2. INTRODUCTION
Body temperature is normally maintained within a range of 37 – 38°c ,
normal body temperature is generally considered to be 37°c .
BODY TEMPERATURE
3. PHYSIOLOGY
Normal body temperature is
maintained by a complex regulatory
system in the anterior hypothalamus,
preoptic area, temperature sensitive
area, thermal set point.
4. PATHOGENESIS
Substances the mediate the elevation of core body temperature
There are two types; exogenous and endogenous pyrogens.
PYROGENS
EXOGENOUS PYROGENS
It is derived from outside of the host, such as microorganisms, toxins and
microbial products
They are generally large molecules – cannot pass blood brain barrier
They induce the release of endogenous pyrogens from macrophages.
5. PATHOGENESIS
ENDOGENOUS PYROGENS
Endogenous pyrogens are derived from the macrophages.
They are small molecules – can pass blood brain barrier
Pyrogen cytokines trigger the
hypothalamus to release PGE2,
resulting in:
1. Resetting of thermostatic
temperature
2. Activation of vasomotor center
3. Vasodilatation
4. Heat production
6. PYREXIA OF UNKNOWN ORIGIN
ORIGINAL DEFINITION (Petersdotf anf Beeson, 1961)
Temperature ≥ 38.3ºC (101ºF) on several occasions
Fever ≥ 3 weeks
Failure to reach a diagnosis despite 1 week of inpatient investigations or
3 outpatient visits
NEW DEFINITION (Petersdotf anf Beeson, 1961)
Temperature ≥ 38.3ºC (101ºF) lasting for more than 14 days without an
obvious cause despite a complete history, physical examination and routine
screening with laboratory evaluation
7. FACTORS
FACTORS THAT MAY HAVE CONTRIBUTED TO
THE DIFFICULTY IN FINDING THE CAUSE OF FEVER INCLUDE:
A common illness that does not have the usual symptoms – may be
asymptomatic
Illness whose symptoms appear later
Illnesses with possibly delayed positive test
Person is unable to communicate about other symptoms
Genetic condition that causes periodic fever.
8. COMMON CAUSES
COMMON CAUSES OF PYREXIA OF UNKNOWN ORIGIN
40%
25%
15%
10%
10%
Infection (40%) Malignancy (25%)
Autoimmune Disease (15%) Others/ Miscellaneous (10%)
Undiagnosed (10%)
9. CLASSIFICATION
DURACK AND STREET’S CLASSIFICATION
1. Classical
2. Nosocomial
3. Neutropenic
4. Pyrexia of unknown origin with HIV infection
11. 1. CLASSICAL
CLASSIC PYREXIA OF UNKNOWN ORIGIN
Temperature >38.3°C (100.9°F)
Duration of >3 weeks
Evaluation of at least 3 outpatient visits or 3 days in hospital
AETIOLOGIES
1. Infections
2. Malignancies
3. Collagen vascular disease
4. Others / miscellaneous which includes drug-induced fever
12. 1. CLASSICAL
A. INFECTIONS
Bacterial
Abscesses, tuberculosis, uncomplicated UTI, endocarditis, osteomyelitis,
sinusitis, prostatitis, cholecystitis, empyema, biliary tract infection,
brucellosis, typhoid, etc.
Viral
Cytomegalovirus, infectious mononucleosis, HIV, etc.
Parasites
Malaria, toxoplasmosis, leishmaniasis, etc.
Fungal
Histoplasmosis, etc.
As the duration of fever increases, infectious etiology decreases. Malignancy and
factitious fevers are more common in patients with prolonged pyrexia of unknown origin
16. 1. CLASSICAL
C. MISCELLANEOUS
FACTITIOUS FEVER
Central
1. Brain tumor
2. Hypothalamic dysfunction
Peripheral
1. Hyperthyroidism
2. Pheochromocytoma
Munchausen syndrome
Munchausen by proxy
THERMOREGULATORY DISORDER
17. FEVER PATTERN
• Intermittent Fever
Any fever characterized by intervals of normal temperature
Malaria, pyaemia, septicemia
• Continuous Fever
Temperature remains above normal throughout the day and does
not fluctuate more than 1C in 24 hours
Lobar pneumonia, Typhoid, Meningitis, UTI, Brucellosis
• Remittent Fever
A fever pattern in which temperature varies during each 24 hour
period but never reaches normal.
