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A CONCEPTUAL ANALYSIS OF FEVER

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Inflammatory reactions could be both beneficial and detrimental to the brain, depending on strengths of their activation in various stages of neurodegeneration.

Fever, an elevation in core body temperature above the daily range for an individual, is a characteristic feature of most infections but is also found in a number of noninfectious diseases such as autoimmune and autoinflammatory diseases (1). Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other from the temperature of the blood bathing the region (1,2). Inflammation is the body's response to harmful stimuli. Inflammatory processes lead to both local and systemic reactions and may be either acute or chronic. The five classic signs of local inflammation are redness, swelling, heat, pain, and loss of function. There are various signs of a systemic reaction, the most important of which is fever (2).

KEY TEACHING POINTS

$1·       The normal human temperature is considered to be 37 °C, but may vary by up to 1 °C in healthy individuals (3).

$1·       Elevated core temperature is a common finding in intensive care, affecting up to 70 % of patients (4).

$1·       Hyperthermia also has no agreed definition; it has been defined as a core temperature above 38.2 °C, irrespective of the cause (5).

In critically ill patients, inflammation is commonly observed to aid repair after traumatic or infective insults.

 

Sepsis accounts for up to 74 % of fever in hospitalised patients and, of the remainder, malignancy, tissue ischaemia, and drug reactions account for the majority. Neurogenic fever, and fevers associated with endocrinopathy, are rarer (6). 

Severity: A fever can be:

$1·       Low grade, from 100.5–102.1°F or 38.1–39°C

$1·       Moderate, from 102.2–104.0°F or 39.1–40°C

$1·       High, from 104.1–106.0°F to or 40.1-41.1°C

$1·       Hyperpyrexia, above 106.0°F or 41.1°C

The height of the temperature may help indicate what type of problem is causing it.

Many disorders can cause fever. They are broadly categorized as

$1       Infectious (most common)

$1       Neoplastic

$1       Inflammatory (including rheumatic, nonrheumatic, and drug-related)

$1·       Fever in patients with malignancy is reported to be sepsis related in around two thirds of cases (7).

$1·       The tumour is the direct cause of fever in less than 10% of febrile episodes; tumour necrosis and production of pyrogenic cytokines is the likely pathogenesis (7).

Specific patient and external factors also influence which causes are most likely.

$1ü  Patient factors include health status, age, occupation, and risk factors.

$1ü  External factors are those that expose patients to specific diseases, through infected contacts, local outbreaks, disease vectors, a common vehicle (food, water), or geographic location (residence in or recent travel to an endemic area).

 

Fever is encountered or experienced frequently by healthcare professionals and laypersons alike. Its meaning is assumed to be clear and universally understood, when in actuality the interpretation is often uniquely personal (8). Similarly, the definition of fever within the nursing and medical literature varies widely. In numerous articles, it is defined and operationalized as simply an elevation of body temperature (9, 10). Fever was then considered to be synonymous with infectious disease as, until the mid-19th century, most of these diseases were grouped under the generic term of ‘fever’ (10).

Fever: protection response

Animal models have repeatedly shown that fever is an important feature of the acute phase response, and is associated with improved survival and shortened duration of illness (11).  In one such study, induced bacterial peritonitis in mice and found that those with febrile core temperatures had decreased bacterial load and improved survival in comparison with normothermic controls (12). Fever exerts an overall adverse effect on the growth of bacteria and on replication of viruses. It also enhances immunological processes, including activity of interleukin-1 (IL-1), T-helper cells, cytolytic T-cells, B-cell and immunoglobulin synthesis (13). Fever per se is self-limiting and rarely serious that the cause is known and fluid loss is replaced. With fever, unlike hyperthermia, body temperature is well controlled by a hypothalamic set- point that balances heat production and heat loss that effectively does not rise up relentlessly and does not exceed an upper limit of 42 ° C (14). Within this upper range, 40 ° C to 42 ° C, there is no evidence that the fever is injurious to tissue. About 20 percent of children seen in the emergency room have temperatures over 40 ° C but they usually have a full recovery. If there is morbidity or mortality, it is due to the underlying disease. The associated fever may well be protective (14).

LENGTH OF TIME:   A fever can be:

$1·       Acute if it lasts less than 7 days

$1·       Sub-acute, if it lasts up to 14 days

$1·       Chronic or persistent, if it persists for over 14 days

$1·       Fevers that exist for days or weeks with no explanation are called fevers of undetermined origin (FUO).

TREATMENT:

Specific causes of fever are treated with anti-infective therapy; empiric anti-infective therapy is required when suspicion of serious infection is high.

Whether fever due to infection should be treated with antipyretics is controversial. Experimental evidence, but not clinical studies, suggests that fever enhances host defenses.

Fever should probably be treated in certain patients at particular risk, including adults with cardiac or pulmonary insufficiency or with dementia.

