This document provides an overview of pyrexia of unknown origin (PUO). It defines PUO and discusses the etiology, epidemiology, differential diagnosis, diagnostic approach and algorithm. Common causes of PUO include infections, non-infectious inflammatory diseases and neoplasms. The diagnostic approach involves history, physical exam, obligatory tests and guided diagnostic tests. Positron emission tomography (PET)/computed tomography (CT) has a high diagnostic yield. Treatment may involve empirical trials of antibiotics, antitubercular drugs, colchicine, non-steroidal anti-inflammatory drugs or glucocorticoids. The prognosis of unexplained PUO is generally favorable.

1. PYREXIA OF UNKNOWN ORIGIN
DR MD AFGAN SK
POST GRADUATE TRAINEE
DEPARTMENT OF GENERAL MEDICINE
R G KAR MEDICAL COLLEGE & HOSPITAL

3. OVERVIEW
1. Definition of fever , Physiology and Pathogenesis
2. Definition of PUO
3. Etiology &Epidemiology
4. Differential Diagnosis
5. Approach to a patient
• Algorithm
• First stage diagnostic tests
• FDG PET/CT
• Later stage diagnostic tests
6. Treatment
7. prognosis

4. FEVER
• In ≥ 18 yrs of age mean oral temperature 36.6◦c
• Temperature of >37.7 ◦c (99.9◦c ),which represents 99th percentile of
healthy individual ,defines fever .

5. PHYSIOLOGY

6. PATHOGENESIS OF FEVER

7. Fever of unknown origin = any febrile
illness without any obvious etiology

8. Older Definition
Originally defined by Petersdorf and Beeson in 1961
 an illness of >3 weeks duration
Fever of ≥38.3°C (≥101°F) on two occasions and
 an uncertain diagnosis despite 1 week of inpatient evaluation

9. 1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of ≥3 weeks
3. No known immunocompromised state
4. Diagnosis that remains uncertain after a thorough history-taking,
physical examination, and the following obligatory investigations:
NEWER DEFINITION
ESR and CRP level; platelet ; leukocyte count and differential; Hb ;
electrolytes, creatinine, total protein, ALP, ALT, AST, LDH , creatine
kinase, ferritin, ANA, and RA factor; protein electrophoresis;
urinalysis; blood cultures (n = 3); urine culture; chest x-ray;
abdominal USG ; and tuberculin skin test (TST) or IGRA

10. Inflammation of unknown origin(IUO)
Presense of elevated inflammatory markers a period of atleast 3
weeks in an immunocompetent patient with normal body
temperature ,for which a final explanation is lacking despite
history –taking ,physical examination and obligatory test.

11. Common etiology
1.Infections (43%)
2.NIID (20%)
3.Neoplasm (14%)
4.Miscellaneous (7%)
5.Unknown (16%)
Change of spectrum of disease
Use of antibiotics
Availability of new diagnostic technique

12. ETIOLOGY & EPIDEMIOLOGY

13. MCC in non western countries : infections (50% TB)
MCC in Western countries :Noninfectious inflammatory disease (NIDDs)
• Autoimmune
• Autoinflammatory
• Granulamatous
• Vasculitis
Among western cohort more than 1/3 rd patients undiagnosed
/unexplained .
BUT WHY ?
1.seek medical advice earlier
2.Better diagnostic techniques

14. DIFFENTIAL DIAGNOSIS

17. DIFFENTIAL DIAGNOSIS
• Atypical presentation of common disease >>>>> a very rare disease
• Like atypical presentation of Endocarditis,diverticulitis ,endocarditis
,extra pulmonary TB >>>> Q fever ,Whipple disease
• Adult –onset still`s disease ,PMR,large vessel vasculitis
,SLE>>>>hereditary autoinflammatory syndrome
• Mc cancerous cause of FUO : malignant lymphoma

18. • Drug induced fever :
allopurinol, CBZ, lamotrigine, phenytoin, furosemide , antimicrobial
,quinidine
Fever persists >72 hrs after discontinuation of suspected drug
;unlikely cause is the drug
• Exercise induced hyperthermia
an elevated body temp that is A/w moderate to strenuous exercise
lasting from 1/2hr up to several hours without an increase in CRP level
or ESR.
• Factitious fever
Artificially induced e.g ( iv injection of contaminated water )
• Fraudulent fever : patients manipulates thermometer

19. APPOACH TO THE PATIENT

20. FIRST STAGE DIAGNOSTIC TEST
Potentially diagnostic clues(PDCs) :all localizing signs ,symptoms &
abnormalities potentially pointing toward a diagnosis
History
Fever pattern
duration of fever :longer the duration less likely infection and
malignancy
Medical history
Recent drug use
Family history
Sexual history ,travel history ,animal contacts

