologic damage.  

– Specifically, the Purkinje cells in the cerebellar cortex are sensitive to heat damage, which can lead to long-lasting cerebellar dysfunction.[6]

Cardiovascular

– Acutely, a hyperthermic patient will tend to be hypotensive with a high cardiac output due to blood redistribution and nitric-oxide-induced vasoconstriction. In severe fever, such as heatstroke, an electrocardiogram may show T-wave abnormalities, QT and ST changes, and conduction defects. In addition, serum troponin I levels may be significantly raised.[7]

Gastrointestinal

– Above 40 C (104 F), there is a reduction in blood flow to the GI tract. In addition, oxidative stress, denatured proteins, and damaged cell membranes are evident, increasing the potential for releasing pro-inflammatory cytokines, GI inflammation, and edema.[8]

Liver

– Elevated liver enzymes (AST/ALT) are observed in individuals with body temperatures above 40 C, with severe cases leading to permanent hepatocellular damage requiring a liver transplant. It is important to note that liver function may continue to decline even after correcting hyperthermia. For this reason, a clinician should trend the patient's liver enzymes to ensure no ongoing liver damage exists.[9]

Kidney

– Patients with an increased body temperature are at a significantly greater risk for acute kidney injury (AKI). An increase in body temperature by only 2 C leads to a decrease in the glomerular filtration rate (GFR), which continues to fall with a further rise in temperature. Lab studies will show an increase in plasma creatinine and urea. Additionally, a hyperthermic state stimulates the renin-angiotensin-aldosterone system (RAAS), leading to a subsequent reduction in blood flow to the kidney.[10]

Hemostasis

– Inhibition of platelet aggregation, spontaneous bleeding, increased clotting times, thrombocytopenia, and increased plasma fibrin degradation productions are classically seen in hyperthermic patients.[11]”

– Things get more complicated in serious disease territory. We also have evidence that for some diseases like influenza or chickenpox antifever drugs do not help you to heal faster. 

#Ahkee S, Srinath L , Ramirez J. Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. 1997. 

https://europepmc.org/article/med/9076300

Quote: “Elderly patients with community-acquired pneumonia may not have a systemic inflammatory response characterized by fever and leukocytosis. We compared lack of fever and leukocytosis with mortality in elderly patients with community-acquired pneumonia. Patients with fever and leukocytosis (group A, 47 patients) were compared with those without fever and leukocytosis (group B, 17 patients). Comparison of the two groups by unpaired, two-tailed t test showed that lack of fever and leukocytosis correlated with mortality. Hospitalized elderly patients who have community-acquired pneumonia without fever and leukocytosis are seven times more likely to die than those who have these symptoms. Future research in the adjunct use of immune modulators such as granulocyte colony-stimulating factor in these patients should be encouraged.”

#Shann F, Barker J, Poore P. Clinical signs that predict death in children with severe pneumonia. Pediatr Infect Dis J. 1989

https://pubmed.ncbi.nlm.nih.gov/2696926/

Quote: “It is important to define clinical signs that can be used to identify children who have a high risk of dying from pneumonia so that these children can be given more intensive therapy. We prospectively studied 748 children in Papua New Guinea who had severe pneumonia, as defined by the World Health Organization. There was a very high mortality in children with a prolonged illness, severe roentgenogram changes, cyanosis, leukocytosis, hepatomegaly or inability to feed, and there was a trend toward a higher mortality in children with grunting or severe chest indrawing. Afebrile malnourished children had a particularly high mortality, but afebrile children had an increased mortality only if they were malnourished, and malnourished children had an increased mortality only if they were afebrile. Mortality was not increased in very young children or in children with tachypnea or tachycardia. The World Health Organization has suggested that most children with pneumonia in developing countries can be treated with penicillin but has recommended that children who are cyanotic or too sick to feed be treated with chloramphenicol because of their high risk of dying; our findings confirm that children who are cyanotic or too sick to feed have a very high risk of dying from pneumonia.”

