SHA

A
MIK
SIE
JAS SUBJECT: Medicine 2 DATE: July 02, 2008
N
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
RAI
S
FAR TRANSGROUP:SMV
A
HU
JOS
DEFINITION
•
RCO
MA Classic definition by Petersdorf &Beeson, 1961
Y - An illness that is characterized by a
ISA temperature of 38.3°C or greater on
DY multiple occasions that lasts three weeks
CAN or longer, and that remains undiagnosed COMMON CAUSES OF CLASSIC FUO
NG after one week of in-hospital evaluation.
• Durack & Street, 1991
KRI
A Table 2. Causes of FUO in Adults
EIS - Proposed a new system of classification of Petersd
NE FUO orf Larson, Knockaert
Klejin
& Featherslone & Vanneste &
AN * (-) for any laboratory results Category Beeson Petersdorf Babbaers
(1997)
167
H (1961) (1982) (1992)
cases
KYT Table 1. Modifications of FUO definition by Durack & Street, 1991 100 105 cases 187 cases
ON IMMUNO- cases
HIV –
AAR DEFICIENT NOSOCOMIA Infections 36 31 23 26
CLASSIC ASSOCIAT
NEUTROPEN L
ED Malignancy 19 31 7 12.5
HE
ALP IC
Hospitalized Collagen-
Patients not 15 9 22 24
vascular disease
LA
, Acute
in other Confirmed
Has < 500 case, No
KAR
Patient categories HIV Others 23 7 23 8
neutrophils infection
G
type fever ≥ 3 positive Undiagnosed 7 12 25 30
PEN when
weeks
KC admitted *Naproxen – treatment for rheumatic fever
Duration of
ADI
illness
- test after 3 days = (-) fever → not infectious
AN 3 days or (+) fever → infectious
while 3 days or
MA 3 days 4 weeks 3 days
under 3 OPD visits
AM as OPD
investigati Table 3. Causes of FUO in Children
on
NA
Pizzo, et Mc
MO Septic Lohr &
Infections, Perianal al. Chung
F MAI, TB, thrombo- Hendley
malignanci infection, Category (1972) (1980)
non- phlebitis, (1974)
100 99
BUF
Example of es, aspergillosis 84 cases
Hodgkin’s sinusitis, C. cases cases
DIE etiology inflammato ,
lymphoma difficile
GOL ry disease candidemia Infections 82 33 29
A colitis
EZR Malignancy 20 18 11
Collagen-vascular
KIX
CATEGORIES disease
6 13 8
Diagnostic Categories of FUO
RIZ
NEY Miscellaneous 10 15 19
LAI • Infections – most common cause of
Undiagnosed 12 19 32
AN classical FUO
 Systemic
XTI
CES Table 4. Local Experience (PGH, 1975-1990), unpublished
OPS  Localized Number (%)
HO • Neoplasms Infections 34 (46.6)
• Collagen-vascular disease Malignancy 20 (27.4)
CE
VIN
Collagen-vascular (autoimmune) 10 (13.7)
E  Inflammatory diseases
Hypersensitivity 2 (2.7)
 CTD, autoimmune diseases
ESS
DEN Unknown 7 (9.6)
ILLE • Miscellaneous causes Total 73 (100)
CEC  Drug fever Source: M.F. Mendoza MD, 29th PSMID Conv
 Pulmonary embolism
JAM
KC Table 5. Diagnostic Categories of 72 Patients with FUO at the Santo
OY  Factitious fever Tomas University Hospital
PIP • Undiagnosed Number (%)
Infections 44 (61)
CH
Neoplasms 9 (13)
NRI
HEI
T Connective tissue disease 4 (6)
BAR Miscellaneous 3 (4)
RYL Unknown 12 (17)
SHE
INFECTIONS
LH
1. TB
RAP
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A
TIN 2. Abdominal abscess
AIN 3. Cryptic abscess
ALL 4. Typhoid fever
TTE
YVE
RY
MA
 SUBJECT: Medicine 2 DATE: July 02, 2008
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
TRANSGROUP:SMV

5. Chronic active hepatitis MISCELLANEOUS CAUSES

6. Infective endocarditis • Pulmonary embolism
7. Leptospirosis • Chronic hepatitis
8. Pyelonephritis • Other granulomatous diseases
9. Malaria • CNS causes
10. Chronis sinusitis
• Cyclic neutropenia
11. Toxoplasmosis
12. Osteomyelitis • Factitious fever
• GHVD
- Predominant cause in developing countries HYPERSENSITIVITY DISEASES
- High in infants and children • Drug fever
- Vary according to place (country) • Erythema multiforme – skin infection
Ex. Visceral Leishmaniasis – Middle East
• Allergic vasculitis
Melioidosis – South East Asia & Australia
K Fujimoto Disease – Japan • Serum sickness
- Cervical lymphadenopathy • Milk allergy
- Malaise • Halothane sensitization
- Fever • Post-pericardiotomy syndrome

