FUO Basics

FUO Basics

Patty W. Wright, MD & C. Buddy Creech, MD, MPH

with appreciation to William Goins, MD and Bryan Youree, MD

March 2011

Objectives

To discuss the definition of fever of unknown origin

(FUO) the classifications of FUO the most common etiologies of FUO the diagnostic work-up of patients with

FUO

What is a normal body temperature?

Normal Body Temperature (Adults)

1 million axillary temperatures measured twice daily in 25,000 healthy adults

Mean temperature: 37°C (36.2 – 37.5°C)

Readings >38.0°C were deemed as “suspicious/probably febrile”

Thermometers may have read 1.4 – 2.2°C (2.6 – 4.0°F) higher than today’s instruments

Wunderlich C. Das Verhalten der Eigenwärme in Krankenheiten. Leipzig, Germany: Otto Wigard;1868.Mackowiak, et al., JAMA 1992;268:1578


Patients 148 healthy adults

Method Oral temp with electronic thermometer

Frequency 1 – 4 times daily for 3 days

Mean 36.8 ± 0.4°C (98.2 ± 0.7°F)

Upper limits of normal

37.2°C (98.9°F) in the early morning

37.7°C (99.9°F) overall

Mackowiak, et al., JAMA 1992;268:1578


Mean temperature varied diurnally Low: 6 AM Peak: 4 – 6 PM Mean variability: 0.5°C (0.9°F)

Women had slightly higher temperatures

Black subjects tended to have higher temperatures than whites

Mackowiak, et al., JAMA 1992;268:1578

Normal Temperature Curves (Children)

What is hyperthermia?

Hyperthermia

Unregulated elevation of temperature

Does not involve hypothalamic thermoregulatory center

Cytokines not directly involved

Mechanisms of Hyperthermia

1. Excessive heat production

• Exertional hyperthermia

• Thyrotoxicosis• Pheochromocytoma• Cocaine• Delerium tremens• Malignant

hyperthermia

2. Disorders of heat dissipation

• Heat stroke• Autonomic

dysfunction

3. Disorders of hypothalamic function

• Neuroleptic malignant syndrome

• CVA• Trauma

What is fever?

Fever

Resetting of the thermostatic set-point in the anterior hypothalamus

Initiation of heat-conserving mechanisms

Cytokine-mediated

What is a Fever of Unknown Origin?

Fever of Unknown Origin

Temp > 101°F (38.3°C) on several occasions

Fever of at least 3 weeks duration

No diagnosis after a 1 week evaluation in the hospital or (in the modern era) a reasonable outpatient work-up

Petersdorf RG, Beeson PB. Medicine 1961;40:1-30.

Historical Causes of FUO

Hippocrates: Excess of yellow bile Middle Ages: Demonic possession

(encephalitis?) 18th Century: Friction associated with

the flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines

Categories of FUOFeature Nosocomial Neutropenic HIV-

associatedClassic

Patient’s situation

Hospitalized, acute care, no infection when admitted

Neutrophil count <500/µL or expected to reach that level in 1-2 days

Confirmed HIV-positive

All others with fevers for ≥3 weeks

Duration of illness

3 days b 3 days b 3 days b

(or 4 weeks as outpatient)

3 days b or 3 outpatient visits

aAll require temperatures of ≥38.3°C (101°F) on several occasions.bIncludes at least 2 days’ incubation of microbiology cultures.

Modified from DT Durack, AC Street, in JS Remington, MN Swartz (eds): Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

What are the three most common causes of FUO (in general)?

Classifications of FUO

Modified from DT Durack in Mandell, Bennett, and Dolin. Principles and Practice of Infectious Diseases, 2005. 6th ed.

Evolving Etiology of FUO in Adults

Mourad, et al. Arch Intern Med. 2003;163:545

Magnitude of Fever 102°F rule

Most noninfectious disorders in adults are associated with temperatures ≤ 102°F

Best used to exclude noninfectious causes of fever

106°F Temperatures ≥ 106°F are rarely due to

infection Examples: central fever, drug fever, NMS,

malignant hyperthermia

Causes of FUO in AdultsType Common Uncommon Rare

Infections TB ExtrapulmonaryRenalMeningitisMiliaryIntra-abdominal abscess

LiverSplenicPancreaticPerinephricPsoasPlacental

Pelvic abscess

SBE

CMV

Toxo

Salmonella enteric fever

Intra/perinephric abscess

Splenic abscess

Dental abscess

Brain abscess

Vertebral osteo

Listeria

Yersinia

Brucellosis

Relapsing Fever

Rat-bite fever

Chronic Q fever

Cat-scratch fever

HIV

EBV

Malaria

Whipple’s disease

Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.

What is the most common malignancy causing FUO?

