Multisystem Processes & Disorders

Fever of unknown origin: workup algorithm

Clinical Overview and When to Suspect Fever of Unknown Origin

— Temperature >38.3°C (101°F) on multiple occasions

— Duration ≥3 weeks

— No diagnosis after appropriate initial outpatient or inpatient workup (typically 3 outpatient visits or 3 days inpatient, or 1 week of "intelligent invasive ambulatory investigation")

— Classic FUO — immunocompetent adult; etiology in roughly 1/3 infection, 1/4 malignancy/neoplasm, 1/5 noninfectious inflammatory (NIID like adult-onset Still's, GCA, vasculitis), and up to 50% remain undiagnosed in modern series — many of those resolve spontaneously

— Nosocomial FUO — hospitalized ≥48h, fever workup negative after 3 days; think C. difficile, drug fever, catheter-related infection, sinusitis from NG tubes, DVT/PE, acalculous cholecystitis

— Neutropenic FUO — ANC <500; broaden to fungal (Candida, Aspergillus) and resistant gram-negatives after 4–7 days of empiric antibiotics

— HIV-associated FUO — disseminated MAC, TB, CMV, lymphoma, histoplasmosis dominate; CD4 count drives differential

Board pearl: In elderly FUO, giant cell arteritis and intra-abdominal abscess are disproportionately common; in young adults, adult-onset Still's disease and lymphoma climb the list. Geographic and exposure context (TB endemic area, tick exposure, animal contact) reshapes the differential before any test is ordered.

Classic FUO definition (Petersdorf, modified Durack-Street):

Four categories of FUO — each has its own pretest probability framework:

When to suspect on Step 3: persistent documented fevers despite reassuring initial outpatient labs, prolonged constitutional symptoms (weight loss, night sweats), or fever after travel/exposure with negative basic infectious workup.

Avoid the trap of labeling self-limited viral syndromes (<3 weeks) as FUO — these are prolonged febrile illnesses, not FUO, and warrant observation rather than aggressive workup.

Presentation Patterns and Key History

— Ask about timing (evening spikes in TB, lymphoma, Still's; double quotidian in Still's and miliary TB; tertian/quartan in malaria)

— Rigors suggest bacteremia, abscess, malaria, cholangitis — not typical of drug fever or NIID

— Travel — malaria, typhoid, dengue, leishmaniasis, schistosomiasis, melioidosis, returning traveler with eosinophilia

— Animal contact — cats (Bartonella, toxoplasmosis), rodents (leptospirosis, hantavirus), livestock (Q fever, brucellosis), birds (psittacosis), reptiles (Salmonella)

— Tick/insect — Lyme, ehrlichiosis, anaplasmosis, RMSF, babesiosis, tularemia

— Sexual history — HIV acute retroviral syndrome, secondary syphilis, disseminated gonococcus

— IV drug use — endocarditis (right-sided, S. aureus), epidural abscess, HCV-related vasculitis

— Occupational — healthcare (TB, factitious), farming, slaughterhouse, spelunking (histoplasmosis)

Step 3 management: On day 1 of the FUO workup, stop all nonessential medications and reassess in 72 hours — defervescence confirms drug fever and avoids an expensive cascade.

Document the fever itself — patient-recorded temperatures with a reliable thermometer over ≥1 week distinguishes true FUO from factitious fever (most common in healthcare workers, female, psychiatric overlay).

Exposure history is the single highest-yield section:

Medication and supplement review — drug fever is widely missed. Classic culprits: beta-lactams, sulfonamides, phenytoin, allopurinol, isoniazid, procainamide, heparin, antipsychotics (NMS), and recent immunotherapy/checkpoint inhibitors. Fever typically begins 1–3 weeks after starting the drug; relative bradycardia and eosinophilia support the diagnosis.

Family history — periodic fever syndromes (FMF, TRAPS, hyper-IgD), hereditary cancers, autoimmune disease.

Review of systems must be exhaustive — headache (GCA, meningitis), back pain (osteomyelitis, endocarditis), oral ulcers (Behçet, lupus), rash (Still's salmon rash, endocarditis, vasculitis).

Physical Exam Findings (and Hemodynamic Assessment when relevant)

— Pulse-temperature dissociation (relative bradycardia) — typhoid, Legionella, brucellosis, leptospirosis, drug fever, factitious fever, CNS lesions, lymphoma

— Persistent tachycardia with hemodynamic instability → escalate toward sepsis, endocarditis, PE

— Sustained fever >41°C (hyperpyrexia) suggests CNS injury, heatstroke, NMS, serotonin syndrome, malignant hyperthermia — not classic infection

— Skin/nails — Janeway lesions, Osler nodes, splinter hemorrhages (endocarditis); Still's salmon-pink evanescent rash; erythema chronicum migrans; erythema nodosum (sarcoid, TB, IBD); palpable purpura (vasculitis)

— Eyes — Roth spots, scleritis (GPA, RA), uveitis (Behçet, sarcoid, TB), choroidal tubercles

— Temporal arteries — tenderness, beading, pulselessness in adults >50 → GCA

— Oral cavity — poor dentition (subacute endocarditis seeding), aphthous ulcers

— Lymph nodes — generalized (HIV, lymphoma, syphilis) vs. localized (Bartonella, TB, lymphoma)

