by author Diagnostics in fever of unknown origin an introduction

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1 Diagnostics in fever of unknown origin an introduction Dr Alastair McGregor Department of Infectious Diseases & Tropical Medicine, London North West Hospitals NHS trust Hon Sen Clinical Lecturer, Imperial College London

2 FUO a traditional definition Fever of unknown origin Defined in 1961 by Petersdorf and Beeson 1. A temperature greater than 38.3 C on several occasions 2. Of more than 3 weeks' duration of illness, and 3. Without diagnosis despite 1 week of inpatient investigation

3 Year But the causes have changed Infection (%) Neoplasm (%) NIID (%) Misc. (%) Undiagnosed (%) Location Author USA Petersdorf USA Larson Belgium Knockaert Netherlands De Kleijn Netherlands Bleeker-Rovers Belgium Vanderschueren

4 Why has the epidemiology changed Changing epidemiology of infection TB Rheumatic fever Changing demographics Newly recognised diseases Ageing population Immunosuppression Migration Advances in diagnostics Echocardiography Bacteriology Imaging Polymerase chain reaction Validated serological tests

5 Infections Most common infectious causes of FUO Tuberculosis Abscesses Osteomyelitis Endocarditis Bronchoscopy/ Induced sputum CT / CT-PET MRI Automated blood culture Infectious mononucleosis Computed Tomography Serological tests Serological tests 16S PCR of valves

6 Non infectious inflammatory disease Adult Still's disease Giant cell arteritis (GCA) Polyarteritis nodosa Takayasu's arteritis Behcet s disease Granulomatosis with polyangiitis (Wegener s)

7 Malignancy Common malignancies to present with FUO: Lymphoma, especially non-hodgkin's Leukemia Renal cell carcinoma Hepatocellular carcinoma Sundry liver metastases

8 Various diagnostic stratagems Hurley DL. Fever in adults. Postgraduate Med 1983; 74: Vickery DM, Quinnell RK. Fever of unknown origin. JAMA 1977; 238: De Kleijn EMH, Van Lier HJJ, Van Der Meer JWM and the Netherlands FUO study group. Fever of unknown origin (FUO). Medicine 1997; 76: Knockaert DC. Diagnostic strategy for fever of unknown origin in the ultrasonography and computed tomography era. Acta Clin Belg 1992; 47: De Kleijn EMH, Knockaert DC, Van Der Meer JWM. Fever of unknown origin: a new definition and proposal for diagnostic workup. Eur J Intern Med 2000; 11: 1 3. Beresford RW, Gosbell IB. Pyrexia of unknown origin: causes, investigation and management. Intern Med J Sep;46(9):1011-6ẸSCMID elibrary

9 Sensitivity of tests Bleeker-Rovers CP, Vos FJ, de Kleijn EM et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86(1):26.

10 Author / year Number Role of CT-PET Mean age (years) (range) Study design Patients with diagnosis n (%) Abnormal FDG- PET/PET-CT n (%) Helpfulness of FDG-PET/PET- CT n (%) Lorenzen (17-78) Retrospective 13 (81.3%) 12 (75.0%) 11 (68.8%) Kjaer (27-82) Retrospective 12 (63.2%) 10 (52.6%) 3 (15.8%) Buysschaert (34-68) Prospective 39 (52.7%) 53 (71.6%) 19 (25.7%) Bleeker-Rovers (18-82) Retrospective 19 (54.3%) 15 (48.6%) 13 (37.1%) Bleeker-Rovers (26-87) Prospective 35 (50.0%) 33 (47.1%) 23 (32.9%) Keidar (24-82) Prospective 29 (60.4%) 27 (56.3%) 22 (45.8%) Balink (23-91) Retrospective 44 (64.7%) 41 (60.3%) 38 (55.9%) Federici (25-74) Retrospective 7 (70.0%) 5 (50.0%) 5 (50.0%) Ferda (15-89) Retrospective 44 (91.7%) 44 (91.7%) 43 (89.6%) Dong MJ1, Zhao K, Liu ZF, Wang GL, Yang SY, Zhou GJ. A meta-analysis of the value of fluorodeoxyglucose-pet/pet-ct in the evaluation of fever of unknown origin. Eur J Radiol Dec;80(3):