Enteric Fever, Bacterial Endocarditis, Viral Pneumonia
18. FEVER PATTERN
• Relapsing Fever
An acute infection with recurrent episodes of fever caused by
spirochetes of the genus Borrelia which are borne by ticks or lice.
• Undulant Fever
An infectious disease due to the bacteria Brucella.
It is called undulant because the fever is typically undulant, rising and
falling like a wave.
It is also called brucellosis after its bacterial cause
19. FEVER PATTERN
• Relapsing Fever
An acute infection with recurrent episodes of fever caused by
spirochetes of the genus Borrelia which are borne by ticks or lice.
• Undulant Fever
An infectious disease due to the bacteria Brucella.
It is called undulant because the fever is typically undulant, rising and
falling like a wave.
It is also called brucellosis after its bacterial cause
21. 2. NOSOCOMIAL
NOSOCOMIAL PYREXIA OF UNKNOWN ORIGIN
Temperature > 38.3°C
Patient hospitalized ≥ 24 hours but no fever or incubating on admission
Evaluation of at least 3 days
More than 50% of patients with nosocomial PUO are due to infection
Focus on sites where occult infections may be sequested, such as:
- Sinusitis of patients with NG or Oro-tracheal tubes
- Prostatic abscess in a man with urinary catheter
25% of non-infectious cause includes:
- Acalculous colecystitis
- Deep vein thrombophlebitis
- Pulmonary embolism
22. 3. NEUTROPENIC
IMMUNE DEFICIENT / NEUTROPENIC PUO
Temperature >38.3°C
Neutrophil count ≤ 500 per mm3
Evaluation of at least 3 days
Patients on chemotherapy or immune deficiencies are susceptible to:
- Opportunistic bacterial infection
- Fungal infections such as candidiasis
- Infections involving catheters
- Perianal infections
Examples of etiological agent:
- Aspergillus
- Candida
- CMV
- Herpes simplex
23. 4. HIV-ASSOCIATED
IMMUNE DEFICIENT / NEUTROPENIC PUO
Temperature > 38.3°C
Duration of > 4 weeks for outpatients, > 3 days for inpatients
HIV infection confirmed
HIV infection alone may be a cause of fever
Common secondary causes include:
- Tuberculosis
- CMV infection
- Non-hodgkin lymphoma
- Drug-induced fever
24. CLINICAL APPROACH
PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH
1. Onset
a. Acute
b. Gradual
2. Character
2. Antecedents
a. Dental extraction
b. Urinary catheterization
HISTORY OF PRESENTING ILLNESS
25. CLINICAL APPROACH
PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH
4. Associated symptoms
Chills and rigors
Night sweats
Loss of weight
Cough and dyspnea
Headache
Joint pain
Abdominal pain
Bone pain
Sore throat
Dysuria and rectal pain
Altered bowel habit
Skin rash
26. CLINICAL APPROACH
PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH
PAST MEDICAL HISTORY
PAST SURGICAL HISTORY
DRUG HISTORY
FAMILY HISTORY
27. CLINICAL APPROACH
PYREXIA OF UNKNOWN ORIGIN : A CLINICAL APPROACH
Travel
Residential area
Occupation
Contact with domestic / wild animals / birds
Diet history
Sexual orientation
Close contact with TB patients
28. PHYSICAL EXAMINATION
Pattern of fever – continuous, intermittent, relapsing
Ill or not ill
Weight loss – chronic illness
Skin rash
GENERAL
HANDS
Stigmata of infective endocarditis
Vasculitis changes
Clubbing
Presence of arthropathy
Raynaud’s phenomenon
29. Drug injection sites (IV drug usage)