— Cardiac — new regurgitant murmurs

— Abdomen — hepatosplenomegaly (lymphoma, endocarditis, malaria, visceral leishmaniasis, EBV); RUQ tenderness (liver abscess, cholangitis)

— GU/pelvic and rectal — prostatic abscess, tubo-ovarian abscess, perirectal abscess — frequently skipped, frequently the answer

— Joints/spine — septic arthritis, spondylodiscitis, sacroiliitis

— Neuro — focal deficits (brain abscess, endocarditis emboli)

Key distinction: Endocarditis vs. Still's disease — both feature fever and arthralgias, but endocarditis has persistent fever with new murmur, embolic phenomena, while Still's shows quotidian fever spikes with evanescent rash and ferritin >10,000.

Repeat the exam daily — FUO findings are often transient. New murmurs, rashes, joint effusions, or lymphadenopathy emerge over time and reorient the differential.

Vital signs and pattern recognition:

Targeted exam stations (high yield for FUO):

Diagnostic Workup — Initial Labs / Imaging / ECG / Biomarkers

— CBC with differential — neutrophilia (bacterial, Still's), lymphocytosis (viral, lymphoma), eosinophilia (parasites, drug, DRESS, lymphoma, adrenal insufficiency), pancytopenia (marrow infiltration, HLH, miliary TB, leishmaniasis)

— Peripheral smear — malaria, babesiosis, ehrlichia morulae, blasts

— CMP — transaminitis (hepatitis, granulomatous disease, drug), alkaline phosphatase elevation (lymphoma, granulomatous hepatitis, hepatic abscess)

— LDH — elevated in lymphoma, HLH, PCP, hemolysis

— ESR and CRP — nonspecific but ESR >100 narrows differential to GCA, abscess, endocarditis, osteomyelitis, malignancy

— Ferritin — >10,000 ng/mL is highly suggestive of adult-onset Still's, HLH, or macrophage activation syndrome

— UA and urine culture, blood cultures ×3 from separate sites over 24h (off antibiotics if feasible)

— HIV Ag/Ab + RNA viral load (acute HIV may be Ab-negative)

— TB testing — IGRA preferred over PPD in BCG-vaccinated; CXR

— Hepatitis B and C serologies

— RPR/treponemal test

— ANA, RF, anti-CCP if joint or autoimmune features; ANCA if pulmonary-renal syndrome

— TSH — thyroiditis can present as FUO

— CK — myositis, NMS

— SPEP if elderly, weight loss, anemia

— Procalcitonin — supports bacterial etiology but does not exclude

— CXR for all

— CT chest/abdomen/pelvis with contrast — high yield for abscess, lymphadenopathy, occult malignancy

— ECG — conduction delays suggest Lyme carditis, endocarditis with abscess, sarcoidosis

Step 3 management: Order the minimum-necessary first-tier panel plus three sets of blood cultures and CT C/A/P before invoking advanced imaging. Avoid empiric antibiotics in stable patients — they obscure cultures and delay diagnosis. Exceptions: suspected endocarditis, neutropenic fever, GCA with visual symptoms (start steroids), or hemodynamic instability.

First-tier evaluation (every FUO patient, before any "advanced" testing):

Imaging baseline:

Diagnostic Workup — Advanced or Confirmatory Studies

— Echocardiography — TTE first; TEE if prosthetic valve, persistent bacteremia, or high suspicion despite negative TTE (sensitivity 90%+ vs. ~60% for TTE)

— Repeat blood cultures with extended incubation — for HACEK organisms, Bartonella, Brucella, Coxiella; notify the lab

— Serologies — Bartonella, Brucella, Coxiella burnetii (Q fever), Legionella urinary antigen, EBV, CMV, parvovirus B19

— Cryoglobulins, complement (C3/C4) — vasculitis, endocarditis, cryoglobulinemic vasculitis

— Bone marrow biopsy — for unexplained cytopenias, suspected lymphoma, hematologic malignancy, miliary TB, leishmaniasis, HLH; send for flow, cytogenetics, AFB, fungal, and leishmania PCR

— Lymph node excisional biopsy (not FNA) — when persistent lymphadenopathy; preserve architecture for lymphoma diagnosis

— Liver biopsy — for granulomatous hepatitis, unexplained transaminitis with hepatomegaly

— Temporal artery biopsy — adults >50 with headache, jaw claudication, ESR >50 — do not delay steroids while awaiting biopsy

— FDG-PET/CT — recommended by European and increasingly US guidelines as the highest-yield single test after CT in undifferentiated FUO; identifies vasculitis (large-vessel inflammation), occult malignancy, deep abscess, osteomyelitis. Diagnostic yield ~50%

— MRI — spine for vertebral osteomyelitis/discitis; brain for CNS lymphoma, abscess

— Tagged WBC scan — alternative when PET unavailable; better for infection than inflammation

CCS pearl: In an inpatient CCS FUO case, after negative first-tier workup and CT, order FDG-PET/CT and TEE before invoking empiric therapy. Reassess every 48 hours; advance the clock and re-examine the patient — new findings often emerge on day 5–7.

