This presentation focuses on the entity known as pyrexia of unknown origin / fever of unknown origin. It demonstrates both common and rare causes, and the epidemiological trend, its clinical presentation, management and prognosis.

1. PYREXIAOF UNKNOWNORIGIN
DR. KD DELE | DEPARTMENT OF FAMILY MEDICINE |DORA NGINZA HOSPITAL

2. OUTLINE
Introduction and Definitions
EpidemiologicalTrend
Aetiologies and Special Considerations
Evaluation:
History and Examination
Investigations
Treatment and Prognosis

3. INTRODUCTION
& DEFINITION

4. Definition
OLD DEFINITION(PETERSDORF
AND BEESON 1961)
1. Fever higher than 38.3oC on several
occasions, usually interpreted as at
least three
2. Duration of fever > 3 weeks
3. Uncertain diagnosis after one week
of study in hospital
NEW DEFINITION:(DURACK AND
STREET 1995)
1. Fever higher than 38.3oC on several
occasions.
2. Duration of fever > 3 weeks
3. → 3 outpatient visits, or 3 days in
hospital without elucidation of the
cause or 1 week of “intelligent and
invasive” ambulatory investigation

5. Definition
The core concept of PUO, despite
variations in definition, is that:
there is a significant fever that has
persisted for longer than an acute
self‐limiting illness would be expected
to
and that
the disease has not been identified
despite reasonable investigations in
whatever setting is appropriate,
either inpatient or outpatient

6. NEW
DEFINITION
EXPANSION
1. Classical PUO
2. Nosocomial PUO
3. Neutropenic PUO
4. HIV-Associated
5. (Transplant)

7. NEW
DEFINITION
EXPANSION
Some authors have argued the
exclusion of patients who are currently
immune‐compromised or have been
recently immune‐compromised.
This is not needed as they are often
much more at risk of opportunistic
infections and require a different
approach to investigations and a greater
need for empirical and definitive

8. NOSOCOMIAL
PUO:
3 days of investigation including at
least 2 days incubation of cultures are
the minimum requirement for
diagnosis.
This is new onset fever in hospitalized
patient who is receiving acute care & in
whom infection was not manifest or
incubating on admission.

9. NEUTROPENIC
PUO:
Diagnosis is invoked if specific cause is
not identified after 3 days of
investigations including 2 days
incubation of cultures
PUO in patient whose neutrophil count
<500/ul or is expected to fall to that
level in 1-2days.

10. HIV
ASSOCIATION
PUO:
Diagnosis is invoked if
appropriate investigation over 3 days including 2 days
incubation of cultures reveals no source
Temp >38.3oc on several occasions over a
period of
>4 weeks for outpatients
or
>3 days for hospitalized
patients with HIV
infection.

11. EPIDEMIOLOGY

12. Aetiology:Classical PUO

13. EpidemiologicTrend: PUO

14. EpidemiologicTrend: PUO

16. AETIOLOGY:
PUO

17. Aetiology:
Infectious
BACTERIAL
◦ Occult abscess
◦ Complicated urinary tract infection
◦ Culture negative endocarditis
◦ Osteomyelitis
◦ Tuberculosis
◦ Coxiella burnetti (Q fever)
◦ Rickettsial infections
◦ Enteric fever
◦ Brucellosis

18. Aetiology:
Infectious
• Epstein–Barr virus
• Cytomegalovirus
• Human immunodeficiency virus
Viral
• Malaria
• ToxoplasmosisParasitic
• HistoplasmosisFungal

19. Aetiology:
Inflammatory
Giant cell arteritis
Adult Still’s disease
Systemic lupus erthymatosus
Polyarteritis nodosa
Granulomatosis with polyangitis (Wegener
granulomatosis)
Familial Mediterranean fever
Rheumatic fever
Rheumatoid Arthritis

20. Aetiology:
Neoplastic
Non-Hodgkin lymphoma
Leukaemia
Renal cell carcinoma
Hepatocellular carcinoma
Metastatic lesions (commonly hepatic metastasis
from adenocarcinomas)
Others include: pancreatic and colonic
carcinomas, sarcomas

21. Aetiology:
Miscellaneous
Drugs
Cirrhosis
Pulmonary embolism
Inflammatory bowel disease
Sarcoidosis
Hyperthyroidism, Phaeocromocytoma
Factitious fever

22. Aetiology:
Miscellaneous
• SOL,
• Pontine CVA,
• Encephalitis
Intracerbral e.g.
• Familial Mediterranean Fever
Metabolic / inherited e.g.
• post MI (Dressler's syndrome)
Tissue infarction e.g.

