Pyrexia of unknown origin (PUO) is defined as a fever over 38°C lasting three weeks or longer without a diagnosis despite extensive investigation. There are various types of PUO, including classic, nosocomial, neutropenic, and HIV-associated, each with specific characteristics and diagnostic criteria. Effective management requires thorough diagnostic workup and ideally should delay therapy until the cause is identified to ensure the correct treatment.

1. PYREXIA OF
UNKNOWN
ORIGIN
(PUO)

2. FEVER OF
UNKNOWN
ORIGIN

4. PATHOGENESIS
exogenous
(Endo pyrogens)
Fever-systemic
response of
body
to injury.

6. DEFINITION OF PUO
• Pyrexia of unknown origin (PUO) may be
defined as any febrile illness (temperature
greater than 38°C) lasting 3 weeks or
longer, without any obvious cause and
failure to reach a diagnosis despite one
week of inpatient investigation.
• In these conditions there is thus a
special need for a lab diagnosis
to guide the choice of
appropriate therapy.

7. 1. Fever ≥ 38.3°C (>101°F) on several
occasions
DEFINITION OF PUO

8. 1. Fever ≥ 38.3°C (>101°F) on several
occasions
2. Duration ≥ 3 weeks
DEFINITION OF PUO

9. 1. Fever ≥ 38.3°C (>101°F) on several
occasions
2. Duration ≥ 3 weeks
3. Failure to reach a diagnosis
despite
1 week appropriate in-hospital
investigation
or 3 outpatient visits
DEFINITION OF PUO

10. 1
TYPES OF PUO
• Classic PUO
• Nosocomial PUO
• Neutropenic PUO
• HIV associated PUO

11. CLASSIC PUO
• Petersdrof & Beason (1961)
• Temperature > 38ºC (101ºF
• Occurring for more than three weeks
• Inspite of investigations on three OPD visits or three
days of stay in hospital or one week of invasive
ambulatory investigations is called classic PUO.
• Acute PUO : 7-10 Day
• Chronic PUO : > 3 weeks or longer

12. NOSOCOMIAL PUO
• When temperature more than 38.3ºC(> 101°F).
• hospitalized patient who is receiving acute care and in
whom infection was not manifest or incubating on
admission is called nosocomial PUO.
• Three days of investigations including at least two days
incubation of microbiology cultures is the minimum
requirement for this diagnosis
Examples: Septic thrombophlebitis, sinusitis,
Clostridium difficile colitis, drug fever

13. MODE OF
INFECTION
CAUSATIVE ORGANISMS PATHOLOGY
IV Line Staph.aureus,Staph. epidermidis Septic
phlebitis
IV Fluids Coagulase negative
Staph.,Enterobacter,Citrobacter,
Serratia,Ps.cepacia,
Septicemia
Prosthetic
devices
Coagulase negative Staph.,
Facultative Gm-ve bacilli,
Diphtheroids, Fungi
Infective
endocarditis,
Osteomyelitis
Endotracheal
tubes
Staph. Aureus , H. influenzae Sinusitis,
Pneumonia
Urinary
catheters
E. coli, Klebsiella, Enterococci,
Proteus
UTI
Nosocomial PUO –infections-50%, Non-infectious-25%

14. NEUTROPENIC PUO
• Less than 500 neutrophils mm-3
• Fever ≥ 38.3°C (>101°F) on several occasions
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of microbiological
cultures)
• It is also called immunodeficient PUO.
Examples: Perianal infection, aspergillosis, candidemia

15. HIV-ASSOCIATED PUO
• Confirmed HIV infection
• Fever ≥ 38.3°C (>101°F) on several occasions
• Duration of ≥4 weeks (outpatients) or
• ≥4 days in hospitalized patient
• Diagnosis uncertain after 3 days
despite appropriate investigations
(including at least 48-h incubation of microbiological
cultures)
Examples: M. avium/M. intracellulare infection, tuberculosis,
non-Hodgkin's lymphoma, drug fever

16. 1. INFECTIONS
Bacterial infections:
 Enteric fever (Salmonella spp.)
 Urinary tract infections (Escherichia Coli)
 Lung abscess and other deep abcesses
 Septicemia associated with pneumonia, infective endocarditis.
 Tuberculosis( mycobacterium tuberculosis)
 Brucellosis (Brucella spp.)
 Rheumatic fever (Streptococcus spp.)
 Relapsing fever (Borrelia recurrentis)
 Leptospirosis (leptospira)
 Typhus fever (Rickettsia prowazekii)
 Q fever (Coxiella burnetii)
ETIOLOGY

17. Non Bacterial infections:
- Viral infections
- Infectious mononucleosis (E.B. virus)
- Cytomegalovirus infection
- Hepatitis A virus infections
- Hepatitis B virus infections
- Rubella and other infectious fevers without rashes
- HIV infection
-