Second-tier testing, guided by initial clues:

Functional and advanced imaging:

Tissue is the answer when imaging localizes — biopsy with histopathology, AFB stain, fungal stain, and culture.

Risk Stratification or First-Line Management Logic

— Step 1: Confirm fever objectively (in-office or inpatient monitoring rules out factitious fever)

— Step 2: Stop nonessential medications, observe 72h for drug fever defervescence

— Step 3: Complete first-tier panel + CT C/A/P + blood cultures ×3

— Step 4: Pursue PDCs ("potentially diagnostic clues") — any abnormal exam finding, lab, or imaging result guides directed testing; resist shotgun ordering

— Step 5: If still undiagnosed and stable, proceed to FDG-PET/CT and consider tissue biopsy of any abnormality

— Step 6: If undiagnosed and clinically well, watchful waiting with serial re-evaluation is appropriate — about 50% of modern FUO resolves spontaneously

— Empiric antibiotics — mask endocarditis, delay diagnosis

— Empiric steroids — mask lymphoma, GCA biopsy, infection; only acceptable when GCA is strongly suspected with visual symptoms

— Empiric antitubercular therapy — reserved for high pretest probability with declining clinical status and inability to obtain tissue

— Hemodynamic instability or sepsis physiology → broad-spectrum antibiotics after cultures

— Neutropenic fever → cefepime or piperacillin-tazobactam within 1 hour

— Suspected GCA with vision threat → high-dose prednisone immediately, biopsy within 1–2 weeks

— Culture-negative endocarditis with embolic events → empiric coverage per IDSA

Board pearl: The single biggest scoring error on FUO vignettes is starting empiric antibiotics or steroids in a stable patient. The correct answer is almost always further diagnostic testing — PET/CT, TEE, bone marrow, or temporal artery biopsy — depending on the clue planted in the stem.

Decision framework once classic FUO is established:

Empiric therapy traps — avoid in stable patients:

Indications to break the "no empiric therapy" rule:

Pharmacotherapy — First-Line Drug Regimen

— Culture-positive endocarditis — pathogen-directed per IDSA; e.g., nafcillin or cefazolin for MSSA, vancomycin for MRSA, ampicillin + ceftriaxone for Enterococcus faecalis (gentamicin-sparing regimen)

— Tuberculosis — RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) ×2 months, then INH/RIF ×4 months; add pyridoxine

— Adult-onset Still's disease — NSAIDs for mild; prednisone 0.5–1 mg/kg/day for moderate; IL-1 (anakinra) or IL-6 (tocilizumab) for refractory

— Giant cell arteritis — prednisone 40–60 mg/day (1 mg/kg if vision-threatening, start IV methylprednisolone 1 g ×3 days); tocilizumab as steroid-sparing

— Lymphoma — oncology-directed chemoimmunotherapy (R-CHOP, ABVD, etc.)

— HLH — HLH-94 protocol (etoposide + dexamethasone); treat trigger

— Brucellosis — doxycycline + rifampin or streptomycin ×6 weeks

— Q fever endocarditis — doxycycline + hydroxychloroquine ×18+ months

— Bartonella endocarditis — doxycycline + gentamicin or rifampin

Step 3 management: When a Step 3 stem describes a stable FUO patient and asks "next best step in management," the answer is almost never an antibiotic — it is a diagnostic test or specialist referral. Match the empiric regimen to the specific syndrome only after diagnosis.

There is no "first-line drug" for FUO itself — treatment is etiology-driven. Empiric therapy without a target is the wrong answer unless one of the destabilizing scenarios in chunk 6 applies.

Common etiology-directed regimens once diagnosed:

Drug fever management: Stop the offending agent — fever resolves within 48–72 hours. Document the reaction in the chart and on the patient's allergy list. Avoid rechallenge.

Antipyretic stewardship: Scheduled acetaminophen masks the fever pattern and impairs diagnostic clarity — use sparingly and document patient comfort, not as primary therapy.

Procedures / Revascularization / Invasive Management (or expanded pharmacology if non-procedural)

— Excisional lymph node biopsy — preferred over core or FNA for suspected lymphoma; preserves architecture for flow cytometry, IHC, cytogenetics

— Bone marrow aspirate + biopsy — sent for histology, flow, cytogenetics, AFB smear/culture, fungal culture, and leishmania PCR if exposure history

— Temporal artery biopsy — 2–3 cm segment ideally; skip lesions exist, so contralateral biopsy if first is negative and suspicion remains high; start steroids immediately — do not wait for biopsy (yield preserved up to 2 weeks)

— Liver biopsy — for granulomatous hepatitis, unexplained hepatomegaly + abnormal LFTs; sent for AFB, fungal stains

— Endomyocardial biopsy — rare; for suspected cardiac sarcoid, giant cell myocarditis

— Image-guided drainage — both diagnostic and therapeutic for abscess

— TEE is the dominant procedure — indication: persistent bacteremia, prosthetic valve, suspected paravalvular abscess, conduction block on ECG

— Surgical valve replacement — for endocarditis with HF, abscess, large vegetation (>10 mm with embolic event), or fungal etiology

CCS pearl: On the CCS simulator, advance the clock after ordering biopsy or PET — these results take 24–72 hours. Use the interval to reassess the patient, repeat exam, and trim unnecessary orders. Premature empiric therapy contaminates the diagnostic trail and lowers the score.