23. Aetiology:
DrugsCausing
Fever
• Erythromycin
• Isoniazid
• Nutrofurantoin
• Penicillin
Antibiotics:
• Captopril
• Hydralizine
• Hydrochlorothiazide
• Methyl Dopa
• Nifedepine
• Diltiazem
Antihypertensives:

24. Aetiology:
DrugsCausing
Fever
• Carbamazepine
• Phenytoin
Anticonvulsants
• Ibuprofen
• Naproxen
Non‐steroidal Anti‐inflammatories
Thyroid Hormone Replacement
• Allopurinol
• Cimetedine
• Clifibrate
• Heparin
• Phenytoin
• Procainamide
• Quinidine
• Meperidine
Others:

25. Aetiology:
DrugsCausing
Fever
Others:
◦ Allopurinol
◦ Cimetedine
◦ Clifibrate
◦ Heparin
◦ Phenytoin
◦ Procainamide
◦ Quinidine
◦ Meperidine

26. SPECIAL
CONSIDERATIONS

27. Tuberculosis
PUO usually occurs in
the background of
Extrapulmonary /
DisseminatedTB.
It is one of the most
predominant causes of
PUO of infectious
origin.
A high index of
suspicion is needed:
PulmonaryTB in
HIV/AIDS is often
subtle (you may get
normal CXR in 15 –
30%).
Sputum tests may be
negative
Purified protein
derivative (PPD) skin
test is positive +ve <
50% ofTB patients
with PUO.
EmpiricalTB
treatment may be
indicated in these
patients.

28. Abscess
Usually located in abdomen or pelvis.
May be secondary to appendicitis or diverticulitis.
Pyogenic liver abscess usually follow biliary tract
disease or abdominal suppuration.
Amoebic liver abscess is similar to pyogenic →
amoebic serology is positive > 95% of
cases.(Positive Indirect Hemagglutination (IHA)
Antibody, ELISA)
Splenic abscess is usually secondary to
hematogenous seeding.
Perinephric or renal abscess is usually secondary
to UTI.

29. Bacterial
Endocarditis
Culture remains negative in 5% of patient.
• Coxiella burnetii → no growth.
• HACEK group (fastidious gram-negative bacteria) → incubate blood 7 –
21 days, slow growing
• Brucella → requires special media
• Legionella / Mycoplasm / Chlamydia → usually takes a longTime
• Fungal → usually sterile
Culture negative is likely with the following organisms:
Peripheral signs may not be detected.
Right-side endocarditis lack murmurs

30. Malignancy
Lymphoma:
Fever is a well-recognized manifestation
Source of fever : production of cytokines
Fever is a negative prognostic factor
Leukaemia: M. Myeloma (fever means infection)

31. Malignancy
Renal Cell Carcinoma (Adult)
Fever is there – only 20% present with
fever
Microscopic haematuria
WilmsTumor (Children)
Peak incidence 2-3 years.
Abdominal mass but FEVER can be a
presentation.
HCC or secondary metastasis to the liver

32. Malignancy
SolidTumour
Fever is rare except:
◦ Secondary metastasis to the liver:
◦ Ductal obstruction or perforation like
cholangiocarcinoma or ampulla carcinoma
◦ Lung carcinoma with obstruction and pneumonia.