PARASITIC INFECTIONS AS CAUSE OF FUO AGENTS COMMONLY ASSOCIATED WITH DRUG-

- may occur with other concomitant cause INDUCED FEVER
• Schistosoma • Allopurinol (Zyloprim)
• Leishmaniasis • Captopril (Capoten)
• Toxoplasmosis • Cimetidine (Tagamet)
• Others – Fasciola, Amoeba • Clofibrate (Atromid-S)
• Erythromycin
MALIGNANCIES & FUO • Heparin
• Hematologic and solid tumors: • Hydralazine (Apresoline)
 Lymphoma • Hydrochlorothiazide (Esidrix)
 Acute leukemia (children) • Isoniazid
 Hypernephroma (Renal cell CA) • Meperidine (Demerol)
 Bone sarcoma • Methyldopa (Aldomet)
 Atrial myxoma • Nifedipine (Procardia)
 GI – gastric CA, liver, colon • Nitrofurantoin (Furadantin)
• Penicillin
MALIGNANCY (Neoplasms)
• Frequency decreasing • Phenytoin (Dilantin)
• Higher in elderly • Procainamide (Pronestyl)
• More in developed country • Quinidine
• Infection is secondary
HIV-RELATED FUO
• Opportunistic infections
COLLAGEN-VASCULAR DISEASE (Autoimmune)
 Atypical manifestations
• Systemic Lupus Erythematosus  Prior antibiotic prophylaxis
• Rheumatoid arthritis • Mycobacterial infection – most common in the
• Systemic vasculitis Philippines
• Mixed connective tissue disease • Collagen-vascular – uncommon
• Rheumatic fever (most common due to • Pneumonia – other countries
presence of Streptococcus
pneumoniae/viridans → heart valves, kidney) NOSOCOMIAL FUO
• Others e.g. Still’s disease • > 48 hours in hospital or at least 3 days before
the start of fever
CONNECTIVE TISSUE DISEASE • Risk factors
• Young adults –SLE  Urinary & respiratory instrumentation
• Still’s disease (JRA)  Surgery
• Elderly – Temporal arteritis and Polymyalgia  IV devices
rheumatica
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 Drugs
• More in developed countries  Immobilization
 SUBJECT: Medicine 2 DATE: July 02, 2008
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
TRANSGROUP:SMV

- Fracture in sensitive areas (thigh, 2. Blood or BMA C/S

pelvis) - 3 aerobic and anaerobic in the 1st 2
- ICU days of hospitalization
3. PPD test
IMMUNODEFICIENT FUO 4. Subsequent tests must be individualized
A. Immunosuppression C. Use of specific test
 Infection 1. Autoantibody screening
 Atypical manifestation 2. Specific PCR
 GVHD in transplants 3. Imaging
B. Neutropenic - X-ray
 Bacteremia & sepsis - Isotope scanning
 Fungal infection 4. Tumor markers
* TB – cause of prolong fever
COMMON APPROACH TO FUO
FUO General Consideration
1. Well organized systemic approach DIAGNOSTIC ADVANCES
2. Age group difference • Ultrasonography
3. Duration of fever → > 3 weeks • Echocardiography
4. Type of hospital • CT scan
5. Immune state/underlying diseases • Magnetic Resonance Imaging (MRI) – identify
- DM, collagen problem which part is affected
• Labelled WBC – Indium, Technetium
Evaluation of FUO
- Starts with very good history and PE • Gallium scan
1. History – documented fever • Angiography
 Recent travel • PET scan
 Exposure to pets/animals • Venous duplex imaging of LE
 Work environment
 Family history Table 6. Diagnostic Categories of 72 Patients with FUO at the Santo
Tomas University Hospital
 Medication Tuberculosis, malignancy,
2. PE – subtle signs and symptoms Chest radiograph Pneumocystis carinii
 Nausea pneumonia
 Aaaa CT of abdomen or pelvis with
Abscess, malignancy
contrast agent
 Oral ulcers Gallium 67 scan Infection, malignancy
 Fundoscopy Indium-labeled leukocytes Occult septicaemia
 Petechial/splinter hemorrhages Acute infection and
Technetium Tc 99m inflammation of bones and
USEFUL LABORATORY EXAMINATIONS soft tissue
Malignancy, autoimmune
DIAGNOSIS MRI of brain
conditions
• More aggressive and rapid evaluation for PET scan Malignancy, inflammation
critically ill patients – as soon as possible Transthoracic or
• Evaluation slow and deliberate (out-patient) for transesophageal Bacterial endocarditis
the chronically ill echocardiography
Venous Doppler study Venous thrombosis
EVALUATION OF A PATIENT WITH FUO
A. No obvious cause, systemic symptoms not TUMOR MARKERS
disabling • Diagnostic
 OPD work-ups  α feto protein (AFP)
- CBC with ESR  β HCG
- Urinalysis • Highly supportive
- Chest x-ray
 C19-9
- Alkaline phosphatase, SGOT
- ANA, other serologic tests  CA125
- Blood culture  CEA
- Stool for guiac  PSA
• Others
B. Persistence of fever or clinical deterioration –
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hospitalization
NON SPECIFIC INFLAMMATORY MARKERS
1. Repeat tests done in OP setting
• Procalcitonin
 SUBJECT: Medicine 2 DATE: July 02, 2008
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
TRANSGROUP:SMV

