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Noninfectious causes
of fever in adults
Abstract: Fever is a common clinical sign encountered in hospitalized patients and often
represents the cardinal sign of infectious processes. However, a number of noninfectious
etiologies causing fever should be considered prior to initiating broad-spectrum antibiotic
therapy. Reducing unnecessary antibiotic use is crucial in an era of increasing resistance.

By Gregory M. Steele, MSN, RN, FNP-BC, OCN; Carlos Franco-Paredes, MD, MPH; and
Daniel B. Chastain, PharmD, AAHIVP

ever is both a common presenting symptom one culture. However, the presence of fever is not a
F and sign identified during routine patient
care in a variety of clinical settings. In the
predictor of positive culture results. The absence of
fever is actually not a reliable predictor for the absence
outpatient and hospital settings, fever may be observed of bacteremia.2 Despite this, empiric antibiotic therapy
in up to 30% to 50% of patients, with the highest in- is commonly initiated as a result of this nonspecific
cidence among those admitted to critical care, which sign (pending additional clinical information).
may be the results of many etiologies.1,2 Fever is also a Emerging antibiotic resistance, due to overpre-
common complaint in the primary care setting, with scribing practices or poor prescribing practices, is also
approximately one-third of ambulatory care patients a major concern. In the United States, antibiotic-
reporting fever to their primary care provider (PCP).1,3 resistant pathogens were responsible for 2 million
Among hospitalized patients, documentation of illnesses and 23,000 deaths in 2011.4-6 The majority of
fever in most cases prompts the collection of at least antibiotic prescriptions are written in the outpatient
Keywords: antibiotic resistance, antibiotics, fever, infection, noninfectious fever

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 Noninfectious causes of fever in adults

setting. Advanced practice providers (APPs), a group

that consists of both NPs and physician assistants, are Frequent noninfectious etiologies of
a growing segment of the PCP workforce. When look- fever2,10-12,14,15,22,25-30,32-34,38,39,41,44-48
ing at overall prescribing practices by provider group, Rheumatic and autoimmune diseases
APPs are responsible both for the highest number of • Systemic lupus erythematosus
antibiotic prescriptions and greatest use of broad- • Behçet syndrome
• Rheumatoid arthritis
spectrum antibiotics.5 It is important to recognize that
fever is often the result of a noninfectious etiology. The Neoplastic
purpose of this article is to discuss common noninfec- • Lymphomas
• Leukemias
tious causes of fever in both ambulatory care and hos- • Hypernephromas
pital settings.
Drug induced
• Beta-lactam antimicrobials
■ Pathophysiology of fever and hyperthermia • Sulfa drugs
Normal body temperature in healthy individuals is • Antiepileptic medications (such as phenytoin,
carbamazepine)
typically 98.6° F (37° C), but may vary by 0.9° F (0.5°
• Neuroleptic malignant syndrome (caused by antipsy-
C) to 1.8° F (1° C) throughout the body and at various chotic drugs such as haloperidol)
anatomic sites.7 The hypothalamic thermoregulatory • Serotonin syndrome (caused by selective serotonin
center regulates body temperature, balancing metabolic reuptake inhibitor)
• Antiarrhythmics (such as amiodarone)
heat production with heat released through respiration • Antiretroviral medications (such as abacavir)
and evaporation. Disruption of thermoregulatory
Crystal-induced arthropathies
mechanisms impairs the body’s ability to maintain a • Gout (urate crystals)
state of normothermia. • Pseudogout (calcium pyrophosphate)
Increased body temperature is commonly referred
Thromboembolism
to as pyrexia (also known as fever) or hyperthermia.8 • DVT of lower or upper extremities
Although often used interchangeably, these terms • Pulmonary embolism
represent two distinct entities. Fever is the result of Intra-abdominal
an increase in the hypothalamic set point, maintained • Acute pancreatitis
by heat-generating and heat-preserving thermoeffec- • Acalculous cholecystitis
tors through endogenous pyrogenesis and antipyretic Pulmonary
pathways.8 Neuronal activation leads to vasoconstric- • Aspiration pneumonitis (chemical pneumonitis)
• ARDS
tion, shunting blood from the periphery to internal
organs to conserve heat. Both thermogenesis from Central nervous system
muscles and increased hepatic metabolism can con- • Hemorrhagic stroke
• Ischemic stroke
tribute to increases in temperature. By comparison, • Subarachnoid hemorrhage
hyperthermia is often a combination of exogenous
Endocrine
heat exposure and the loss of the body’s capacity to • Hyperthyroidism (thyroid storm)
lose heat. In these cases, temperatures will frequently • Adrenal insufficiency
exceed 105.8° F (41° C).2
Immune-mediated transfusion reactions
Fever, most commonly defined as core temperature • Transfusion of blood products (febrile nonhemolytic
of 101° F (38.3° C) or higher, is a hallmark clinical sign transfusion reaction)
in many infectious diseases.7 Development of a fever is
the result of a complex interaction with exogenous Noninfectious etiologies of fever or hyperthermia
pyrogens (typically microbial pathogens) or pyrogenic include autoimmune diseases, trauma, inflammatory
cytokines, including tumor necrosis factor (TNF)- conditions, environmental stressors, or drugs and may
alpha, interleukin (IL)-1, IL-6, ciliary neurotrophic increase body temperature (see Frequent noninfectious
factor, interferon (IFN)-gamma, and IFN-alpha re- etiologies of fever). Some clinical clues may be identified
leased by myeloid and endothelial cells, with the fenes- in patients with fever from a noninfectious origin
trated capillaries comprising the organ vasculosum (see Distinguishing infectious vs. noninfectious causes
lamina terminalis in the anterior hypothalamus.9,10 of fever).

