Probing Evolution

Fever Can Hurt or Help, Depending on What Started It

#3. Stopping fever during infection might increase disease transmission in the population.

“Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever,” William Osler, known as the Father of Modern Medicine and one of the “greatest diagnosticians ever to wield a stethoscope,” said at the 1896 American Medical Association meeting in Atlanta.

Fever? Perhaps the better word would be infectious diseases. As per the 1990 work of the English Hippocrates, Thomas Sydenham: Fever is the “nature’s engine which she brings into the field to remove her enemy.” And the enemy is infections. Still, what is the fascination with fever?

Contents:
1. Sources of Fever
2. When Fever Saves: Infectious Diseases
3. Consequences of Stopping Fever During Infection
4. When Fever Kills: Non-infectious Diseases
5. When Fever Kills: Hyperthermia
6. Article Highlights

1. Sources of Fever

The cut-off body temperature for fever is ≥38.3°C (101.0°F). It can go up to 41°C. Microbes cause the majority of fever cases. They trigger the production of pro-inflammatory cytokines that act on the brain’s temperature regulatory centre called the hypothalamus. Elevated pro-inflammatory cytokines, hence, sustains the fever. As follows, fever starts to go down as anti-inflammatory cytokines kick in.

Fever need not necessarily be microbial in origin. Pharmacological drugs, such as antimicrobials, antidepressants, opioids, psychedelics, neuroleptics, anaesthetics, etc., may also induce fever. These drugs do so by inhibiting heat dissipation towards the periphery (e.g., sweating), disrupting hypothalamic temperature regulation, or damaging tissues and cause inflammation. Other sources of fever include brain injury (from physical trauma or stroke), thyroid or adrenal problems, organ damage such as acute respiratory syndrome (ARDS) or gastrointestinal bleeding, or autoimmune disorders.

All these triggers of fever have this in common: Inflammation. However, when is fever beneficial or harmful depends on the underlying cause.

2. When Fever Saves: Infectious Diseases

ICU patients inflicted with infectious diseases survived better if the body generates a fever, in comparison to no fever or hyperthermia (fever of ≥40°C). There are a few reasons why the fever is protective against infections:

• Human pathogens (bacteria, viruses, etc.) replicate best at below 37°C.
• Antibiotics’ efficiency increases with higher body temperatures.
• Immune cells work better at higher body temperatures.

It is not limited to humans, a 2015 paper in Nature Reviews Immunology said. Even plants that arise about 1.5 billion years ago fare better against microbial infections when its leaves’ temperature increase. Cold-blooded animals — e.g., reptiles, fishes, and insects — tend to seek out warmth when attacked by infections, despite bearing the risk of being hunted. Give these animals fever-lowering drugs, and then they won’t bother.

“The evolutionary conservation of the fever response over millions of years is in line with its protective role — the survival benefit conferred on the host outweighs the metabolic cost of elevating core body temperatures during infection,” the 2015 review concluded. Even during pregnancy and in infants, fever is not deadly, as some might think it is.

3. Consequences of Stopping Fever During Infection

Does that mean inhibiting fever makes infectious diseases worse? That depends on the type of infections, according to a 2015 review titled “Fever and sickness behaviour: Friend or foe?” The use of fever-lowering drugs increases the risk of death in sepsis cases, for example, but not respiratory infections such as influenza or the common cold. Similarly, in Covid-19, there is no substantial harm in taking fever-lowering drugs like ibuprofen.

But one caveat is that reducing fever might slow down recovery and prolong virus shedding in cases of respiratory infections. If so, then it might indirectly harm others by increasing the chance of disease transmission to others.

As the 2015 review explained: “Despite the common practice of using antipyretics, such as paracetamol and ibuprofen, for fever and pain relief in patients with acute respiratory infections we still know very little concerning whether the quest for symptom relief actually comes at the cost of increasing the viral transmission at the population level.”

4. When Fever Kills: Non-infectious Diseases

Analyzing data from 269,078 from 129 ICUs in Australia and New Zealand, a 2012 study found that fever (> 39°C) is an independent risk factor for death in the non-infection group. In the infection group, fever was protective and lowering it proved to be detrimental. In that same year, another study also derived at similar results — that fever-lowering drugs increased the death rate in the sepsis and not the non-sepsis group.

Reviewing these studies, the 2015 review concluded that feverish patients struck with non-infectious diseases should take fever-lowering drugs. In contrast, fever should be left alone in cases of infections.

Although these studies did not categorize the source of fever in the non-infection group, it is probably a combination of the factors mentioned above. For example, fever following an acute brain injury is an independent risk factor for death; in this case, fever-lowering drugs are a must, even at high doses.

5. When Fever Kills: Hyperthermia

Another situation when fever kills is when it reaches above 40°C and does not go down; a condition called hyperthermia. The most common cause of hyperthermia is heatstroke. But no matter the source is an infectious disease or not, it is lethal as it destroys the host cell membranes, proteins, enzymes, and DNA. It is also a sign of a severe cytokine storm and multi-organ damage.

“Hyperthermia above 40 °C appears to carry high mortality by whatever cause,” a 2016 review printed in Critical Care summarized. “Early recognition, immediate cooling, and organ support are the mainstays of treatment…” Fever-lowering drugs are ineffective as the body takes time to process it. Even in survivors, they face life-long consequences of poor health and shortened lifespan, as the 2016 review discussed.

6. Article Highlights

• Fever can be both microbial or non-microbial in origin, as long as it initiates inflammation.
• Fever-lowering drugs are not ideal for infections, although the aftermath of doing so depends on the type of infection.
• Fever-lowering drugs are ideal for non-infectious diseases.
• Fever-lowering drugs are ineffective in hyperthermia cases, which are deadly and must be cooled down, regardless of whether the source is an infection or not.

This article is inspired by Swcman.