1 FEVER OF UNKNOWN ORIGIN
FUO FEVER OF UNKNOWN ORIGIN UFO NIRAJ PATEL, MD, MS INFECTIOUS DISEASES AND IMMUNOLOGY
2 Just a side note, we will be describing various ways to take a temperature
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
Many causes of fever: infectious, autoimmune, oncologic Fever is centrally-mediated
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 Evaluation includes careful H&P and lab assessment No agreed upon definition *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, Pizzo et al, Feigin and Shearer Jacobs and Schutze, 1998
8 FUO: CAUSES Bacterial Parasitic Viral Fungal Others 6-20% 11-15% 1-5%
` 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 6-20% 11-15% 1-5% In substantial number of cases, no etiology is established *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;
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 Duration, height, pattern: parents can mistake normal variations in body temperature Assessed: rectal temp most accurate, oral temp for older child Associated signs and symptoms? Absence can signal factitious fever Responds to meds: absent response suggests noninflammatory (dysautonomia, ectodermal dysplasia, thalamic dysfunction, diabetes insipidus)
12 IF THERMOMETERS COULD TALK. . .
13 FEVER PATTERN CAUSES Pyogenic, TB, JIA, lymphoma Intermittent (hectic)
Viral infections, endocarditis, sarcoid, lymphoma Typhoid, typhus, brucellosis Malaria, rat-bite fever, borrelia infection, lymphoma Metabolic, CNS dysregulation, periodic disorders, immunodeficiency Intermittent (hectic) Remittent Sustained Relapsing Recurrent Remittent: fluctuating peaks that do not return to normal Sustained: no fluctuation (or intermittent if antipyretics) Relapsing: periods of afebrile for one or more days Recurrent: fever > 6 months
14 FUO: SIGNS & SYMPTOMS Red eyes Gastrointestinal complaints
Limb or bone pain KD, leptospirosis, measles Salmonellosis, intraabdominal abscess, CSD, IBD Osteomyelitis, leukemia
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 Patient or parent may recall infomration that was omitted, forgotton, or deemed unecessary Subtle abnormalities not appreciated become apparent
16 EXPOSURES Travel history Tick bites Pica (geophagia)
Foods (raw meat, unpasteurized cheese) Malaria, coccidioidomycosis RMSF, lyme disease Toxocariasis, toxoplasmosis Brucellosis, hepatitis, toxoplasmosis
17 ZOONOSES Animal Viral Bacterial Parasitic Mycotic Dog Rabies
Leptospirosis Toxocariasis Ringworm Cat B. henselae T. gondii Birds Arbovirus Psittacosis None Histo/Crypto Reptiles Salmonellosis Rodents Rat-bite fever Babesiosis Hamster LCM C. jejuni Cestoidiasis Cattle Brucellosis
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 Humans are incidental hosts for leptospirosis
23 Humans become infected by entry of leptospira through contact of mucosal surfaces or abraided skin with contaminated soil, water, or animal tissues. Also direct contact with infective urine or fuids.
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 Extrapulmonary TB more likely to cause FUO
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 Relative bradycardia Constipation can be an early symptom
28 WORLDWIDE DISTRIBUTION OF SALMONELLA TYPHI
Incidence of typhoid fever ♦ Strongly endemic ♦ Endemic ♦ Sporadic cases
31 TOXOCARIASIS Geophagia Loeffler pneumonia BEWARE! Sandbox
Loeffler’s pneumonia: Parasites migrating through the lung
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 Also occurs in patients without predisposing heart disease
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) cases per year in U.S. (Texas and California)
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 Genitourinary infections include orchitis, epididymitis Diagnosis by culture
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 Fever typically occurs every other day or every third day Cerebral malaria is a medical emergency Malaria may be delayed for months after travel
38 THIN BLOOD SMEAR Gametocytes and ring forms by falciparum
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 CSD is common cause of FUO
40 SKIN PAPULES AXILLARY LYMPH NODE
GRANULOMATOUS CONJUNCTIVITIS SPLENIC LESIONS Typical clinical findings of Bartonella henselae infection (cat-scratch disease). Simple papule at the scratch site on the leg (A) of a young boy, and the face of a young girl (B). Papular lesion on the arm and axillary lymphadenopathy in an adolescent (C). Papular lesion and fluctuant, enlarged lymph nodes in the supraclavicular and neck areas of an adolescent girl who frequently cuddled her kitten over her chest and shoulder (D). Granulomatous conjunctivitis and preauricular lymphadenopathy in a 12-year-old boy (E). Histologic specimen of an excised neck mass showing a lymph node with granuloma and stellate microabscess (hematoxylin & eosin 200×) (F). Computed tomography of the abdomen without contrast in a young girl with fever of unknown origin showing multiple hypodense areas in the spleen (G), which changed minimally following administration of contrast. Gadolinium-enhanced axial magnetic resonance imaging showing bone marrow enhancement of the ilium in a 6-year-old girl who came to attention for fever of unknown origin and right hip pain (H). Computed tomography of the neck showing superficial necrotizing mass (I), and delayed phase of technetium-99 bone scan showing increased uptake in the skull (J) (and ilium: not shown) in a 5-year-old with persistent fever and hip pain while being treated with amoxicillin for lymphadenitis; she had no signs or symptoms referable to the skull finding. (K) Erythema nodosum in a 7-year-old girl with axillary lymphadenopathy. (Courtesy of J.H. Brien © (A, B, E, H) Scott & White Memorial Hospital, Temple, TX; S.S. Long (C, D, F, K) and E.D. Thompson (G, I, J), St. Christopher’s Hospital for Children, Philadelphia, PA.)
41 SUMMARY Most common cause of FUO is infectious
FUO requires thorough history and physical examinations (often more than once!)
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) A. Brucella malitensis B. Bartonella hensalea
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
Possible diagnoses Chest radiograph Tuberculosis, malignancy, Pneumocystis carinii pneumonia CT of abdomen or pelvis with contrast agent Abscess, malignancy Gallium 67 scan Infection, malignancy Indium-labeled leukocytes Occult septicemia Technetium Tc 99m Acute infection and inflammation of bones and soft tissue MRI of brain PET scan Malignancy, autoimmune conditions Malignancy, inflammation Transthoracic or transesophageal echocardiography Bacterial endocarditis Venous Doppler study Venous thrombosis Roth AR and Basello GM. : Approach to the Adult Patient with Fever of Unknown Origin Am Fam Physician. 2003;68: Review.
47 EXPOSURES TO ANIMALS