33. Collagen-Vascular-Disease
No diagnostic serology. (Seronegative disease)
The syndrome needs to be
identified for diagnosis, eg:
Giant cell arteritis } → 15% of PUO
Polymyalgia Rheumatica }
Behcet’s Disease
Relapsing polychondritis

34. Collagen-
Vascular-
Disease
Adult Onset Still’s Disease
◦ Age 16 – 35 with (-ve) RF & ANA
◦ Fever is high and spiking with temperature up
to 41.6oC (hectic)
◦ Fever is either intermittent or remittent (peaks
typically at night)
◦ Most patient seek medical attention within 2
weeks.
◦ A distinctive evanescent macular or papular
rash is typically present during the course of the
illness.
◦ Diagnosis is strictly a clinical: RF is almost
uniformly negative.
◦ Other features: myalgias, arthritis, leucocytosis
(neutrophils), hepatosplenomegaly &
lymphadenopathy, high serum ferritin (> 2000)

35. VascularCauses
Pulmonary Emboli
• 50% are febrile
• Fever is characteristic (< 39oC)
• Patient typically has
predisposing factors : cancer or
recent immobility, family
history, recent surgery,
polycythaemia.
Hematoma in closed space
• Haemorrhage in the
retroperitoneal space
• Within the wall of an aneurysm
or dissection of the thoracic or
abdominal aorta.

36. Factitious Fever
A small percentage of cases of
PUO are factitious / False fever:
Thermometer manipulation
using external heat or substitute
thermometer. —Genuine fever
(self induced)
Administration of pyrogenic
substances (bacterial
suspensions)
Generally young women with
connection to health care often
nurses or doctors –
These patients either created
factitious fever by manipulation
of the thermometer or
fraudulent fever by self-induced
means.

38. PYREXIAOF
UNKNOWN
ORIGIN
The majority of disease remaining after an initial
NEGATIVE workup are:
◦ 1. Neoplasm
◦ 2. Seronegative collagen vascular disease
◦ 3. ProgressiveTuberculosis
◦ 4. Increasing Drug Addition
◦ 5. Elderly with Endocarditis
◦ 6. HIV with or without infection or malignancy
◦ 7. Prosthetic devices / implants
◦ 8.Travel

39. EVALUATION OF
PUO

40. Finding the
cause: History
How long has the fever lasted?
Is it increasing?
Is it increasing rapidly?
Has the fever gone away?
How many days did it take for the fever to go
away?
Do you have alternating chills and fever?
How frequently does it alternate (days, hours)?

41. Finding the
cause: History
Did it occur within four to six hours after exposure
to something that you might be allergic to?
Does the fever follow an up and down pattern (is it
high, then lower, then high)?
Did it develop suddenly?
Does the temperature go up and down suddenly
(spike) or does it change slowly?
Does it go away and then come back again daily?
Rx depends on the duration and cause of the
fever, and on other accompanying symptoms.

42. Travel History:
Travel to an area known to be endemic for certain disease:
Name of the area, duration of stay
Onset of illness (incubation period). E.g.

43. Finding the
cause: History
The history for PUO should be highly detailed.
As noted, he characteristics of the fevers,
including duration, accompanying symptoms such
as rigors and drenching sweats, timing of fevers,
and any precipitating events, should be sought.
Symptoms concurrent to the febrile illness will
often be the key to identification of cause.
If none is forthcoming, it is particularly important
to elicit several key features of the more common
and severe aetiologies.

44. Finding the cause: History
Unintentional weight los neoplastic process / Malignancy
Back Pain TB Spondylitis, Bone Metastasis
Drenching night sweats Haematological malignancy,Tuberculosis.
Headache Chronic Meningitis,Giant cell arteritis (GCA)
RUQ Pain Liver Abscess
LUQ Pain SplenicAbscess
Oral & Genital Ulcer Behcet’s Disease
JawClaudication / unilateral retro‐orbital
headache
Temporal Arteritis
Subtle changes in behaviour Granulomatous Meningitis
Joint pain, particularly early in the morning Inflammatory arthritis

45. Finding the
cause: History
Past medical history
Risk of immunosuppression, e.g. Prolonged
steroid use, surgeries and prosthetic materials
Thromboembolic disease risk factors, such as
previous episodes, prolonged immobility and oral
contraceptive
Family history of malignancy and fevers
Recent additions or changes to medications
Travel history, both local / domestic and
international

