Fever of unknown origin differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

Overview

1. Fever can be the presenting symptom with many diseases, it is therefore important to differentiate fever of unknown origin from all those diseases which present with fever.
2. Because of the broad range of differential diagnosis they can be grouped into four categories based on their etiology.

• Infectious
• Malignant
• Inflammatory
• Miscellaneous

Differential diagnosis

Infectious

These patients mostly have a history of hospitalization, surgical procedures, contact with infected person or travel to an endemic place.

Examples include:

• Histoplasmosis
• Abscess
• Subacute bacterial endocarditis
• Q fever
• Brucellosis
• Toxoplasmosis
• Leptospirosis
• Ehrlichiosis
• Anaplasmosis
• Tuberculosis
• Infectious mononucleosis.

Malignant

They are mostly accompanied by loss of weight, decrease in appetite, lymph node enlargement and aquagenic pruritic mostly occurring after hot shower.

Examples include:

• Hodgkin lymphoma
• myeloproliferative disorders
• Colorectal carcinoma
• Hepatocellular carcinoma
• Renal cell carcinoma
• carcinoma of CNS etc.

Autoinflammatory/Rheumatologic

Mostly they have multi organ involvement and lymphadenopathy along with joint symptoms may be present.

Examples include:

• Systemic lupus erythematosus
• Takayasu Arteritis
• Polyarteritis nodosa
• Polymyalgia rheumatica
• Sarcoidosis etc.

Miscellaneous

Mostly does not belong to any of the above.

Examples include:

• Familial Mediterranean fever
• Drug fever
• Thyroiditis
• Hypertriglyceridemia etc.