18. Non Bacterial infections:
- Parasitic infections
- Malaria (Plasmodium spp.)
- Hepatic amoebiasis (Entamoeba histolytica)
- Visceral leishmanisis (kala azar)
- Filariasis (Woucheria bancrofti)
- Toxoplasmosis
- Trypanosomiasis
-

19. Non Bacterial infections:
- Fungal infections
- Histoplasmosis
- Coccidioidomycosis
2. NEOPLASM
Haematological neoplasms
Non-Hodgkin lymphoma
Leukemia
Hodgkin’s disease
Other

20. Non Bacterial infections:
- Fungal infections
- Histoplasmosis
- Coccidioidomycosis
2. NEOPLASM
Haematological neoplasms Solid tumors
Non-Hodgkin lymphoma Renal carcinoma
Leukemia Colon
Hodgkin’s disease Liver
Other Other

21. 3. CONNECTIVE TISSUE DISORDER
• Systemic lupus erythmatus(SLE)
• Polyartheritis nodosa
4.GRANULOMATUS DISEASE
• Sarcoidosis
• Crohn’s Disease
5. DRUG REACTIONS
• Drug induced fever

23. DIFFERNTIAL
DIAGNOSIS
DIAGNOSTIC STRATEGIES

24. laboratory diagnostic
Microbiology
history Physical,laboratory
examination
Pattern of organ
involvement
epidemiology
Differential diagnosis
Diagnosis
DIAGNOSTIC STRATEGIES
Therapeutic trial

25. History
• Recent travel to tropics, particularly where
there is malaria.
• Exposure to pets and other animals
• Sexual history
• Work environment
• Contact with other people with similar
symptoms
• Family history
• Past medical history list of medications
• Include OTC
• Transfusion, vaccination, allergies
• Tobacco, alcohol, illegal drugs
• Surgery, dentist, pedicare
DIAGNOSTIC STRATEGIES

26. physical findings in patients with FUO
• Lymphadenopathy and pallor are common in infections
• Splenomegaly are mainly associated with infections and
neoplasms
DIAGNOSTIC STRATEGIES

27. Temperature chart raises in patients with FUO
• Double quotidian- stills
• kala-azar
• Malaria
• Miliary tuberculosis
• Intermittent-hectic:- abscess,lymphoma
• Chills & rigors
• Bacteremia
• Cholangitis
• pyelonephritis
• Pneumonia
• Typhoid
• Abscess
DIAGNOSTIC STRATEGIES

28. Petechiae,splinter, hemmorages, subcutaneous nodules, clubbing on
skin and nails
DIAGNOSTIC STRATEGIES

29. Deep venous tenderness at lower extremieties
DIAGNOSTIC STRATEGIES

30. DIAGNOSTIC STRATEGIES

31. Ulceration and tender tooth of oropharynx
DIAGNOSTIC STRATEGIES

32. Enlarged iliac crest, lymph nodes, splenomegaly of abdomen
DIAGNOSTIC STRATEGIES

33. Nodules, enlargement, tenderness of thyroid
DIAGNOSTIC STRATEGIES

34. Chancroid tubercle, petechiae, roth’s spot of fundi or conjunctiva
DIAGNOSTIC STRATEGIES

35. DIAGNOSTIC STRATEGIES

36. Intensive weight loss
DIAGNOSTIC STRATEGIES

37. LABORATORY
DIAGNOSIS

38. BACTERIAL INFECTIONS
• SPECIMENS
• Blood : for blood cultures, peripheral blood smear,
hematology, serology and other tests.
• Urine: for UTI
• Sputum: in cases of lung infections
• Pus: in localised abcesses

39. PATHOLOGICAL fINDINGS
• INITIAL TESTS
• Haematology tests:
• Hemoguobin
• Total leucocyte count
• Differential leucocyte count
• Erythrocyte sedimentation rate
• Peripehral Blood Smear(Thick/ thin)

40. BACTERIAL INFECTIONS
• COLLECTIONS
• Specimens should be collected prior to antimicrobial
therapy.
• Blood is collected in Blood culture bottles for
cultures and in a sterile vial for serology.
• Mid-stream urine specimen should be collected in a
sterile universal container.

41. BACTERIAL INFECTIONS
• CULTURE
• Blood culture:
• 5 ml of blood is collected in each bottle of 50 ml
glucose broth and 50 ml Sodium tourcholate broth.
• These broths are incubated at 37°C for 24 hours.
• Subculture it on blood agar(from glucose broth)
and MacConkey agar (from taurcholate broth).
• Incubate both the plates at 37°C for 24 hours.

