pyrexia of unknown origin · 2020. 7. 6. · original definition (by petersdorf and beeson,1961)...
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PYREXIA OF
UNKNOWN ORIGIN
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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]
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Classification of PUO
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
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COMMON CAUSES OF PUO
Infection (40%)
Malignancy (25%)
Autoimmune Disease (15%)
Undiagnosed(10%)
Others/
Miscellaneous (10%)
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Causes of FUO(in India)
Infectious 53%
#1: TB (45%)
Neoplasm: 17%
#1: NHL (47%)
Collagen Vasc.: 11%
#1 SLE: 45%
Miscellaneous: 5%
Undiagnosed: 14%
Kejariwal D et al. J Postgrad Med. 2001 Apr-Jun; 47(2):104-7.
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FUO by the Decades
I n f e c t i o us
24%
M a l i g n a n cy
15%
R he um
24%
Ot he r
8%
U nk now n
29%
I n f e c t i o us
29%
M a l i g n a n cy
16%R he um
25%
Ot he r
13%
U nk nown
17%
I n f e c t i o us
31%
M a l i gna nc y
24%
R he um
15%
O t he r
13%
U nk now n
17%
I n f e c t i o u s
3 6 %
M a l i g n a n c y
1 9 %
R h e um
1 8 %
O t h e r
1 8 %
U n k n o w n
9%
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Classic PUO
3 common etiologies which account for the
majority of classic PUO:
Infections
Malignancies
Collagen Vascular Disease
Others/Miscellaneous which includes drug-
induced fever.
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Infections
Bacterial: abscesses, TB, complicated
UTI, endocarditis, osteomyelitis, sinusitis, Lyme
disease, prostatitis, cholecystitis, empyema, bili
ary tract
infection, brucellosis, typhoid, leptospirosis, Q
fever, borreliosis, etc.
Parasite:
Malaria, toxoplamosis, leishmaniasis, etc.
Fungal: histoplasmosis, etc.
Viral: CMV, infectious mononucleosis, HIV, etc.
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Infections
As duration of fever increases, infectious
etiology decreases
Malignancy and factitious fevers are more
common in patients with prolonged FUO.
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Malignancies
HaematologicalLymphoma
Chronic leukemia
Non-haematologicalRenal cell cancer
Hepatocellular carcinoma
Pancreatic cancer
Colon cancer
Hepatoma
Myelodysplastic Syndrome
Sarcomas
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Collagen vascular disease /
Autoimmune disease
Polyarteritis nodosa
Giant cell arteritis
Kawasaki disease
Still’s disease
Adult Still's disease
Polymyalgia rheumatica
Temporal arteritis
Rheumatoid arthritis
Rheumatoid fever
Inflammatory bowel disease
Reiter's syndrome
Systemic lupus
erythematosus
Vasculitides
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Others/miscellaneous
Drugs:
penicilin, phenytoin, captopril, allopurinol, eryth
romycin, cimetidine, etc.
Hyperthyroidism
Alcoholic hepatitis
Sarcoidosis
Inflammatory bowel disease
Deep Venous Thrombosis
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Roth AR and Basello GM. Am Fam Physician. 2003 Dec 1;68(11):2223-8.
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Nosocomial PUO
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 oro-tracheal tubes.
- Prostatic abscess in a man with a urinary catheter.
25% of non-infectious cause includes:- Acalculous cholecystitis,
- Deep vein thrombophlebitis
- Pulmonary embolism.
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Neutropenic PUO
Patients on chemotherapy or immune deficiencies are susceptible to:- Opportunistic bacterial infection
- Fungal infections such as candidiasis
- Bacteremic infections
- Infections involving catheters
- Perianal infections.
Examples of aetiological agent:- aspergillus
- Candida
- CMV
- Herpes simplex
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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
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A ClinicalApproach
Pyrexia of Unknown Origin
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History Taking
History of Presenting Illness (HOPI)
1。Onset
- acute: Malaria, pyogenic infection
- gradual: TB, thyphoid fever
2。Character
high grade fever: UTI, TB, malaria, drug
3。Pattern
sustained/persistent: Thyphoid fever, drugs
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intermittent fever:
◼ Daily spikes: Abscess, TB, Schistosomiasis
◼ Twice-daily spikes: Leishmaniasis
◼ Saddleback fever: Leptospirosis, dengue,borrelia
-relapsing/ recurrent fever: Non-falciparum malaria, Brucellosis, Hodgkin’s lymphoma
4。Antecedents
- prior to onset of fever:
dental extraction: Infective endocarditis
Urinary catherization: UTI, bacteremia.
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5。Associated symptoms
Chills & rigors
bacterial, rickettsial and protozoal disease,
influenza, lymphoma, leukaemia, drug-induced
Night sweats
TB, Hodgkin’s lymphoma
Loss of weight
Malignancy, TB
Cough and Dyspnoea
Miliary TB, multiple pulmonary emboli, AIDS patient with PCP, CMV.