FUO is a procedure-by-biopsy disease — the diagnostic procedures themselves are the high-yield "interventions."

Tissue acquisition strategy:

Interventional cardiology in FUO:

Bronchoscopy with BAL ± transbronchial biopsy — for cavitary or nodular pulmonary lesions, suspected TB, fungal, PCP

Lumbar puncture — when CNS signs, persistent headache, or suspected neurosyphilis, cryptococcal meningitis, CNS lymphoma; send opening pressure, cell count, protein, glucose, cytology, flow, India ink, cryptococcal antigen, VDRL, AFB, fungal cultures, viral PCRs

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher proportion of noninfectious inflammatory disease, particularly giant cell arteritis and polymyalgia rheumatica — up to 25% of elderly FUO

— Occult malignancy more common — solid tumors (renal cell, colon, hepatocellular) and lymphoma

— Intra-abdominal abscess — diverticular, hepatobiliary, perinephric — often without classic peritoneal signs

— Endocarditis — degenerative valve disease, prosthetic valves, recent GU/GI procedures

— Drug fever — polypharmacy raises baseline risk; review every medication

— Lower threshold for temporal artery biopsy and ESR/CRP

— Age-appropriate cancer screening catch-up — colonoscopy, mammography, low-dose chest CT if smoker

— FDG-PET/CT especially high-yield in this group

— Adjust vancomycin, aminoglycosides, beta-lactams, antifungals (fluconazole, voriconazole) by CrCl

— Avoid gentamicin when possible — newer endocarditis guidelines minimize aminoglycoside use except for synergy in selected enterococcal disease

— Iodinated contrast — weigh against CT yield; consider non-contrast CT or MRI; hydrate; hold metformin if eGFR <30

— Gadolinium — avoid in eGFR <30 (NSF risk) unless group II agent and necessary

— Avoid hepatotoxic agents — RIPE regimen needs LFT monitoring, especially in baseline cirrhosis; consider modified regimen

— Voriconazole, fluconazole, isoniazid, rifampin — adjust or avoid

— Acetaminophen dosing capped at 2 g/day in cirrhosis

Board pearl: In an elderly patient with FUO, headache, jaw claudication, scalp tenderness, or new visual symptoms → immediate high-dose steroids + temporal artery biopsy within 1–2 weeks. Delay risks permanent monocular blindness.

Elderly FUO (>65 years) — fundamentally different epidemiology:

Atypical presentations — elderly often have blunted fever response, so even low-grade temperatures (>37.8°C) sustained warrant FUO workup. Delirium, anorexia, and functional decline may be the only manifestations.

Workup adjustments:

Renal impairment considerations:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, or Other Demographic Subgroups

— Common FUO causes include pyelonephritis, chorioamnionitis, listeriosis, viral hepatitis, CMV, parvovirus B19, and TB reactivation

— Avoid ionizing radiation when possible — prefer MRI without gadolinium and ultrasound; CT only when essential with abdominal shielding

— Avoid teratogenic drugs — fluoroquinolones, tetracyclines, sulfonamides in third trimester, methotrexate, mycophenolate

— TB treatment in pregnancy — INH, rifampin, ethambutol acceptable; avoid pyrazinamide in US guidelines (used internationally); add pyridoxine

— Listeriosis — ampicillin; high fetal mortality

— Steroids — prednisone preferred (placental metabolism); avoid dexamethasone unless fetal indication

— Infection dominates (~50%) — viral, UTI, osteomyelitis, EBV, CMV, Bartonella (cat-scratch), Kawasaki disease

— Kawasaki disease — fever ≥5 days plus 4 of 5 criteria (conjunctivitis, mucositis, rash, extremity changes, cervical lymphadenopathy); IVIG + aspirin within 10 days to prevent coronary aneurysms

— JIA (systemic) — quotidian fevers, salmon rash, arthritis; pediatric counterpart of Still's

— Malignancy — leukemia, lymphoma, neuroblastoma

— Periodic fever syndromes — PFAPA (most common), FMF, TRAPS

— CMV, EBV/PTLD, invasive fungal (Aspergillus, mucormycosis), PCP, BK virus, nocardia

— Galactomannan, beta-D-glucan, CMV PCR, EBV PCR are first-line

— Lower threshold for chest CT and bronchoscopy

Step 3 management: In a child with ≥5 days of fever and mucocutaneous findings, diagnose Kawasaki clinically and give IVIG within 10 days — echocardiogram for baseline coronary assessment, repeat at 2 and 6 weeks.

Pregnancy:

Pediatrics — FUO definition modified: fever ≥8 days without diagnosis after initial evaluation

Immunocompromised (non-HIV) — solid organ and stem cell transplant:

Returning travelers — malaria must be ruled out within 24 hours in any febrile traveler from endemic areas; thick and thin smears ×3, rapid antigen test.