In a 1989 study with 72 children with chickenpox, a prolonged time to total scabbing and no alleviation of symptoms in the group treated against fever was found. But they were also cautious and wrote that the question of whether fever reduction prolongs viral illness can not be with their study. 

#Doran et al. Acetaminophen: for chickenpox? More harm than good. 1989. 

https://www.jpeds.com/article/S0022-3476(89)80461-5/abstract

Quote: “We found that the number of days until the appearance of the last new vesicle and the time to total healing were the same in both groups, but children treated with acetaminophen sustained a longer time to total scabbing than did a placebo-treated control

group. In addition, the children treated with acetaminophen fared no better with symptoms than did a placebo treated group.”

In the following randomized controlled trial study, no difference was found in viral shedding, temperature or clinical symptoms in patients with and without influenza. 

#Jefferies S. et al. Randomized controlled trial of the effect of regular paracetamol on influenza infection. 2015.

https://onlinelibrary.wiley.com/doi/10.1111/resp.12685

Quote: “To our knowledge this is the first randomized, double-blind, placebo-controlled trial on the effect of paracetamol  in  patients  with  confirmed  influenza infection.  Regular  daily  administration  of  the maximum recommended dose of paracetamol for 5 days had no effect on viral shedding, temperature or clinical symptoms in participants with PCR-proven influenza infection. It is difficult to infer benefit or harm given the lack of effect of regular paracetamol administered early in the course of an influenza-like illness in this trial; thus, recommendations for or against this practice in the community cannot be made based on these findings.”

Eyers S, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. 2010 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951171

Quote: “Results

Eight studies from three publications met the inclusion criteria. No human studies were identified. The risk of mortality was increased by antipyretic use in influenza-infected animals with a fixed effects pooled odds ratio of 1.34 (95% CI 1.04–1.73). An increased risk was observed with aspirin, paracetamol and diclofenac.

Conclusion

In animal models, treatment with antipyretics for influenza infection increases the risk of mortality. There are no randomized placebo-controlled trials of antipyretic use in influenza infection in humans that reported data on mortality and a paucity of clinical data by which to assess their efficacy. We suggest that randomized placebo-controlled trials of antipyretic use in human influenza infection are urgently required, and that these are sufficiently powered to investigate a potential effect on mortality.”

– But we are also running into ethics problems here that make clinical trials difficult. In one study doctors gave strong anti fever treatment to critical care patients – but had to stop after mortality shot up. 

#Schulman et al. The Effect of Antipyretic Therapy upon Outcomes in Critically Ill Patients: A Randomized, Prospective Study. 2005.

https://www.liebertpub.com/doi/10.1089/sur.2005.6.369

Quote: “Results: Between December, 2002 and September, 2003, 572 patients were screened, of whom 82 met criteria for enrollment. Forty-four patients were randomized to the aggressive group and 38 patients were randomized to the permissive group for a total of 961 and 751 ICU days, respectively. There were 131 infections in the aggressive group and 85 infections in the permissive group (4 ± 6 vs. 3 ± 2 infections per patient, p = 0.26). There were seven deaths in the aggressive group and only one death in the permissive group (p = 0.06, Fisher Exact Test). The study was stopped after the first interim analysis due to the mortality difference, related to the issues of waiver of consent and the mandate for minimal risk.

Conclusions: Aggressively treating fever in critically ill patients may lead to a higher mortality rate.”

– Overall we have strong indications that more people may survive serious infectious diseases with a fever.

It is important to note that this doesn’t apply to all diseases, especially in non-infectious cases, like hematoma, myocardial infarction or deep vein thrombosis, fever can be largely damaging. The following study represents one such result. 

#Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004 

https://pubmed.ncbi.nlm.nih.gov/15241093

Quote: “Measurements and main results: We measured ICU and hospital length of stay, mortality rate, and discharge disposition. The presence of elevated body temperature was associated with a dose-dependent longer ICU and hospital length of stay, higher mortality rate, and worse hospital disposition. The most important predictor of ICU length of stay was the number of complications (beta =.681) followed by elevated body temperature (beta =.143). In the matched, weighted population, the presence of elevated body temperature was associated with 3.2 additional ICU days and 4.3 additional hospital days.

