Fever unknown Origin

Fever Unknown Origin
Diagnosis and Management
Budi Riyanto

“ Humanity has but three great enemies;
Fever, Famine and War. Of these by far
the most terrible , is fever.”
( Sir William Osler, Father of Modern medicine)

• Fever is an common feature of many
illness. In majority cases the diagnosis is
diagnosed or fever disappears
spontaneous.
• When fever persist and underlying
diagnosis is not obvious, it presents a
challenge for patient and physician
FEVER
Budi Riyanto JADE 2014

FEVER .. ??
• All the human being must have been
expérience with Fever
• Fever : Normal / Physiologic, but also is can
sign of pathologic process / worst sign
• But … some people always think the fever
must be resolve in short time and a “simple /
easy problems”

Fever
• Fever:
Abnormal increase in body temperature,
oral -more than 37.6 °C (100.4 °F)
Rectal – more than 38 °C (101 °F)
• Homeostatic mechanism : fluctuation of ±1
to 1.5 °C

FEVER UNKNOWN
ORIGIN
Budi Riyanto JADE 2014 7

Original Definition
(by Petersdorf and Beeson, 1961)
• Temperatures ≥ 38.3ºC (101ºF) on several occasions
• Fever ≥ 3 weeks
• Failure to reach a diagnosis despite 1 week of
inpatient investigations or 3 outpatient visits [1 IP / 3
OP]

Cases illustration
• A 50 year old man was admitted with fever of
three weeks duration.
– On examination there was hepatosplenomegaly.
– Routine urine and blood examinations were
normal.
– Widal test and Mantoux test were negative. Chest
X-Ray and HIV were negative.

• A 49 year old man came to hospital with :
– Pain in the right loin and fever of one month
duration.
– Loss of appetite and loss of weight were present.
– He was investigated for UTI.
– Repeated URE and urine cultures were negative.
– Renal angle was dull but non tender.
– CT scan of abdomen was diagnostic
Cases illustration

Classification of FUO
Category Definition Aetiologies
Classic • Temperature >38.3°C (100.9°F) ;
• Duration of >3 weeks
• Evaluation of at least 3 outpatient
visits or 3 days in hospital
• Infection
• Malignancy
• collagen vascular disease
Nosocomial • Temperature >38.3°C
• Patient hospitalized ≥ 24 hours but no
fever or incubating on admission
• Evaluation of at least 3 days
• Clostridium difficile enterocolitis
• drug-induced
• pulmonary embolism
• septic thrombophlebitis,
• sinusitis
Immune
deficient
(neutropenic)
• Temperature >38.3°C
• Neutrophil count ≤ 500 per mm3
• Evaluation of at least 3 days
• Opportunistic bacterial infections,
• aspergillosis,
• candidiasis,
• herpes virus
HIV-
associated
• Temperature >38.3°C
• Duration of >4 weeks for outpatients,
>3 days for inpatients
• HIV infection confirmed
• Cytomegalovirus,
• Mycobacterium avium-intracellulare
complex,
• Pneumocystis carinii pneumonia,
• drug-induced,
• Kaposi’s sarcoma, lymphoma

Frequency base on etiology FUO
Infection (40%)
Malignancy
(25%)
Autoimmune
Disease (15%)
Others/
Miscellaneous
(10%)
Undiagnosed
(10%)

Infections
• Bacterial: abscesses, TB, complicated UTI,
endocarditis, osteomyelitis, sinusitis, Lyme
disease, prostatitis, cholecystitis, empyema,
biliary tract infection, brucellosis, typhoid,
leptospirosis, Q fever, borreliosis, etc.
• Parasite: Malaria, toxoplasmosis, leishmaniasis,
etc.
• Fungal: histoplasmosis, etc.
• Viral: CMV, infectious mononucleosis, HIV, etc.

Malignancies
• Haematological
– Lymphoma
– Chronic leukaemia
• Non-haematological
– Renal cell cancer
– Hepatocellular carcinoma
– Pancreatic cancer
– Colon cancer
– Hepatoma
– Myelodysplastic Syndrome
– Sarcomas

Others/miscellaneous
• Drugs: penicillin, phenytoin, captopril, allopurinol,
erythromycin, cimetidine, etc.
• Hyperthyroidism
• Alcoholic hepatitis
• Sarcoidosis
• Inflammatory bowel disease
• Deep Venous Thrombosis

NOSOCOMIAL FUO
• After 3 days of hospitalization
• Risk factors encountered in hospital
– Surgical procedure
– Urinary and respiratory instrumentation
– IVFD / devices
– Transfusion related viral infections
– Drug therapy
– Post Myocardial infarction syndrome
– Pulmonary thromboembolism
– Immobilisation

Nosocomial FUO
• More than 50% of patients with nosocomial PUO are
due to infection.
• Focus on sites where occult infections may be
sequestered, such as:
- Sinusitis of patients with NG or orotracheal tubes.
- Prostatic abscess in a man with a urinary catheter.
• 25% of non-infectious cause includes:
- Acalculous cholecystitis,
- Deep vein thrombophlebitis
- Pulmonary embolism.

Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.

HIV-associated PUO
• HIV infection alone may be a cause of fever.
• Common secondary causes include:
- Tuberculosis
- Toxoplasmosis
- CMV infection
- P. carinii infection
- Salmonellosis
- Cryptococcosis
- Histoplasmosis
- Non-Hodgkin's lymphoma
- Drug-induced fever

DIAGNOSIS

Approach to patient with FUO
• Stage 1: Careful history taking, physical
examination and screening tests
• Stage 2: Review the history, repeating physical
examination
• Stage 3: Specific diagnostic tests & noninvasive investigations
• Stage 4: Invasive tests

Diagnosis
Hx taking P.E Lab/Imaging

1st
• History taking “Fever”
• Occupation
• Exposure to animals
• Travel history
• Family history

History Taking of Fever
Fever
• Onset
• Character
• Pattern
Fever
• Antecedent
• Associated symptoms
Fever
• Past medical history
• Past surgical history
• Social history

Onset • Acute
• Gradual
Malaria , pyogenic infection
TB, typhoid
Character High Malaria , UTI ,TB, drug
Pattern • Sustainable/persistent
• Intermittent
• Relapsing
Typhoid, drug
Daily (abscess),twice daily(
leishmaniasis),saddle back (dengue
. leptospira, borellia)
Malaria ,lymphoma
Antecedent Prior onset the fever Dental extraction
(endocarditis),urinary
catheterization (UTI, bacteremia)
Associated
symptoms
• Chills,
• Night sweat,
• Loss weight,
• Dyspnea,
• Headache,
• Joint pain
25
Type of fever and diseases

 Travel
 amoebiasis, typhoid fever, malaria, Schistosomiasis
 Residential area
 malaria, leptospirosis, brucellosis
 Occupation
 farmers, veterinarian, slaughter-house workers = Brucellosis
 workers in the plastic industries = polymer-fume fever
 Contact with domestic / wild animal / birds :
 Brucellosis, psittacosis (pigeons), Leptospirosis, Q fever, Toxoplasmosis
 Diet history
 unpasteurized milk/cheese = Brucellosis
 poorly cooked pork = Trichinosis
 IVDU = HIV-AIDS related condition, endocarditis
 Sexual orientation = HIV, STD, PID
 Close contact with TB patients
Social history and risk of infection

 Past Medical History
 Malignancy = leukemia, lymphoma, hepatocellular carcinoma
 HIV infection
 DM
 IBD
 collagen vascular disease-SLE, RA, giant cell arteritis
 TB
 Heart disease: valvular heart disease
 Past Surgical History
 Post splenectomy/ post- transplantation
 Prosthetic heart valve
 Catheter, AV fistula
 Recent surgery/ operation
Medical history

Physical Examination
Hand
Arm
Head and Neck
Face and mouth
Chest
Abdomen
CNS

Body site Physical finding diagnosis
Head Sinus tenderness sinusitis
Temporal artery nodules & reduced pulsation Temporal arteritis
oropharynx ulceration Disseminated
Histoplasmosis
Tender tooth Periapical abscess
Fundi / conjunctiva Choroid tubercle Disseminated
granulomatosis
Petechiae, Roth’s spots Infective endocarditis
Thyroid thyroid enlargement Thyroididtis
Physical examination:

Body site Physical finding Diagnoses
Heart murmur myxomas, endocarditis
Abdomen Enlarged iliac crest lymph nodes ,
spleenomegaly
lymphomas., disseminated
granulomatosis
Rectum Perirectal fluctuance and
tenderness
Abcess
Prostatic tenderness Abcess
Lower limbs deep vein tenderness DVT & thrombophlebitis
Skin & nail Petechiae, splinter hemorrhages,
subcutaneous nodules, clubbing
Vasculitis, endocarditis

Contribution to
diagnosis
ID
n (%)
CVD+MD
n(%)
ND
n(%)
UD
n(%)
total
History 14 (53.8) 31 (77.5)* 6(43) 0 51
Physical
Examination
11 (42.3) 23(57.5) 5(35.7) 0 39
Biochemical
test
7(27)* 23(57.5) 8(57.1) 0 38
CONSTRIBUTION BASELINE FINDING
Bilgul Mete,Int. J. Med. Sci. 2012, 9
Note :
ID : Infectious Diseases,CVD:Collagen Vascular Diseases, MD : Miscellaneous diseases,UD : Undiagnosed
* p< 0,001 when compared to other groups