Complications and Adverse Outcomes

— Endocarditis — septic emboli (stroke, splenic/renal infarct, mycotic aneurysm), heart failure from valve destruction, paravalvular abscess with conduction block

— Tuberculosis — miliary spread, meningitis, Pott's disease, adrenal insufficiency, ARDS

— Lymphoma — tumor lysis syndrome on treatment initiation, SVC syndrome, marrow failure, CNS involvement

— Giant cell arteritis — irreversible monocular or binocular blindness, aortic aneurysm/dissection (lifelong risk, screen with imaging)

— Still's disease — macrophage activation syndrome (MAS) — life-threatening cytokine storm with cytopenias, hyperferritinemia, hepatic dysfunction, DIC

— HLH — multiorgan failure, mortality >40% even with treatment

— Intra-abdominal abscess — sepsis, fistula formation, hemorrhage

— CT contrast nephropathy in CKD

— Bleeding/infection from biopsies (liver, bone marrow, lymph node)

— Pneumothorax from transbronchial biopsy

— Steroid complications when empirically given without diagnosis — hyperglycemia, infection unmasking, psychiatric, osteoporosis

— Antibiotic complications — C. difficile, drug rash/DRESS, AKI, ototoxicity, masking of culture data

— Weight loss, sarcopenia, deconditioning

— Venous thromboembolism (inflammatory state)

— Anxiety, depression, healthcare cost burden

— Diagnostic delay in time-sensitive disease (GCA blindness, lymphoma staging)

Key distinction: HLH vs. sepsis — both present with fever and cytopenias, but HLH has ferritin often >10,000, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis on marrow, and elevated soluble IL-2 receptor. Antibiotics will not save the HLH patient; etoposide + dexamethasone will.

Complications of the underlying etiology — the dominant source of morbidity in FUO:

Complications of diagnostic workup itself:

Prolonged unexplained fever consequences:

Mortality — varies by etiology; malignancy-related FUO carries the worst prognosis, NIID intermediate, undiagnosed self-limited FUO best (most resolve).

When to Escalate Care — ICU, Consult, or Inpatient Triage

— Hemodynamic instability, sepsis physiology

— Neutropenia or significant immunocompromise

— Inability to complete outpatient workup (functional limitation, social barriers)

— Suspected endocarditis, meningitis, miliary TB, or acute leukemia

— Rapidly progressive clinical course or organ dysfunction

— Need for invasive procedures (biopsy, drainage) not feasible outpatient

— Septic shock requiring vasopressors

— Respiratory failure (PCP, miliary TB, ARDS from MAS)

— DIC with active bleeding

— Suspected HLH/MAS with multiorgan failure — early HLH-94 protocol

— Status epilepticus or coma (CNS infection, vasculitis)

— Acute aortic dissection (Takayasu, GCA aortitis)

— Infectious disease — culture-negative endocarditis, returning traveler, transplant, HIV, persistent undiagnosed FUO at week 3

— Rheumatology — suspected vasculitis, Still's, lupus, sarcoidosis, periodic fever syndromes

— Hematology/oncology — abnormal smear, lymphadenopathy, cytopenias, suspected lymphoma or HLH

— Cardiology — endocarditis, pre-TEE evaluation, conduction abnormalities

— Surgery/IR — abscess drainage, excisional biopsy

— Ophthalmology — visual changes (urgent for GCA, uveitis)

— Pulmonary — bronchoscopy for pulmonary infiltrates, cavities

— Hemodynamically stable, ambulatory, no end-organ dysfunction

— Reliable follow-up infrastructure

— Patient can monitor and document temperatures

— Initial workup negative and no red flags

CCS pearl: On CCS, early ID and rheumatology consults in undiagnosed FUO after 1 week of negative workup demonstrate appropriate stewardship of resources. Document fever curve, weight, and exam findings at each clock advance.

Inpatient admission criteria for FUO:

ICU escalation triggers:

Consultant playbook — which specialist when:

Outpatient management is acceptable when:

Key Differentials — Same-Category Causes (Other Febrile Syndromes)

— EBV mononucleosis — pharyngitis, posterior cervical lymphadenopathy, splenomegaly, atypical lymphocytes, heterophile or EBV serologies

— Acute CMV — mono-like without pharyngitis; common in young adults

— Acute HIV — fever, rash, mucocutaneous ulcers, lymphadenopathy 2–4 weeks after exposure; HIV RNA PCR diagnostic before Ab seroconversion

— Parvovirus B19 — slapped cheek in children, arthralgias in adults

— Familial Mediterranean fever — Mediterranean ancestry, 12–72h fever episodes, serositis, MEFV mutation; colchicine prophylaxis

— TRAPS — TNF receptor mutation, prolonged episodes (1–4 weeks); anti-IL-1 or anti-TNF

— Hyper-IgD syndrome (mevalonate kinase deficiency) — childhood onset, cervical lymphadenopathy

— PFAPA — pediatric; periodic fever, aphthous stomatitis, pharyngitis, adenitis; tonsillectomy curative

— Factitious fever — manipulated thermometer, often healthcare worker; simultaneous oral + rectal temps differ

— Munchausen — self-induced infection by injecting contaminated material; polymicrobial bacteremia clue

— Functional/habitual hyperthermia — low-grade temperatures in young women, no inflammatory markers, benign course

— Relative bradycardia, eosinophilia, normal physical exam despite high fever

— Resolution within 48–72h of drug discontinuation

Key distinction: True FUO vs. periodic fever syndrome — FUO is continuous or near-continuous documented fever for ≥3 weeks; periodic fevers are discrete, stereotyped episodes with complete asymptomatic intervals. Approach and treatment diverge entirely.

