Category Archives: Fever

Why does the same virus cause one symptom in one person and another in a different one?

30 Sunday Apr 2017

Posted by in Bacteria, Epigenetics, Fever, Infection, Virus

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Question details: For example, for a GI bug, some of my kids will have vomiting, others will have diarrhea, or one unfortunate one will end up with both.

Differences in either genetics and/or exposure (dose) might lead siblings to have different symptoms to the same illness and the two reasons aren’t mutually exclusive.

No two individuals have the exact same biomedical profile, not even identical (monozygotic) twins*.

These differences form the essential basis for differences in symptoms and severity for the same illness among individuals. However, apart from genetic and immunity differences between hosts, differences in severity of exposure could also explain why this happens, with the sibling with greatest exposure, i.e., dose, more likely to suffer the most severe symptoms. The same sibling repeatedly suffering more severe outcomes for shared illnesses would suggest greater likelihood of underlying genetic difference(s) being at play.

To successfully infect means to first successfully enter a cell, replicate inside it and finally spread to neighboring cells and beyond. Each disease-causing microbe thus evolves to express molecules that mimic those that bind certain cell-surface receptors and this process then serves as its entryway into a particular cell. This preference of a particular microbe to infect certain tissues is its Tissue tropism – Wikipedia. For e.g., the cold virus, Rhinovirus – Wikipedia, and Influenza – Wikipedia primarily target the epithelial cells of the upper respiratory tract, Viral hepatitis – Wikipedia the liver, etc.

Though cells obviously differ in the panoply of what they express on their surface, there’s also considerable overlap between different tissues and these overlaps differ between individuals, both in strength and variety. Thus, given the processes of genetic and somatic recombination, and epigenetics, even related individuals differ in their relative susceptibility to various disease-causing microbes.

This is why some people might get Zika fever – Wikipedia and never know since their symptoms stayed so mild while others may get fever (systemic involvement), joint pain (musculoskeletal) and rashes on their torso (skin) while still others could develop debilitating muscle weakness and pain, Guillain–Barré syndrome – Wikipedia, symptoms that could even be life-threatening.

With a GI tract illness, only vomiting suggests a stringently self-limiting infection that stayed restricted to the upper GI tract, diarrhea suggests a spread into the lower GI tract while both vomiting and diarrhea suggest the most severe outcome, i.e., persistent infection effects in both upper and lower GI tract. Again, simple dose differences in initial exposure could be a trivial explanation for a one-off outcome difference of this kind.

* Tim D. Spector’s long-term studies on identical and fraternal twins show that ‘twins rarely die of the same disease‘ (Why do identical twins end up having such different lives?).

https://www.quora.com/Why-does-the-same-virus-cause-one-symptom-in-one-person-and-another-in-a-different-one/answer/Tirumalai-Kamala

Since inflammation is the body’s natural response to help heal an injured or infected area, why is it common practice to “reduce” inflammation?

16 Wednesday Nov 2016

Posted by in Fever, Inflammation

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Culture often trumps science even when it’s to the detriment of health. Unnecessary and even harmful suppression of certain types of inflammation falls in such a category. The cultural aspect here perhaps started with fever phobia (1). Fever is after all one of the most commonly recognized signs of generalized, widespread inflammation in the body. Thus this answer focuses on how as an example of inflammation it’s become common practice to reduce fever even though doing so may often be counter-productive in more than one way.

Fever phobia is exaggerated fear of its potentially serious, irreversible consequences, such as febrile seizures, brain damage, coma, convulsions, dehydration and even death, especially in children (2). Coined in 1980 (3), even today careful meta-analyses of studies probing the public’s, and in particular parents’, attitude to fever find that this exaggerated fear of fever has hardly abated (2), meaning it’s stably entrenched as a cultural attribute.

