Fever of Unknown Origin

Differential Overview

Infection

❑ HIV

❑ Tuberculosis

❑ Endocarditis

❑ Osteomyelitis

❑ Malaria

❑ Syphilis

❑ Zoonosis

❑ Typhoid fever

❑ Chronic meningococcemia

Neoplasm

❑ Lymphoma

❑ Liver metastases

❑ Renal cell carcinoma

❑ Atrial myxoma

Collagen-Vascular Disease

❑ Giant cell arteritis

❑ Systemic lupus erythematosus

❑ Vasculitis

❑ Rheumatic fever

❑ Still disease

Other

❑ Drugs

❑ Heat stroke

❑ Factitious

❑ Malignant hyperthermia

❑ Multiple pulmonary emboli

Diagnostic Approach

Fever of unknown origin (FUO), when a fever over 101°F (38.5°C) remains unexplained for longer than 3 weeks, is usually a result of infection (40%), neoplasm (20%), or collagen-vascular disease (20%). It is most commonly caused by an atypical presentation of a common disease. Always document the fever before pursuing the evaluation.

Consider relatively hidden (deep) sites: retroperitoneum (hematoma or infection), bone, dental, sinus, ovary, prostate, subphrenic (following abdominal surgery), renal, spleen, or prostheses. With FUO in a hospitalized patient, consider sequestered sites (e.g., sinuses in intubated patients or implanted hardware), indwelling lines, C. difficile, or drug reactions. With FUO in a neutropenic patient, consider catheters, perianal infections, Candida, and Aspergillus. Cardinal signs may be absent, e.g., meningitis with opportunistic pathogens without meningismus in 63%, and pneumonia without purulent sputum in 92%. Neutropenic fevers are usually due to bacteremia, with fungal organisms becoming predominant after 7 days of unremitting fever. Fever may also be due to the underlying neoplasm, drugs such as antibiotics, or blood products.

Examine for subtle clues:

• Petechial eruptions in meningococcemia and Rocky Mountain Spotted Fever

• Pustular lesions in gonococcemia or staphylococcal sepsis

• Ecthyma gangrenosum in Pseudomonas sepsis

• Splinter hemorrhages, conjunctival hemorrhages, Roth spots, Osler nodes, and Janeway lesions in endocarditis

• Choroidal tubercles in miliary tuberculosis and candidemia

• Splenomegaly in endocarditis, lymphoma, and cirrhosis

• Hepatic bruit or friction rub in subphrenic abscess

• Temporal artery or scalp tenderness or jaw claudication in giant cell arteritis

• Epitrochlear lymphadenopathy in syphilis

Extreme elevations of fever (.40°C) are found in heat stroke, hypothalamic dysfunction, meningitis, midbrain hemorrhage, falciparum malaria, Rocky Mountain Spotted Fever, typhus, sepsis, malignant hyperthermia, and hypernephroma.

Relative bradycardia occurs in salmonellosis (typhoid fever), meningitis with increased intracranial pressure, mycoplasma and legionella pneumonia, factitious fever, tularemia, brucellosis, mumps, hepatitis, and with concomitant beta blockers. Bradycardia in fever may also signal cardiac conduction abnormalities in acute rheumatic fever, Lyme disease, viral myocarditis, or endocarditis with valve ring abscess.

Relapsing fevers (days of fever alternating with days without) occur in brucellosis (fever with physical activity), Hodgkin disease, extrapulmonary tuberculosis, malaria, and Lyme disease. Hectic fever (difference between peak and trough .1.5°C) suggests abscess, pyelonephritis, ascending cholangitis, tuberculosis, lymphoma, and drug reactions. Absence of diurnal variation suggests a central source. Reversal of the diurnal pattern (“typhus inversus”) occurs with disseminated tuberculosis, typhoid fever, polyarteritis nodosa, and salicylate toxicity.

FUO in patients from the developing world include tuberculosis, typhoid, amebic liver abscesses, AIDS, and geographically restricted infections such as malaria, schistosomiasis, brucellosis, kala azar, filariasis, or Lassa fever. They may present after long incubation or latency periods.

When FUO lasts longer than 6 months, consider factitious fever, granulomatous hepatitis, neoplasm, Still disease, infection, collagen-vascular disease, or exaggerated circadian rhythm.

Patients who remain undiagnosed have a good prognosis (83% resolution in 1 year, 4% mortality).

Clinical Findings

HIV  Fever may be a prominent manifestation of acute or chronic HIV infection. It may be caused by the HIV infection itself, or it may be secondary to immunosuppression, with mycobacterium avian-complex, toxoplasmosis, cytomegalovirus, tuberculosis, pneumocystis, salmonellosis, cryptococcosis, histoplasmosis, non-Hodgkin lymphoma, or drug fever as causes.

Tuberculosis  Suspect tuberculosis in high-risk patients such as HIV-infected persons, homeless persons, recent Southeast Asian immigrants, or Native Americans. When FUO exists, tuberculosis is usually extrapulmonary (bones, nodes, renal, genitals, or liver).

Endocarditis  Examine closely for splinter hemorrhages, splenomegaly,
clubbing, conjunctival petechiae, or tender nodules on the hands (Osler nodes).