Conclusion: In a large cohort of neurologic ICU patients, after we controlled for severity of illness, diagnosis, age, and complications, elevated body temperature was independently associated with a longer ICU and hospital length of stay, higher mortality rate, and worse outcome.”

A review paper looked into the research regarding the effects of fever treatment in critical care. Authors included 10 observational studies reporting on fever-mortality associations of ICU patients, 3 experimental studies investigating the effect of antipyretic treatment on mortality of ICU patients, and 2 meta-analyses of relevant experimental studies. 

They found cases both where it was beneficial and where it was detrimental. So it depends on the disease and cause of the fever and it is not possible to say an overarching statement. 

#Kiekkas P, Aretha D, Bakalis N, Karpouhtsi I, Marneras C, Baltopoulos GI. Fever effects and treatment in critical care: literature review. Aust Crit Care. 2013

https://pubmed.ncbi.nlm.nih.gov/23199670/

Quote: “Recently published studies 40,41,45–47 significantly complement the implications for antipyretic treatment in critically ill adults. For septic shock patients46 and for those with cerebral damage,12–14 fever suppression and maintenance of normothermia improves outcomes and is strongly recommended. For febrile ICU adults without septic shock or cerebral damage, evidence comes from studies with considerable disparities among their design, participants, data analysis and findings. Thus, recommendations for antipyretic treatment could be developed through consensus derived by an expert opinion group.50 Fever suppression can sometimes be of benefit for patients with severe sepsis, chronic respiratory or heart failure, and severe hemodynamic instability.23,24 In these groups, assessment of the need for antipyretic treatment could be primarily based on continuous monitoring of cardiorespiratory parameters.”

Another study suggested that treatment of fever in ICU patients may not be useful unless they have cranial trauma or significant hypoxemia. 

#Gozzoli V, Schöttker P, Suter PM, Ricou B. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med. 2001 

https://pubmed.ncbi.nlm.nih.gov/11146708/

Quote: “Abstract

Background: Antipyresis is a common clinical practice in intensive care, although it is unknown if fever is harmful, beneficial, or a negligible adverse effect of infection and inflammation.

Methods: In a randomized study, rectal temperature and discomfort were assessed in 38 surgical intensive care unit patients without neurotrauma or severe hypoxemia and with fever (temperature >/=38.5 degrees C) and systemic inflammatory response syndrome. Eighteen patients received external cooling while 20 received no antipyretic treatment.

Results: Temperature and discomfort decreased similarly in both groups after 24 hours. No significant differences in recurrence of fever, incidence of infection, antibiotic therapy, intensive care unit and hospital length of stay, or mortality were noted between the groups.

Conclusions: These results suggest that the systematic suppression of fever may not be useful in patients without severe cranial trauma or significant hypoxemia. Letting fever take its natural course does not seem to harm patients with systemic inflammatory response syndrome or influence the discomfort level and may save costs.”

#Launey et al. Clinical review: Fever in septic ICU patients - friend or foe? 2011. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218963/pdf/cc10097.pdf

Quote: “Fever is a basic response triggered by an infectious or a non-infectious process. The balance of benefit to harm of fever in septic ICU patients is complex. This balance is likely to be dependent on the stage and severity of the infection, on the intensity of the immune response, on the extent of systemic inflammatory response-induced collateral tissue damage as well as on the underlying physiological reserve of the patient (Table 1). On the other hand, the widespread use of antipyretic methods in ICU patients is not supported by clinical data and fever control may be harmful, particularly when an infectious

disease is progressing. We await appropriately designed, prospective randomised trials to define patient groups likely to benefit from or be harmed by antipyretic treatment. The decision to introduce an antipyretic therapy should be well balanced according to the presence of neurological injuries and/or underlying cardiac disease and the absence of sepsis.” 