So what was the source or impetus for fever phobia in recent times? Quite plausibly, reports of higher risks of death from pediatric febrile seizures helped imprint a cultural fear of fever. For example, as far back as 1950 a study reported a 11% mortality risk for children with febrile seizures (4). Since most parents have limited knowledge of fever especially its many benefits (5, 6), fear of febrile seizures quickly permeated and became embedded culturally. This even when studies find up to a third of children brought to clinics aren’t truly febrile (1, 7, 8, 9). Some examples of fever phobia:

  • 85% of surveyed US parents reported they’d wake a child to administer antipyretics (10) even though pediatricians recommend against it (11).
  • 33 to 65% of surveyed UAE and Israeli parents reported giving acetaminophen for temperatures <38oC, i.e., for temperatures not likely to be fever (12, 13).
  • 74% of surveyed Canadian parents considered fever to be dangerous and 90% always attempted to treat it (14).

Multiple other sources including but not limited to pharmaceutical companies, the media and pediatricians further helped embed the cultural fear of fever. For example, studies frequently find that pediatricians widely perceive fever to be dangerous (15) and advocate treating even mild fevers with antipyretics. For e.g., a 1992 survey found 65% of pediatricians perceived fevers to be dangerous and 72% often or always recommended antipyretic Rx (11).

It’s only much more recently that much larger, much more thorough studies found that long-term mortality risk isn’t increased in children with febrile seizures. For e.g., a Danish study on 1675643 children (yes, a study with >1 million children!) born between 1977 and 2004 found 132 of 100000 children died within 2 years of a febrile seizure compared to 67 among those who didn’t (16), i.e., ~2X increased risk. However, more careful analysis showed short-term mortality risk among children with simple febrile seizure, i.e., no recurrence, was similar to those without. The short-term mortality risk was only increased among those with recurrent febrile seizures, which ‘was partly explained by pre-existing neurological abnormalities and subsequent epilepsy‘ (16). More importantly, long-term mortality rates were similar among children who either experienced febrile seizures or didn’t. Moreover recent studies suggest a strong influence of genetic risk factors for recurrent, familial febrile seizures (17, 18). Since such recurrent febrile seizures are much more rare, specific genetic risk factors thus imply vast majority of fevers, especially in children, have low risk for them and for their recurrence.

At least four problems ensue from widespread exaggerated perception of the danger of fever and the knee-jerk response to immediately reduce it.

  • One, studies suggest antipyretics don’t prevent febrile seizures (19, 20, 21, 22).
  • Two, antipyretics themselves can have severe, though rare, side-effects such as liver or renal failure, GI tract ulcers  (1) and even Stevens-Johnson syndrome (23) or asthma (24, 25).
  • Three, often parents inadvertently compound such risks by giving incorrect doses of antipyretics (12). For e.g., a study found as many as 50% of US parents did so (26).
  • Four, antipyretics such as paracetamol may delay recovery from infections or impede generation of effective immune responses to vaccines.
    • Antipyretics delay malaria parasite clearance for example (27).
    • Widespread antipyretic use may even help spread infectious diseases such as flu (28), perhaps because patients stay sick and retain higher infectious viral titers longer.
    • In recent years, it’s become more commonplace for pediatricians (29, 30, 31, 32) and even the US Advisory Committee on Immunization Practices (ACIP) (33) to recommend prophylactic antipyretic Rx prior to vaccinations to minimize the febrile response even though this is counter-productive. For e.g., individuals pre-treated with antipyretics have decreased immune responses to vaccines. This is seen not just in children (to DTaP + HBV + IPV/Hib*) (34) but also in adults (to HBV) (35).

* DTaP = Diphtheria-Tetanus-acellular Pertussis vaccine; HBV = Hepatitis B vaccine; IPV = Inactivated Polio vaccine; Hib = Haemophilus influenzae vaccine.

Bottomline, such a state of affairs suggests scientists communicate poorly with medical doctors and both communicate poorly with the general public. As a result, both doctors and the general public are less well aware of the more recently discovered myriad benefits of inflammation and fever. This has allowed older cultural beliefs to stay entrenched and thus trump science in the optimal management of inflammation in general and of fever in particular.

Bibliography

1. Wallenstein, Matthew B., et al. “Fever literacy and fever phobia.” Clinical pediatrics 52.3 (2013): 254-259.

2. Purssell, Edward, and Jacqueline Collin. “Fever phobia: The impact of time and mortality–A systematic review and meta-analysis.” International journal of nursing studies (2015).

