Differential Diagnosis of Fever:
(Defined as a body temperature ≥37.2°C (99.0°F) in the morning or ≥37.7°C (100.0°F) in the afternoon).
Inpatient with source
Systemic Inflammatory Disorders
Most cases of fever seen in the outpatient setting are due to viral illness and will resolve in <2 weeks.
Leukopenia is most often due to viral illness but may also be seen in patients with autoimmune or marrow infiltrative disorders.
Bacterial infection is more likely if the patient is seriously ill (eg, pale, dyspneic, cool, clammy, hypotensive, tachycardic, cyanotic, confused or with an otherwise altered mental state).
Immature neutrophils (band forms), toxic granulations, or Döhle bodies on a blood smear may indicate a bacterial cause of fever.
Inpatient with source
Intravascular catheters (bacteremia), urinary catheters (urinary tract infection), nasogastric tubes (sinusitis), foreign bodies (infected prosthetic joint, vascular graft, or pacemaker), and blood transfusions (febrile transfusion reaction).
Check all invasive sites for signs of infection, inspect dependent parts of the body for skin breakdown (redness, warmth, tenderness, swelling, discharge), examine the legs for swelling, and look for medications associated with hyperthermia or fever.
The most common infectious cause is tuberculosis; intra-abdominal or pelvic abscess is another common cause. Vertebral osteomyelitis is occasionally characterized by FUO without localizing back pain or symptoms.
Endocarditis - usually associated with culture-negative organisms, such as Coxiella burnetii, Bartonella quintana, or the HACEK organisms (Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae).
Febrile illnesses are often associated with rash. The distribution of the rash (eg, extremities [Rocky Mountain spotted fever], trunk [eg, infectious mononucleosis, typhoid fever], or palms and soles [eg, syphilis]), the chronicity of the rash relative to fever, and the character of the rash (eg, vesicular [eg, smallpox, chickenpox] or petechial [eg, vasculitis]) are important in determining a potential cause. Some fever-associated skin lesions suggest serious underlying illnesses, such as Janeway lesions, Osler nodes, or subconjunctival petechiae, which occur in patients with infective endocarditis.
Lymphocytosis with atypical lymphocytes is associated with acute Epstein-Barr virus, cytomegalovirus, and HIV infections; monocytosis can be seen with typhoidal disease and tuberculosis.
Systemic Inflammatory Disorders
One of the more common vasculitides is temporal arteritis, which can present as FUO in adults aged >50 years, even in the absence of the classic symptoms of headache, jaw claudication, or polymyalgia rheumatica. Other vasculitides (eg, granulomatosis with polyangiitis [Wegener granulomatosis]) and systemic inflammatory disorders (eg, systemic lupus erythematosus, adult-onset Still disease) should also be considered.
The most common FUO-associated malignancy is non-Hodgkin lymphoma. Renal cell carcinoma, any malignancy that metastasizes to the liver, and leukemia are other common causes.
Typical Laboratory Evaluation for Persistent Fever
For all patients:
Complete blood cell count with differential, peripheral blood smear
Comprehensive metabolic panel
Urinalysis and microscopy
Blood and urine cultures
Antinuclear antibody and rheumatoid factor testing; ESR and total CRP
HIV antibody testing
For selected patients:
Viral serology in patients with mononucleosis-like syndrome (cytomegalovirus, heterophil)
Q fever serology (if exposure to farm animals)
Hepatitis serology (if abnormal liver enzyme levels)
Differential Diagnosis of Hyperthermia
The most important causes of severe hyperthermia are heat stroke, malignant hyperthermia, neuroleptic malignant syndrome, and the serotonin syndrome.
The first sign of serious heat stroke is the absence of sweating and warm, dry skin. Fans, cooling blankets, ice packs, cold intravenous fluids, and oxygen are used; for severe hyperthermia, cold gastric and peritoneal lavage is also used.
The findings of acute confusion, hyperthermia, tachycardia, and persistent epistaxis after exertion under direct sunlight are suggestive of exertional heat stroke. Heat stroke is defined by core temperature >40 C (104 F) and central nervous system dysfunction (eg, altered mental status).