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 Noninfectious causes of fever in adults

■ Etiology of noninfectious causes of fever traumatic brain injuries but occurs less commonly in
Rheumatic diseases, including vasculitis, connective ischemic stroke.2,14 Compared with fevers caused by
tissue diseases, and granulomatous diseases, may be infections, central fever occurs earlier and lasts longer
responsible for fever in up to 30% of patients with with higher temperatures.
fever of unknown origin.11,12 Consequently, pyrogenic Confirming the diagnosis of central fever remains
cytokines play a direct role in temperature elevation, a challenge.14 In the setting of negative cultures, chest
as described above, while also modifying hepatic pro- radiographs, and fever onset within 3 days, the prob-
tein synthesis, including increasing: C-reactive protein, ability of central fever is high. Empirical antimicrobial
serum amyloid A, ceruloplasmin, alpha-1-antitrypsin, therapy is often initiated early in these patients but
haptoglobin, fibrinogen, and C1 inhibitors; pyrogenic should promptly be discontinued if the cultures and
cytokines also decrease transferrin, albumin, and fi- chest radiographs are negative. Treatment should be
bronectin, many of which are tests performed during directed at lowering body temperature through intra-
routine workup.12 vascular or surface cooling devices.
Initial workup should include a thorough exam Thomboembolism. Venous thromboembolism
of mucous membranes, eyes, lymph nodes, temporal (VTE) has been identified as a noninfectious cause of
arteries, liver, spleen, and skin in addition to anti- fever.15 Vascular damage initiates the coagulation pro-
nuclear antibody and rheumatoid factor testing.11 cess.16 Recruitment of inflammatory cells, growth
Although the antinuclear antibody and rheumatoid factors, and cytokines, including ILs, TNF-alpha, and
factor are sensitive, they lack specificity, and are there- IFN-gamma, soon follows.17 Although the precise
fore most useful in confirming a clinical diagnosis. mechanism of fever has not been described, fever
Importantly, bacterial, mycobacterial, and fungal associated with a pulmonary embolism (PE) and
cultures must be obtained to rule out infectious deep vein thrombosis (DVT) are likely the result of
etiologies. Diagnostic imaging may be of benefit, par- a complex interaction between direct vascular irrita-
ticularly in patients with positive rheumatologic test- tion, inflammatory cytokines, tissue necrosis, and
ing. Confirming or excluding a diagnosis may require hemorrhage.18
invasive diagnostics with lymph node, tissue, or bone Most often, fever is due to a PE but has also been
marrow biopsies.11,13 observed with DVT.18 Signs and symptoms are com-
Intracranial hemorrhage/ischemic stroke. Central monly observed in these patients.19 Typically, fever
fever occurs in up to 70% of patients admitted with associated with VTE is low grade (less than 100.9° F
neurologic conditions.14 Alterations in body tempera- [38.3° C]) but rarely greater than 102° F (38.9° C) and
ture are due to the loss of hypothalamic control. Central occurs for a short duration. Rates of fever are similar
fever is likely in patients with subarachnoid hemor- in patients with or without pulmonary hemorrhage
rhages, intraventricular hemorrhages, brain tumors, or or infarction.20 Initiation of anticoagulation resolves

