ENAM MEDICAL COLLEGE

1. An Update on
‘Pyrexia of Unknown Origin’
Speaker
Dr. AL TARIQUE
Registrar- Medicine

2. Pyrexia of Unknown Origin
• A temperature above 38°C on multiple occasions for
more than 3 weeks, without diagnosis, despite initial
investigation in hospital for 1 week.
• The definition has been relaxed to allow for investigation
over 3 days of inpatient care, three outpatient visits or 1
week of intensive ambulatory investigation.

3. Aetiology
Infections, 30%
Malignancy, 20%
Connective tissue
disorders, 15%
Miscellaneous, 20%
Idiopathic, 15%

4. Specific locations
 Abscesses:
 Hepatobiliary
 diverticular
 urinary tract (including prostate)
 pulmonary
 CNS
Infections (~30%)

5.  Infections of oral cavity, head and neck
 Infective endocarditis
 Bone and joint infections

6.  Specific organisms
 Tuberculosis
 HIV-1 infection
Other viral infection
 Cytomegalovirus (CMV),
 Epstein–Barr virus (EBV)

7. Fungal infections
Aspergillus spp.
Candida spp. or dimorphic fungi
Infections with fastidious organisms
Bartonella spp.
Tropheryma whipplei

8. Specific patient groups
Recently spent time in a region with geographically restricted
infection
• Malaria
• Dengue
• Rickettsial infections
• Brucella spp.

9. • Amoebic liver abscess
• Enteric fever
• Leishmania spp.
• Middle east respiratory syndrome
coronavirus

10. Residence in or travel to region with endemic infection
• TB
• Extensively drug resistant TB
• Brucella spp.
• HIV 1
• Trypanosoma cruzi

11. • Infections related to prosthetic materials and surgical
procedures
• Pneumonia
• Urinary tract infection
• Central venous catheter infections
Nosocomial infections

12. HIV-positive individuals
• Acute retroviral syndrome
• AIDS-defining infections
Disseminated Mycobacterium avium complex, Pneumocystis
carinii, CMV and others

13. Malignancy (~20%)
Haematological malignancy
Lymphoma
Leukaemia
Solid tumours
Renal cell carcinoma
Hepatocellular carcinoma
Carcinoma of colon
Gastric carcinoma

14. Connective tissue disorders (~15%)
Older adults
Temporal arteritis/Polymyalgia rheumatica
Younger adults
Still’s disease (juvenile rheumatoid arthritis)
Systemic lupus erythematosus (SLE)
Vasculitic disorders
Polymyositis
Rheumatic fever

15. Miscellaneous (~20%)
Cardiovascular
Atrial myxoma
Aortitis
Aortic dissection
Respiratory
Sarcoidosis
Pulmonary embolism
Extrinsic allergic alveolitis

16. Gastrointestinal
Inflammatory bowel disease
Alcoholic liver disease
Pancreatitis
Endocrine/metabolic
Thyrotoxicosis
Thyroiditis
Phaeochromocytoma

17. Haematological
Haemolytic anaemia
Thrombotic thrombocytopenic purpura
Myeloproliferative disorders
Inherited
Familial Mediterranean fever
Periodic fever syndromes

18. Drug reactions / Drug induced fever
Allopurinol, Carbamazepine, Lamotrigine, Phenytoin,
Sulfasalazine, Frusemide
Antimicrobials
Sulfonamides, Minocycline, Vancomycin, β-lactam antibiotics
and isoniazid.
Cardiovascular drug : Quinidine
Factitious fever

19. Structured Approach
Pyrexia of unknown origin

20. Fever > 38°C (100.4°F) and illness lasting > 3 weeks, without
diagnosis, despite initial investigation during 3 days of inpatient care
or after more than three outpatient visits.
History and physical examination
Stop antibiotic treatment and glucocorticoids

21. Obligatory investigations:
ESR & CRP, Hemoglobin, Platelet Count, Leukocyte Count&Differential,
Electrolytes & Creatinine, Total Protein, Protein Electrophoresis,
Alkaline Phosphatase, ALT, AST, LDH, Creatine Kinase,
Antinuclear Antibodies, Rheumatoid Factor,
Urinalysis, Blood Cultures, Urine Culture,
Chest X-ray, Abdominal Ultrasonography, Tuberculin Skin Test

22. Exclude manipulation with thermometer
Stop or replace medication to exclude drug fever
PDCs present PDCs absent or misleading

23. PDCs present PDCs absent or misleading
Guided diagnostic tests Cryoglobulin & fundoscopy
NO DIAGNOSISDIAGNOSIS
FDG-PET/CT
(or labeled leukocyte scintigraphy or
gallium scan)

24. Scintigraphy abnormal Scintigraphy normal
Confirmation of abnormality
(e.g. biopsy, culture)
• Repeat history &
physical examination
• Perform PDC-driven
invasive testing
NO DIAGNOSISDIAGNOSIS
DIAGNOSIS NO DIAGNOSIS

25. Stable condition:
Follow-up for new PDCs
Consider NSAID
Deterioration :
Further diagnostic tests
Consider therapeutic trial
Chest and abdominal CT
Temporal artery biopsy (>55years)
NO DIAGNOSISDIAGNOSIS

26. Potentially diagnostic clues (PDCs)
• The most important step in the diagnostic workup is the
search for potentially diagnostic clues (PDCs) through
complete and repeated history taking and physical
examination and the obligatory investigations.

27. • PDCs are defined as all localizing signs, symptoms, and
abnormalities potentially pointing toward a diagnosis.

