| Type of disorder | Common | Uncommon | Rare |
|---|---|---|---|
| Malignancy/neoplastic disorders | Lymphomaa Hypernephromas/renal cell carcinoma (RCC) | Pre-leukemias (AML)a Myeloproliferative disorders (MPDs) | Atrial myxomas Multiple myeloma Colon carcinoma Pancreatic carcinoma CNS metastases Hepatomas Liver metastases |
| Infectious diseases | Miliary TB SBE Brucellosisa Q fevera | Intra-abdominal/pelvic abscess Intra/perinephric abscess Typhoid fever/enteric feversa Toxoplasmosis Cat scratch disease (CSD)a EBV CMV HIV Extrapulmonary TB (renal TB, CNS TB) | Periapical dental abscess Chronic sinusitis/mastoiditis Subacute vertebral osteomyelitis Aortoenteric fistula Relapsing fevera Rat-bite fevera Leptospirosisa Histoplasmosis Coccidiomycosis Visceral leishmaniasis (kala-azar) LGV Whipple’s diseasea Castleman’s diseasea (MCD) Malaria Babesiosis Ehrlichiosis |
| Rheumatologic/inflammatory disorders | Adult Still’s diseasea Giant cell arteritis (GCA)/temporal arteritis (TA)a | PAN/MPAa Late-onset rheumatoid arthritis (LORA)a SLEa | Takayasu’s arteritisa Kikuchi’s diseasea Sarcoidosis (CNS) Felty’s syndrome Gaucher’s disease Polyarticular gouta Pseudogouta Schnitzler’s syndromea Behçet’s diseasea FAPA syndromea (Marshall’s syndrome) |
| Miscellaneous disorders | Drug fevera Alcoholic cirrhosisa | Subacute thyroiditisa Regional enteritis (Crohn’s disease)a | Pulmonary emboli (small/multiple) Pseudolymphomas Kikuchi’s diseasea Rosai–Dorman diseasea Erdheim–Chester disease (ECD)a Cyclic neutropeniaa Familial periodic fever syndromesa
associated periodic syndrome (TRAPS)
syndrome Systemic mastocytosis Hypothalamic dysfunction Hypertriglyceridemia Factitious fevera |
a Also cause of recurrent FUOs.
Disorders with FUO potential include any not easily diagnosed disorder with prolonged fevers, travel-related infections with prolonged fevers presenting in nonendemic areas, any relapsing/recurrent disorder with prolonged fevers, or any disorder with prolonged fevers with unusual clinical findings.
Abbreviations: CNS = central nervous system; TB = tuberculosis; SBE = subacute bacterial endocarditis; CMV = cytomegalovirus; HIV = human immunodeficiency virus; EBV = Epstein–Barr virus; LGV = lymphogranuloma venereum; PAN = periarteritis nodosa; MPA = microscopic polyangiitis; SLE = systemic lupus erythematosus; FMF = familial Mediterranean fever; MCD = multicentric Castleman’s disease; FAPA = fever, aphthous ulcers, pharyngitis, adenitis; TNF = tumor necrosis factor; AML = acute myelogenous leukemia.
Diagnostic approach to FUOs
In patients presenting with prolonged fevers, the clinician should first determine if the patient indeed has an FUO. Because there are many causes of FUO, there is no “cookbook or algorithmic approach” for diagnosing FUOs. In medicine, the history provides important initial diagnostic clues and a general sense of the likely FUO category, e.g., weight loss with early anorexia suggests malignancy, arthralgias/myalgias suggest a rheumatic/inflammatory disorder, and fever with chills suggests an infectious etiology.