3. Schmitt, Barton D. “Fever phobia: misconceptions of parents about fevers.” Archives of Pediatrics & Adolescent Medicine 134.2 (1980): 176.

4. Ekholm, Erik, and Kalevi Niemineva. “On Convulsions in Early Childhood and Their Prognosis An investigation with follow‐up examinations of patients treated for convulsions at the Children’s Clinic of Helsinki University.” Acta paediatrica 39.1 (1950): 481-501.

5. Evans, Sharon S., Elizabeth A. Repasky, and Daniel T. Fisher. “Fever and the thermal regulation of immunity: the immune system feels the heat.” Nature Reviews Immunology 15.6 (2015): 335-349. http://www.nature.com/nri/journa…

6. Harden, L. M., et al. “Fever and sickness behavior: Friend or foe?.” Brain, behavior, and immunity 50 (2015): 322-333. https://www.researchgate.net/pro…

7. Casey, Rosemary, et al. “Fever Therapy: An Educational Intervention for Parents.” Pediatrics 73.5 (1984): 600-603. http://www.healthnet.org.np/eboo…

8. Wammanda, R. D., and S. O. Onazi. “Ability of mothers to assess the presence of fever in their children: Implication for the treatment of fever under the IMCI guidelines.” Annals of African medicine 8.3 (2009). http://www.ajol.info/index.php/a…

9. Graneto, JOHN W., and DAVID F. Soglin. “Maternal screening of childhood fever by palpation.” Pediatric emergency care 12.3 (1996): 183-184.

10. Crocetti, Michael, Nooshi Moghbeli, and Janet Serwint. “Fever phobia revisited: have parental misconceptions about fever changed in 20 years?.” Pediatrics 107.6 (2001): 1241-1246.

11. May, Ariane, and Howard Bauchner. “Fever phobia: the pediatrician’s contribution.” Pediatrics 90.6 (1992): 851-854.

12. Betz, Martin G., and Anton F. Grunfeld. “‘Fever phobia’ in the emergency department: a survey of children’s caregivers.” European Journal of Emergency Medicine 13.3 (2006): 129-133.

13. Bilenko, Natalya, et al. “Determinants of antipyretic misuse in children up to 5 years of age: a cross-sectional study.” Clinical therapeutics 28.5 (2006): 783-793.

14. Enarson, Mark C., et al. “Beliefs and Expectations of Canadian Parents Who Bring Febrile Children for Medical Care.” Pediatrics (2012): peds-2011. http://pediatrics.aappublication…

15. El-Radhi, A. S. “Fever management: Evidence vs current practice.” World J Clin Pediatr 1 (2012): 29-33. http://www.wjgnet.com/2219-2808/…

16. Vestergaard, Mogens, et al. “Death in children with febrile seizures: a population-based cohort study.” The Lancet 372.9637 (2008): 457-463. https://www.researchgate.net/pro…

17. Saghazadeh, Amene, Mario Mastrangelo, and Nima Rezaei. “Genetic background of febrile seizures.” Reviews in the Neurosciences 25.1 (2014): 129-161. Genetic background of febrile seizures

18. Boillot, Morgane, et al. “Novel GABRG2 mutations cause familial febrile seizures.” Neurology Genetics 1.4 (2015): e35. http://www.ncbi.nlm.nih.gov/pmc/…

19. Schnaiderman, D., et al. “Antipyretic effectiveness of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic usage.” European journal of pediatrics 152.9 (1993): 747-749.

20. van Stuijvenberg, Margriet, et al. “Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences.” Pediatrics 102.5 (1998): e51-e51. http://repub.eur.nl/pub/8923/979…

21. Esch, Adrianus van, et al. “A study of the efficacy of antipyretic drugs in the prevention of febrile seizure recurrence.” Ambulatory Child Health 6.1 (2000): 19-25.

22. El-Radhi, A., and W. Barry. “Do antipyretics prevent febrile convulsions?.” Archives of disease in childhood 88.7 (2003): 641. http://adc.bmj.com/content/88/7/…

23. Maggio, Maria Cristina, et al. “Stevens–Johnson syndrome and cholestatic hepatitis induced by acute Epstein–Barr virus infection.” European journal of gastroenterology & hepatology 23.3 (2011): 289.