28. Pyrexia of unknown origin
A Clinical Approach

29. History taking
History of presenting complaint-
1. Onset :
Acute : Malaria, Pyogenic infection
Gradual : TB, Typhoid fever
2. Character
High grade fever : UTI, Malaria
Low grade fever : TB

30. 3.Pattern: Despite historical claims, pattern of fever are not
especially helpful in establishing a specific diagnosis.
• Continued fever: Fluctuation of fever not >1°C ,does not touch
baseline.
• Intermittent fever: Fever that persist for several hours ,always touches
baseline
• Remittent fever: Fever fluctuates > 2°C , does not touch the baseline.

31. 4.Associated symptoms
• Chills and rigors : acute pyelonephritis, acute cholangitis,
subphrenic abscess, pyogenic lung abscess, SBE, lobar
pneumonia
• Night sweats : TB, infective endocarditis
• Loss of weight : Malignancy, Vasculitis, TB, HIV, IBD,
thyrotoxicosis

32. Cough : TB, PE, Q fever, sarcoidosis, legionnaire’s disease.
Nasal symptoms : sinusitis, GPA, relapsing fever, psittacosis
Confusion : TB, Cryptococcus, Sarcoid, enteric fever.
Arthralgia : SLE, infective endocarditis, Lyme disease,
brucellosis, enteric fever.

33. 5. Antecedents -prior to onset of fever:
 Dental extraction – infective endocarditis
 Urinary catherization – UTI, bacteremia

34.  History of past illness
• Past history of infection . e.g. malaria, kala-azar, tuberculosis.
• History of recent dental procedure.
• History of surgery and trauma.
• History of neoplasia, connective tissue disorders, prosthetic
valve, liver disorder.

35.  Sexual history
• HIV 1 transmission
 Family history
• TB, familial Mediterranean fever.
 History of Intravenous drug injection or receipt of
blood products
• HIV -1, HBV and HCV

36.  Travel history
• Amoebiasis, typhoid fever, malaria, schistosomiasis
 Occupation
• E.g. anthrax in leather tannery workers
 History of Animal exposures
• Brucellosis, Toxoplasmosis, Leptospirosis, Q fever,
Psittacosis
 Diet history
• Consider undercooked meats , shellfish, unpasteurized
dairy products or well water

37. Pyrexia of unknown origin
Physical examination

38.  Observations
• Temperature
• Sweating
• Weight loss
• Respiratory distress
• Pallor
• Jaundice
• Altered consciousness

39.  Skin
• Generalised erythema
• Rash-HIV, EBV, SLE, Vasculitis,
still’s disease, endocarditis
• IV injection track marks
• Surgical scars
• Prosthetic devices, e.g. central
venous catheters
• Tattoos

40.  Hands and nails
• Signs of chronic liver disease
• Splinter hemorrhages
• Finger Clubbing
• Janeway lesions
• Vasculitis lesions

41.  Oropharynx
• Dental caries
• Tonsillar enlargement or
exudate
• Candidiasis

42.  Eyes
• Conjunctivitis –leptospirosis, relapsing fever,
spotted fever, trichinosis
• Uveitis- TB, sarcoid, adult Still’s disease, SLE,
Behcet’s disease
• Roth’s spot in infective endocarditis
• Hemorrhages & exudates – cytomegalovirus
retinitis
• Choroidal lesions of tuberculosis

43. Head and neck
• Lymphadenopathy-
Lymphoma, TB, EBV, CMV,
HIV, Toxoplasmosis
• Parotidomegaly

44. Neurological
• Neck stiffness
• Photophobia
• Delirium
• Focal neurological
signs

45.  Abdomen
• Hepatomegaly- TB, EBV, malignancy, malaria, enteric fever,
granulomatous hepatitis, visceral leishmaniasis
• Splenomegaly – Leukaemia, Lymphoma, TB, IE, CMV, EBV, sarcoid,
enteric fever
• Renal – Chronic pyelonephritis, perinephric abscess, renal tumor
• Mass lesions
• Surgical drains

46.  Heart and Lungs
• Tachycardia, hypotension
• Murmurs or prosthetic heart sounds
• Pericardial rub
• Signs of consolidations
• Pleural or pericardial effusions

47. Musculoskeletal
• Joint swelling, erythema or
tenderness
• Localised tender spine
suggestive of epidural
abscesses or discitis
• Draining sinus of chronic
osteomyelitis

48.  Genitalia and rectum
• Epididymo-orchitis
• Ulceration and discharge
• Testicular swelling or
nodules
• Inguinal lymphadenopathy
• Prostatic tenderness

49. Treatment
Supportive treatment
• Paracetamol
• Tepid sponging
• Replacement of salt and
water is important in
patients with drenching
sweats.
According to cause

50. Prognosis
• The overall mortality is 30-40%, mainly attributable to
malignancy in older patients.
• If no cause is found, the long term mortality is low and fever
often settles spontaneously.

51. Home massage
• PUO is far more often caused by an atypical presentation of a
rather common disease than by a very rare disease.
• Because of unavailability of all diagnostic facilities and the
poverty of general population, PUO can not be evaluated in
every case

52. • The most likely cause of PUO, like all other countries of the
world, is infection in our country.
• Studies support that 50% of cases are caused by infections,
eg, tuberculosis in western nations.

53. • As the duration of fever increases, the likelihood of an
infectious cause decreases.
• Empirical therapeutic trials with antibiotics, glucocorticoids,
or antituberculous agents should be avoided in PUO except
when a patient’s condition is rapidly deteriorating.

54. THANK YOU