Understanding What Causes a Fever Other Than Infection

While most people associate fever with infection, a significant number of fevers are triggered by non-infectious causes. It's crucial to recognize the many other factors that can elevate the body's temperature, as this understanding is key to proper diagnosis and treatment. This article explores the various non-infectious reasons for a fever, answering the question of what causes a fever other than infection.

Quick Summary

A fever can result from a wide array of non-infectious conditions, including autoimmune disorders, medication side effects, malignant diseases, and inflammatory responses from surgery or trauma, all of which prompt the body's thermoregulatory center to raise its temperature set point.

Key Points

• Autoimmune Triggers: Conditions like rheumatoid arthritis, lupus, and adult Still's disease can cause fever by creating widespread inflammation and cytokine release.

• Medication Side Effects: Drug fever, caused by certain antibiotics, anticonvulsants, or other medicines, can manifest as a fever that resolves when the drug is stopped.

• Malignancy as a Cause: Cancers, especially lymphomas and leukemias, can release pyrogenic substances, leading to a neoplastic fever that is often intermittent and can be a sign of the disease.

• Surgical and Inflammatory Response: Postoperative fevers are common and typically non-infectious, stemming from the inflammatory reaction to tissue trauma during surgery.

• Hypothalamic Dysfunction: Damage to the brain's temperature-regulating center from stroke or hemorrhage can cause a 'central fever' unrelated to infection.

• Diagnosis by Exclusion: Non-infectious fevers are often diagnosed after an extensive workup rules out any infectious causes, as the symptoms can overlap significantly.

The Body's Thermostat: How Non-Infectious Triggers Cause Fever

The human body tightly regulates its core temperature through a sophisticated system centered in the hypothalamus, often called the body's thermostat. A fever, or pyrexia, is a controlled increase in this hypothalamic set point, driven by immune-related molecules called pyrogens. Traditionally, pyrogens are released in response to infectious agents, but the immune system can be activated by other stimuli as well. In non-infectious fevers, the immune system responds to conditions like tissue damage, abnormal cells, or certain chemicals rather than a microbial invasion. This complex process often leads to prolonged, intermittent, or difficult-to-diagnose fevers that require a different approach to care.

Autoimmune and Inflammatory Disorders

Systemic inflammatory and autoimmune diseases are prominent non-infectious culprits behind fever. In these conditions, the body's immune system mistakenly attacks its own healthy tissues, leading to systemic inflammation and the release of pyrogenic cytokines such as interleukin-6 (IL-6) and tumor necrosis factor (TNF)-$\alpha$. This continuous state of internal conflict can cause persistent, low-grade fevers that do not respond to typical fever-reducing medications like acetaminophen, or more rarely, high-spiking temperatures.

Common autoimmune causes of fever

• Rheumatoid Arthritis (RA): A chronic inflammatory disorder primarily affecting the joints, but can also cause systemic symptoms, including fever.
• Systemic Lupus Erythematosus (SLE): Known for its ability to affect any organ system, lupus frequently causes fever, along with fatigue and joint pain.
• Adult Still's Disease: A rare inflammatory condition featuring high, daily fevers, a distinct rash, and joint pain.
• Vasculitis Syndromes: Inflammation of the blood vessels, as seen in conditions like Giant Cell Arteritis, can cause fever and other systemic symptoms.

Drug-Induced Fever

Certain medications can cause a fever as a side effect, a phenomenon known as drug fever. This reaction can occur through several mechanisms, most commonly as a hypersensitivity or allergic reaction. It is a diagnosis of exclusion, meaning other causes must be ruled out first. The fever typically resolves within 48 to 72 hours of discontinuing the offending drug. Hundreds of medications have been implicated, but some classes are more commonly associated than others.

Classes of drugs that can cause fever

1. Antimicrobials: Penicillins, cephalosporins, and sulfonamides are frequent causes.
2. Anticonvulsants: Medications like phenytoin and carbamazepine are well-documented triggers.
3. Cardiovascular Agents: Some antiarrhythmics (e.g., quinidine) and vasodilators can cause fever.
4. Chemotherapy Drugs: Cancer treatments can cause fever by killing cancer cells and releasing pyrogenic substances, or as a side effect of the drugs themselves.
5. Anesthetic Agents: In susceptible individuals, inhaled anesthetics and muscle relaxants can trigger malignant hyperthermia, a life-threatening hypermetabolic state characterized by dangerously high body temperature.

Malignancies and Neoplasms

Cancerous tumors, especially those affecting the blood and lymphatic system (hematological malignancies), can induce fever directly. This is known as neoplastic fever or a paraneoplastic syndrome. Cancers can release pyrogenic cytokines or trigger the host's macrophages to release them, causing the hypothalamic set point to increase.