24. El-Radhi, A. Sahib M. “Why is the evidence not affecting the practice of fever management?.” Archives of disease in childhood 93.11 (2008): 918-920.

25. McBride, John T. “The association of acetaminophen and asthma prevalence and severity.” Pediatrics 128.6 (2011): 1181-1185. http://pediatrics.aappublication…

26. LI, SIU FAI, BRITT LACHER, and ELLEN F. CRAIN. “Acetaminophen and ibuprofen dosing by parents.” Pediatric emergency care 16.6 (2000): 394-397.

27. Brandts, Christian H., et al. “Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria.” The Lancet 350.9079 (1997): 704-709.

28. Earn, David JD, Paul W. Andrews, and Benjamin M. Bolker. “Population-level effects of suppressing fever.” Proceedings of the Royal Society of London B: Biological Sciences 281.1778 (2014): 20132570. http://rspb.royalsocietypublishi…

29. Kohl, Katrin S., et al. “Fever after immunization: current concepts and improved future scientific understanding.” Clinical infectious diseases 39.3 (2004): 389-394. Current Concepts and Improved Future Scientific Understanding

30. Marcy, S. Michael, et al. “Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation.” Vaccine 22.5 (2004): 551-556. http://www.lareb.nl/LarebCorpora…

31. Lewis, Karen, et al. “The effect of prophylactic acetaminophen administration on reactions to DTP vaccination.” American Journal of Diseases of Children 142.1 (1988): 62-65.

32. Moshe, M., et al. “Acetaminophen prophylaxis of adverse reactions following vaccination of infants with diphtheria-pertussis-tetanus toxoids-polio vaccine.” The Pediatric infectious disease journal 6.8 (1987): 721-724.

33. Centers for Disease Control and Prevention. Pertussis vaccination: use of acellular pertussis vaccines among infants and children recommendations of the Advisory Committee on Immunization Practices (ACIP). Pertussis Vaccination: Use of Acellular Pertussis Vaccines Among Infants and Young Children Recommendations of the Advisory Committee on Immunization Practices (ACIP)

34. Prymula, Roman, et al. “Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials.” The Lancet 374.9698 (2009): 1339-1350. https://ttuhsc.edu/amarillo/som/…

35. Doedée, Anne MCM, et al. “Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials.” PloS one 9.6 (2014): e98175. http://journals.plos.org/plosone…

https://www.quora.com/Since-inflammation-is-the-bodys-natural-response-to-help-heal-an-injured-or-infected-area-why-is-it-common-practice-to-reduce-inflammation/answer/Tirumalai-Kamala

What causes a lower-than-average body temperature?

01 Monday Aug 2016

Posted by in Fever

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‘Let’s say someone normally runs an oral temperature of 96.6°. What causes this?‘.

Nothing abnormal if this person’s baseline temperature is lower than the consensus average of 36.8 +/- 0.4 oC (98.2 +/- 0.7 oF). As well, gender, age and time of reading greatly contribute to temperature variability.

In a 2002 meta-analysis of several oral, rectal, tympanic (ear-canal) and axillary (armpit) temperature studies (1), normal oral temperature ranged from 35.7 to 37.7 oC (96.26 to 99.86 oF) for men, and from 33.2 to 38.1 oC (91.76 to 100.58 oF) for women (see figures below).

‘If that person has a temperature of 99°, is that then a fever?’ Is it similar to someone with an average oral temperature of 98.6° being at 101°?‘.

Could be, provided temperature stayed elevated for a while and was accompanied by changes in other vital signs, i.e., respiratory rate, pulse rate and blood pressure.

History of Average Body Temperature

For long, the notion prevailed that 37 oC (98.6 oF) was the average healthy body temperature. How did we arrive at this? Astonishingly enough for such a basic human health vital sign, mainly from one 19th century study. In his 1868 study, Carl Reinhold August Wunderlich apparently analyzed >1 million axillary (armpit) temperature readings from ~25000 subjects (2). Doing so, he concluded that

  • 37 oC (98.6 oF) was the mean temperature of healthy adults.
  • It had a range from a low of 36.2 oC (97.2 oC) to 37.5 oC (99.5 oF).
  • It had a circadian rhythm, being lowest between 2 and 8AM and highest between 4 and 9 PM.
  • Women generally have slightly higher temperatures and greater variability compared to men.
  • There might be racial differences in body temperatures.
  • Temperatures in the old tend to be ~0.5 oC (~0.9 oF) lower than in the young.

