What’s causing your patient’s fever?

A look at fever pathophysiology, causes and common treatments

At this point in the year, a fever is a red flag that may suggest influenza or COVID-19, though research suggests as many as 30% of COVID-19 patients do not experience fever. As it’s not possible to distinguish COVID-19 from influenza or other conditions in the prehospital care environment, proper infection control measures should be taken with any patient with an elevated body temperature. That said, let’s explore the pathophysiology of fever, and what else could be causing your patient’s fever, other than COVID-19.

The normal human body temperature is usually about 37°C (98.6°F), although it can vary by individual, age and time of day. This temperature is a balance between the heat lost by the body and the heat produced by tissues and is regulated by the anterior hypothalamus in the brain. The hypothalamus acts like a thermostat and ensures that the body stays at a set temperature. Although individuals can have varying baseline set points, fever is typically defined when body temperature is above 38°C (100.4°F).

Pathophysiology of fever

Although individuals can have varying baseline set points, fever is typically defined when body temperature is above 38°C (100.4°F).
Although individuals can have varying baseline set points, fever is typically defined when body temperature is above 38°C (100.4°F).

The first step in the chain of events that leads to a fever is the detection or creation of pyrogens. Pyrogens can be from both external and internal sources. Commonly bacterial toxins and the bacteria themselves will act as pyrogens but self-produced cytokines can also cause fever. Cytokines are cell signaling proteins released by immune cells activated by a pathogen. Certain cytokines act as pyrogens and lead to a fever.

Pyrogens cause increased synthesis of prostaglandin E2 (PGE2) in the brain, which increases the hypothalamic temperature set point. PGE2 production is also increased throughout the body, which is why muscle aches and pains commonly accompany fevers.

In the brain, an increased temperature set point causes the body to want to produce more heat to maintain this newer higher temperature. Therefore, there is vasoconstriction and increased heat production in the body’s periphery. The vasoconstriction leads to blood being shunted away from the periphery to the vital organs, which is why feverish patients often feel cold despite having a fever. Additionally, shivering is a way for the body to use up ATP (energy) and produce heat to maintain a high temperature.

Causes of fever

There are a lot of things that can cause a fever, the most common being infection. Once the immune system is activated by the invading pathogen, a fever develops via the process described above. Bacteria and viruses can both cause infection and lead to fevers, but not every patient with an infection will have a fever. There are many parts of the body that can be infected, which is why it’s important to ask about other symptoms in order to better pinpoint where the fever is coming from. A cough may point to a respiratory infection from COVID-19 or influenza, while an ulcer may represent cellulitis from staph. Infection is the most common cause of fever but below are the some of the other etiologies.

  • Inflammatory. Autoimmune diseases, such as rheumatoid arthritis, adult still’s disease and lupus can cause fever as well due to an overreactive immune system.
  • Drugs. Many prescribed medications can cause a drug fever, an adverse reaction to a new medication that can present like an allergic reaction. Usually, these occur soon after a new drug is started but can occur weeks or even months after a medication is started. Common medications implicated include antibiotics, antihistamines, antiepileptics, NSAIDs, antihypertensives, antiarrhythmics and antithyroid drugs.
  • Cancer. Lymphomas and leukemias often present with an insidious low-grade fever and night sweats. Usually, this won’t be a one-time occurrence, but instead something that has been happening for months. Febrile patients who have a history of unexplained weight loss and fevers for an extended period of time should raise your suspicion for a possible malignancy.
  • Disordered heat homeostasis. The hypothalamus is responsible for regulating body temperature, therefore, if the hypothalamus is damaged, heat homeostasis may be affected. This means that head trauma and strokes can cause fever as well.


Technically, hyperthermia differs from fever because there is no change in the hypothalamic set point. Instead, the body has an uncontrolled rise in temperature and cannot lose enough heat to compensate. Regardless, the patient will have a high body temperature reading, similar to a fever. Often, this is due to heat stroke, when a patient becomes overheated in a warm environment. As we start moving into colder weather, other causes of hyperthermia to be aware of include:

  • MDMA (ecstasy) causes vasoconstriction, leading to decreased heat dissipation
  • Neuroleptic malignant syndrome, caused by medications with dopamine, antagonist properties, most commonly the anti-psychotics. Symptoms include fever, muscle rigidity and altered mental status.
  • Serotonin syndrome, caused by excess serotonin, usually due to use of multiple drugs that work on serotonin receptors such as anti-depressants. Symptoms include fever, myoclonus and altered mental status.

Common fever treatments

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil) and naproxen (Aleve) work by inhibiting cyclooxygenase enzyme 2 (COX 2), an enzyme responsible for synthesizing PGE2. These NSAIDs also affect COX 1, an enzyme involved in platelet function and gastric protection. The COX 2 inhibition is the mechanism by which these medications are anti-pyretic, but GI symptoms can accompany their use, due to the COX 1 inhibition. A selective COX 2 inhibitor, such as celecoxib (Celebrex), will only have an antipyretic effect, without affecting the GI system or platelets.

Aspirin works similarly to NSAIDs, although it has more effect on COX 1 than COX 2. This is why it’s associated with an anti-platelet effect and used during a myocardial infarction or to help prevent future vascular events. At higher doses, it will have an anti-pyretic effect via COX 2 inhibition.

Although the mechanism of action for acetaminophen (Tylenol) isn’t entirely known, it is believed to affect the COX pathway as well. One theory is that the oxidized form in the brain is able to inhibit COX, leading to decreased PGE2 production.

Read next: How will COVID-19 impact the 20/21 influenza season?

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