What is a non infection cause of fever? Exploring non-pathogenic reasons for elevated body temperature

September 30, 2025 •

4 min read

While most people associate fever with an infection, up to 30% of fevers of unknown origin can be traced back to a non-infectious inflammatory disease, according to some studies. This highlights the importance of understanding what is a non infection cause of fever and looking beyond common culprits when seeking a diagnosis.

Quick Summary

Fever can result from various non-infectious conditions, such as autoimmune diseases, medication side effects, certain cancers, and central nervous system injuries. These fevers stem from inflammation or altered thermoregulation rather than from a pathogenic source like bacteria or viruses.

Key Points

Autoimmune flare-ups: Chronic inflammation from conditions like lupus or rheumatoid arthritis can trigger a persistent, low-grade fever.
Medication side effects: A variety of drugs, most notably certain antibiotics, anticonvulsants, and antiarrhythmics, can induce a fever as an adverse reaction.
Malignancy-related fever: Cancers such as lymphoma and renal cell carcinoma can cause fever as a paraneoplastic syndrome due to the release of inflammatory cytokines.
Central nervous system injury: Trauma or disease affecting the brain's hypothalamus can disrupt the body's thermoregulation, resulting in a central fever.
Thromboembolic events: Blood clots, such as in a pulmonary embolism, can cause a low-grade fever due to inflammation in the affected tissues.
Diagnosis by exclusion: Non-infectious fevers are often diagnosed by ruling out other causes after extensive testing for infection comes back negative.

What is a fever?

Before exploring non-infectious causes, it's crucial to understand what a fever is and how it differs from hyperthermia. A fever, or pyrexia, is a controlled increase in the body's thermoregulatory 'set-point,' which is centrally managed by the hypothalamus in the brain. It is often a protective response to an inflammatory trigger, leading the body to generate and conserve heat to raise its temperature. In contrast, hyperthermia is an uncontrolled increase in body temperature that overwhelms the body's heat-loss mechanisms, typically caused by external factors like heatstroke or certain drugs. Antipyretic medications like acetaminophen work by lowering the hypothalamic set-point, but this may not be effective for all causes of non-infectious fever.

Autoimmune and inflammatory diseases

These conditions cause the body's immune system to mistakenly attack its own tissues, leading to chronic inflammation and the release of pyrogenic cytokines that trigger a fever. Fevers in these cases tend to be chronic or recurrent rather than acute, and they are a common cause of fevers of unknown origin, especially in developed countries.

Rheumatoid Arthritis (RA): A chronic inflammatory disorder affecting the joints, RA can cause a persistent, low-grade fever.
Systemic Lupus Erythematosus (SLE): An autoimmune disease that can affect multiple organs, lupus often presents with fever, fatigue, and joint pain.
Giant Cell Arteritis (GCA): This inflammatory condition of the blood vessels can cause fever, along with headache and jaw pain, especially in older adults.
Adult-onset Still's Disease (AOSD): A rare systemic inflammatory disorder, AOSD is characterized by high, spiking fevers and a salmon-colored rash.
Gout: An inflammatory arthritis caused by urate crystals, gout can mimic an infectious condition, presenting with fever, pain, and swelling in the affected joint.

Drug-induced fever

In some instances, the body reacts to a medication by triggering a febrile response, known as drug fever. This is a diagnosis of exclusion, meaning other causes must be ruled out first. It is a relatively common adverse drug reaction, especially in hospitalized patients.

Antibiotics: Certain antibiotics, particularly beta-lactams and sulfonamides, are among the most common culprits.
Anticonvulsants: Medications like phenytoin and carbamazepine can cause drug fever.
Antiarrhythmics: Drugs used to treat irregular heartbeats, such as quinidine, are known to cause a febrile reaction.
Mechanisms: Drug fever can occur through various mechanisms, including hypersensitivity reactions, altered thermoregulation, or idiosyncratic reactions.

Malignancy-associated fever

Fever is a well-known paraneoplastic syndrome, meaning it is a symptom caused by the cancer itself rather than by a co-occurring infection. This is believed to be due to the release of pyrogenic cytokines from the tumor cells or surrounding immune cells.

Lymphomas: Both Hodgkin's and non-Hodgkin's lymphoma are frequently associated with fever.
Renal Cell Carcinoma (RCC): Up to 20% of patients with RCC may present with fever as a symptom.
Leukemia: Certain types of leukemia can induce fever.
Diagnosis: Neoplastic fever can be difficult to distinguish from infectious fever, often requiring a thorough workup.

Central nervous system (CNS) disorders

Damage or disruption to the thermoregulatory centers in the brain, particularly the hypothalamus, can lead to what is known as a central or neurogenic fever. This type of fever is often resistant to conventional antipyretics.

