F EVER OF U NKNOWN O RIGIN

1. FUO FEVER OF UNKNOWN ORIGIN UFO NIRAJ PATEL, MD, MS INFECTIOUS DISEASES AND IMMUNOLOGY

3. OBJECTIVES • Know the causes of fever of unknown origin (FUO) • Know the diagnostic evaluation for FUO, and that history taking is a KEY element • Describe the clinical presentations, risk factors, and diagnosis of various causes of FUO

4. PATHOGENESIS OF FEVER PAMPS TLRs

5. DEFINITIONS* • FUO: fever > 101ºF, > 3 weeks of uncertain etiology after 1 week of intensive evaluation • Fever without a source (FWS): Fever ≤ 1 week of unclear etiology after initial evaluation *Long et al, Principles and Practice of Pediatric Infectious Diseases

6. OBJECTIVES • Know the causes of fever of unknown origin (FUO) • Know the diagnostic evaluation for FUO, and that history taking is a KEY element • Describe the clinical presentations, risk factors, and diagnosis of various causes of FUO

7. FUO: MOST COMMON CAUSES* Infectious > CTD > Neoplasm *Others: Drug fever Factitious fever CNS dysfunction CTD = Connective Tissue Disease Brewis, 1965 Pizzo et al, 1975 Feigin and Shearer 1976 Jacobs and Schutze, 1998

8. Bacterial ` Urinary Tract Infection Osteomyelitis Endocarditis Bartonella henselae Brucellosis Leptospirosis Abscess (pelvic, liver, perinephric) Mastoiditis (chronic) Pyelonephritis Psittacosis Q fever RMSF Tularemia Tuberculosis Sinusitis Salmonellosis Parasitic Malaria Toxoplasmosis Visceral larva migrans Viral CMV Hepatitis viruses EBV Systemic viral syndrome Fungal Blastomycosis Histoplasmosis Others Malignancies Collagen vascular disease Kawasaki’s Disease Hemophagocytic lymphohistiocytosis Inflammatory bowel disease Drug fever Kikuchi-Fujimoto disease FUO: CAUSES 6-20% 11-15% 1-5% *Long et al, Principles and Practice of Pediatric Infectious Diseases

9. AGENTS ASSOCIATED WITH DRUG FEVER Antimicrobial Ampicillin Cephalothin Isoniazid Mebendazole Penicillin G Sulfonamide Trimethoprim-sulfa Vancomycin Antineoplastic L-Asparaginase Bleomycin Cytarabine Daunorubicin Hydroxyurea 6-mercaptopurine Cardiovascular Furosemide Hydralazine Nifedipine Procainamide Quinidine Other Allopurinol Cimetidine Folate Interferon Iodide Metroclopramide CNS Amphetamine Carbamezepine Haloperidol Phenobarbitol Phenytoin Anti-inflammatory Aspirin Ibuprofen Adapted from Mackowiak PA. Arch Intern Med 1987; 106-728

10. OBJECTIVES • Know the causes of fever of unknown origin (FUO) • Know the diagnostic evaluation for FUO, and that history taking is a KEY element • Describe the clinical presentations, risk factors, and diagnosis of various causes of FUO

11. HISTORY: FEVER CHARACTERISTICS • Duration, height and pattern • Method used to assess • Fever confirmed by someone else • Associated signs and symptoms • Responds to antipyretic medications

12. IF THERMOMETERS COULD TALK. . .

13. Intermittent (hectic) Remittent Sustained Relapsing Recurrent Pyogenic, TB, JIA, lymphoma Viral infections, endocarditis, sarcoid, lymphoma Typhoid, typhus, brucellosis Malaria, rat-bite fever, borrelia infection, lymphoma Metabolic, CNS dysregulation, periodic disorders, immunodeficiency CAUSES FEVER PATTERN www.uptodate.com

14. Red eyes Gastrointestinal complaints Limb or bone pain KD, leptospirosis, measles Salmonellosis, intraabdominal abscess, CSD, IBD Osteomyelitis, leukemia FUO: SIGNS & SYMPTOMS

15. FUO: HISTORY IS CRITICAL • Detailed H&P is MOST important • Ask, ask, ask! • Repetition of clinical assessment is often necessary • Recall of information • New physical exam findings

16. Travel history Tick bites Pica (geophagia) Foods (raw meat, unpasteurized cheese) Malaria, coccidioidomycosis RMSF, lyme disease Toxocariasis, toxoplasmosis Brucellosis, hepatitis, toxoplasmosis EXPOSURES

17. ZOONOSES

18. DIAGNOSTIC EVALUATION COMPREHENSIVE HISTORY • Including travel history, contact with animals, hobbies PHYSICAL EXAMINATION • Growth Chart • Thorough general examination • Notation of mouth ulcers, exanthem, joint abnormalities, lymph nodes

19. DIAGNOSTIC EVALUATION* TESTS • CBC with differential • ESR and CRP • CMP, Uric Acid • Serum quantitative immunoglobulins • Urinalysis and Urine Culture • CXR and blood culture (prolonged or recurrent fever) *Long et al, Principles and Practice of Pediatric Infectious Diseases

20. OBJECTIVES • Know the causes of fever of unknown origin (FUO) • Know the diagnostic evaluation for FUO, and that history taking is a KEY element • Describe the clinical presentations, risk factors, and diagnosis of various causes of FUO