Causes of FUO

Type Common Uncommon Rare

Malignancy Lymphoma

Liver/CNS mets

Hypernephromas

Hepatomas

Pancreatic CA

Preleukemias

Colon CA

Atrial myxomas

CNS tumors

Myelodysplastic diseases


Causes of FUOType Common Uncommon Rare

Rheumatologic Still’s disease

Temporal Arteritis

PAN

RA

SLE

Vasculitis

Felty’s syndrome

ARF

Behcet’s disease

FMF

Cryoglobulinemia

Reiter’s syndrome

Rheumatic fever

Wegener’s disease

Sarcoidosis


Causes of FUO

Type Common Uncommon Rare

Misc Drug Fever

Cirrhosis

Alcoholic hepatitis

Granulomatous hepatitis

Cerebrovascular accident

Hyperthyroidism

Addison’s disease

PE/DVT

Kikuchi’s disease

Hyper IgD syndrome

Crohn’s disease

Ulcerative colitis


Drug Fever

Diagnosis of exclusion Approximately 10% of fevers in hospitalized

patients Look “well” Relative bradycardia may occur Usually no rash Fever usually returns to normal within 3 days

May take longer if accompanied by a rash

Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85-91.*****************************************

Causes of FUO in Children

Series Cases Infxn CVD Neoplasm Misc Undiagnosed

McClung (60’s) 99 29% 11% 8% 19% 32%

Pizzo (70’s) 100 52% 20% 6% 10% 12%

Steele (80’s) 109 22% 6% 2% 3% 67%

Chantada (80’s)

113 36% 13% 10% 22% 19%

Muoaket (80's) 221 78% 5% 2% - 15%

Most common infectious etiologies in children:Bartonella, EBV, CMV, Histoplasmosis, Blastomycosis, TB

What is periodic fever?

Periodic Fever

Periodic is different from sporadic, intermittent, occasional

Periodicity involves having repeated cycles appearing at regular intervals

Periodic Fever Syndromes Non-familial

PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis)

Familial Familial Mediterranean Fever (FMF) Hyper IgD Syndrome (HIDS) TNF-receptor associated periodic syndrome

(TRAPS or Hibernian Fever) Muckle-Wells Syndrome (MWS) Familial Cold Urticaria (FCU) Cyclic Hematopoesis (CH)

PFAPA Case Definition

Periodic fevers beginning before the age of 5 years

At least one clinical criterion (ulcers, pharyngitis, adenitis)

Absence of cough, purulent rhinitis, or otitis on examination

Asymptomatic periods between attacks Normal growth and development Exclusion of cyclic neutropenia

PFAPA Registry (Vanderbilt)

In 1997, parents of registry patients were contacted by telephone to collect information on patients believed by their physicians to have PFAPA

94 patients were available, 83 with long-term follow-up data

Characteristics of PFAPA Patients

Thomas KT, et al. J Pediatr. 1999;135:15-21.

Original Registry Follow-up

Number of Patients 94 83

Female 42 36

Male 52 47

Onset of PFAPA 2.8 years -

Duration of each episode 4.8 days 4.2 days

Episodes per year 11.5 10.0

Symptom-free Interval 28.2 days 41.2 days **

PFAPA Symptoms, by ReportOriginal Registry (66) Follow-up (82)

Aphthous Ulcers 67% 70%

Pharyngitis 65% 72%

Lymphadenopathy 77% 88%

Chills 80% 80%

Cough 20% 13%

Coryza 18% 15%

Headache 65% 60%

Abdominal pain 45% 49%

Rash 15% 9%


Efficacy of Treatment

Treatment No. of Episodes

Not Effective

Somewhat Effective

Moderately Effective

Very Effective

Acetaminophen 80 55% 26% 15% 6%

Ibuprofen 67 15% 31% 21% 33%

Antibiotics 71 92% 6% 0% 3%

Prednisone 49 10% 4% 10% 76%

Cimetidine 28 57% 4% 11% 29%

Tonsillectomy 4 25% 0% 25% 50%

T & A 47 14% 14% 0% 72%


Familial Periodic Fever Syndromes

FMF TRAPS HIDS MWS/FCU CH

Duration of Attack

1-3 days Days-weeks 3-7 days Days-weeks 4-7 days

Clinical Features

Serositis; scrotal pain

Conjunctivitis, myalgias

Cervical adenitis, vomiting

Urticaria, deafness, cold intolerance

Aphthous stomatitis, adenitis

Skin Erysipelas-like lesions

Tender red plaques

Maculo-papular rash

Urticaria Furuncles

Amyloidosis Frequent Variable Low risk Very Frequent

Unknown

Inheritance AR AD AR AD AD

Ancestry Jewish, Turkish, Armenian

Scottish/Irish Dutch, French German, English, French

None

What is the diagnostic work up for FUO?