Malignant hyperthermia is an inherited skeletal muscle disorder characterized by a hypermetabolic state precipitated by exposure to volatile inhalation anesthetics (eg, halothane, isoflurane, enflurane, desflurane, sevoflurane) and depolarizing muscle relaxants (eg, succinylcholine, decamethonium). Malignant hyperthermia usually occurs on exposure to the drug. Increased intracellular calcium leads to sustained muscle contractions, with resultant skeletal muscle rigidity and masseter spasm, tachycardia, hypercarbia, hypertension, hyperthermia, tachypnea, and cardiac arrhythmias. Rhabdomyolysis and acute kidney failure can develop. Malignant hyperthermia is life threatening if not treated immediately.
Treatment includes discontinuing the offending drug and providing supportive care (eg, hydration, oxygen, cooling measures). Dantrolene sodium, a skeletal muscle relaxant, is the treatment of choice.
Neuroleptic Malignant Syndrome
The neuroleptic malignant syndrome is a life-threatening disorder caused by an idiosyncratic reaction to neuroleptic tranquilizers and some antipsychotic agents. The most common offending neuroleptic agents are haloperidol and fluphenazine. The syndrome can occur with all drugs that cause central dopamine receptor blockade and usually occurs soon after starting a new drug or with dose escalation. Most patients with the syndrome develop muscle rigidity, hyperthermia, cognitive changes, autonomic instability, diaphoresis, sialorrhea, seizures, arrhythmias, and rhabdomyolysis within 2 weeks after initiating the drug. Death may occur from respiratory or cardiac failure, disseminated intravascular coagulation, or acute kidney failure. Drug therapy with dantrolene sodium and/or bromocriptine decreases mortality and symptom duration.
Patients with serotonin syndrome present with high fever, muscle rigidity, and cognitive changes. Unique findings include shivering, hyperreflexia, myoclonus, and ataxia. The serotonin syndrome is most often caused by the use of selective serotonin reuptake inhibitors. Stopping the offending medication(s) and supportive care are the mainstays of therapy.
Differntial Diagnosis of febrile viral illness
Group A Streptococcus
Clinical manifestations of measles include fever, cough, sore throat, coryza, conjunctivitis, and lymphadenitis. Koplik spots may precede generalized rash. The diagnosis is established via serology.
Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia, and anemia. Fever in the setting of malaria is often intermittent. The diagnosis of malaria is established by visualization of parasites on peripheral smear.
The typical cycle (uncommon) consists of a cold phase (chills, shivering), then a hot phase (high-grade fevers), then a sweatingstage (diaphoresis, fever resolution). Headache, malaise, myalgias, vomiting, and diarrhea are often seen. Anemia andthrombocytopenia are classic. Blood smears are the diagnostic gold standard.
Clinical manifestations of mononucleosis include fever, malaise, and pharyngitis. Lymphadenopathy and splenomegaly may be present along with atypical lymphocytosis. The diagnosis is established via serology. Not associated with significant arthritis.
Acute human immunodeficiency virus (HIV) infection
Clinical manifestations of acute HIV infection may include fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache. The diagnosis is established via immunoassay and/or an HIV virologic (viral load) test.
Group A Streptococcus
Clinical manifestations of group A Streptococcus infection include fever, myalgia, cutaneous manifestations (cellulitis, fasciitis), pharyngitis, and shock. The diagnosis established by positive cultures from the blood or other tissues.
Meningococcal infection may be associated with meningitis and hemorrhagic rash. The diagnosis is established based on cerebrospinal fluid examination.
Causing Arthritis: Dengue fever; Chikungunya
Chikungunya virus infection is more likely to cause high fever, severe arthralgia, arthritis, rash, and lymphopenia, whereas dengue virus infection is more likely to cause neutropenia, thrombocytopenia, hemorrhage, shock, and death. The diagnosis of dengue fever is established via polymerase chain reaction (PCR) or serology.
Symptoms and signs of Zika virus infection include fever, rash, headache, arthralgia, myalgia, and conjunctivitis.
Parvovirus infection can present with acute and symmetric arthritis or arthralgia, most frequently involving the small joints of the hands, wrists, knees, and feet. Rash may or may not be present. The diagnosis is established via serology.
Clinical manifestations of rubella include low-grade fever, coryza, conjunctivitis, and lymphadenopathy. Macular rash begins on the face and spreads to the trunk, and arthritis may be present. The diagnosis is established via serology.