Serpa Neto A, Pereira VG, Colombo G, Scarin FC, Pessoa CM, Rocha LL. Should we treat fever in critically ill patients? A summary of the current evidence from three randomized controlled trials. Einstein (Sao Paulo). 2014 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879924/

Quote: “Fever is a nonspecific response to various types of infectious or non-infectious insult and its significance in disease remains an enigma. Our aim was to summarize the current evidence for the use of antipyretic therapy in critically ill patients. We performed systematic review and meta-analysis of publications from 1966 to 2013. The MEDLINE and CENTRAL databases were searched for studies on antipyresis in critically ill patients. The meta-analysis was limited to: randomized controlled trials; adult human critically ill patients; treatment with antipyretics in one arm versus placebo or non-treatment in another arm; and report of mortality data. The outcomes assessed were overall intensive care unit mortality, changes in temperature, intensive care unit length of stay, and hospital length of stay. Three randomized controlled trials, covering 320 participants, were included. Patients treated with antipyretic agents showed similar intensive care unit mortality (risk ratio 0.91, with 95% confidence interval 0.65-1.28) when compared with controls. The only difference observed was a greater decrease in temperature after 24 hours in patients treated with antipyretics (-1.70±0.40 versus - 0.56±0.25ºC; p=0.014). There is no difference in treating or not the fever in critically ill patients.”

#Schell-Chaple HM, et al. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. Body temperature and mortality in patients with acute respiratory distress syndrome. Am J Crit Care. 2015 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464553/

Quote: “Results

Mean baseline temperature was 37.5°C (SD, 1.1°C; range, 27.2°C-40.7°C). At baseline, fever (≥ 38.3°C) was present in 23% and hypothermia (< 36°C) in 5% of the patients. Body temperature was a significant predictor of 90-day mortality after primary cause of ARDS and score on the Acute Physiology and Chronic Health Evaluation III were adjusted for. Higher temperature was associated with decreased mortality: for every 1°C increase in baseline temperature, the odds of death decreased by 15% (odds ratio, 0.85; 95% CI, 0.73-0.98, P = .03). When patients were divided into 5 temperature groups, mortality was lower with higher temperature (P for trend=.02).

Conclusions

Early in ARDS, fever is associated with improved survival rates. Fever in the acute phase response to lung injury and its relationship to recovery may be an important factor in determining patients' outcome and warrants further study.”

– And there is very little clinical evidence that stopping fever leads to better health outcomes. But there are important exceptions, like neurological injuries and stroke. We definitely need a lot more research.

#Drewry AM, et al. Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2017 

https://pubmed.ncbi.nlm.nih.gov/28221185/

Quote: “Data synthesis: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation.

Conclusions: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.”

#Holgersson J et al. Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses. 2022. 

https://www.bmj.com/content/bmj/378/bmj-2021-069620.full.pdf

Quote: “In this systematic review with meta-analyses and trial sequential analyses, we showed that fever therapy does not seem to affect the risk of death or serious adverse events in febrile adults. We found almost no signs of statistical heterogeneity, and none of the predefined subgroup analyses showed evidence of a difference in all cause mortality or serious adverse events, which supports the validity of our meta-analysis results. We found insufficient evidence to confirm or reject the hypothesis that fever therapy influences quality of life or non-serious adverse events.”

In the following randomized controlled trial, researchers suppressed fever with ibuprofen in one group of critically ill patients with sepsis and compared the effects to the placebo group. Although the treatment group exhibited significant reductions in fever, heart rate, lactate levels, and oxygen consumption values, no differences in oxygen delivery, organ failure–free days, or mortality were found.

#Bernard GR et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. 1997. 

https://pubmed.ncbi.nlm.nih.gov/9070471/

Quote: “​​Results: In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. With ibuprofen therapy there was no increased incidence of renal dysfunction, gastrointestinal bleeding, or other adverse events. However, treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days (mortality, 37 percent with ibuprofen vs 40 percent with placebo).