46. Physical Examination
Detailed examination of the skin, eyes, ears, nose, throat, neck, chest, and
abdomen to look for the cause of the fever is imperative.
◦ Measurement of fever
◦ Lymphadenopathy
◦ Scalp tenderness
◦ Hepatosplenomegaly
◦ Cardiac murmurs
◦ Respiratory auscultation
◦ Rashes

47. Physical Examination
Symptoms and Examination findings may Indicate the source of fever / PUO.
It is important to be able to place the patient into possible categories
It is also important to note that the likelihood that a patient's illness belongs to
one of these specific categories depends heavily on their
◦ clinical scenario,.
◦ age and
◦ presence of risk factors, such as zoonotic or occupational exposures

48. INVESTIGATIONS

49. Investigations
Although non‐specific investigations are not
recommended,
baseline blood tests,
urine microscopy and culture and
a chest X‐ray
are minimally invasive and useful when combined
with appropriate history and examination

50. Baseline Blood Panel
Baseline Bloods include:
◦ Erythrocyte sedimentation rate (ESR)
◦ C‐reactive protein (CRP)
◦ A full blood count (FBC) with differential white cell
count
◦ Creatinine, electrolytes
◦ Liver function tests (LFT)
◦ Rheumatoid factor (RF)
◦ Antinuclear antibodies (ANA)
◦ Three blood cultures (BC) from separate venepunctures
◦ Human immunodeficiency virus (HIV)

51. Baseline Blood Panel
Other second line investigations include:
◦ Hepatitis B virus (HBV)
◦ Hepatitis C virus (HCV)
◦ Lactate dehydrogenase (LDH)
◦ Ferritin
◦ Thyroid function test (TFT)
◦ Serum protein electrophoresis (EPG)
◦ Serology (and other special investigation) – crag,
cmv, rpr, etcetera

52. Other DiagnosticTesting
Urinalysis
Sputum culture and forTB analysis
Lumbar Puncture forCSF analysis
CXR.

53. RoleOf Lab Investigations
Full Blood Count
◦ Anaemia if present → suggest a serious underlying disease
◦ Leukocytosis → occult bacterial infection
◦ Lymphocytosis & atypical Lymphocyte → Infectious mononucleosis
◦ Leucopenia and Lymphopenia → advanced HIV
◦ Leukoerythroblastic Anaemia → DisseminatedTB
◦ Thrombocytopenia → Malaria/Leukemia
◦ Peripheral Blood → Malaria

54. ESR
If elevated → significant inflammatory process
Greatest use in establishing a serious underlying disease,
If very high → ESR > 100 mm/h:Tuberculosis / Myeloma /Temporal arteritis
58% → malignancy like Lymphoma/myeloma
25% → Infection like Endocarditis / Giant cell arteritis
Note: ↑ High ESR → lacks specificity: • Drug Reaction / Thrombophlebitis /
Nephrotic Syndrome } may cause very high ESR
Normal ESR may still have → significant inflammatory process is absent

55. CRP
CRP level may be useful cross reference for ESR
More sensitive and specific indicator of an “acute phase” inflammatory
metabolic response.
ESR & CRP are elevated in:
1. Bacterial Infection
2. Neoplasm
3. Immunological-mediated inflammatory states
4.Tissue infarction

56. Cultures
Blood Culture
◦ Obtain more than 3 blood cultures from separate sites over 24 hr
period prior to antibiotics eg, if Infective Endocarditis is
suspected
Sputum: ForTuberculosis
Any Other Body Fluids: CSF/urine/pleural or peritoneal
fluid
Bone marrow aspirate: forTuberculosis/Brucellosis
Lymph node aspirate: egTB

57. Other MarkersOf Inflammation:
Acute Phase Proteins
Proteins Increased Proteins Decreased
Fibronogen Albumin
Ferritin Transferrin
Plasminogen
Fetoprotein
Protein S
Ceruloplasmin

58. Laparoscopy
To visualize and biopsy the pathology in
the abdomen e.g.
◦ Tuberculous peritonitis
◦ Peritoneal carcinomatosis