42. BACTERIAL INFECTIONS
• CULTURE
• Urine culture:
• Mid stream urine sample is inoculated on blood
agar and MacConkey agar.
• These media are incubated at 37°C for 24 hours.
• If renal tuberculosis is suspected, culture should
be inoculated into Lowenstein-Jensen medium.

43. BACTERIAL INFECTIONS
• CULTURE
• Sputum culture:
• sample is inoculated on blood agar and MacConkey
agar.
• These media are incubated at 37°C for 24 hours.
• If Pulmonary tuberculosis is suspected, culture
should be inoculated into Lowenstein-Jensen
medium.and are incubated at 37°C for 6 weeks.

44. BACTERIAL INFECTIONS
• CULTURE
• Pus culture:
• Pus is inoculated on glucose broth, blood agar and
MacConkey agar.
• These media are incubated at 37°C for 24 hours.
• If M.tuberculosis is suspected, culture should be
inoculated into Lowenstein-Jensen.
• If anaerobic organism are suspected, sample must
be collected in Robertson cooked meat medium for
the site of collection and processed under
anaerobic condition.

45. BACTERIAL INFECTIONS
• IDENTIFICATION
• On the basis of:
• Colony morphology
• Gram’s staining
• Biochemical reactions
• Agglutination reactions (for salmonella)
• For M.tuberculosis:
• Zeihl-Neelsen’s staining(for AFB detection)
• Further confirmed by culture and biochemical
reactions

46. BACTERIAL INFECTIONS
• SEROLOGY
• Human immunodeficiency virus
• Salmonellosis (Widal test)
• Brucellosis
• Tularemia
• EBV (Paul-Bunnel test)
• Cytomegalic Inclusion virus
• Other viral infections ( Hepatitis antigens)
• Toxoplasmosis
• Fungal infections

47. PARASITIC INFECTIONS
• Stained peripheral blood thick and thin
smears are used as diagnostics for:
• Malaria
• Leishmaniasis
• Filariasis
• Toxoplasmosis
• Wet mount film may show microfilaria in case of
filariasis.
• Serology is useful in ameobiasis.

48. VIRAL INFECTIONS
• Viral infections can be identified by
• Tissue culture
• Serological tests.
• Molecular methods (NASBA, PCR) for
• Hepatitis virus
• HIV
• Cytomegalovirus
• Peripheral blood smear (infectious
mononucleosis)

49. fUNGAL INFECTIONS
• Specimen may be cultured on Sabourd’s Dextrose
Agar(SDA) and brain Heart infusion agar(BHI).
and incubated at 37°C and 25°C for 7 days.
• Identification:
• Based on colony morphology
• Grams Staining(for yeast)
• KOH mount(for hyphae and yeast)

50. Other diagnostic tests
• Skin test:
• Mantoux test(Intradermal tuberculin test)
Negative tuberculin test result still does not
rule out tuberculosis
• Skin test for Histoplasmosis, coccidiodomycosis,
sarcoidosis.

51. Other diagnostic tests
• Haematology:
• Total leucocyte count (TLC)
• Differential leucocyte count (DLC)
(these are non specific tests)
• Erythrocyte sedimantation Rate (ESR)

52. Other diagnostic tests
• Biopsy:
• If with evidence of organ involvement.
• Most definitive approach to investigation of
neoplastic cause in PU0
• Helpful in diagnosis of tuberculosis

53. Other diagnostic tests
• Bone Marrow:
• Recommended as an important tool for detection
of occult infection and malignancy
• In immuno competent children occasionally
useful for diagnosis of selected infectious
diseases especially brucellosis and typhoid fever

54. THERAPEUTIC TRIALS
• If patient is deteriorating and is haemodynamically
unstable:
• Institute empirical therapy (especially neutropenic, HIV)
• Supportive & Symptomatic therapy
• If patient is stable:
• Empiric use of antibiotics, NSAID’s & Corticosteroids
may be misleading as determination of a new finding is
difficult.
• Temp fall may be fortuitous or due to drug effect.
• False sense of therapeutic & diagnostic security,
interfere with finding a diagnosis.
• Spontaneous resolution of fever
• Iatrogenic complications

55. CONCLUSION
• To reach diagnosis in PUO is long and time consuming.
• The investigation and management of a patient with PUO
requires persistence and an informed and open mind in
order to reach the correct diagnosis.
• Therapy should be delayed till cause is determined, so that
it can be correctly treated.
• Non specific management is rarely curative & has the
potential to delay diagnosis.
• Most people with PUO have a treatable disease presenting
in an unusual manner.
• The aim in the investigation of such cases is to initiate
appropriate treatment.
• In infections, finding the right antibiotic may be life-
saving so take appropriate cultures before starting
antibiotic therapy.