Distinguishing infectious vs. noninfectious causes of fever2,7,9,10,13,15,32-34

Signs or symptoms Infectious Noninfectious

Chills or rigors +++ –
Leukocytosis* +++ +
Pulse-temperature dissociation** + +++
Continuous fever*** + +++
Hemodynamic instability and lactic acidosis +++ –

+++(frequently occurs); + (infrequently occurs); – (does not occur)

*Acute necrotizing pancreatitis may be associated with systemic inflammatory response syndrome with leukocytosis and increased respiratory rate without
evidence of an infectious process
**Lack of increase in heart rate of 10 beats/minute per 1° of temperature increase in Celsius scale that may be present in drug-induced fever but sometimes seen in
patients with infections caused by intracellular organisms (for example, pneumonia from Legionella bacterium)
***Continuous fever is defined by fever that remains most of the time above 100.9° F (38.3° C)

40 The Nurse Practitioner • Vol. 43, No. 4 [Link]

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 Noninfectious causes of fever in adults

fever, but higher mortalities persist compared with membranes in the exudative phase; approximately 7
those without fever. days later, the proliferative phase begins with develop-
Aspiration pneumonitis. Inhalation of oropharyn- ment of pulmonary fibrosis and interstitial inflamma-
geal or gastric contents into the lungs may lead to a tion.25 Although most patients recover within 21 days,
variety of syndromes, including chemical pneumonitis, some advance to the fibrotic stage, which is character-
primary bacterial aspiration pneumonia, or secondary ized by worsening fibrosis and bullae formation.
bacterial infection following chemical pneumonitis.21 An ARDS diagnosis is based on the presence of
Large volume (greater than 0.3 mL/kg of body weight hypoxemia in the setting of bilateral or alveolar inter-
or 20 to 25 mL in adults) aspiration of acidic gastric stitial infiltrates occurring within 7 days of insult
contents (pH less than 2.5) is required to cause chemi- (known collectively as the Berlin definition).24,26 Clini-
cal pneumonitis.22 cal features observed in ARDS may mimic a variety of
Subsequently, corrosive damage
to the alveolar cells occurs followed
by neutrophil invasion with con- Inhalation of oropharyngeal or gastric contents
comitant release of proinflammatory into the lungs may lead to chemical pneumonitis
cytokines. Due to gastric acid inhib- or bacterial aspiration pneumonia.
iting bacterial growth, gastric con-
tents are typically sterile. Secondary
bacterial infections occur more frequently in patients other noninfectious diseases, including interstitial
receiving gastric acid suppressing medications. pneumonia, eosinophilic pneumonia, bronchiolitis
Symptom onset, fever, hypoxia, dyspnea, and cough obliterans organizing pneumonia, diffuse alveolar
occur rapidly within hours following aspiration.22 Ra- hemorrhage, hypersensitivity pneumonitis, and car-
diographic imaging reveals pulmonary infiltrates in the diogenic pulmonary edema.27
dependent portions of the lungs depending on patient Identification of the underlying condition is more
positioning. Clinical and radiographic improvement vital than incorrectly identifying an infectious pneu-
occurs quickly (within days) in the majority of patients, monia as the cause of respiratory failure, as no specific
whereas some rapidly develop respiratory failure and drug therapy exists for ARDS. Treatment is supportive
acute respiratory distress syndrome (ARDS). with noninvasive or mechanical ventilation with low
Initial improvement is followed by clinical deterio- tidal volumes, fluid conservation, and managing the
ration in a small subset of patients who develop secondary underlying condition.
bacterial infection following chemical pneumonitis. Blood product transfusion. Approximately 90% of
Treatment primarily revolves around supportive care critically ill patients in ICUs are anemic, and 40% of
involving patient repositioning and pulmonary care; these receive a transfusion during their hospitalization
however, empirical antibiotics are frequently started.21 (accounting for the 15 million units transfused annu-
Early discontinuation of antibiotics is indicated in ally).28 Although benefits are obvious, transfusions and
patients experiencing rapid clinical improvement and therapeutic plasma exchange may result in acute or
in those with negative or contaminated microbiologic delayed reactions, including allergic, acute, or delayed
samples. hemolytic transfusion reaction; febrile nonhemolytic
ARDS. Refractory hypoxemia is the hallmark of transfusion reaction; acute lung injury; circulatory
ARDS.23 Increased alveolar permeability and collapse overload; graft versus host disease; iron overload;
develop following direct or indirect lung injury, includ- or infections.28-30 No specific signs or symptoms are
ing aspiration of gastric contents; lung contusion or able to differentiate transfusions, and therapeutic
trauma; inhalation of toxic substances; drug overdose; plasma exchange related reactions from other medical
transfusions; or infectious pneumonia. The progression problems.
of ARDS is characterized by three distinct phases.24 Transfusion and therapeutic plasma exchange related
Alveolar edema, in addition to proinflammatory and reactions typically occur within 24 hours but as soon as
pyrogenic cytokines within the interstitial and alveolar 15 minutes following completion (depending on sever-
spaces, recruits neutrophils, which causes further al- ity).28-30 Fever, chills, pruritus, hives, hypotension, and
veolar damage with subsequent development of hyaline respiratory distress are observed most frequently. Clinical

