This document presents a case study of a 39-year-old male presenting with pyrexia of unknown origin (PUO) lasting 4 weeks with night sweats, lethargy, aches and pains. Initial investigations and antibiotics provided no diagnosis. Further testing for various infections and rheumatological/immunological conditions was also negative. The patient was eventually referred to rheumatology and diagnosed with Adult Still's Disease based on elevated inflammatory markers and improvement on steroids. The document then reviews PUO in general including definitions, prevalence, diagnostic workup including history, exams, imaging and biopsy, and outcomes which are often undiagnosed but prognosis remains good.

1. Pyrexia of Unknown Origin
Michael-John Devlin
(CT2 Infectious Diseases)
09/12/13

2. Aims
• Case history of Pyrexia of Unknown Origin
(PUO)
• Discussion on investigation and outcomes of
PUO

3. Case
• 39 year old male
• 4 week history
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night sweats
Lethargy
“aches and pains”
general flu like symptoms
episode of swollen testes

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No past medical history
No regular medications
No family history
Accountant
Married with 2 children
Non smoker, no C2H50H
Travel history recent trip to France and trip to
India at age 19

5. Examination
RR 18
Sats 98%
RA
HR 110
BP 110/70
T 39.1
– CVS: ? extra heart sound
– Respiratory and Abdominal: nil of note
– Joint examination: myalgia and arthralgia
– Testicular examination: no swelling
– No lymphadenopathy
– No rash

6. 16/09/13
3/10/13

11. Belfast Trust Antibiotic Protocol

12. 16/09/13
Tazocin and Gentamicin
24/09/13

14. Referral to ID
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HIV
Q-Fever
Blood cultures x 3
Sputum AFB x 3
T. Pallidium
EBV
Leptospiral
Bartonella
Erythrovirus B19
B12 and Folate
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Toxoplasma
Monospot
CMV
Brucella
Mumps
AI Profile
ACE
Immumoglobulins
Iron

15. x3
x3

23. Referred to Rheumatology
• High ESR and ferritin with PUO alongside
myalgia and arthralgia in the absence of
infection
? Adult Still’s Disease

24. • Prednisolone
• Significant improvement in symptoms

25. 30/09/13
Prednisolone
03/10/13

26. Discussion

27. “Fever of >38.3°c on
several occasions persisting
without a diagnosis for at
least 3 weeks despite at
least one week of
investigations in hospital”

28. • Modified into 4 different subtypes:
– Classic (>38° > 3 weeks or > 2 visits or > 3 days inpatient)
– Nosocomial (>38° > 3 days and not present on admission)
– Immune deficient (>38° > days and negative cultures at 48
hours)
– HIV related (>38° > 3 weeks or > 3 days inpatient)

31. Prevalence
• Two main studies quoted in the literature
• Iikuni et al
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Kitasato University Hospital, Japan; 1982-1992
5245 patients of which
153 were classified as PUO (2.9%)
Only one centre and ? inclusion criteria
• Bleeker-Rovers et al
– Multicentre study in the Netherlands 2003-2005
– 73 patients
– Excluded were immunocompromised defined as neutropenic,
HIV positive, hypogammaglobulinaemia or steroid use

32. Work Up
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History
Examination
Basic Investigations
Specialist Investigations

33. History
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Occupation and animal exposure
Travel history
Immunosuppression
Drug and toxin history
Localizing symptoms

34. www.gamapserver.who.int/GlobalAtlas

35. Drugs
• Antibiotics (sulfonamides, penicillins, nitrofurantoin, vancomycin,
antimalarials)
• H1 and H2 antihistamines
• Antiepiletpics (barboturates and phenytoin)
• Iodides
• NSAIDS (including salicylates)
• Antihypertensives (hydralazine, methyldopa)
• Antiarrhyhmic drugs (quinidine, procainamide)
• Antithyroid drugs

36. Examination
Examination and
re-examination

39. Nuclear Imaging
• Gallium-67 or Indium-111
• Sensitivity of 67% and 78% respectfully
• Specificity of 78% and 94% in chronic infections
• 145 cases: 29% gallium useful compared to 14% CT and
6% USS
• FDG-PET or PET/CT
• No large prospective studies
• Sensitivity of 88-99% and specificity of 77-90%

40. Biopsy
• Guided examination and previous
investigations
• Bone Marrow Biopsy
• Less than 2% helped with diagnosis

41. Outcome
• Knockaert et al
– 199 patients; 61 discharged without diagnosis
• 12 had definite diagnosis within 2 months
• 31 became symptom free without a diagnosis
• 18 experienced symptoms for years; 10 became
symptom free at time of publish and 6 had died with
only 2 of the deaths being attributed to the PUO

42. Conclusion
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Wide Spectrum; keep an open mind
History and examination vital
Basic investigations
Targeted investigations
Undiagnosed prognosis still good

43. References
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Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases.
Medicine (Baltimore) 1961; 40:1
Estee Torok, Ed Moran, Fiona Cooke. Oxford Handbook of Infectious Diseases and
Microbiology. Oxford Press
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicentre study of
fever of unknown origin: the yield of a structured diagnostic protocol. Medicine
(Baltimore) 2007 86:26
Mourad O, Palda V, Detsky AS. A comprehensive evidence based approach to fever
of unknown origin. Arch Intern Med 2003; 163:545
Nurhan Ergul, Tevfik Fikret Cermik. FDG-PET or PET-CT in Fever of Unknown Origin:
The diagnostic role of underlying primary disease. Int J Mol Imaging 2011
Varghese et al. Investigation and management of pyrexia of unknown origin in
adults. BMJ 2010 vol 341 878-881
Paul M Arnow, John P Flaherty. Fever of Unknown Origin. Lancet 1997 350 575-80
www.WHO.org
www.uptodate.com

44. • With thanks to ;
Dr. Claire Donnelly (Infectious Diseases Consultant)