Question 4 Supporting Evidence Dr. MJ Devlin

Pyrexia of Unknown Origin

Michael-John Devlin (CT2 Infectious Diseases)

09/12/13

Aims

• Case history of Pyrexia of Unknown Origin (PUO)

• Discussion on investigation and outcomes of PUO

Case

• 39 year old male

• 4 week history • night sweats• Lethargy• “aches and pains” • general flu like symptoms• episode of swollen testes

• 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

– CVS: ? extra heart sound – Respiratory and Abdominal: nil of note– Joint examination: myalgia and arthralgia – Testicular examination: no swelling– No lymphadenopathy– No rash

RR 18Sats 98% RAHR 110BP 110/70T 39.1

Examination

16/09/13

3/10/13

Belfast Trust Antibiotic Protocol

Tazocin and Gentamicin

16/09/13

24/09/13

Referral to ID

• HIV• Q-Fever• Blood cultures x 3• Sputum AFB x 3• T. Pallidium• EBV• Leptospiral• Bartonella• Erythrovirus B19• B12 and Folate

• Toxoplasma• Monospot• CMV• Brucella• Mumps• AI Profile• ACE• Immumoglobulins• Iron

x 3

x 3

Referred to Rheumatology

• High ESR and ferritin with PUO alongside myalgia and arthralgia in the absence of infection

? Adult Still’s Disease

• Prednisolone

• Significant improvement in symptoms

Prednisolone

03/10/13

30/09/13

Discussion

“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”

• 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)

Prevalence

• Two main studies quoted in the literature• Iikuni et al

– 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

Work Up

• History • Examination• Basic Investigations• Specialist Investigations

History

• Occupation and animal exposure• Travel history• Immunosuppression• Drug and toxin history • Localizing symptoms

www.gamapserver.who.int/GlobalAtlas

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

Examination

Examination and re-examination

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%

Biopsy

• Guided examination and previous investigations

• Bone Marrow Biopsy• Less than 2% helped with diagnosis

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

Conclusion

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

References • 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

• With thanks to ;

Dr. Claire Donnelly (Infectious Diseases Consultant)