Flaws of Wunderlich’s Average Body Temperature Measurements

Since Wunderlich’s time, thermometer precision has vastly improved while temperature readings have expanded from axillary to oral, rectal and tympanic (ear canal). Do these changes impact this vital sign average? They do and how!

Shockingly, a 1992 re-appraisal (3) states that very few studies tried to replicate Wunderlich’s data. It further states such studies had several flaws,

  • Done >40 years prior, i.e., prior to 1992.
  • Small numbers of subjects (4, 5, 6).
  • Took only single temperature readings from a large number of subjects (7, 8).

This 1992 study also highlights the many drawbacks of Wunderlich’s data, namely,

  • Cumbersome thermometers.
  • Needed to be read in situ, i.e., while still in contact with the body.
  • When used for axillary (armpit) measurements, they took 15 to 20 minutes to equilibrate.

This 1992 study instead took repeat oral temperature readings at 1 to 4 prescribed times per day in 148 subjects, aged 18 through 40 years. Cohort had 122 men (88 black, 32 white, 1 Hispanic, 1 Oriental) and 26 women (17 black and 9 white) (see data in figure below).

It concluded

  • ‘Thirty-seven degrees centigrade (98.6 oF) should be abandoned as a concept relevant to clinical thermometry; 37.2 oC (98.9 oF) in the early morning and 37.7 oC (99.9 oF) overall should be regarded as the upper limit of the normal oral temperature range in healthy adults aged 40  years or  younger, and  several of Wunderlich’s other cherished dictums should be revised’.
  • That 36.8 +/- 0.4 oC (98.2 +/- 0.7 oF) is the normal range of oral temperature.
  • Most importantly and with special relevance to this question, that individual variability ‘limits the application of mean values derived from population studies to individual subjects‘, and ‘maximum oral temperature, like the mean temperature, exhibited by any population varies according to time of day‘.

A 1998 review (9) further asserts that Wunderlich’s thermometers may have been calibrated as much as 1.4 to 2.2 oC (0.72 to 2.16 oF) higher than modern-day thermometers. In other words, it’s normal for average body temperatures to trend lower than what conventional wisdom suggests.

Bibliography

1. Sund‐Levander, Märtha, Christina Forsberg, and Lis Karin Wahren. “Normal oral, rectal, tympanic and axillary body temperature in adult men and women: a systematic literature review.” Scandinavian journal of caring sciences 16.2 (2002): 122-128. http://www.chainon.me/wp-content…

2. Wunderlich C. Das Verhalten der Eiaenwarme in Krankenheiten. Leipzig, Germany: Otto Wigard; 1868.

3. Mackowiak, Philip A., Steven S. Wasserman, and Myron M. Levine. “A critical appraisal of 98.6 F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich.” Jama 268.12 (1992): 1578-1580.

4. HORVATH, STEVEN M., H. Menduke, and GEORGE MORRIS PIERSOL. “Oral and rectal temperatures of man.” Journal of the American Medical Association 144.18 (1950): 1562-1565.

5. LINDER, FORREST E., and HUGH T. CARMICHAEL. “A biometric study of the relation between oral and rectal temperatures in normal and schizophrenic subjects.” Human Biology 7.1 (1935): 24-46.

6. Tanner, J. M. “The relationships between the frequency of the heart, oral temperature and rectal temperature in man at rest.” The Journal of physiology 115.4 (1951): 391-409. The relationships between the frequency of the heart, oral temperature and rectal temperature in man at rest

7. Whiting, Madeline H. “On the association of temperature, pulse and respiration with physique and intelligence in criminals: a study in criminal anthropometry.” Biometrika 11.1-2 (1915): 1-37.

8. Ivy, Andrew C. “What is normal or normality?.” Quarterly Bulletin of the Northwestern University Medical School 18.1 (1944): 22.