Disease	History	Physical examination	Laboratory or radiological findings
Subacute Bacterial endocartitis	Recent dental procedures, Joint pain, decrease weight, Night sweats, back pain	Heart murmur, splinter hemorrhages, Janeway lesions, Roth spots, enlarged spleen.	Elevated WBCs, decreased platelets, Elevated ESR , presence of Cryoglobulins
Abscess	GI, genitourinary, Pelvic procedure or infection , fever, chills, decrease weight, night sweats.	RUQ tenderness ( subphrenic Abscess),hepatomegaly (hepatic abscess), splenomegaly ( splenic abscess), tenderness on DRE ( pelvic abscess).	Elevated WBCs and ESR, elevated platelets, Positive CT/MRI findings
Tuberculosis of CNS	Previous tuberculosis, Altered mental status, Headace	Morning temperature spikes, relative bradycardia, Abducens palsy.	CSF: Increased lymphocytes, increased RBCs, decreased glucose, increased lactate, positive AFB stain and Culture.
EBV infection	Exposure to saliva ( kissing disease ) , upper respiratory tract infection	Enlarged lymph nodes, palatal petechiae, enlarged tonsils, enlarged spleen.	Positive monospot test, decreased WBCs, decreased lymphocytes, atypical lymphocytosis, positive PCR, positive IgM EBV VCA titers, enlarged spleen, increased LFTs.
CMV infection	Exposure to body fluids or blood transfusion	Enlarged lymph nodes, palatal petechiae, enlarged tonsils, enlarged spleen.	Negative monospot test, decreased WBCs, decreased lymphocytes, atypical lymphocytosis, positive PCR, increased IgM, increased LFTs
HIV infection	Exposure to body fluids (blood, breast milk, semen and vaginal secretions), IV drug abuse, weight loss, night sweats .	Generalized lymphadenopathy, pharyngeal and palatal petechiae.	Decreased lymphocytes, decreased platelets, positive HIV serology and PCR , increased viral load.
Toxoplasmosis	Exposure to cat feces or consumption of uncooked meat, joint pain.	Chorioretinitis, enlarged lymph nodes, enlarged spleen.	Atypical lymphocytes, increased IgM titers ( toxoplasma serology), Positive MRI/CT scan finding in brain ( ring enhancing lesions ).
Ehrlichiosis/ Anaplasmosis	Recent insect (Tick) exposure, Headache, muscle aches, fatigue,	Relative bradycardia, enlarged spleen.	Decreased WBCs, decreased platelets, inclusions in Monocytes (Ehrlichiosis ) and Granulocytes (Anaplasmosis ), positive serology.
Leptospirosis	Exposure to water contaminated with animal (Rodents) urine, common in surfers, Flu like symptoms, Headache.	Calf tenderness, Photophobia, Jaundice, conjunctival suffusion without exudate, enlarged liver.	Increased WBCs, Decreased platelets, increased LFTs, Increased creatinine kinase, positive serology.
Brucellosis	Exposure to animals or contaminated dairy products (milk, cheese), Headache, muscle aches, fatigue,	Muscle (Thigh) tenderness, Spine tenderness, enlarged lymph nodes, enlarged spleen.	Positive serology, increased LFTs , Atypical lymphocytes, positive blood culture.
Histoplasmosis	Cave exploration, Mississippi and Ohio river valleys location, weight loss, night sweats	Palatal/tongue ulcers, enlarged spleen, enlarged liver.	Decreased WBCs, decreased platelets, increased LFTs, positive serum and urine antigen test.
Q fever	Exposure to cattle/sheep amniotic fluid, night sweats, weight loss, prosthetic heart valve.	Relative bradycardia, heart murmur, enlarged spleen.	Decreased platelets, increased LFTs, positive PCR
SLE	Young female, joint pain, recurrent infections, fatigue, headache, hair loss, anemia	Multiple mucosal ulcers, malar rash, enlarged lymph nodes, enlarged spleen, Osler nodes, Roth spots, heart murmur (endocarditis),	Pancytopenia, increased ANA, increased C reactive protein, increased ferritin, positive ds DNA, decreased complement.
Giant cell temporal arteritis	Old age, amaurosis fugax, jaw pain, headache (unilateral), muscle aches. .	temporal artery nodules and tenderness, jaw tenderness, pallor of optic disc.	Elevated ESR, positive imaging findings, positive biopsy (granulomatous inflammatory).
Poly arteritis nodosa	Fever, weight loss, fatigue, abdominal pain, black stools, rashes, livedo reticularis, neurologic problems, edema.	Increased blood pressure, skin purpura.	Elevated ESR, increased creatinine, positive hepatitis B serology, fibrinoid necrosis on biopsy.
Takayasu arteritis	Headache, joint pain, weight loss, edematous face, claudication, skin nodules, neurologic deficits	Unequal B.P in arms, bruits over larger arteries.	Elevated ESR, positive imaging findings, positive biopsy (granulomatous inflammatory).
Sarcoidosis	Arthritis, headache, eye problems, hearing problems, peripheral neuropathy, parotitis, skin nodules.	Enlarged lymph nodes, erythema nodosum, facial nerve palsy, Argyll Robertson pupil, uveitis, enlarged liver.	Decreased WBCs, decreased platelets, increase Eosinophils, hypercalcemia, hypercalciuria, increased ACE levels in blood.
Hodgkin lymphoma	Radiation exposure, fever, night sweats, fatigue, bone pain, pruritis.	Enlarged lymph nodes, enlarged liver, enlarged spleen,	lymphopenia, eosinophilia, increased basophils, increased LDH, positive CT/MRI, Reed Sternberg cells on lymph node biopsy.
CNS Malignancies	Headache, vomiting, altered mental status, seizures.	Cranial nerves abnormalities, optic disc swelling	Positive CT/ MRI of brain, CSF increased protein and RBcs
Hepatocellular Carcinoma	Abdominal pain, family history, alpha 1 anti trypsin deficiency, Cirrhosis, Chronic Hepatitis Band C infection.	Enlarged Liver, ascites, abdominal tenderness	Increased LFTs, Increased AFP, increased ALP, Malignant cells on biopsy, positive imaging.
Chronic lymphocytic leukemia	fever, weight loss, night sweats	Enlarged lymph nodes, enlarged spleen.	Elevated ESR, positive coombs test, Smudge cells on blood smear, Leukocytosis.