Conclusions: In patients with sepsis, treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever, tachycardia, oxygen consumption, and lactic acidosis, but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival.”

In another recent observational study, researchers investigated the effect of fever and antipyretic treatment in critically ill patients with or without sepsis. They found out that patients with sepsis, fever independently predicted the decreased mortality and use of anti-fever treatment was an independent factor in increased mortality. However, in the patients without sepsis, only high fever (≥39.5°C) was independently associated with increased mortality, and no associations were found with use of antipyretic medication and mortality. However, the authors of the paper warn against the certainty of causality. 

#Lee BH, et al. Fever and Antipyretic in Critically ill patients Evaluation (FACE) Study Group. Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study. Crit Care. 2012 

https://pubmed.ncbi.nlm.nih.gov/22373120/

Quote: “Results: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected].

Conclusions: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.

[...]
Although we reported associations and cannot assume causality, our finding was consistent with previous studies [26,27], suggesting that fever could be a host response that protects against infectious diseases [11-13] and use of antipyretic treatments to suppress the febrile response to infection might worsen outcomes [14,15].”

#Markota A, Skok K, Kalamar Ž, Fluher J, Gorenjak M. Better Control of Body Temperature Is Not Associated with Improved Hemodynamic and Respiratory Parameters in Mechanically Ventilated Patients with Sepsis. J Clin Med. 2022 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911511/

Quote: “The need for temperature modulation (mostly cooling) in critically ill patients is based on the expected benefits associated with decreased metabolic demands. However, evidence-based guidelines for temperature management in a majority of critically ill patients with fever are still lacking. The aim of our retrospective single-site observational study was to determine the differences in ICU treatment between patients in whom their temperature remained within the target temperature range for ≥25% of time (inTT group) and patients in whom their temperature was outside the target temperature range for <24% of time (outTT group). We enrolled 76 patients undergoing invasive mechanical ventilation for respiratory failure associated with sepsis. We observed no significant differences in survival, mechanical ventilation settings and duration, vasopressor support, renal replacement therapy and other parameters of treatment. Patients in the inTT group were significantly more frequently cooled with the esophageal cooling device, received a significantly lower cumulative dose of acetaminophen and significantly more frequently developed a presence of multidrug-resistant pathogens. In our study, achieving a better temperature control was not associated with any improvement in treatment parameters during ICU stay. A lower prevalence of multidrug-resistant pathogens in patients with higher body temperatures opens a question of a pro-pyrexia approach with an aim to achieve better patient outcomes.”

However, in case of septic shock, external cooling (not through antipyretics) decreased vasopressor requirements and early mortality. Even though the results of this study seem in disagreement with the two studies above, it is important to note that there are significant differences in the condition of the patients, the method of fever suppression, and the measured outcomes. So there is definitely a big need for more research before the causality is established. 

#Schortgen F, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 

https://pubmed.ncbi.nlm.nih.gov/22366046/

Quote: “Measurements and main results: Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013).

Conclusions: In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.”

– If a fever is not dangerously high and you can bear it, you are supporting your defenses and may even get healthy a bit faster. But if you feel really bad and are healthy in general, taking a pill against pain and fever will make you feel better quicker, at the cost of a slightly less effective immune defense. 

In the following, one can find a short summary of some cases where fever had favorable outcomes. 

#Wrotek et al., Let fever do its job: The meaning of fever in the pandemic era. 2020. 