Within the febrile-illness category, distinguishing FUO from look-alikes:

Prolonged self-limited viral illness (<3 weeks):

Recurrent/periodic fever syndromes (distinct entity from FUO):

Habitual/factitious hyperthermia:

Drug fever — discussed in chunk 2; often miscategorized

Key Differentials — Other-Category Causes (Non-Infectious Mimickers)

— Subacute (de Quervain) thyroiditis — post-viral, tender thyroid, elevated ESR, low TSH, low RAIU; self-limited; NSAIDs or steroids

— Pheochromocytoma — paroxysmal fever, hypertension, headache, palpitations; plasma metanephrines

— Adrenal insufficiency — fever, hypotension, hyperkalemia, hyponatremia, eosinophilia; cosyntropin stimulation

— Pulmonary embolism — low-grade fever in up to 50%; consider in immobilized FUO patient

— Deep vein thrombophlebitis — septic pelvic thrombophlebitis post-partum/post-pelvic surgery; fever despite antibiotics, responds to heparin

— Sarcoidosis — bilateral hilar adenopathy, elevated ACE, hypercalcemia, anergy; biopsy non-caseating granulomas

— Crohn disease — extraintestinal fever may precede GI symptoms

— Hemolysis (any cause) — fever, jaundice, anemia, elevated LDH, low haptoglobin

— Hematoma resorption — large retroperitoneal or intramuscular hematomas cause low-grade fever

— Takayasu arteritis — young women, large-vessel vasculitis, pulse deficits, claudication

— Polyarteritis nodosa — medium-vessel, mononeuritis multiplex, renal involvement, hepatitis B association

— Cogan syndrome — interstitial keratitis + vestibuloauditory dysfunction

— CNS lesions — stroke, tumor, hemorrhage in hypothalamus can produce central fever

— Anticholinergic toxicity, serotonin syndrome, NMS, malignant hyperthermia — drug-induced hyperthermia distinct from infectious fever; managed by withdrawal + cooling + specific antidotes (dantrolene, cyproheptadine, bromocriptine)

Board pearl: When the FUO vignette features back pain, weight loss, and microscopic hematuria in an older adult, think renal cell carcinoma — classic paraneoplastic FUO. CT or MRI of the kidneys is diagnostic.

Endocrine masquerades:

Thromboembolic disease:

Granulomatous disease:

Hematologic non-malignant:

Vascular inflammation beyond GCA:

Hypothalamic/central:

Secondary Prevention / Discharge Medications / Long-Term Plan

— Clear diagnosis (or "undifferentiated, resolved") in discharge summary

— Medication reconciliation — especially if drug fever was identified; update allergy list with the offending agent

— Pending studies tracked with explicit follow-up responsibility (PET findings, biopsy results, serologies still pending) — a common patient safety failure point

— Endocarditis — complete IV antibiotic course (typically 4–6 weeks via PICC), weekly labs (CBC, BMP, drug levels), repeat echo, dental clearance, AHA endocarditis prophylaxis for future procedures (high-risk lesions: prosthetic valve, prior endocarditis, congenital heart disease, transplant valvulopathy)

— Tuberculosis — DOT (directly observed therapy) preferred; monthly LFTs, vision/color testing for ethambutol, public health reporting

— Giant cell arteritis — prolonged steroid taper over 1–2 years; PJP prophylaxis if prednisone ≥20 mg for >4 weeks; bisphosphonate + calcium/vitamin D for bone protection; statin and ASA per cardiovascular risk; aortic imaging surveillance

— Adult-onset Still's — long-term DMARD/biologic, monitor ferritin and inflammatory markers

— HIV — initiate ART, OI prophylaxis based on CD4

— Lymphoma — oncology longitudinal care, surveillance imaging

— Smoking cessation, alcohol reduction (especially with hepatotoxic regimens)

— Travel medicine consultation if future travel planned

— Sexual health counseling if STI identified

Step 3 management: At discharge, schedule 2-week clinic follow-up for all FUO patients regardless of resolution status — many undiagnosed cases declare themselves in the post-discharge interval. Provide return precautions for recurrent fever, new neurologic symptoms, or weight loss.