21. THE ORIGIN OF FUO. . .

22. LEPTOSPIROSIS • Zoonotic infection, worldwide • Fever, conjunctivitis, rash, myalgias of calf and lumbar region • Severe: jaundice, renal dysfunction, hemorrhagic pneumonitis, circulatory collapse • Risk factors: contact with animal urine, contaminated soil or water (swimming) • Diagnosis: Leptospira IgG, IgM by ELISA

25. TUBERCULOSIS • Mycobacterium tuberculosis • Pulmonary (CXR: calcifications, infiltrate, hilar lymphadenopathy) • Extrapulmonary (disseminated TB, tuberculoma) • Risk factors: HIV, IV drug use, incarcerated, homeless shelter, nursing home, foreign-born • Diagnosis: PPD, CXR, sputum for acid fast bacilli, early morning gastric aspirate

27. SALMONELLOSIS • Nontyphoidal Salmonella: fever, abdominal cramps, diarrhea • Typhoidal Salmonella: fever, rose spots, abdominal pain, malaise, hepatosplenomegaly • Fever-pulse dissociation (S. typhi) • Risk factors: travel (typhoid fever), reptiles, contaminated foods (nontyphoidal) • Blood and stool culture

28. WORLDWIDE DISTRIBUTION OF SALMONELLA TYPHI Incidence of typhoid fever♦ Strongly endemic♦ Endemic♦ Sporadic cases

29. ROSE SPOTS

30. TOXOCARIASIS • Toxocara canis and toxocara cani • Visceral Larva Migrans: younger children (<5) • fever, HSM, bronchospasm, myocarditis, nephritis • Risk factors: contact with sandboxes, feces of dogs and cats, geophagic pica • Diagnosis: Toxocara IgG by ELISA, peripheral eosinophilia

31. TOXOCARIASIS Geophagia Loeffler pneumonia BEWARE! Sandbox

32. ENDOCARDITIS • Prominent or new murmur • S. aureus and viridans streptococci • HACEK (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, CArdiobacterium hominis, Eikenella corrodens, Kingella kingae) • Risk factors: congenital heart disease, indwelling catheter • Diagnosis: multiple large volume blood cultures

33. BRUCELLOSIS • Zoonotic infection transmitted from animals to humans (accidental hosts) • Ingestion of infected foods, contact with infected animals, or inhalation of aerosols • Unpasteurized milk, cheese the main ingestion source in developing countries (goat and bovine)

34. BRUCELLOSIS CLINICAL FINDINGS • Nonspecific: fever, chills, weakness, fatigue, malaise, body aches, anorexia • Osteoarticular involvement common: knees, hips, ankles in children; sacroiliitis in adults • GI complaints (30% have nausea, vomiting) • Neurobrucellosis including meningitis, encephalitis

35. MALARIA • Relapsing fever, chills, rigors, sweats • Cerebral malaria: seizures, confusion, coma, death • Plasmodium species, transmitted by Anopheles mosquito • Risk factors: travel to endemic area • Diagnosis: thick and thin smears

38. THIN BLOOD SMEAR

39. CAT SCRATCH DISEASE • Bartonella henselae • Isolated lymph node involvement • Hepatosplenic involvement is hallmark • Diagnosis: serology or biopsy of lesions in lymph node/liver/bone marrow • Treatment: supportive or antibiotics

40. SKIN PAPULES AXILLARY LYMPH NODE GRANULOMATOUS CONJUNCTIVITIS SPLENIC LESIONS

41. SUMMARY • Most common cause of FUO is infectious • FUO requires thorough history and physical examinations (often more than once!)

42. T HE END

43. Case 1 • A 10 year old female presents to the office with a 3 week history of fever. She has had fatigue, headache, and anorexia during this period. She was seen 2 weeks prior and a workup including CBC with differential, BMP, blood and urine cultures were negative. • She lives on a farm and has rabbits, cats, dogs, horses, and a bearded dragon. • On PE, T 101.8, non-toxic appearing. She has a 2cm axillary lymph node. Skin exam is significant for the following:

44. Case 1 (cont) Which of the following is the most likely etiologic agent for the clinical findings? A. Brucella malitensis B. Bartonella hensalea C. Streptobacillus moniliformis D. Francisella tularensis

45. Case 1 answer • The correct answer choice is (B), Bartonella hensalea. Bartonella hensalea is characterized by • Choice (A), Brucella malitensis causes brucellosis, a zoonotic disease characterized by undulating fever and is spread by contact with infected animals (sheep, cattle, pigs) or unpasteurized diary products. Francisella tularensis result in recurrent staphylococcal infections. However, usually associated with elevated white blood cell count and delayed umbilical cord separation. Associated features of scoliosis and retained primary teeth are not associated with LAD or (B) chronic granulomatous disease (CGD). HyperIgM (D) and severe combined immunodeficiency (E) usually present with hypogammaglobulinemia, particularly IgG and IgA. Severe combined immunodeficiency also usually presents in the first year of life.

46. DIAGNOSTIC IMAGING IN PATIENTS WITH FUO Roth AR and Basello GM. : Approach to the Adult Patient with Fever of Unknown OriginAm Fam Physician. 2003;68:2223-8. Review.

47. EXPOSURES TO ANIMALS