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 Noninfectious causes of fever in adults

assessment and patient history in combination with in- Urgent surgical management via cholecystectomy or
formation obtained from blood bank personnel are vital percutaneous cholecystostomy is required.
to distinguishing transfusion and therapeutic plasma Thyroid storm. Excessive release of thyroid hor-
exchange related reactions from infections. mones yields a hypermetabolic state known as thyroid
Acute pancreatitis. Pancreatic enzyme activation storm.41 Although rare, thyroid storm usually follows
leads to autodigestion of the pancreas with resultant a precipitating event, such as surgery, anesthesia, trau-
inflammation, which is known as acute pancreatitis.31 ma, high doses or withdrawal of thyroid hormone,
Etiologies of acute pancreatitis are dominated by iodinated contrast, or amiodarone. Signs and symp-
gallstones and alcohol abuse followed by hypertriglyc- toms may mimic those observed in infections, such as
eridemia, drugs, pancreatic strictures, and rarely, infec- tachycardia and fever (including hyperpyrexia) due to
tions.32-34 Patients generally present with acute onset, adrenergic activation.
epigastric pain that may radiate to the back with ac- No universally validated criteria or tools currently
companying nausea and vomiting. Physical findings exist for diagnosing thyroid storm except for a scoring
may include fever, tachypnea, hypotension, and hy- system developed by Burch and Wartofsky in 1993.41,42
poxemia depending on severity. As a result, clinical features are the focus of diagnosis
Diagnosis of acute pancreatitis requires two of the rather than lab abnormalities, which are comparable
following three criteria: characteristic abdominal pain, to those found in hyperthyroidism. Prompt multifac-
serum amylase or lipase at least three times the upper eted treatment aimed at decreasing adrenergic activa-
limit of normal, and inflammatory changes visualized tion, as well as blocking thyroid hormone production,
on computed tomography (CT) scan.31,32 Historically, secretion, and systemic activation, is required due to
uncontrolled studies suggested antimicrobial therapy high mortalities.41,43
may decrease infection and mortalities, but random- Crystal-induced arthropathies. Gout, a metabolic
ized, double-blind, placebo-controlled trials refute this disease, is characterized by hyperuricemia resulting
recommendation.35-37 Antibiotics should be withheld from diets high in purines, alcohol consumption, di-
regardless of type or severity of pancreatic disease uretic therapy, and impaired renal elimination.44,45
unless a confirmed infection is documented.38 Approximately 1% to 2% of adults in the developed
world and 4% in the United States
are affected by gout, with higher
Although the mechanism is not fully rates in males and increasing inci-
understood, drug fever may be the result dence until 70 years of age.45 Acute
of hypersensitivity reactions. gouty arthritis may mimic infectious
conditions, and therefore, should be
considered in the differential diag-
Acalculous cholecystitis. Acalculous cholecystitis nosis of individuals presenting with fever, pain, ery-
results from biliary stasis rather than gallstones or thema, and swelling—particularly around single or
biliary sludge occluding the cystic duct as observed in multiple joints.44,45 Inflammation typically accompa-
acute cholecystitis.39,40 Risk factors for developing acal- nies cellulitis and acute gouty arthritis, which focuses