Discharge planning hinges on the diagnosed etiology — generic FUO has no "standard discharge regimen," but several universal principles apply:

Documentation and care coordination:

Etiology-specific long-term plans:

Vaccinations — update per CDC schedule, especially before initiating immunosuppression; live vaccines contraindicated on biologics or high-dose steroids

Lifestyle and risk reduction:

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— 2 weeks post-discharge — clinical reassessment, fever log review, pending labs

— 4–6 weeks — repeat inflammatory markers (ESR, CRP), CBC, CMP

— 3 months — repeat targeted imaging if abnormality persisted

— 6–12 months — if undiagnosed FUO resolved, no further routine workup needed

— GCA on steroids — monthly visits initially; ESR/CRP at each visit (relapse signal); blood pressure, glucose, weight, bone density at 1–2 years; ophthalmology referral for baseline

— Tuberculosis — monthly sputum cultures until conversion, LFTs (especially first 2 months), visual acuity and color vision (ethambutol), symptom review for neuropathy (INH)

— Endocarditis — weekly CBC, BMP, ESR, CRP during IV therapy; TTE at completion as new baseline; dental evaluation; PICC site checks

— Lymphoma — oncology-driven surveillance imaging and labs

— Still's/MAS — ferritin, CBC, LFTs, triglycerides

— Many FUO patients have deconditioning, sarcopenia, fatigue — physical therapy referral, nutritional counseling

— Address persistent fatigue (post-infectious, drug effect, depression) — screen with PHQ-9

— Sleep hygiene, gradual return-to-work plan

— Set realistic expectations — up to 50% of modern FUO remains undiagnosed; spontaneous resolution is common and reassuring

— Discuss when to re-present — recurrent documented fever, weight loss, focal symptoms

— Steroid education — adrenal suppression, do not abruptly stop, sick-day rules, infection vigilance

— Antibiotic stewardship — avoid future unnecessary courses

— Vaccination updates and live-vaccine restrictions on immunosuppression

Board pearl: In a patient on long-term prednisone ≥20 mg/day for ≥4 weeks, start PJP prophylaxis with TMP-SMX, supplement vitamin D + calcium, and consider bisphosphonate. Missing PJP prophylaxis is a high-yield Step 3 management error.

Universal follow-up cadence:

Etiology-specific monitoring:

Rehab and functional recovery:

Counseling content:

Ethical, Legal, and Patient Safety Considerations

— Tuberculosis — public health reporting required in all US jurisdictions; contact tracing initiated by health department

— HIV (newly diagnosed) — reportable in all states; partner notification obligations vary

— Syphilis, gonorrhea, chlamydia — reportable

— Brucellosis, Q fever, malaria, typhoid, viral hemorrhagic fevers — reportable; brucellosis exposure to lab personnel triggers PEP protocol

— Suspected bioterrorism agents (anthrax, tularemia, plague) — immediate public health notification

— Bone marrow, liver, lymph node biopsies — discuss bleeding, infection, pneumothorax (when applicable), and the possibility that the biopsy will be nondiagnostic, prompting repeat procedures

— Empiric steroids before GCA biopsy — patient must understand the risk-benefit (vision preservation vs. steroid harms and possible delayed diagnosis)

— Decisional capacity in delirious febrile patient — assess capacity in real time; use surrogate decision-maker per state hierarchy when incapacitated

— Avoid confrontation; engage psychiatry; do not abruptly discharge — these patients have a real psychiatric illness with high mortality

— Document objective evidence of factitious nature; protect against unnecessary invasive procedures

— Pending results at discharge are a documented sentinel-event source — explicit handoff to PCP, written communication, patient awareness of pending studies

— Medication reconciliation, especially when drug fever identified

— PICC line management for outpatient antibiotics — clear instructions, home health coordination, weekly labs

— Empiric broad-spectrum antibiotics in stable FUO is both a patient safety and stewardship failure — promotes resistance, C. difficile, and diagnostic delay

— Document rationale when starting empiric therapy

— Avoid shotgun serologic panels — order tests with clear pretest probability

— FDG-PET/CT is expensive but cost-effective when appropriately staged after first-tier negative

Step 3 management: When TB is diagnosed, report to the local health department on day of diagnosis, place patient in airborne isolation (negative-pressure room, N95), and initiate contact tracing — failure to do so is both a legal and patient safety violation.

Mandatory reporting obligations:

Informed consent edge cases:

Factitious fever and Munchausen — ethical navigation:

Transition-of-care patient safety:

Antimicrobial stewardship:

Cost and value-based care:

High-Yield Associations and Rapid-Fire Clinical Facts

— Ferritin >10,000 → Still's disease, HLH/MAS, severe infection

— ESR >100 → GCA, abscess, endocarditis, multiple myeloma, malignancy

— Relative bradycardia + fever → typhoid, Legionella, brucellosis, drug fever, factitious

— Eosinophilia + fever → DRESS, parasites (Strongyloides, Trichinella), Churg-Strauss/EGPA, lymphoma, adrenal insufficiency

— Quotidian or double-quotidian fever spikes → adult-onset Still's, miliary TB, hepatic abscess, malaria

— Salmon-pink evanescent rash with fever → Still's disease

— Jaw claudication + headache + visual changes (elderly) → GCA

— Splinter hemorrhages, Janeway lesions, Osler nodes → infective endocarditis

— Erythema nodosum + bilateral hilar adenopathy → Löfgren's syndrome (sarcoidosis)

— Headache + fever + cat exposure → Bartonella (cat-scratch) or toxoplasmosis

— Fever + livestock contact → brucellosis, Q fever

— Fever + tick exposure + thrombocytopenia + transaminitis → ehrlichiosis/anaplasmosis