Intracranial Hemorrhage: Conditions like subarachnoid or intraventricular hemorrhage are a significant cause of central fever.
Traumatic Brain Injury (TBI): Brain trauma can lead to hypothalamic damage and subsequent central fever.
Brain Tumors: Tumors can directly affect the brain's temperature regulation.

Other miscellaneous causes

Several other medical conditions and events can trigger a non-infectious fever.

Thromboembolic Events: Conditions like a pulmonary embolism (PE) or deep vein thrombosis (DVT) can cause low-grade fever due to inflammation and tissue irritation.
Acute Pancreatitis: Inflammation of the pancreas can lead to fever, along with abdominal pain and elevated pancreatic enzymes.
Endocrine Disorders: Conditions such as a thyroid storm (severe hyperthyroidism) can cause dangerous hyperpyrexia due to an increased metabolic rate. Adrenal insufficiency can also sometimes be associated with fever.
Blood Product Transfusions: Reactions to blood transfusions, such as febrile nonhemolytic transfusion reaction, can cause fever and chills, typically within 24 hours.
Post-operative Complications: Following surgery, conditions like blood clots or deep-seated inflammation can cause a fever.

Comparison of infectious vs. non-infectious fever

To aid in diagnosis, clinicians often look for key differences between infectious and non-infectious fevers. The table below summarizes some of these distinctions.


Feature	Infectious Fever	Non-Infectious Fever
Onset	Often acute (≤ 4 days)	Can be chronic or recurrent
Pattern	Varies; sometimes with chills and rigors	Variable, may be continuous or intermittent; some patterns are known (e.g., Pel-Ebstein fever in Hodgkin's lymphoma)
Associated Symptoms	Often accompanied by signs related to the infection (e.g., cough, urinary symptoms)	Specific to the underlying non-infectious cause (e.g., joint pain in RA, rash in drug fever)
Response to Antibiotics	Improves with targeted antibiotic therapy	Not responsive to antibiotics; may resolve upon stopping causative drug or with cancer treatment
Response to NSAIDs	Often effective in reducing fever	Variable; some neoplastic fevers may respond to NSAIDs, while central fevers may not

Conclusion

While fever is most commonly caused by an infection, a significant number of cases are due to non-infectious causes such as autoimmune disorders, drug reactions, malignancies, and CNS conditions. For fevers that are chronic, recurrent, or lack other signs of infection, exploring these alternative etiologies is crucial for an accurate diagnosis and effective treatment. The appropriate treatment strategy depends entirely on identifying the specific underlying cause rather than simply focusing on the symptom of fever itself. Early and accurate diagnosis of these non-infectious fevers can prevent unnecessary use of antibiotics and lead to a more targeted and successful management plan. For individuals with persistent or unexplained fever, a thorough medical evaluation is essential to pinpoint the root cause and ensure proper care. To further explore fever management, visit the National Institutes of Health website for detailed information about conditions that can cause fever(https://pubmed.ncbi.nlm.nih.gov/29528880/).

Frequently Asked Questions

Doctors determine if a fever is non-infectious by performing a comprehensive medical evaluation, which includes a detailed patient history, physical examination, and laboratory tests. If cultures for bacteria, viruses, and fungi all come back negative after a reasonable period, and the fever persists, non-infectious causes are investigated further.

While emotional stress is not a direct cause of a true fever, it can sometimes raise body temperature through hormonal responses, a phenomenon called psychogenic fever. This is distinct from a fever caused by inflammation or disease and does not involve a change in the hypothalamic set-point.

Drug fever is a febrile reaction that starts after a medication is administered and resolves once the offending drug is discontinued. Treatment involves identifying and stopping the causative agent. This is typically a diagnosis of exclusion, and the fever should resolve within 48 to 72 hours after stopping the medication.

No, autoimmune diseases do not always cause fever. However, in many cases, especially during a disease flare-up, the systemic inflammation can trigger a fever. These fevers are often low-grade and persistent, distinguishing them from the acute, high fevers common in infections.

Certain cancers, particularly blood-related cancers like lymphomas, can release substances called pyrogenic cytokines, such as interleukin-6, which directly act on the hypothalamus and increase the body's temperature set-point. This is considered a paraneoplastic syndrome, a symptom caused by the cancer itself.

A central fever is caused by damage or dysfunction in the brain's thermoregulatory centers, often due to conditions like stroke, hemorrhage, or traumatic brain injury. It is characterized by high, persistent temperatures that are often resistant to standard antipyretics. Management often involves more aggressive cooling measures and specific medications to address the underlying neurological issue.

The danger of a non-infectious fever depends on the underlying cause. While some conditions may cause mild, manageable fevers, others, such as thyroid storm or certain malignancies, can cause high, life-threatening temperatures. It is important to identify the cause to determine the appropriate course of action and manage any potential risks.