https://academic.oup.com/emph/article/9/1/26/5998648#312624980

Quote: “Building on previous theoretical and basic scientific research on fever, recent observational trials in humans have examined the use of antipyretics and fever on disease outcomes. Inhibition of fever with acetaminophen has been linked with delayed recovery, including from chickenpox and malaria [50, 51]. The use of NSAIDs has been linked with complications, including empyema and prolonged hospitalization, in children and adults with lower respiratory tract infections, reviewed in [52]. Potentially beneficial effects of fever have also been reported in observational trials. In a prospective trial that examined the effect of mitochondrial genetic variants in patients with sepsis, the mitochondrial haplotype H was linked with higher febrile temperatures and improved survival; overall, the best survival occurred in those with the highest core temperature within the first 24 h [53]. In two studies of sepsis and severe infection in Sweden and Denmark, each involving more than 2000 patients, fever was associated with lower mortality, and those with the highest body temperatures had the best survival [54, 55]. Young et al. [56] showed that lower temperatures were associated with higher mortality among a cohort of 269,078 ICU patients with infection in New Zealand and Australia, and the same result was seen in a cohort numbering 366, 973 in the UK. In a recent observational study of patients with COVID-19 pneumonia, it was found that having a fever (≥39°C) was associated with better survival [57], although another study involving COVID-19 showed a positive association between fever and more severe cases [58].”

In the following section of their paper, authors summarize a number of studies that did not find a significant improvement upon suppression of fever. However, it is important to note that we need much more research, since there are also cases and diseases that suppressing fever does not effect the duration of illness. 

#Wrotek et al., Let fever do its job: The meaning of fever in the pandemic era. 2020. 

https://academic.oup.com/emph/article/9/1/26/5998648#312624980

Quote: “Evidence from randomized controlled trials suggests that intervening to reduce fever does not improve patients’ survival. In the HEAT trial, Young et al. [59] randomized critically ill patients to fever suppression with acetaminophen versus a group with fever but not receiving acetaminophen. No improvement in survival was seen in the acetaminophen group, but no clear harm was seen either. In a randomized controlled trial in ICU patients, ibuprofen did not improve survival [60]. Some human trials have shown harm from reducing the body temperature lower than normal in critically ill patients with infection. In 2013, a randomized, although not blinded, trial using chilled intravenous saline to induce hypothermia in patients with meningitis was stopped early after an interim review revealed increased mortality in the intravenous cooling group [61]. A more recent trial studied mechanical cooling of critically ill patients with septic shock. This trial randomized patients to induced hypothermia using external chilled circulating water, compared to those receiving usual care, which included some medications such as acetaminophen. The trial was also terminated early after enrolling 436 of a planned 560 patients; interim analysis pointed to higher mortality in the mechanical cooling group [62]. A meta-analysis of randomized controlled trials comparing aggressive treatment of fever versus usual care found no survival benefit from aggressive fever reduction [63]. Even medically fragile patients, including those with heart disease and limited physiological reserves, did not benefit from intensive efforts to reduce body temperature [63]. Taken together, these studies suggest that survival outcomes of patients with infection are not improved by interventions used to lower body temperature and suppress fever. On the contrary, randomized trials of body temperature reduction using intravenous or mechanical cooling have shown a signal of harm. These results are in line with increased mortality seen in observational trials [56] and suggest that interfering with the physiologic set point for body temperature can have unintended consequences.”

The following study found that flu patients coming to hospital without fever were staying  longer (median length of stay, 2.4 vs 1.9 days; P = .015) and were more likely to die in the hospital even after controlling for confounders. 

Smith BJ, Price DJ, Johnson D, Garbutt B, Thompson M, Irving LB, Putland M, Tong SYC. Influenza With and Without Fever: Clinical Predictors and Impact on Outcomes in Patients Requiring Hospitalization. Open Forum Infect Dis. 2020 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580166/

Quote: “Of 578 influenza inpatients, 219 (37.9%) had no fever at presentation. Fever was less likely in individuals with a nonrespiratory syndrome (adjusted odds ratio [aOR], 0.44; 95% CI, 0.26–0.77), symptoms for ≥3 days (aOR, 0.53; 95% CI, 0.36–0.78), influenza B infection (aOR, 0.45; 95% CI, 0.29–0.70), chronic lung disease (aOR, 0.55; 95% CI, 0.37–0.81), age ≥65 (aOR, 0.36; 95% CI, 0.23–0.54), and female sex (aOR, 0.69; 95% CI, 0.48–0.99). Patients without fever had lower rates of testing for influenza in the emergency department (64.8% vs 77.2%; P = .002) and longer inpatient stays (median, 2.4 vs 1.9 days; P = .015). These patients were less likely to receive antiviral treatment (55.7% vs 65.6%; P = .024) and more likely die in the hospital (3.2% vs 0.6%; P = .031), and these differences persisted after adjustment for potential confounders.”

