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)

Budi Riyanto JADE 2014 3

• 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


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


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


http://www.powerpointstyles.com/

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


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Date post:	07-May-2015
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Fever unknown Origin

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