fuo basics patty w. wright, md & c. buddy creech, md, mph with appreciation to william goins, md...
TRANSCRIPT
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
Normal Body Temperature (Adults)
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
Normal Body Temperature (Adults)
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
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
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
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
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
Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 1996;10:111-127.
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%
Thomas KT, et al. J Pediatr. 1999;135:15-21.
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%
Thomas KT, et al. J Pediatr. 1999;135:15-21.
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
*****************************************
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
*****************************************
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.
Case Presentation- “Sara”
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.
Case Presentation- “Sara”
Does Sara have an FUO?
What additional history would you like to obtain?
Case Presentation- “Sara”
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
Case Presentation- “Sara”
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?
Case Presentation- “Sara”
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?
Case Presentation- “Sara”
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
Case Presentation- “Sara”
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?
Case Presentation- “Sara”
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
Case Presentation- “Sara”
What disease do you think Sara has, and how would you diagnose it?
www.cdc.gov
Case Presentation- “Sara”
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?