Fever of Unknown Origin (FUO)

1. Fever of Unknown Origin (FUO) Nosocomial FUO Neutropenic FUO Classic FUO • Fever duration > 3 weeks • No diagnosis after ≥ 3 visits or 3 days of hospitalization with appropriate investigation • Fever duration > 3 days • Fever acquired after ≥ 24 hours in hospital • No diagnosis after 3 days of appropriate investigation • Fever duration > 3 days • Neutrophil count ≤ 500 and negative cultures at 48 hours • No diagnosis after 3 days of appropriate investigation

2. “Appropriate Investigation” Thorough history and physical exam Diagnostic testing Imaging Labs CXR • CBC with differential • Basic metabolic panel • Liver panel • Urinalysis, including microscopy and culture • Blood cultures

3. FUO: Etiology Infection Systemic Inflammatory Disease Malignancy Miscellaneous Causes

4. FUO: Infections Common Causes Account for about 20-40% of cases Abscess Endocarditis Tick-borne disease Tuberculosis Sinusitis Osteomyelitis CMV, EBV Complicated UTI

5. FUO: Systemic Inflammatory Young Adults Older Adults • Account for about 10-30% of cases • Common causes vary by age Still’s disease Temporal arteritis Rheumatoid arthritis variants Polymyalgia rheumatica SLE Others: polyarteritis nodosa, granulomatous diseases

6. FUO: Malignancies Common Causes • Account for 20-30% of cases • Fevers may persist for months or years Leukemia Lymphoma Renal cell carcinoma GI malignancies CNS malignancies Hepatocellular carcinoma

7. FUO: Miscellaneous Causes Reported Causes Account for 10-20% of cases Subacute thyroiditis Drug fever Pheochromocytoma Antimicrobials HLH Anticonvulsants Familial fevers NSAIDs NMS Cardiac meds

8. Next steps… Labs All patients: LDH, ESR, CRP, HIV, rheumatoid factor, ANA Risk factor specific: TB skin test or IGRA, SPEP/UPEP, blood smear, CMV serology, EBV serology, lumbar puncture, fungal culture, Q fever testing, Bartonella serology, Brucella serology, etc. Imaging All patients: CT chest and abdomen, echocardiogram Risk factor specific: head/spine imaging, venous duplex Biopsy? Therapeutic trials?

9. Hemophagocytic Lymphohistiocytosis Hemophagocytic = phagocytosis of blood cells and their precursors Histiocytoses = disorders in which accumulation of macrophages occurs Primary HLH Secondary HLH Children, often before 1 year of life. Genetic causes. Children and adults, many triggers. Some genetic predisposition (up to 14% adults with mutations). 50-75% mortality without prompt treatment. Even with treatment high mortality.

10. Normal Physiology

11. HLH Pathophysiology

12. HLH Causes Up to 25% idiopathic. In adults, up to 50% due to malignancy. Autoimmune diseases Infections Viral: EBV, CMV, HIV, VZV, Influenza, Parvovirus, Hepatitis SLE, vasculitis, adult onset Still’s Malignancy Bacterial: Mycobacterium, Rickettsia, Babesia Prolonged stimulation of immune system prior, toll receptors involved? Lymphoma’s and leukemia’s, solid tumors Fungal: Histoplasmosis Malignant cell activation of proinflammatory cytokines, dysregulation of bone marrow, chemo affects *Macrophage-activating syndrome Parasitic: Leishmania, Plasmodium

13. HLH Suspicion and Diagnosis Potential lab findings: cytopenias, low fibrinogen, high ferritin, LP with elevated protein and lymphocytic pleocytosis 2004 Criteria: 5/8 required New (2005) Criteria for MAS: • Fever >38.5 • Splenomegaly • At least 2 cytopenias (hgb <9, platelets <100,000, neutrophils <1000) • Fasting TG’s >265 mg/dL • Fibrinogen <150 mg/dL • Elevated IL-2 CD25 2SD above ULN • Low or absent NK cell cytotoxic activity • Ferritin >500 • Hemophagocytosis in bone marrow, spleen, lymph node or liver • Platelet count <262 • AST >59 • WBC <4.0 • Fibrinogen <2.5 g/L • CNS dysfunction • Hemorrhages • Hepatomegaly

14. HLH Treatment Extensive search for underlying cause Corticosteroids +/- IVIG, *immunosuppressives Treat underlying cause *etoposide, intrathecal methotrexate for CNS, cyclophosphamide; rituximab in EBV, alemtuzumab (antibody against CD25), plasma exchange last line