11 Outcomes Outcomes are good 61 cases of undiagnosed FUO for 2 months Definitive diagnosis in 20% Resolution in 67% Death in 3% 37 patients followed for 6 months 41% recovery 41% persistent 3% died Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Arch Intern Med 1996; 156:618. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore) 2007; 86:26.

12 Infectious Diseases lump biopsy History A practical FUO flowchart Cross sectional imaging Cancer Pulmonary lesion Bronchoscopy Examination Type CT PET Basic blood tests Inflammatory / rheumatology Auto antibodies

13 Cases

14 Case 1 - History 65 year old woman No past medical history Complains of 6 weeks of fever and sweats. Negatives: No cough / chest symptoms No altered bowel habit No urinary symptoms No rash No sore throat / sinus pain / headache / muscle pains No localising symptoms of any sort

15 Case 1 - Examination Vital signs normal except for temperature Pulse 90 bpm Blood Pressure 130/65 mmhg, Resps 18 bpm, Sat 99% On air, Temperature 39.2 o C Examination of chest, abdo, CVS all normal No palpable nodes, pharynx normal

16 HIV negative Blood cultures negative Blood film: Neutropenia. Platelet clumps noted therefore platelet count likely to be higher. Few neutrophils seen with normal morphology. Some small mature lymphocytes. No circulating blasts.

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18 a) More blood cultures b) Upper GI endoscopy c) CT whole body d) CT PET e) Call the haematologist f) Glandular fever serology g) Hepatitis virus serology h) Autoantibodies i) ECHO j) Other Next Steps?

19 Chest CT: Unremarkable Further results Abdo CT: non specific fat stranding in the porta hepatis, in close relation to the duodenum and head of the pancreas Impression of minor swelling of the pancreatic head, but no discrete mass lesion. Periportal oedema Nonspecific low volume peripancreatic and mesenteric lymphadenopathy.

20 Further results 1 Multiple blood cultures negative Hepatitis A-E negative EBV: VCA and EBNA IgG positive CMV: IgG positive OGD with duodenal biopsies normal

21 But over this time

22 Next Steps? a) More blood cultures b) Upper GI endoscopy c) CT whole body d) CT PET e) Call the haematologist f) Repeat glandular fever serology g) Repeat hepatitis virus serology h) Autoantibodies i) ECHO j) Other

23 ANA negative ANCA negative ENA equivocal CMV IgM borderline ECHO normal Next Steps Bone marrow trephine shows normal cellularity and grade 2 reticulin. Marrow appears active with myeloid cells showing marked eosinophilia and mildly expanded erythroid cells. No lymphoma or leukemia infiltration is noted on staining for CD20, CD79a, CD3 & CD5. Patient begins to improve after 8 weeks of fever Haematology arrive and perform a bone marrow

24 Wreghitt T, Behr S, Hodson J, Irwin D. Feverish granny syndrome. Lancet Dec 23-30;346( ):1716.

25 How was the diagnosis confirmed?

26 Case 2 - History 30 year old male Pakistani origin, plenty of preceding travel Background of Crohn s disease from 2000 Small bowel resections 2002/3, 2009 Multiple treatments azathioprine, methotrexate, mercaptopurine, infliximab, adalimumab (most recently) TPN (Hickman line) from 2012

27 8 months prior to presentation: 4 weeks fever, dry cough, headache Unremarkable examination Bloods ESR 112mm/hr Hb 100g/L WCC 4.1x10 9 /L (Neuts 2.9, Lymphocytes 0.9) CRP 52 mg/l U&E/LFT normal Blood cultures Case 2 - History 2 4 sets negative 1x aerobic bottle: GPR diphtheroid