Diagnostic Testing for FUO in Children First tier

CBC, CMP, blood/urine cultures, ESR/CRP, EBV, CMV, CSD serology, TST

Second tier Fungal serology; CT chest, abdomen, pelvis with

contrast Third tier

Gallium or Indium scan; bone scan

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CBC w/ diff, chemistries, LFTs, blood cultures x3, UA, urine culture, ESR, CRP, ANA, RF, HIV ab, PPD, CXR

Diagnostic Algorithm for FUO in Adults

Positive Findings YesOrder appropriate and

specific diagnostic testing

Complete History and Physical Assessment

No

Positive Results YesOrder appropriate follow-up

diagnostic testing

CT of chest/abdomen/pelvis with contrast

Adapted from Roth AR, Basello GM. Approach to the Adult Patient with fever of unknown origin. Am Fam Physician. 2003;68:2223-8.

No

Additional Workup for FUO in Adults

If symptoms of “mono” syndrome CMV antibodies EBV antibodies HIV viral load Toxoplasmosis serologies

If exposure risk factors Q-fever serology

If abnormal liver enzyme test results Viral hepatitis serologies

Mourad, et al. Arch Intern Med. 2003;163:545

Urine & sputum cultures for AFB, VDRL,

HIV test, CMV & EBV serology

Diagnostic Algorithm for FUO in Adults

TTE/TEE, LP, gallium scan,

sinus films

Nonhematologic

Malignancies

Assign to most likely category

Hematologic

Mammography, Chest CT with contrast,

Upper/lower endoscopy, bone scan, gallium scan

No Dx?

Peripheral smear, SPEP

Infection Autoimmune Miscellaneous

No Dx? No Dx? No Dx?

BM biopsy Brain MRI; Biopsy of LN, skin lesions,

or liver

TA biopsy, LN biopsy

RF, ANA Order appropriate

diagnostic tests based on

information from history

Roth AR, Basello GM. Approach to the Adult Patient with fever of unknown origin. Am Fam Physician. 2003;68:2223-8.

Liver Biopsy & Bone Marrow Biopsy

Diagnostic yield of liver biopsy 14% - 17%

Hepatomegaly on exam or abnormal LFT’s not helpful in predicting abnormal biopsy result

Complication rate 0.06% - 0.32%

Diagnostic yield of bone marrow cultures in immunocompetent individuals 0% - 2%

Mourand et al. Arch Intern Med 2003;163:545

Volk et al. J Clin Pathol 1998;110:150 Riley et al. J Clin Pathol 1995:48:706

FUO Prognosis

Determined primarily by the underlying disease

Outcome worst for neoplasms If undiagnosed after extensive

evaluation, adults generally have favorable outcome and fever usually resolves after 4-5 weeks

Larson et al. Medicine 1982;61:269

Where is the world’s tallest thermometer?

WORLD'S TALLEST THERMOMETER BAKER, CALIFORNIA

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Case Presentation- “Connor”

Connor is an 18 month old male with a one year history of periodic fevers to 104.

Between each ‘episode’ the child has grown well and has appeared healthy and active

Occasionally there are uncomplicated URI’s and gastroenteritis, but these episodes seem ‘different.’

What additional information would you like to obtain from Connor’s parents?

Case Presentation- “Connor”

During each episode, his parents report that he has pharyngitis and aphthous ulcers in the mouth.

What disease do you think Connor has and how would treat him?

PFAPA

Treatment is with prednisone 2mg/kg as a single dose at the beginning of each episode. Rarely, children will require a second dose 24 hrs

later. Treatment typically results in immediate resolution

of fever and other symptoms. Primary side effect of treatment is shortening

of the interval between episodes. PFAPA typically spontaneously resolves prior

to adolescence.

Case Presentation- “Kyle”

Kyle is a 7 year old male with daily fever to 103 for 3 weeks and a 10-pound weight loss. He denies other symptoms.

He reports no unusual exposures or travel. He attends 2nd grade.

On examination, his temperature is 104. There are no focal findings, though there is a hint of abdominal discomfort.

How would you proceed with his work-up?

Case Presentation- “Kyle”

CBC WNL. EBV and CMV titers c/w past infection.

ALT 60. AST 36. ESR 52. CRP 9 (nml < 10). Abdominal ultrasound normal.

What additional work up would you consider at this time?

Cat Scratch Disease

Abdominal CT confirmed small microabscesses in the spleen and liver

Bartonella serologies revealed an IgG>1:512 consistent with diagnosis of disseminated CSD

Additional history revealed that the patient’s family bought a new kitten about 1 month prior to presentation.

Cat Scratch Disease

Treatment not recommended for otherwise uncomplicated CSD in kids

Treatment with azithromycin is recommended for patients who are immunocompromised

May consider treatment for disseminated disease

While a h/o scratches and local skin eruption/LAD are common, they are not universal.