Osteomyelitis  Subacute in onset, there is dull, constant pain and soft tissue swelling/tenderness over the involved bone, with low-grade fever.

Malaria  Suspect malaria if the patient has a history of recent travel to the tropics. Tertian malaria, with fever every 2 to 3 days, occurs in P. vivax or
P. ovale. Quartan malaria, in P. malariae, returns every fourth day. P. falciparum malaria may have fever at irregular intervals. A palpable spleen and tender liver are often present in chronic malaria.

Syphilis  Secondary syphilis presents with a papulosquamous rash involving the palms and soles, and generalized lymphadenopathy. A Jarisch-Herxheimer reaction, characterized by fever, increased rash, and malaise, may appear with treatment.

Zoonosis  Should be considered in animal handlers, veterinarians, and butchers. Common syndromes include Lyme disease with erythema migrans at a deer tick bite site and arthritis; brucellosis with splenomegaly, lymphadenopathy, and hepatomegaly after drinking unpasteurized milk; and tularemia with fever and tender nodes in hunters and trappers.

Typhoid fever  The fever progressively increases each night without tachycardia or rigors. Rose spots appear within the first week, as a rose-red 2 to 3 mm macule on the abdomen with blanching and a central punctum.
Foul-smelling pea-soup diarrhea subsequently develops.

Chronic meningococcemia  The fever is intermittent with days during which the patient appears well. A maculopapular rash and arthralgias or arthritis wax and wane with the fever. Splenomegaly may be found in 20%.

Lymphoma  Fever is the presenting symptom (often with drenching night sweats), especially in Hodgkin lymphoma, or with disease confined to the retroperitoneum or marrow. A Pel-Ebstein pattern of relapsing fever of 3 to 10 days duration with a 3 to 10 day afebrile interlude is seen in 16%. Non-Hodgkin lymphoma often presents with fever, lymphadenopathy, hepatosplenomegaly, and bone pain (especially sternal).

Liver metastases  Fever is usually a late phenomenon in a patient with a known primary tumor. The liver contains hard palpable nodules.

Renal cell carcinoma  The classic triad of gross hematuria, flank pain, and a palpable abdominal mass occurs in only 10%. Systemic symptoms of fatigability, weight loss, and cachexia are frequent. Renal vein involvement may produce a new left varicocele and lower extremity edema. Hormone secretion may produce hypertension, galactorrhea, feminization or masculinization, Cushing syndrome, or symptomatic hypercalcemia.

Atrial myxoma  A changing murmur with tumor plop, embolic phenomena, and Raynaud syndrome signal this rare phenomenon.

Giant cell arteritis  Consider when an elderly patient develops a new headache associated with a tender, ropy, or nodular temporal artery and/or fever. Polymyalgia rheumatica with proximal muscle pain and weakness is also part of the spectrum.

Systemic lupus erythematosus  Fever can be caused by the lupus itself or by a complicating infection. Malar rash, Raynaud syndrome serositis, and arthritis are important clues.

Vasculitis  Consider vasculitis in a patient with systemic illness with glomerulonephritis, palpable purpura, necrotic skin lesions, mononeuritis multiplex, or pulse asymmetry.

Rheumatic fever  An antecedent sore throat, arthralgias or arthritis, carditis, and erythema marginatum are clues to diagnosis.

Still disease  It occurs in a young adult with high fever, evanescent rash (coinciding with fever spikes), lymphadenopathy, hepatosplenomegaly, and arthralgias.

Drugs  Fever may be due to serum sickness, allergy, or immune-mediated
vasculitis. A maculopapular rash, eosinophilia, and absence of chills are clues. Antibiotics (especially penicillin and sulfonamides), phenytoin,
isoniazid, thiouracils, procainamide, quinidine, methyldopa, hydralazine, barbiturates, allopurinol, captopril, quinidine, and phenolthalein are notable causes. Drugs producing immediate fever include amphotericin, bleomycin, high dose cyclophosphamide, and antithymocyte globulin.

Heat stroke  Patients present with high fever, absence of sweating, delirium, or coma. Suspect in hot weather, with precipitants of exercise in high heat and humidity, or drugs such as anticholinergics, antiparkinson agents, diuretics, and phenothiazines.

Factitious  There are two types: manufactured fever and self-injection with
foreign substances. Clues include medical training, failure to follow a normal diurnal pattern, excessively high temperature (106° to 107°), lack of tachycardia or diaphoresis with fever, and normal temperature immediately after a (false) high reading.

Malignant hyperthermia  Extreme temperature elevations may occur in patients taking general anesthetics (halothane or succinylcholine), MAO inhibitors combined with meperidine, or neuroleptics, including phenothiazines, haloperidol, fluoxetine, tricyclic antidepressants, and metoclopramide (neuroleptic malignant syndrome). Rigidity is present.

Multiple pulmonary emboli  Consider in a patient with transient migratory pleuritic chest pain and shortness of breath.

Pictures

Book Source Details

• Book Title: Field Guide to Bedside Diagnosis
• Author(s): David S. Smith
• Year of Publication: 2007
• Copyright Details: Field Guide to Bedside Diagnosis, Copyright © 2007 Lippincott Williams & Wilkins.

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