The following study suggests that influenza patients treated with antipyretics were sick about 3.5 days longer than patients who did not receive antipyretics.

#Plaisance KI et al. Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. 2000

https://pubmed.ncbi.nlm.nih.gov/11130213/

Quote: “The challenge data analyzed in our investigation offer potentially important insight into possible effects of antipyretic therapy on the course of clinical infections. In the investigation, a striking correlation existed between antipyretic therapy and duration of illness in subjects infected experimentally with influenza A and S. sonnei. No such relationship existed in volunteers infected with R. rickettsii. Influenza A-infected subjects who received antipyretic agents during their illness were sick, on average, 3.5 days longer than those not receiving antipyretic agents (8.8 ± 2.3 days vs 5.3 ± 3.0 day, p<0.001). ”

Quote: “Antipyretic therapy might prolong some infections because it alleviates fever and, thereby, abrogates the reported potentiating effect of fever on resistance to infection.2 In our study, S. sonnei-infected subjects exhibited significant reductions in core temperature in association with antipyretic therapy. Influenza A-infected subjects did not, however, in spite of the fact that antipyretic therapy appeared to prolong their illness. Whatever the mechanisms responsible, antipyretic drugs prolonged the course of both rhinovirus5 and varicella virus infections.4 Our study suggests that such agents might have a similar effect on influenza A infections. In view of the potential clinical importance of these preliminary observations, we believe they merit further investigation in a prospective, randomized, placebo-controlled trial.”

However, later other studies pointed out that there might have been confounding parameters, like the severity of disease, since the treated subjects had actually higher temperatures. 

Eyers S, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. 2010 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951171

Quote: “There was one publication which included data from six clinical trials of intranasal challenge with influenza A, in which aspirin or paracetamol were offered for symptomatic relief. Influenza infected subjects who received antipyretics were sick on average 3.5 days longer than those not receiving such treatment. In a multivariate analysis which considered clinical variables such as maximum temperature and maximum number of symptoms, only antipyretic therapy exhibited a statistically significant relationship with duration of illness. However, antipyretic treatment was not randomized, and subjects treated with antipyretics had higher maximum temperatures and more marked symptoms, suggesting that the association is likely to have been confounded by the severity of the illness.13”

But authors also point out the lack of proper studies in humans. 

Eyers S, et a. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. 2010 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951171

Quote: “Not only were there no randomized controlled trials of antipyretic use in influenza infection in humans that reported data on mortality, but there was also a paucity of clinical data by which to assess their efficacy. The human studies identified either lacked a placebo group,30–33 a virologic diagnosis of influenza,27–29 or randomization of antipyretic treatment13 which made interpretation of results difficult. There was also little uniformity of outcomes, with factors such as length of illness, amount of viral shedding and disease complications often not recorded. As a result, there is little evidence on which to assess the effect of antipyretics on the severity and/or duration of influenza infection in humans.”

#Kai Kupferschmidt. Fight the Flu, Hurt Society? Reducing fever may help spread infectious disease and increase deaths. 2014. 

https://www.science.org/content/article/fight-flu-hurt-society

Quote: “When you've got the flu, it can't hurt to take an aspirin or an ibuprofen to control the fever and make you feel better, right? Wrong, some scientists say. Lowering your body temperature may make the virus replicate faster and increase the risk that you transmit it to others. A new study claims that there are at least 700 extra influenza deaths in the United States every year because people suppress their fever.

As a result, if you have the flu and you're taking medication "it may actually be more important that you stay at home because you could be a greater risk to others," says David Earn, a mathematician at McMaster University in Hamilton, Canada, and one of the authors of the paper. Some scientists call that claim premature, however.”