Epithrochlear and axillary nodes (lymphoma, sarcoidosis, focal infection)
Skin
ARMS
HEAD AND NECK
Feel temporal arteries (tender and thicken)
Eyes – iritis / conjunctivitis
Jaundice (ascending cholangitis)
Fundus – choroidal tubercle (miliary TB), Roth’s spot (infective
endocarditis) and retinal hemorrhage (leukemia)
Lymphadenopathy
PHYSICAL EXAMINATION
30. Butterfly rash
Mucous membranes
Seborrhoic dermatitis (HIV)
Mouth ulcers (SLE)
Buccal candidiasis
Teeth and tonsil infections (abscess)
Parotid enlargement
Ears – otitis media
FACE AND MOUTH
CHEST
Bony tenderness
Cardiovascular – murmurs
Respiratory – signs of pneumonia, tuberculosis, empyema and lung
cancer
PHYSICAL EXAMINATION
32. Signs of meningism (chronic TB meningitis)
Focal neurological signs (brain abscess, mononeuritis multiplex in
plyarthritis nodosa)
PHYSICAL EXAMINATION
CENTRAL NERVOUS SYSTEM
33. a. Full blood count
b. ESR and CRP
c. BUSE
d. LFTs
e. Blood culture
f. Serum virology
g. Urinalysis and culture
h. Sputum culture and sensitivity
i. Stool FEME and occult blood
j. Chest x-ray
k. Mantoux test
INVESTIGATION
STAGE 1 – SCREENING TESTS
34. a. Repeat history and examination
b. Protein electrophoresis
c. CT (chest, abdomen, pelvis)
d. Autoantibody screen
e. Electrocardiogram (ECG)
f. Bone marrow examination
g. Lumbar puncture
h. Temporal artery biopsy
i. HIV test counselling
j. Ultrasonography
INVESTIGATION
STAGE 2
35. INVESTIGATION
STAGE 3
• Tuberculosis, malignancy, Pneumocystis carinii pneumoniaChest radiograph
• Abscess, malignancy
CT of abdomen or pelvis with contrast
agent
• Infection, malignancyGallium 67 scan
• Occult septicemiaIndium-labeled leukocytes
• Acute infection and inflammation of bones and soft tissueTechnetium Tc 99m
• Malignancy, autoimmune conditionsMRI of brain
• Malignancy, inflammation
PET scan
• Bacterial endocarditis
Transthoracic or transesophageal
echocardiography
• Venous thrombosisVenous Doppler study
36. a. Treat TB
b. Endocarditis
c. Vasculitis
d. Trial of aspirin / steroids
INVESTIGATION
STAGE 4
37.
38. 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.
39. THERAPEUTIC TRIALS
WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS?
Therapeutic trials consist of combination of broad spectrum antibiotics and
are given in :-
1. Patient who is very sick to wait.
2. All tests have failed to uncover the etiology.
40. PROGNOSIS
WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS?
Prognosis is determined primarily by the underlying disease.
Outcome is worst for neoplasms.
PUO patients who remain undiagnosed after extensive evaluation generally
have a favorable outcome and the fever usually resolves after 4 - 5 weeks
41. SUMMARY
WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS?
PUO is often a diagnostic dilemma, quandary.
Infections comprise ~30% of cases
Bone marrow biopsies are of low diagnostic yield
Diagnostic approach should occur in a step-wise fashion based on the H&P
Patient’s that remain undiagnosed generally have a good prognosis
42. REFERENCES
WHAT IS THE BEST THERAPEUTIC TRERAPY FOR PUO PATIENTS?
1. Nelson Essenssials Of Pediatrics 6th Edition
2. Harrison’s Principles Of Internal Medicine 18th Edition.
3. Mandell, Bennet & Dolin’s, Principle Of Infectious Disease 6th Edition.