Drugs that inhibit brain cyclooxygenase effectively reduce fever:

$1·       Acetaminophen 650 to 1000 mg / 6 h

$1·       Ibuprofen 400 to 600 mg /6 h

Postoperative fever:

Has a highly variable course and many different causes; discussed in the learning card on perioperative management. One of the most important outcomes of this research in recent years has been the discovery of a single mononuclear cell product, (IL-1, whose effects include induction of fever and activation of T-lymphocytes (14). Numerous substances from outside the body, exogenous pyrogens (ExPs), initiate the fever cycle. Endotoxin of Gram-negative bacteria is the most potent ExPs. The ExPs stimulate monocytes, fixed-tissue macrophages and reticuloendothelial cells to produce and release endogenous pyrogens, of which IL-1 is the most important. IL-1 acts on the hypothalamic thermoregulatory center through mediators, particularly PGE2, to raise the thermostatic set-point (14). The hypothalamic center accomplishes heat production by inducing shivering and heat conservation through vasoconstriction. At an established degree, fever is regulated by this centre (even at a temperature of over 41.0°C) and heat production approximates loss, as in health, though at a higher level of the set-point. Therefore fever does not climb up relentlessly. IL-1 has other functions, including: Playing a primary role in the induction of inflammatory responses, such as neutrophil accumulation and adherence, and vascular changes (14).

The Hippocratic writings contain evidence that fever was thought to be beneficial to the infected host, “fever was beneficial in ophthalmia” and it cured it. Since Hippocrates believed in the benefit of fever, he placed little emphasis on the treatment of it (15).

Thomas Sydenham (1624-1689), he clearly regarded fever as beneficial as witnessed by his remark “fever is a mighty engine which nature brings into the world to remove her enemies” (15). 

Conflicts of interests None stated by the authors

Financing None stated by the authors.

REFERENCES

1.     Lee-Chiong TL Jr, Stitt JT. Disorders of temperature regulation. Compr Ther 1995; 21:697.

2.     Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders; 2014.

3.     Niven DJ, Gaudet JE, Laupland KB, et al. Accuracy of peripheral thermometers for estimating temperature: a systematic review and meta-analysis. Ann Intern Med 2015; 163:768.

4.     Circiumaru B, Baldock G, Cohen J. A prospective study of fever in the intensive care unit. Intens Care Med. 1999;25(7):668–73. doi: 10.1007/s001340050928. 

5.     Zimmerman JL, Hanania NA. Hyperthermia. In: Hall JB, Schmidt GA, Wood LDH, editors. Principles of critical care. 3. New York, NY: McGraw-Hill Inc; 2005. p. 1678. 

6.     Brief report: incidence, etiology, risk factors, and outcome of hospital-acquired fever: a systematic, evidence-based review. Kaul DR, Flanders SA, Beck JM, Saint S. J Gen Intern Med. 2006 Nov;21(11):1184-7.

7.     Causes of fever in cancer patients (prospective study over 477 episodes). Toussaint E, Bahel-Ball E, Vekemans M, Georgala A, Al-Hakak L, Paesmans M, Aoun M Support Care Cancer. 2006 Jul; 14(7):763-9.

8.     Mackowiak PA, Bartlett JG, Borden EC, Goldblum SE, Hasday JD, Munford RS, Nasraway SA, Stolley PD, Woodward TE , Concepts of fever: recent advances and lingering dogma. Clin Infect Dis. 1997 Jul; 25(1):119-38.

9.     McGowan JE Jr, Rose RC, Jacobs NF, Schaberg DR, Haley RW; Fever in hospitalized patients. With special reference to the medical service. Am J Med. 1987 Mar 23; 82(3 Spec No):580-6.

10.  Currie MR; The rise and demise of fever nursing. Int Hist Nurs J. 1997 Autumn; 3(1):5-19.

11.  Arons MM, Wheeler AP, Bernard GR; Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med. 1999 Apr; 27(4):699-707.

12.  Jiang Q, Cross AS, Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immun. 2000 Mar; 68(3):1265-70.

13.  Nahas GG, Tannieres ML, Lennon JF; Direct measurement of leukocyte motility: effects of pH and temperature.Proc Soc Exp Biol Med. 1971 Oct; 138(1):350-2.

14.  A Sahib Mehdi El-Radhi; Fever management: Evidence vs current practice. World J Clin Pediatr. 2012 Dec 8; 1(4): 29–33.

15.  Major RH. A history of medicine. Precursors of Galen.Springfield: Thomas CC; 1954. pp. 174–188.

 

Lizzeth Karina Ordonez Perez , Maria Virginia Pinzon Fernandez ,  Luisa Fernanda Zuniga Ceron,  Jahn Sebastian Saavedra Torres. De la Facultad de Medicina, Universidad del Cauca, Popayan, Colombia.