9. Mackowiak, Philip A. “Concepts of fever.” Archives of Internal Medicine 158.17 (1998): 1870-1881.

https://www.quora.com/What-causes-a-lower-than-average-body-temperature/answer/Tirumalai-Kamala

How does the immune system know how to raise the body’s temperature in response to an infection?

25 Wednesday Nov 2015

Posted by in Fever, Immune System, Infection

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Question continued: I’ve read somewhere that when the body is infected by viral or  bacterial pathogens, the immune system raises the body temperature to help fight the spread of infection. How does the immune system know how to do such a thing? It almost sounds as if the immune system has a brain of its own. I mean it  may sound silly, but – does it? Who designed it to be able to fight off infections or even know what an infection is or when it’s inside the body?

Answer by Tirumalai Kamala:

Fever results not from the immune system alone but from immune system plus hypothalamus.

Infections typically target specific cells, tissues and organs. This is called Tissue tropism. Some pathogens have a broad range, others narrow. Since infections can target every organ from skin, GI tract and lungs to heart and brain, it stands to reason that every cell in the body is immunocompetent enough to signal its distress to its surroundings. How do non-immune cells raise this alarm call? Some approaches are ubiquitous, others are cell- or tissue-specific.  What they have in common is that a ripple effect ensues and brings to the site professional immune system cells such as neutrophils, monocytes, macrophages and lymphocytes to name just a few (Inflammation). Once at the site, these immune cells get activated locally, responding to by-products of the infection.

When immune cells such as monocytes and macrophages are activated, they release a bunch of chemical messengers, aka cytokines such as interleukin-1, -6, tumor necrosis factor and others. These are collectively called endogenous pyrogens (1) because they influence the thermoregulatory set point. This is the first step necessary for the fever response. What’s the thermoregulatory set point? How do endogenous pyrogens influence it? How does fever start and stop?

The thermoregulatory set point
The hypothalamus has thermoregulatory neurons (2). The thermoregulatory set or reference point is established by the firing rate of these neurons.

How endogenous pyrogens influence the thermoregulatory set point
Once released at the site of infection, endogenous pyrogens travel through the blood stream and enter the hypothalamus after crossing the blood-brain barrier with the help of either specialized transporters or at specialized locations. In the hypothalamus they trigger the production of other chemical messengers such as prostaglandin E2 for example, which alter the firing rate of the thermoregulatory neurons. This in turn increases the thermoregulatory set point (1)

The simplified cartoon below summarizes the entire process (3).

  • Infection causes local cells to trigger their distress.
  • Local cell distress brings immune cells to the site.
  • Immune cells get activated by by-products of the infection.
  • Activated immune cells locally secrete among other things, endogenous pyrogens.
  • Endogenous pyrogens travel to the hypothalamus.
  • In the hypothalamus, they cause increase of the thermoregulatory set point.
  • But core temperature is lower than the thermoregulatory set point (shiver, feel cold, seek warmth, etc.).
  • Body adjusts to increase core temperature (blood vessels constrict, metabolic heat rises as does body temperature).
  • Now body core temperature equals the thermoregulatory set point.
  • When infection’s cleared, immune cells stop endogenous pyrogen production.
  • Thermoregulatory set point reverts back to normal.
  • But now core temperature is higher than thermoregulatory set point
  • Body adjusts (sweat, feel hot, seek cool, etc.) until core temperature equals thermoregulatory set point.


Bibliography

  1. Dinarello, Charles A. “Cytokines as endogenous pyrogens.” Journal of Infectious Diseases 179.Supplement 2 (1999): S294-S304.
    oxfordjournals.org

    Cytokines as Endogenous Pyrogens

  2. Boulant, Jack A. “Role of the preoptic-anterior hypothalamus in thermoregulation and fever.” Clinical infectious diseases 31.Supplement 5 (2000): S157-S161. Role of the Preoptic-Anterior Hypothalamus in Thermoregulation and Fever
  3. Cannon, Joseph G. “Perspective on fever: the basic science and conventional medicine.” Complementary therapies in medicine 21 (2013): S54-S60.

https://www.quora.com/How-does-the-immune-system-know-how-to-raise-the-bodys-temperature-in-response-to-an-infection/answer/Tirumalai-Kamala