Cancers most often associated with fever

• Lymphomas (Hodgkin's and non-Hodgkin's): Classic examples where fever, night sweats, and weight loss (B-symptoms) can occur.
• Leukemias: Acute and chronic forms of leukemia can cause fever due to the rapid growth of abnormal cells.
• Renal Cell Carcinoma: This type of kidney cancer can present with fever as a systemic symptom.
• Atrial Myxoma: A rare, benign heart tumor that can lead to fevers and other systemic issues.

Other Miscellaneous Causes

Beyond the categories above, several other non-infectious conditions can trigger a fever. These range from systemic issues to localized events that stimulate a pyrogenic response.

Additional non-infectious fever causes

• Central Nervous System (CNS) Disorders: Damage to the hypothalamus from strokes, hemorrhage, or tumors can impair temperature regulation, causing a fever.
• Postoperative Inflammation: Surgical trauma releases cytokines and other inflammatory mediators, often resulting in a low-grade fever within the first few days after a procedure. This is not an infection but a normal inflammatory response.
• Thromboembolic Events: Conditions like Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) cause inflammation and can lead to a low-grade fever.
• Endocrine Disorders: Thyroid storm, a life-threatening hypermetabolic state from excessive thyroid hormone, can cause hyperpyrexia (very high fever).
• Blood Product Transfusions: Reactions to blood products can trigger an inflammatory response leading to fever.

Distinguishing Non-Infectious and Infectious Fever

Differentiating between an infectious and a non-infectious fever can be challenging and often requires a thorough medical evaluation. While some indicators can provide clues, a definitive diagnosis relies on ruling out infection through various tests.

Feature	Infectious Fever	Non-Infectious Fever
Onset	Often sudden and acute	Can be insidious, persistent, or episodic
Duration	Typically resolves with appropriate treatment	Can be long-lasting or recurrent, depending on the underlying condition
Associated Symptoms	Often includes chills, localized pain, or respiratory/gastrointestinal symptoms	May include joint pain, rash, weight loss, or neurological changes
Response to Antipyretics	Usually responds well (e.g., to acetaminophen)	May show only a partial or inconsistent response
Lab Findings	May show elevated procalcitonin levels, high white blood cell count	Can show markers of inflammation (ESR, CRP), specific antibodies (ANA, RF), or be otherwise unremarkable

Conclusion: Seeking the Right Diagnosis

A fever is a symptom, not a diagnosis in itself. When a fever persists or occurs without a clear infectious cause, it is essential to consider the wide range of non-infectious possibilities. These conditions can sometimes be subtle, and a doctor must consider a patient's full medical history, medication use, and other symptoms to arrive at the correct conclusion. Awareness of these alternative fever sources is vital for guiding the diagnostic process and ensuring timely and appropriate treatment. If you experience a persistent or unexplained fever, consulting with a healthcare professional is the best course of action.

For more information on fever and its causes, please visit the Mayo Clinic website.

Frequently Asked Questions

Can stress or anxiety cause a fever?

Yes, chronic stress and severe anxiety can lead to a psychogenic or stress-induced fever, which is typically low-grade. The mechanism involves the body's stress response affecting the hypothalamic temperature regulation.

How can I tell if my fever is caused by a medication?

A drug-induced fever is a diagnosis of exclusion, meaning other causes must be ruled out. The fever usually subsides 48 to 72 hours after stopping the suspected medication and often has no other clear signs of infection.

Is it normal to get a fever after surgery?

Yes, it is very common. Early postoperative fevers are usually a non-infectious inflammatory response to the tissue trauma of the surgery and generally resolve on their own within a few days.

What is the difference between fever and hyperthermia?

Fever is a regulated increase in the body's temperature set point by the hypothalamus. Hyperthermia is an uncontrolled increase in body temperature that overwhelms the body's heat-loss mechanisms, as seen in conditions like heatstroke or malignant hyperthermia.

Can autoimmune diseases cause a high-grade fever?

While low-grade, persistent fevers are more common, some autoimmune conditions, such as Adult Still's Disease, can cause high-spiking fevers, sometimes occurring once or twice daily.

What should I do if my fever doesn't respond to medicine?

If a fever persists or fails to respond to standard fever-reducing medication, especially if other symptoms are present, it is crucial to consult a doctor for a full evaluation to determine the underlying cause.

Can a blood transfusion cause a fever?

Yes, a febrile non-hemolytic transfusion reaction (FNHTR) is a common, though usually mild, reaction where the recipient's immune system reacts to white blood cells in the transfused blood, causing a fever.