21. FEVER PATTERN
Intermittent pattern :
Any fever characterized by intervals of normal temperature
Malaria, septicemia
Continuous fever:
Temp remains above normal throughout the day
Does not fluctuate more than 1◦c in 24 hrs
Lobar pneumonia ,typhoid, meningitis
Remittent fever :
Daily fluctuation of fever >2 ◦c during 24hrs period
It never touches baseline
Amoebic lever abscess,Infective endocarditidis

22. • Relapsing fever : recurring fever and separated by periods (days
/weeks) with low grade fever or no fever.
E.g lymphoma
• Undulant fever: typically undulant ,rising and falling like a wave
Seen in brucella infection
• Pel –Ebstein `s fever : intermittent low grade fever characterised by
3-10 days of fever with subsequent afebrile periods of 3 -10
days,typical but rare in Hodgkin lymphoma

23. Typical fever pattern rarely observed because of use of antipyretics & partial treatment
with antimicrobials
But when observed ,useful diagnostic clues for infectious diseases without localizing sign
such as malaria , typhoid .
Is pattern of fever useful ?

24. Physical examination
• Document the fever
• Analysing the pattern
• Eye
• Lymph node
• Temporal arteries
• Liver ,spleen
• Skin &mucous membrane

25. Scrub typhus eschar Salmon rash

26. Roth spot
Tb choroidal granuloma

27. INVESTIGATIONS
• Despite high false positive in usg and low sensitivity in CXR ….low cost
diagnostic test remain obligatory .
• Abdominal usg >Abdominal CT because of low cost ,lack of radiation
risk
• Fundoscopy is valuable inv in PUO
Tuberculin skin test or IGRA
• False Negative in milliary TB ,malnutrition ,immunsupressed
• IGRA not influenced by prior BCG vaccines or non Tb mycobacterium.

28. RECURRENT FEVER
• Repeated episodes of fever interspersed with fever free interval
alleast 2 weeks
• Chance of attaining an etiologic diagnosis is <50%
• If fever lasting >2 yrs …very unlikely by infection or malignancy
• History ,physical examination ,laboratory test ,PET/CT only during
febrile episode or abnormal inflammatory markers

29. Fever ≥38.3° C (≥101° F) and illness lasting ≥3 weeks and no known immunocompromised state
History and physical examination
Stop antibiotic treatment and glucocorticoids
Obligatory investigations: ESR or CRP, hemoglobin, platelet count, leukocyte count and differential,
electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH,
creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n = 3), urine
culture, chest x-ray, abdominal ultrasonography, and tuberculin skin test or IGRA
ALGORITHM

30. Exclude manipulations with thermometer
Stop or replace medication to exclude drug fever
PDCs present PDCs absent or misleading
Guided diagnostic tests
Diagnosis No diagnosis

31. Cryoglobulin and funduscopy
FDG-PET/CT (or labeled leukocyte scintigraphy or gallium scan)
Abnormal
Confirmations of abnormalities eg biopsy
,culture
Diagnosis No Diagnosis
Normal

32. Repeat history and physical examination Perform PDC-driven invasive testing
Diagnosis No diagnosis
Chest and abdominal CT ,Temporal artery biopsy (≥55
years)
Diagnosis No Diagnosis
Stable condition: Follow-up for new PDCs
Consider NSAID treatment
Deterioration: Further diagnostic tests
Consider therapeutic trial

33. FLUORPDEOXYGLUCOSE PET/CT
18F –FDG PET/CT has become an established imaging procedure in FUO
Mechanism : FDG accumulates in tissues with high glycolysis rate
Advantages :higher resolution ,greater sensitivity ,high accuracy
Physiological uptake :Brain ,heart ,bowel ,kidneys ,bladder
In periodic fever ,correct timing of PET/CT increases its diagnostic value
A Total diagnostic yield of 50% for PET /CT &40% for PET .

36. LATER STAGE DIAGNOSTIC TESTS
• Lymph node biopsy ,skin biopsy
• Screening chest & abdominal CT :20%
• Temporal artery biopsy :>55ys of age
• Role of liver biopsy :invasive procedure
Complications
Only indications liver disease and miliarry Tb
• Repetition of history and physical examination

37. TREATMENT
Emperical therapeutic trials
1. Antibiotics &Antituberculous therapy
• Diminish culture positivity
• Considered for hemodynamic instability or neutropenia
• ATT trial TST or IGRA positive ,granulomatous disease present
• No response to ATT trial

38. 2. Colchicine ,NSAIDS & Glucocorticoid
• Colchicine : Familial Mediterranean fever
• Glucocorticoid : giant cell arteritis ,polymyalgica rheumatica
• NSAIDS: Adult onset still`s disease
• Masking of symtoms with continued spread of infection
3. Interleukin 1 inhibition
• Anakinra
• FMF , adult onset still`s disease ,periodic syndrome .

39. PROGNOSIS
• Prognosis of Unexplained FUO is favorable
• FUO related mortality have continuously declined over recent
decades
• Majority of fevers are caused by treatable disease