Fever of unknown origin

Panuwat Wongkulab, MD.

Rajavithi hospital
 Definition
• AD 1961, Petersdorf, et al
- Undiagnosed intermittent fever 3 wks, IPD work up 1 wk
• AD 1991, D. T Durack and A.C. street

Knockaert D.C, et al. Journal of internal medicine 2003; 253: 263-275

 Definition

• Why to change
- Difference on spectrum of underlying diseases
- Alteration of immune system
- Duration of investigations
( depend on the type of investigations)

Knockaert D.C, et al. Journal of internal medicine 2003; 253: 263-275

 Epidemiology

The percentage of patients with fever of unknown origin

by causes over the past 40 year

- Systematic review
- Jan 1966 – Dec 2000
- Petersdorf and Beeson criteria
- Exclude immunocompromised
and younger than 18 yr
- N-US, W-EU, Scandinavia
- Most common cause
- ID; Tuberculosis,
intraabdominal abscess
- CA; Hodgkin disease and
non Hodgkin lymphoma
- Temporal arteritis 16-17%

Mourad O, et al. ARCH INTERN MED. 2003 Mar vol 163:545-551

 Epidemiology

- Case review 1990-Mar 2002

- New diagnostic tools; U/S, CT abdomen ( 1980s)
- AD 1961-1990 infection 34%, neoplasm 22.1%, NIID 12.5%, other 15%, undiagnosed 15%
from 692 patient by Knockaert DC, 1992

Distribution of diagnostic categories in series with fever of unknown origin

Knockaert D.C, et al. Journal of internal medicine 2003; 253: 263-275

 Etiology
Common etiology in patients with fever of unknown etiology

Abdurrahman K, et al, Ecpert Rev Anti Infect Ther. 2013;11(8):805-815

 Future change of epidemiology

• Decline of infectious cause

- Widespread available of antibiotic
- Reduction of poverty-related infection
• Antimicrobial resistance
- Empirical treatment related
- eg MDR-TB, GNB, STI
• Technology innovation for diagnose
- Make shift to non-ID
- Drug induced fever, adult-onset Still’s disease, periodic
fever syndrome
• Health systems; Specialty care or generalist

Brown M. Postgrad Med J 2015;91:665-669

 Approach to Classic FUO

1. Meets the definition of FUO

2. Categorized group by history and PE
hallmarks
- CA; significant weight loss, early anorexia
- NIID; + synovitis, x rigors
3. Organized organs involvement
- SLE; x liver
- IE; x hepatomegaly, + splenomegaly

Cunha, et al, The american Journal of medicine( 2015) 128, 1138

 History

• Significant clues from hitory and PE give 62% diagnosed.

However, they could be found in 97% of patients1

1. Elizabeth C, et al, American Family Physician, 2014, Vol 90;91-96

 History
• Infectious cause
- Dentition: apical abscess, subacute IE
• Neoplasm
- Significant weight loss, post-hot bath pruritus, adenopathy
• NIID
- Prominent arthralgias/myalgias ,
- Oral ulcer(Bechet’s diseases, SLE),
- Joint symptoms+ generalized lymphadenopathy (Still’s disease),
- Acalculous cholecystitis (SLE, PA)
- x chill
• Miscellaneous
- Periodicity fever ( cyclic neutropenia)
- Neck/jaw pain ( subacute thyroiditis)
- Medications ( Drug fever)

Cunha, et al, The american Journal of medicine( 2015) 128, 1138

 Drugs fever
Medications that can cause fever of unknown origin

* The literature does not identify individual drugs in these classes

1. Elizabeth C, et al, American Family Physician, 2014, Vol 90;91-96
 Physical examinations
• More attention on eyes, skin, nodes, liver, and spleen
• Infectious cause
- Fever pattern analysis
- Relative bradycardia; enteric fever, leptospirosis
- Fundoscopic exam: Toxoplasmosis, tuberculosis
- Isolated splenomegaly: miliary TB, EBV, CMV, enteric fever, histoplasmosis,
malaria, subacute IE
- Epididymo-orchitis: EBV, renal tuberculosis
• Neoplasms
- Eyes; Roth spots ( lymphoma, atrial myxoma) Retinal hemorrhages (
preleukemia)
- Isolated hepatomegaly: hepatoma, liver metastasis
• NIID
- Morning temperature spikes: PA
- Double quatidian fever: Still’s disease
- Unequal pulsatile: Takayasu’s arteritis
- Lacrimal gland enlargement: late RA, sarcoidosis, SLE
- SLE+ murmur+ neg H/C: Libman-Sacks endocarditis

Cunha, et al, The american Journal of medicine( 2015) 128, 1138

 Fever pattern

malaria

Typhoid fever

Hodkin’s disease
(Pel-Ebstein pattern)

Relapsing fever
(Borreliosis)

William F W, Philip AM, Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 56, 721-731.e1
 Investigations
• No specific guideline developed, but classified to non-specific,
and specific tests
• Investigations driven by clinical clues, local epidemiologic
data, and tests availabilities
• Petersdorf required several investions;1
- Bacteriological and serological tests
- Skin tests
- Radiographs of chest and IVP
• Ultrasound and CT scan are significant role since 1980s2