culous cholecystitis include sepsis, trauma, burns, around a joint in the latter condition. Although mono-
surgery, total parenteral nutrition, and even chronic articular involvement may cause difficulty in distin-
diseases such as diabetes mellitus, cardiovascular dis- guishing it from septic arthritis, joint aspiration with
ease, and end-stage renal disease. Gallbladder stasis subsequent identification of urate crystals by polarized
and distension lead to endothelial injury, inflamma- microscopy should confirm gout.46
tion, and subsequent necrosis, which may result in Drug-induced fever. While frequently cited as the
perforation. cause of fever in clinical practice, drug fever is the true
Clinical manifestations, such as fever, right upper cause of fever in a mere 3% to 5% of cases, with in-
quadrant pain, nausea, and vomiting, are nonspecific creased risk directly correlated with number of drugs
and often indistinguishable from calculous cholecys- prescribed.47 Published cases are extremely heteroge-
titis.38,39 Abdominal ultrasound or CT scan may reveal neous and identify numerous drugs as the ultimate
gallbladder distension without evidence of gallstones. cause (but most frequently, antibiotics, antiepileptics,

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 Noninfectious causes of fever in adults

and antiarrhythmics). Although the mechanism is not clues of noninfectious causes of fever. Suspicion for
fully understood, drug fever may be the result of hy- an alternate diagnosis without clinical signs of sepsis
persensitivity reactions, including a drug reaction with should cause the APP to not initiate antibiotic therapy
eosinophilia and systemic symptoms syndrome, ther- until a diagnosis is firmly established.
moregulatory alterations, or idiosyncratic reactions.48
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• If you prefer to submit your test by mail, record your an- • We also offer CE accounts for hospitals and other healthcare facilities
swers in the test answer section of the CE enrollment form on [Link]. Call 1-800-787-8985 for details.
on page 45. You may make copies of the form.
Each question has only one correct answer. There is no PROVIDER ACCREDITATION
minimum passing score required. Lippincott Professional Development will award 1.0 contact hour for this
Complete the registration information and course evalua- continuing nursing education activity.
tion. Mail the completed form and registration fee of $12.95 Lippincott Professional Development is accredited as a provider of
to: Lippincott Professional Development CE Group, 74 Brick continuing nursing education by the American Nurses Credentialing
Blvd., Bldg. 4, Suite 206, Brick, NJ 08723. We will mail your Center’s Commission on Accreditation.
certificate in 4 to 6 weeks. For faster service, include a fax This activity is also provider approved by the California Board of
number and we will fax your certificate within 2 business Registered Nursing, Provider Number CEP 11749 for 1.0 contact hour.
days of receiving your enrollment form. You will receive Lippincott Professional Development is also an approved provider of
your CE certificate of earned contact hours and an answer continuing nursing education by the District of Columbia, Georgia,
key to review your results. and Florida CE Broker #50-1223.
• Registration deadline is March 6, 2020.

44 The Nurse Practitioner • Vol. 43, No. 4 [Link]

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