 Specific at high titers but not sensitive

• C-reactive protein EMPIRIC STEROIDS
 Positive for bacterial infections • Seldom indicated
• ESR – sensitivity 53%, Low ESR helpful to r/o • Consider cryptic TB
bacteremia  Difficult to exclude
 >80-100 mm/hr useful aid and clinical  Liver and bone marrow biopsy
marker of disease activity for CTD
SELECTED CAUSES OF FUO (Mandell)
INVASIVE DIAGNOSTIC PROCEDURES • Disseminated granulomatosis
A. Tissue diagnosis (Biopsy) • Lymphoma
1. Liver
• Thromboembolic disease
2. Bone marrow
3. Lymph node • Endocarditis
4. Skin nodule/rash and muscle • Adult Still’s disease
5. Temporal artery • Drug fever
B. Angiography • Temporal arteritis and PMR
C. Explratory laparotomy

Table 7. The Value of Exploratory Laparotomy in FUO EVALUATION OF A PATIENT WITH FUO REQUIRES:
Operative findings in 70 FUO cases • Knowledge of those disorders that produce this
Number (%) syndrome (FUO)
Malignant 21 (30.0) • Recognition of the potential significance of
Specific infection 21 (21.4) subtle findings in the history and physical
Indeterminate disease 14 (20.0) examination
Miscellaneous 6 (8.6) • Awareness of the value in the clinical setting of
Nothing found 14 (20.0)
specific diagnostic procedures
Source: Mayo clinic

ESR
NOSOCOMIAL INFECTION
DEFINITION
• Sensitivity 53%
Nosocomial infection – are infectious which are the
• Specificity 33% result of treatment in a hospital or a healthcare service
• (-) PPV for bacteremia 94% unit.
• ↓ ESR (<20 mm/hr) helpful to r/o bacteremia - they appear as fever after 48 hours or more
after hospital admission or within 30 days after
DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN discharge
* see last page - Other known as:
“Hospital-acquired infection”
EMPIRIC TREATMENT “Healthcare-associated infection”
TREATMENT AND MANAGEMENT
• Non-specific treatment is rarely curative and COMMON CAUSES
may delay diagnosis • Urinary tract infection
• NSAIDS – Ibuprofen, Indomethacin, Naproxen • Surgical sites
 Response to ASA & NSAIDS – may mask • Pneumonias
fever of infection
TRANSMISSION
• Naproxen test
• Contact (direct or indirect) transmission
• Therapeutic trial
• Droplet transmission
THERAPEUTIC TRIAL • Airborne transmission
• Specific therapy – specific goal and hypothesis • Common vehicle-borne transmission
• Time limit • Vector-borne transmission
• Regular, reliable observation of vital signs and
clinical conditions PREDISPOSITION INFECTION
• Use drugs with limited spectrum • Host factors – poor state of health, advanced
age, prematurity, immunodeficiency
• May delay diagnosis
• Invasive devices – intubation tubes, catheters,
• Only for seriously ill patients – nosocomial FUO,
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surgical drains
febrile neutropenia
• Host treatments – immunosuppressive,
• Some FUO may resolve spontaneously
antimicrobials or recurrent blood transfusion
 SUBJECT: Medicine 2 DATE: July 02, 2008
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
TRANSGROUP:SMV

PREVENTION
• Isolation
• Handwashing and gloving
• Aprons
• Masks

DIAGNOSIS OF FEVER OF UNKNOWN ORIGIN

Complete history and physical

assessment

Positive findings

No

CBC, electrolytes, LFT, blood culture,

urinalysis, urine culture, ESR, PPD skin test,
chest radiograph

Positive results

No

CT of abdomen/pelvic with
contrast

Assign to most likely

category

Page5
 SUBJECT: Medicine 2 DATE: July 02, 2008
TOPIC: Fever of Undetermined Origin
LECTURER: Mr. Alberto Gabriel
TRANSGROUP:SMV

Infection Malignancie Autoimmune Miscellaneous

Urine and sputum conditions Order
cultures for AFB, Rheumatoid factor, appropriate
VDRL, HIV test; ANA diagnostic tests
serology for CMV, Hematologic Non- based on
EBV, ASO titer Peripheral Hematologic information
(geographically smear, serum Mammography, from the history
specific testing) protein chest CT with No
electrophoresis contrast,
upper/lower
Diagnosis clear endoscopy, bone Temporal artery
No ? scan, gallium 67 biopsy, lymph node
scan biopsy
No
Lumbar puncture,
gallium 67 scan, No
sinus films
Bone marrow
(radiography or CI)
MRI of the brain, biopsy of
suspicious skin lesions or lymph
nodes, liver biopsy, diagnostic
laparoscopy

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