Laboratory studies & investigation in FUO
If any abnormality or clue is noted ,
further investigation is indicated
Abdurachman K, Nurhan E , Sibel YK : Expert Rev Anti Infect Ther,2013,11(8)
CBC with diff count
Blood cultures
Urine cultures
Routine blood liver enzymes and bilirubin
ESR
CRP
Hepatitis serology (if liver enzymes are abnormal)
Urine analysis
Chest radiograph

Free Powerpoint Templates
Page 33
1. Echocardiography
2. Further X ray /
abdomen exam
including scan – IBD,
abscesses, local
sepsis)
3. Barium studies
4. IVU
5. Liver biopsy
Further investigations
6. Exploratory
laparotomy
7. Bronchoscopy

Chest X ray and CT scan
• CT scan provides spatial resolution
• Detect small nodules
• Hilar / mediastinal adenopathy ( lymphoma,
sarcoidosis),can be revealed
• Chest CT very useful in FUO
• Chest CT (from data) :
– Can detect pulmonary TB 91%
– Multi center study : specificity 77%,sensitivity
82%

Contribution of imaging to diagnosis
FUO
Contribution
to diagnosis
ID CVD+
MD
ND UD N/(%)
All imaging studies 21* 17 9 (-) 47(47)
Abdominal USG
(n:48)
4 3 1 (-) 8(16.6)
Chest X-ray (n:96) 8** 3 0 0 11(11.4)
Thorax CT (n:86) 13 11 2 (-) 26(30.2)
Abdominal CT (n:80) 7 6 3 (-) 16(20)
Bilgul Mete, Int. J. Med. Sci. 2012, 9
* p<0.001 when compared to other groups
** p= 0.001 when compared with other groups

Role and Interpretation of Fluorodeoxyglucose-
Positron Emission Tomography/Computed Tomography
in HIV-Infected Patients With Fever of Unknown Origin
(A Prospective Study)
• Objective : study was to evaluate prospectively the usefulness of
fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-
PET /CT ) in investigation of fever of unknown origin (FUO) in HIV-
positive patient ‘s
• Results :
FDG-PET /CT contributed to the diagnosis or exclusion of a focal aetiology of the
febrile stat e in 80% of patients with FUO. The presence of increased FDG uptake in
the central lymph node has 100% specificity for focal aetiology of fever.
Martin C, Castaigne.C , Tondeur M : HIV Medicine.2013;14(8):455-462.

Diagnostic role of imaging
and invasive procedure
Sensitivity Specificity NPV PPV
Thorax CT 100 65 100 55
Abdominal
USG
100 67 100 30
Abdominal
CT
100 44 100 31
Biopsies 85 100 85 100
Bilgul Mete, Int. J. Med. Sci. 2012, 9

If failed…
• Review history & repeat physical
examination !!
• Specific investigations ( not all ..)
• Repeat sampling of blood & other body
fluids.
• Skin tests
• Blood for antibodies – HIV antibodies, CMV
antibodies, EBV antibodies.

MANAGEMENT
 Therapy withheld until cause is
found
 Empirical corticosteroids or anti
inflammatories in temporal
arteritis.
 Change of IV lines, catheters

40
Hx/PE
(+)
finding
Yes
Order appropriate /spec
Dx test
NO
CBC,electrolyte,LFT,
culture,urine,ESR,PPD,
Chest Ro
Positive
finding
yes
Order specific Dx test and follow up
No
CT scan Abd
Infection malignancies
autoimmune miscellaneus

41
FUO
Hx,PE,
Lab/Investigation
Unstable patients
Signs specific
diseases
Immediate Dx test and initial empirical
or specific therapy
Stable patients
Screening lab test
Specific lab or
imaging test
Specific dx,
spec treatment
Repeated hx or
exam,observe
and antipyretic

FUO in HIV cases

PROGNOSIS
• Poorest prognosis - elderly & malignant
• Delay in diagnosis affects prognosis of intraabdominal
infections, miliary tuberculosis, disseminated fungal infections
& recurrent pulmonary emboli
• Undiagnosed PUO for prolonged duration – good prognosis.

Sit with the patient and spend more time to take history
Take history from the patient and not the bystanders
Make a thorough and complete physical examination
Make sure you examine the fundus of the eye
Do appropriate investigations, but not total screening
Order relevant investigations without hesitation
46

Fever unknown Origin

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