— Fever + sub-Saharan travel + parasitemia → malaria (P. falciparum until proven otherwise)

— Fever + IVDU + new murmur → right-sided endocarditis (S. aureus, tricuspid)

— Fever + pancytopenia + hepatosplenomegaly → HLH, leishmaniasis, miliary TB, lymphoma

— Fever + microscopic hematuria + flank mass → renal cell carcinoma

— Fever + recent dental work + new murmur → Streptococcus viridans endocarditis

— Fever + prosthetic valve <2 months → Staphylococcus epidermidis prosthetic valve endocarditis

— Fever + colon cancer association → Streptococcus gallolyticus (bovis) bacteremia → colonoscopy required

— Suspected endocarditis with prosthetic valve → TEE

— Suspected GCA → temporal artery biopsy + immediate steroids

— Undifferentiated FUO after CT → FDG-PET/CT

— Suspected lymphoma → excisional biopsy (not FNA)

— Suspected HLH → bone marrow + soluble IL-2R + ferritin + triglycerides

Board pearl: Streptococcus gallolyticus bacteremia requires colonoscopy — strong association with colorectal neoplasia even in patients without GI symptoms.

Classic disease-clue pairings on FUO vignettes:

Test-of-choice pairings:

Board Question Stem Patterns

— 72-year-old with 4 weeks of low-grade fever, new bitemporal headache, jaw pain with chewing, ESR 105

— Trap answer: Order MRI brain

— Correct answer: Start high-dose prednisone immediately, then temporal artery biopsy within 1–2 weeks

— 28-year-old with 4 weeks of evening fever spikes, evanescent salmon-pink rash on trunk during fevers, arthralgias, ferritin 18,000

— Trap answer: Empiric antibiotics, viral panel

— Correct answer: Adult-onset Still's disease — NSAIDs or prednisone

— Fever, new tricuspid murmur, septic pulmonary emboli on CT

— Correct answer: Blood cultures + TTE; empiric vancomycin (right-sided S. aureus endocarditis); TEE if TTE nondiagnostic

— Started beta-lactam 10 days ago for cellulitis; cellulitis resolved but fever persists, eosinophilia, normal exam

— Correct answer: Stop the antibiotic — drug fever

— Fever, hepatosplenomegaly, pancytopenia, ferritin 25,000, triglycerides elevated, fibrinogen low

— Correct answer: HLH — bone marrow biopsy, send soluble IL-2R, start HLH-94 (etoposide + dexamethasone)

— Three weeks of fever, negative cultures, normal CT C/A/P, normal echo, all serologies negative, patient clinically stable

— Trap answer: Empiric antibiotics, empiric steroids

— Correct answer: FDG-PET/CT or watchful waiting with serial reassessment

— Recent dental cleaning, 3 weeks of low-grade fever, new aortic regurg murmur, splinter hemorrhages

— Correct answer: 3 sets of blood cultures + TTE — subacute bacterial endocarditis (viridans group strep)

— Streptococcus gallolyticus bacteremia, no GI symptoms

— Correct answer: Colonoscopy after endocarditis workup and treatment

Step 3 management: When the stem says "stable patient, negative initial workup, what is the next best step?" — the answer is almost always a diagnostic test, not empiric therapy.

Pattern 1 — The elderly headache:

Pattern 2 — The young adult with rash:

Pattern 3 — The injection drug user:

Pattern 4 — The post-antibiotic fever:

Pattern 5 — The pancytopenic mystery:

Pattern 6 — The negative workup:

Pattern 7 — The dental-work murmur:

Pattern 8 — The colon cancer red herring:

One-Line Recap

Fever of unknown origin (≥38.3°C, ≥3 weeks, undiagnosed after appropriate initial workup) is a diagnostic — not therapeutic — challenge, and the highest-yield Step 3 move is almost always to pursue a targeted next test (CT C/A/P, blood cultures, FDG-PET/CT, TEE, or tissue biopsy) rather than start empiric antibiotics or steroids in a stable patient.

Framework: Confirm objective fever → stop nonessential drugs → first-tier labs + cultures + CT → pursue potentially diagnostic clues → FDG-PET/CT and tissue biopsy if undifferentiated → watchful waiting if stable and undiagnosed (≈50% resolve).

Empiric therapy exceptions (the only times to break the "no empiric treatment" rule): hemodynamic instability/sepsis, neutropenic fever, suspected GCA with visual threat, and culture-negative endocarditis with embolic phenomena.

Pattern-recognition shortcuts: Ferritin >10,000 → Still's/HLH; ESR >100 + elderly headache → GCA; new murmur + IVDU → S. aureus tricuspid endocarditis; relative bradycardia → typhoid/Legionella/drug fever; Strep gallolyticus → colonoscopy; pancytopenia + hyperferritinemia + low fibrinogen → HLH.

Transition-of-care and safety priorities: Report TB and HIV to public health, track pending results explicitly at discharge, document drug-fever culprits as allergies, add PJP prophylaxis and bone protection for patients on chronic high-dose steroids, and schedule 2-week post-discharge follow-up even when fever has resolved — undiagnosed FUO frequently declares itself in the weeks after discharge.