After an FUO category is suggested by historical clues, the physical examination should focus on history relevant findings in the differential diagnosis. The physical examination should not be comprehensive but more importantly should be carefully focused on demonstrating the presence or absence of key findings in the differential diagnosis, e.g., a complete neurologic exam is unhelpful in an FUO patient with probable adult Still’s disease. On physical examination particular attention should be given to eye findings, liver, spleen, lymph nodes, joint findings, and skin lesions (Table 1.2). At this point, based upon the presence or absence of history and physical examination clues, the initial FUO diagnostic workup, e.g., nonspecific laboratory tests, should also be focused on ruling in or ruling out the most likely diagnostic possibilities. Since the patient has already been seen by one or more physicians prior to presentation, routine laboratory tests have already been done, e.g., CBC, liver function test (LFTs), urinalysis (UA), but these tests should be carefully re-reviewed for diagnostic clues, e.g., relative lymphopenia.
| Historical features | Clues from the history | Physical examination findings | Clues from the physical examination | |||
|---|---|---|---|---|---|---|
| Malignant/neoplastic disorders | • PMH/FMH malignancy | → | Possibility of same disease likely | • Fever pattern: | ||
| • HA/mental confusion | → | CNS metastases, lymphomas, multiple myeloma, atrial myxoma (CNS emboli) | Relative bradycardia | → | CNS, malignancies, lymphomas | |
| Hectic/septic fevers (Pel-Ebstein) | → | Lymphomas | ||||
| • Weight loss (with early decreased appetite) | → | Any malignant/neoplastic disorder | • Cranial nerve palsies | → | CNS lymphomas, CNS neoplasms | |
| • Early satiety | → | Lymphomas, any malignant/neoplastic disorder causing splenomegaly | • Fundi: Roth spots | → | Lymphomas, atrial myxoma | |
| • Fundi: cytoid bodies (cotton wool spots) | → | Atrial myxoma | ||||
| • Pruritus (post hot shower/bath) | → | Lymphoma, MPDs | • Fundi: retinal hemorrhages | → | Pre-leukemia (AML) | |
| • Night sweats | → | Any malignant/neoplastic disorder | • Adenopathy | → | Lymphoma, Kikuchi’s disease, Rosai–Dorfman disease | |
| • Abdominal discomfort/pain | → | Hypernephroma, hepatoma, liver metastases, colon carcinoma, pancreatic carcinoma | • Sternal tenderness | → | Pre-leukemia (AML), MPDs | |
| • Heart murmur | → | Marantic endocarditis, atrial myxoma | ||||
| • Testicular pain | → | Lymphoma | • Hepatomegaly | → | Hepatoma, hypernephroma, liver metastases | |
| • Bone pain | → | Multiple myeloma, any malignant/neoplastic disorder with bone involvement | • Splenomegaly | → | Lymphomas, MPDs | |
| • Splinter hemorrhages | → | Atrial myxoma | ||||
| • Epididymitis | → | Lymphomas | ||||
| Infectious diseases | • PMH/FMH of infections | → | Possibility of same disease high | • Fever pattern: | ||
| • HA/mental confusion | → | Brucellosis, CSD, ehrlichiosis, Q fever, malaria, leptospirosis, Whipple’s disease, typhoid fever/enteric fevers, rat-bite fever, relapsing fever, CNS TB, HIV, LGV | Relative bradycardia | → | Typhoid fever/enteric fevers, leptospirosis, Q fever, malaria, babesiosis, ehrlichiosis | |
| Double quotidian fever | → | Visceral leishmaniasis (kala-azar) | ||||
| Camelback fever curve | → | Ehrlichiosis, leptospirosis, brucellosis, rat-bite fever (S. minus) | ||||
| • Recent/similar illness exposure | → | Possibility of same disease high | Morning temperature spikes | → | Miliary TB, typhoid fever/enteric fevers | |
