Fever of unknown origin
Classic FUO: T >38.3°C, ≥3 weeks, no diagnosis after reasonable investigation (≥3 hospital days or ≥3 outpatient visits).
Four FUOs, not one fever
Classic FUO is temperature >38.3°C on several occasions for ≥3 weeks without a diagnosis after ≥3 inpatient days or 3 clinic visits (; Petersdorf, Medicine 1961). Newer papers allow >38°C. It is usually an atypical presentation of a common disease, not a zebra. Up to half remain undiagnosed — and most of those defervesce ().
Classic
Community, ≥3 weeks
Infection 14–59%, rheumatic 2–36%, malignancy 3–28%, miscellaneous 0–18%, undiagnosed 7–51% (). Elderly: rheumatic disease (GCA/PMR) outruns infection.
Nosocomial
First fever >24 h in hospital
Lines, hospital pneumonia, C. diff, sinusitis from NG tubes, VTE, drug fever, C. difficile, wound and hardware. Stop hunting zebras until the catheter has a name.
HIV
Uncontrolled, low CD4
Infection ~88% when mean CD4 is ~58: MAC, PJP, CMV, histo, other viruses. Lymphoma ~7%. Immune reconstitution after ART is on the list ().
Neutropenic
ANC <500, refractory to antibacterials
Fungal ~45%, resistant bacteria / biofilm 10–15%, GVHD ~10%, viral ~5% (). This is when mold-active therapy enters the algorithm.
Travel-associated fever is a separate lane: falciparum malaria first, then typhoid, paratyphoid, leptospirosis, rickettsia, dengue ().
Workup that actually moves
- History: fever pattern, B symptoms, dental disease, valves, travel and birthplace, animals, arthropods, food, transfusions, sex, occupation, TB risks, drugs (including street and herbal), vaccines, procedures, family periodic-fever history.
- Exam: teeth and thrush, sinuses, temporal arteries, thyroid, murmur, abdomen/HSM, fundi, nodes, joints, skin/nails, rectal, genitourinary.
- First labs: CBC, BMP, LFTs, ESR/CRP, UA/culture from a fresh specimen, two blood cultures from different sites with a long incubation, CXR, HIV.
- ESR is chronic inflammation and is falsely high in ESRD, paraprotein, anemia, obesity, age (rule of thumb: men age/2, women age/2 + 10). CRP moves faster and can be low in cirrhosis.
| If still dark | Reach for |
|---|---|
| Infection lane | IGRA, syphilis, EBV serologies, CMV PCR, HBV/HCV, targeted NAAT, thick smear, organism-specific serologies, cultures from every lumen of a CVC |
| Rheum / marrow | ANA, ANCA, RF/CCP, cryos, CK/aldolase, ferritin, SPEP/SFLC, LDH, TFTs, blood smear |
| Imaging map | CT C/A/P (Sn/Sp ~71%), lower-extremity US, TTE/TEE, maxillofacial CT, FDG-PET/CT (Sn ~86%, Sp ~52%, vertex-to-toes with contrast; J Nucl Med 2016;57:1913) |
Etiologies worth naming
| Bucket | Ward hits |
|---|---|
| Infectious | Occult abscess (dental, perianal, brain), endocarditis (HACEK, nutritionally variant strep), HIV, EBV/CMV, complicated UTI, osteomyelitis/septic arthritis, sinusitis, TB (extrapulmonary), nosocomial/hardware, tick-borne, endemic fungi, MAC in low CD4, cat-scratch, Q fever, brucella, bartonella, salmonella, Whipple, malaria in the returned traveler. |
| Malignancy | Lymphoma, leukemia, myeloma, myeloproliferative, RCC, HCC, colorectal, melanoma, pancreatic, Castleman, atrial myxoma. |
| Rheumatic | GCA/PMR (elderly FUO), Adult-onset Still / MAS, RA, SLE, myositis, sarcoid, cryoglobulinemia, PAN, Takayasu, Behçet, ANCA vasculitis, Kikuchi. |
| Other | Drug fever, VTE, hematoma, central fever after SAH/IVH, hyperthyroid, alcoholic hepatitis/cirrhosis, IBD, factitious, HLH, familial periodic fevers (FMF, TRAPS, hyper-IgD, Schnitzler), NMS/serotonin syndrome. |
Drug fever
- Diagnosis of exclusion. Can start any time on the drug; defervescence can take a week after stopping.
- Often looks “too well” for the temperature; relative bradycardia; sometimes rash, LFT bumps, eosinophilia.
- Classics: β-lactams, sulfa, macrolides, AEDs, dexmedetomidine, chemotherapy. Also hypersensitivity including SJS/TEN, Jarisch–Herxheimer, NMS, G6PD.
Mimics that fool ID
- VTE: usually low-grade; only ~6% >38.3°C and 1.4% >38.9°C ().
- Central fever after SAH, intraventricular blood, or a CNS mass (JAMA Neurol 2013;70:1499).
- Adult-onset Still vs HLH: astronomical ferritin, fever, rash, arthritis — still exclude infection and lymphoma before immunosuppression.