59. Histopathological Evaluation
Biopsy
◦ Enlarged lymph node
◦ Granulomatous disease (Tuberculosis)
◦ Metastatic carcinoma
◦ Others
Hepatomegaly or Abnormal LFT
Hepatic Granuloma
◦ Non-caseating:Tuberculosis/Sarcoidosis &
Brucellosis
◦ Caseating:Tuberculosis Bone Marrow
◦ Granuloma ±Tubercle Bacilli →Tuberculosis

60. Biopsy
Aplastic Cells → Leukemia
Leishmania Bodies → Kala-Azar
Atypical Cells → Lymphoma
Atypical Plasma Cells → Multiple myeloma
Pleural or pericardial fluid→ Extrapulmonary
Tuberculosis
Temporal artery biopsy→ Giant Cell Arteritis

61. Imaging
Studies
Aim: to localize abnormalities for definite tests or
treatment
Chest x-ray:
◦ Miliary shadows → disseminated tuberculosis
◦ Atelectasis /↑ Hemi diaphragm / Pleural
Effusion
◦ Mediastinal mass → Lymphoma/Tuberculosis/
Sarcoid
If CXR is Normal → Repeat on weekly basis
Ultra sonography
◦ Hepatic, Splenic, Pancreatic or Subphrenic
Abscess

62. Imaging Studies
CT-Scan
CT scan chest
Mediastinal mass →Tuberculosis/Lymphoma/ Sarcoidosis
Dorsal Spine → Spondylitis and disc space disease
CT-Scan Abdomen → very effective to visualize
All types of abscesses ,
Retroperitoneal tumor, lymph node or haematoma
MRI: Spleen, Lymph NodeAndThe Brain

63. Radionuclear Scanning
BoneTechnetium-99m-scan → osteomyelitis (skeletal),bony metastasis
Gallium scan → occult inflammation, pneumocystis
Indium labeled WBC-scan → occult abscesses
Fluorodeoxyglucose F18 (FDG) PET scanning appears to be superior to other
forms of nuclear imaging – FDG used in PET scans accumulates in tumour and
at sites of inflammation

64. Radionuclear Scanning
Overall Assessment:
Non-specific tests to localize a site for more specific evaluation (such as CT-
scan)
Impressive no. of false (+) and false (-) results
True positive scan only indicates an area of increased uptake → no anatomic
detail

65. TREATMENT
&
PROGNOSIS

66. Treatment
Treatment other than supportive care should not be commenced
until a diagnosis is obtained.
Due to the wide range of differentials, therapeutic trials are not
recommended.
This approach to PUO of awaiting diagnosis before considering
treatment is suggested as the mortality of PUO is low,
And early use of antipyretics or antimicrobials may delay
diagnosis.
The mortality rate for PUO is less than 10%, with most deaths
occurring as a result of malignancy

67. Treatment
In patients with low white cell count or PUO as a complication of
hospitalisation start antibiotics and adjust treatment once the cause is found
Likewise, in cases where severe diagnoses are suspected, such patients should
be treated empirically until the diagnosis can be confirmed or excluded.
These include infective endocarditis, giant cell arteritis and miliary or central
nervous system tuberculosis

68. Prognosis
PUO remains a clinical challenge despite greater understanding of the diseases
responsible and increased access to diagnostic tests.
New technologies, such as FDG‐PET, show promise to aid in diagnosis;
However, detailed history and examination remain the most important steps in
achieving a diagnosis for the patient and guiding further investigation.
Outlook depends on the cause of the fever

69. Prognosis
If no cause is found treatment
with antipyretics can be
instituted to decrease the
effects of the fever especially in
longstanding PUO
If no cause is found
it is important to
follow up and re
evaluate the
patient
Outcome is worst
for neoplasms
PUO patients who remain
undiagnosed after extensive
evaluation generally have a
favourable outcome and the
fever usually resolves after 4-
5 weeks.

70. references
R. W. Beresford , I. B. Gosbell (2016). Clinical Perspectives: Pyrexia of unknown origin:
causes, investigation and management. Internal Medicine Journal, Volume 46, Issue 9,
https://doi.org/10.1111/imj.13180

71. THANKYOU