*****************************************

Case Presentation- “Bill”

Bill is a 74 year old male with CAD and HTN who present to the clinic c/o fever. He reports fevers to 101.7 over the past week. He reports associated fever and malaise. He denies associated GI, GU, or URI symptoms. This is his first health care visit for his fevers.

Does Bill have an FUO?

Case Presentation - “Bill”

Bill has fever (T>101), but the duration is < 3 wks, and he has not had an evaluation.

Bill has a fever of unknown etiology, but not an FUO.

Case Presentation - “Bill”

Bill’s physical exam is negative. Bill has a CBC with diff which shows a mild anemia. U/A was negative. Chemistries and LFT’s were WNL. Bill is advised that he likely has a viral infection and is prescribed acetaminophen, po fluids, and rest. Bill returns to the clinic 1 week later with continued fevers.

What additional history should be obtained?

Case Presentation- “Bill” Additional history…

Travel history, recent & any h/o international travel

Animal exposures Sick contacts Family history of fevers Medications, including herbals & OTC meds

Bill denies any travel, animal or sick contact exposure, or FH of fevers. His meds are stable and include ASA, a beta-blocker, & a statin.

Case Presentation- “Bill”

Bill’s physical exam remains negative. He has additional lab studies including blood and urine cultures, ANA, RF, and HIV ab, all of which are negative. Chest x-ray shows no acute disease. PPD is negative. ESR is elevated at 126 (normal < 20). CRP is 153 (normal < 10).

What disease do you think Bill has, and how would you diagnose it?

Case Presentation- “Bill” Temporal arteritis

May present with only fever and fatigue May have associated HA, jaw claudication, or

visual changes May note nodules or diminished temporal artery

pulsations on exam ESR typically > 50 mm/hr and often > 100 mm/hr Dx with temporal artery biopsy

May need removal of extensive segments as can have patchy involvement of the artery

Rx with steroids

Temporal Arteritis (Giant Cell Arteritis)

www.neuropathologyweb.org

Case Presentation- “Sara”

Sara is a 30 year old female graduate student who presents to your office with fevers to 101.5 for the past month. She reports associated flank pain and dysuria without N/V/D. Exam was negative.

She has been previously evaluated in the student health clinic on 3 occasions. On her first visit, she was noted to have a U/A positive for leukocyte esterase with a negative urine culture. She was given trim-sulfa x 3 days without improvement.


On her second visit, she had a repeat U/A with micro which showed 10-20 WBC with a negative urine cx. She was treated with levofloxacin x 14 days. Her fevers improved while on abx; however, they returned after her abx were d/c’ed.

On her third visit, a CBC w/ diff showed a mild leukocytosis. Her chemistries and LFT’s were WNL. KUB was negative. U/A again had + WBC, so she was treated empirically with metronidazole without relief.


Does Sara have an FUO?

What additional history would you like to obtain?


Sara has had fevers > 101 for > 3 wks and has undergone a basic work-up. She meets the definition of FUO.

Additional history… Travel history, recent & any h/o international travel Animal exposures Sick contacts Family history of fevers Sexual history


Sara reports that she grew up in South Africa and came to the US at 18 years of age to attend college.

She has a pet iguana. She denies sick contacts w/ similar symptoms. No family history of fevers. She is sexually active with her boyfriend of 6

months. He is her second life-time sexual partner.

What additional studies would you obtain at this time?


Additional studies… Gyn exam with STD screening, including tests

for GC, chlamydia, HIV, and trichomonas CT of abdomen and pelvis Blood cultures You also recommend a PPD, but Sara states

that she had BCG vaccination as a child. Do you proceed with PPD testing?


Yes. In the US, we ignore prior BCG vaccination status when interpreting PPD results (i.e. a positive is still a positive regardless of prior vaccination).

www.stanford.edu


Sara’s gyn exam and STD screen are negative. Her CT shows scarring of the right kidney.

She returns at 48 hrs to have her PPD read. She has 12 mm of induration.

Does Sara have a positive or negative PPD?


Patient Status Positive Result

HIV + >5mm

Healthy individuals with exposure history or risk

factors

>10mm

Healthy individuals with no exposure history

>15mm

www.stanford.edu


What disease do you think Sara has, and how would you diagnose it?

www.cdc.gov


Renal Tuberculosis Culture of 3 morning urine specimens for

mycobacteria establishes the diagnosis in 80% to 90% of cases

Urine TB PCR has a sensitivity of 87-100% and specificity of 92-99.8%

Renal TB

www.vetmed.wsu.edu

Summary

FUO is often a diagnostic dilemma Infections, inflammatory disorders, and

malignancy account for the majority of cases Diagnostic approach should occur in a step-

wise fashion based on the H&P Up to 30% of FUO’s in the modern era are

undiagnosed Patients that remain undiagnosed generally

have a good prognosis

What are your questions?

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FUO Basics