Headache
Giant cell arteritis, typhoid fever, sinusitis
Joint pain
RA, SLE, vasculitis
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Abd. PainCholangitis, biliary obstruction, perinephric abscess, Crohn’sdisease, dissecting aneuryms, gynaecological infection
Bone pain
Osteomyelitis, lymphoma
Sorethroat
IM, retropharyngeal abscess, post-Streptococcal infection
Dysuria, rectal pain
Prostatic abscess, UTI
Altered bowel habit
IBD, thyphoid fever, schistosomiasis, amoebiasis
Skin rash
Gonococcal infection, PAN,NHL, dengue fever
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Past Medical HistoryMalignancy = leukemia, lymphoma, hepatocellular ca
HIV infection
DM
IBD
collagen vascular disease-SLE, RA, giant cell arteritis
TB
Heart disease: valvular heart disease
❑ Past Surgical HistoryPost splenectomy/ post- transplantation
Prosthetic heart valve
Catheter, AV fistula
Recent surgery/ operation
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Drug HistoryImmunosuppressive drug/ corticosteroidAnticoagulants: accumulation of old blood in closed space e.g.retroperitoneal, perisplenic
Before fever: drug fever →occur within 3 months after starting taking drugs◼ may cause hypersensitivity and low grade fever, usually associated with
rash◼ Due to the allergic reaction, direct effect of drug which impair temperature
regulation (e.g. phenothiazine)
◼ E.g. Antiarrhythmic drug: procainamide, quinidine; Antimicrobacterial agent: penicillin, cephalosporin, hydralazine
After fever: may modify clinical pictures, mask certain infection e.g.SBE, antibiotic allergy
Family HistoryAnyone in family has similar problem: TB, familial Mediterranianfever
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Social HistoryTravel◼ amoebiasis, typhoid fever, malaria, Schistosomiasis
Residental 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
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Physical Examination
Pyrexia of Unknown Origin
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Examination
General
➢ Pattern of fever
(continous, intermittent, relapsing)
➢ Ill/not ill
➢ Weight loss (chronic illness)
➢ Skin rash
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Hands
Stigmata of Infective Endocarditis
Vasculitis changes
Clubbing
Presence of arthropathy
Raynaud’s phenomenon
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Arms
Drug injection sites (ivdu)
Epitrochlear and axillary nodes
(lymphoma, sarcoidosis, focal infection)
Skin
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Head & neck
Feel temporal arteries (tender & thicken)
Eyes – iritis/conjuctivitis (ct disease – reiter
syndrome)
Jaundice (ascending cholangitis)
Fundi – choroidal tubercle (miliary tb), roth’s
spot (ie) and retinal haemorrhage (leukaemia)
Lymphadenopathy
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Face & mouth
Butterfly rash
Mucous membranes
Seborrhoic dermatitis (hiv)
Mouth ulcers (sle)
Buccal candidiasis
Teeth & tonsils infection (abscess)
Parotid enlargement
Ears – otitis media
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Chest
Bony tenderness
Cvs – murmurs (ie, atrial myxoma), rubs
(pericarditis)
Resp – signs of pneumonia, tb, empyema and
lung ca
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Abdomen
Rose coloured spot (typhoid fever)
Hepatomegaly(sbp, hepatic ca, met)
Splenomegaly(haemopoietic malignancy, ie, malaria)
Renal enlargement(renal cell ca)
Testicular enlargement (seminoma)
Penis & scrotum –discharge/rash
Inguinal ligament
Per rectal exam –mass/tenderness in rectum/pelvis (abscess, ca, prostat itis)
Vaginal Examination– collection of pelvic pus/ Pelvic Inflammatory Disease
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Central Nervous System
Signs of meningism (chronic tb meningitis)
Focal neurological signs (brain
abscess, mononeuritis multiplex in polyarteritis
nodosa)
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Investigation
Pyrexia of Unknown Origin
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Stage 1: Laboratory investigations
Stage 1: (screening
tests)
1. Full blood count
2. ESR & CRP
3. BUSE
4. LFTs
5. Blood culture
6. Serum virology
7. Urinalysis and
culture
8. Sputum culture and
sensitivity
9. Stool FEME and
occult blood
10. CXR
11. Mantoux test
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Stage 2:
1. Repeat history and examination
2. Protein electrophoresis
3. CT(chest, abdomen, p elvis)
4. Autoantibody screen(ANA, RF, ANCA, anti-dsDNA)
5. ECG
Stage 2: Laboratory investigations
6. Bone marrow
examination
7. Lumbar puncture
8. Consider
PSA, CEA
9. Temporal artery
biopsy
10. HIV test
counselling
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Stage 3:
1. Echocardiography
2. Further Ix abdomen (Indium-labelled WC scan –IBD, abscesses, local sepsis)
3. Barium studies
4. IVU
5. Liver biopsy
Stage 3: Laboratory investigations
6. Exploratory
laparotomy
7. Bronchoscopy
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Treat TB,
endocarditis,
vasculitis,
trial of aspirin/ steroids
Stage 4: Laboratory investigations
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Diagnosing
Pyrexia of
Unknown
Origin
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Imaging Studies
• Tuberculosis, malignancy, Pneumocystis carinii pneumoniaChest radiograph
• Abscess, malignancyCT of abdomen or pelvis with
contrast agent
• Infection, malignancyGallium 67 scan
• Occult septicemiaIndium-labeled leukocytes
• Acute infection and inflammation of bones and soft tissueTechnetium Tc99m
• Malignancy, autoimmune conditionsMRI of brain
• Malignancy, inflammationPET scan
• Bacterial endocarditisTransthoracic or transesophageal
echocardiography
• Venous thrombosisVenous Doppler study
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Diagnosis
More invasive testing, such as LP or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation.
When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.