1.Petersdorf RB, et al, Medicine 1961; 40: 1-30 2. .Knockaert D.C, et al. Journal of internal medicine 2003; 253: 263-275
 Initial investigations 2003

Minimum diagnostic evaluation required for a case to qualify as classical fever of unknown origin

Knockaert D.C, et al. Journal of internal medicine 2003; 253: 263-275

 Initial investigations 2014
Minimum diagnostic evaluation to qualify as fever of unknown origin1

Using of interferon-γ release assay (IGRA) has limited sensitivity and specificity for diagnose TB2
Tuberculin skin test perhaps used for diagnose sarcoid2

1.Vanderschueren S, et al Acta Clinica Belgica 2014; Vol69,no 6;pages 412-417 2. Brown M. Postgrad Med J 2015; 91:665-669
 Secondary evaluations

• Non invasive methods provided the most diagnoses, while invasive

procedure gave the highest diagnostic yield1
• Blind pursuit of diagnostic approach, eg. bone marrow, liver biopsy,
or lumbar puncture, rarely rewards for making diagnosis2
• ALP, SPEP, Serum ferritin are the common neglect tests3
• Ferritin level is specific to Still’s diseases, or Hemophagocytic
syndrome, but confused by infection4
• Temporal biopsy on unexpained fever and inflammation in elderly
pt (age ≥55)1is the probably exception2
• Serology tests are also helpful when clues exit2
• Thyroid function test, cryoglobulins, complement studies, SPEP
might be optional2
• Imaging study; CT, PET, PET-CT1,2

1. Elizabeth C, et al, American Family Physician, 2014, Vol 90;91-96 2. Vanderschueren S, et alActa Clinica Belgica 2014, Vol 69; no 6; pages 412-417
3. Cunha BA, et al. Infect Dis Clin North Am, 2007; 21(4):867-915 4. Brown M. Postgrad Med J 2015; 91:665-669
 Secondary investigations

• Imaging studies
- CT chest-abdomen-pelvic sensitivity 82-92% and
specificity 60-70%1
- Echocardiogram requested in suspicious cases1,3
- MRI give benefit on vasculitis on aortic arch and
great vessel of neck1
- F-FDG-PET could find 40% diagnostic yield, and
up to 54% with combined with CT2

1. Elizabeth C, et al, American Family Physician, 2014, Vol 90;91-96

2. Vanderschueren S, et alActa Clinica Belgica 2014, Vol 69; no 6; pages 412-417
3. Cunha, et al, The american Journal of medicine( 2015) 128, 1138
 Secondary investigations

• Invasive tests
- LN biopsy is the most, 10-35% provided positive
results2, avoid in anterior cervical, axillary, or inguinal
area due to minute chance1
- BM biopsy revealed 25% causes of fever, but
culture and aspiration showed only 0-2% results2
- Liver biopsy found out 14-17% final outcome2
• Molecular techniques in immunocompetent pt has
high false positive result in whom the yield is low3

1. Cunha, et al, The american Journal of medicine( 2015) 128, 1138 2. .Elizabeth C, et al, American Family Physician, 2014, Vol 90;91-96
3. Brown M. Postgrad Med J 2015; 91:665-669
 Treatments

• Antipyretic and antimicrobial therapy should be abstinence1 and

reduced the diagnostic rate2
• Empirical therapy is considered in3
- Antituberculous drug for suspected military tuberculosis in elderly
- Culture negative endocarditis
- Naproxen for probable malignancy fever
- Steroid for giant cell arteritis
• “ Doxycycline deficiency disease ”4
- Few patient might be ricketsial, coxiella, and leptospirosis
• Drug resistance bugs should be taken to account in some situations4

1.Knockaert D.C, et al. J Intern Med 2003; 253: 263-275 2. Vanderschueren S, et al Acta Clinica Belgica 2014, Vol 69; no 6; pages 412-417
3. Cunha BA, et al. Infect Dis Clin North Am, 2007; 21(4):867-915 4. Brown M. Postgrad Med J 2015; 91:665-669
 Prognosis

FUO related deaths: comparison with historical series

Non-Hodkin lymphoma had high disproportionally mortality rate

Factors related mortality; age, continuous fever, anemia, leucopenia, LDH level, hepatomegaly

Vanderschueren S, et al, Acta Clinica Belgica 2014, Vol69; no 1 pages12-16

 Current research questions

• Role of PET in the diagnostic algorithm of FUO

• Impact of using IL-1 receptor antagonists, rituximab,
sterioid in high ferritin states
• Cost-effective approach to diagnosis in different
environment, eg IPD vs OPD, ID vs other, bedside vs
remote
• Future cytokine assays determined in FUO

Brown M. Postgrad Med J 2015; 91:665-669

Algorithm

Vanderschueren S, et al, Acta Clinica Belgica 2014, Vol69; no 1 pages12-16

Thank you