| • Surgical/invasive procedures | → | Abscess, SBE | ||||
| • Aortic aneurysm/repair | → | Q fever, enteric fever | Relapsing fevers | → | Brucellosis, malaria, rat-bite fever (S. moniliformis) | |
| • STD history | → | LGV | • Abducens (CN VI) palsy | → | CNS TB | |
| • Recent travel | → | Typhoid/enteric fevers, leptospirosis, malaria, visceral leishmaniasis (kala-azar), brucellosis, Q fever | • Conjunctival suffusion | → | Trichinosis, relapsing fever, leptospirosis | |
| • Conjunctival hemorrhages | → | SBE | ||||
| • Insect exposure | → | Malaria, ehrlichiosis, babesiosis, visceral leishmaniasis (kala-azar), relapsing fever | • Chorioretinitis | → | Toxoplasmosis, TB, histoplasmosis | |
| • Choroid tubercles | → | Miliary TB | ||||
| • Pet/animal contact | → | Q fever, CSD, toxoplasmosis, rat-bite fever, relapsing fever, leptospirosis, brucellosis | • Roth spots | → | SBE | |
| • Palatal petechiae | → | EBV, CMV, toxoplasmosis | ||||
| • Unpasteurized milk/cheese consumption | → | Q fever, brucellosis | • Tongue ulcer | → | Histoplasmosis | |
| • Adenopathy | → | CSD, EBV, CMV | ||||
| • Undercooked meat consumption | → | Toxoplasmosis, trichinosis | • Heart murmur | → | SBE | |
| • Spinal tenderness | → | Subacute vertebral osteomyelitis, typhoid fever/enteric fever, skeletal TB, brucellosis | ||||
| • Blood transfusions | → | Malaria, babesiosis, ehrlichiosis, CMV, HIV | • Hepatomegaly | → | Q fever, typhoid fever/enteric fevers, brucellosis, visceral leishmaniasis (kala-azar), rat-bite fever, relapsing fever | |
| • Poor dentition | → | SBE, apical root abscess | ||||
| • Sleep disturbances | → | Brucellosis, relapsing fever, leptospirosis | • Splenomegaly | → | Miliary TB, EBV, CMV, typhoid fever/enteric fevers, brucellosis, histoplasmosis, ehrlichiosis, malaria, Q fever, SBE, CSD Rat-bite fever, relapsing fever | |
| • Early satiety | → | EBV, CMV, Q fever, brucellosis, SBE, miliary TB | ||||
| • Arthralgias | → | Rat-bite fever, LGV, Whipple’s disease, brucellosis | • Splinter hemorrhages | → | SBE | |
| • Ostler’s nodes/Janeway lesions | → | SBE | ||||
| • Myalgias | → | Q fever, leptospirosis, relapsing fever, trichinosis | • Skin hyperpigmentation | → | Visceral leishmaniasis (kala-azar), Whipple’s disease | |
| • Sinusitis | → | Chronic sinusitis | ||||
| • Night sweats | → | Miliary TB, histoplasmosis | • Epididymitis | → | EBV, renal TB, brucellosis | |
| • Weight loss | → | Miliary TB, histoplasmosis | ||||
| • Tongue pain | → | Histoplasmosis, relapsing fever | ||||
| • Neck pain | → | Subacute vertebral osteomyelitis, chronic mastoiditis | ||||
| • Tender finger tips | → | SBE | ||||
| • Abdominal pain | → | Relapsing fever, leptospirosisv, typhoid fever/enteric fevers, trichinosis | ||||
| • Back pain | → | Subacute vertebral osteomyelitis, brucellosis, SBE | ||||
| • Testicular pain | → | EBV | ||||
| Rheumatic/inflammatory disorders | • PMH/FMH of rheumatic disorders | → | Possibility of the same disease likely | • Fever pattern: | ||
| • HA/mental confusion | → | GCA/TA, CNS sarcoidosis, adult Still’s disease | Double quotidian fever | → | Adult Still’s disease | |
| Morning temperature spikes | → | PAN | ||||
| • Transient facial edema | → | Takayasu’s arteritis | ||||
| • Hearing loss | → | PAN | • Lacrimal gland enlargement | → | LORA, sarcoidosis, SLE | |
| • Nasal stuffiness | → | Sarcoidosis | • Parotid gland enlargement | → | Sarcoidosis | |
| • Joint pain/swelling | → | SLE, LORA, sarcoidosis, adult Still’s disease | • Rash | → |