28 Case 2 History 3 CXR: busy lungfields CT chest/abdo/pelvis Multiple tiny lung nodules and interlobular thickening, Enlarged spleen Bone marrow: Micro: AFB and fungal stains negative Histology: Marrow granulomata Culture: no growth Bronchoscopy: acellular, no organisms grown

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30 Case 2 History 4 Mantoux 31mm Sputum AFB/PCR/culture negative Empiric diagnosis: miliary TB Rifampicin / Isoniazid / Levofloxacin IV Switched to Rif / INH / Moxi PO after 2 month 2 months prior to presentation Rif/ INH (stepdown)

31 At presentation 5 weeks of intermittent fever, night sweats and generally unwell On examination: Cachectic Case 2 History 5 Temperature 37.8 o C Physical examination unremarkable Admitted to hospital

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33 Blood Cultures negative

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35 a) CT chest b) CT PET c) Serum ACE Case 2 - Next Steps? d) Autoantibodies e) Blood cultures (extended incubation) f) ECHO

36 Multiple small pulmonary nodules, in areas coalescing into focal consolidation. Mediastinal lymphadenopathy. 1cm nodule

37 a) CT chest b) CT PET c) Serum ACE Case 2 - Next Steps? d) Autoantibodies e) Blood cultures (extended incubation) f) ECHO

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39 Case 2 - Next Steps a) CT chest b) CT PET c) Serum ACE d) Autoantibodies e) Percutaneous biopsy of nodule f) EBUS and biopsy of carinal nodes g) Blood cultures (extended incubation) h) ECHO

40 Case 2 - Further Investigations Continues to have fevers Further blood cultures: Single BC positive at 5 days Gram = Gram positive rod API = no ID Maldi-TOF = Kocuria sp. (poor confidence)

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42 Case 2 - Further Investigations 2 Ziehl-Neelsen stain: positive 16S rrna sequencing M. chelonae Multiple further BCs (after line removal) Isolated in three bottles from six paired sets

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44 Line removed Biopsy deferred Treated with: amikacin IV clarithromycin clofazimine Case 2 - Outcome Rapid clinical improvement Subsequent radiological resolution

45 Case 3 56 year old man Not quite right for 2 months, after returning from Thailand Documented intermittent fevers for 3 weeks Negatives: No cough / chest symptoms No altered bowel habit No urinary symptoms No rash No sore throat / sinus pain / headache / muscle pains No localising symptoms of any sort

46 Case 3 - Examination Vital signs normal except for temperature Pulse 68 bpm Blood Pressure 150/90 mmhg, Resps 20 bpm, Sat 99% On air, Temperature 37.9 o C Examination of chest, abdo, CVS all normal No palpable nodes, pharynx normal

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49 Case 3 - Further results HIV negative Multiple blood cultures negative Hep A-E, EBV and CMV serology unexciting CXR: suspicion of infiltrate in the RUZ CT chest: normal

50 A) ECHO? Case 3 - What Next? B) More Blood Cultures? C) Further serological tests? D) CT abdo pelvis? E) CT-PET whole body F) Colonoscopy

51 There is a large heterogenous lesion in the mid-portion and lower pole of the right kidney measuring 5.2 x 5.5 x 5.7 cm. This appears to be cortically based. Appearances are highly suspicious for a renal cell carcinoma

52 Nephrectomy Histology report: Case 3 - outcome Right kidney, transperitoneal nephrectomy: Clear cell renal cell carcinoma, max. dimension 60mm No evidence of renal sinus, perinephric fat or lymphovascularinvasion, Renal vein margin free of tumour Two lymph nodes; free of tumour (0/2) TNM staging: pt1b, N0 (<7cm, limited to kidney). No evidence of recurrence at 2 years

53 Summary points New serological tests are available Immunosuppression broadens the differential Speak to the laboratory Early CT scans