Diagnostics in Fever of Unknown Origin – an Introduction

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 ESCMID eLibrary © by author 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 ESCMIDinvestigation eLibrary © by author But the causes have changed

Infection Neoplasm NIID Misc. Undiagnosed Year Location Author (%) (%) (%) (%) (%)

1961 36 19 19 19 7 USA Petersdorf

1982 30 31 16 11 12 USA Larson

1992 22.5 7 23 21.5 26 Belgium Knockaert

1997 26 12 25 8 30 Netherlands De Kleijn

2007 16 7 22 4 51 Netherlands Bleeker-Rovers

2014 17 11 24 10 39 Belgium Vanderschueren ESCMID eLibrary © by author Why has the epidemiology changed

• Changing epidemiology of • Advances in diagnostics infection – Echocardiography – TB – Bacteriology – Rheumatic fever – Imaging – Polymerase chain reaction – Validated serological tests

• Changing demographics • Newly recognised diseases – Ageing population – Immunosuppression ESCMID– Migration eLibrary © by author Infections

Most common infectious causes of FUO

Bronchoscopy/ Computed • Tuberculosis Induced sputum Tomography

CT / • Abscesses CT-PET

• Osteomyelitis MRI

Automated Serological 16S PCR of • Endocarditis blood culture tests valves

ESCMID eLibrarySerological • Infectious mononucleosis tests © by author 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) ESCMID eLibrary © by author Malignancy

Common malignancies to present with FUO: • Lymphoma, especially non-Hodgkin's • Leukemia • Renal cell carcinoma • Hepatocellular carcinoma • Sundry liver metastases ESCMID eLibrary © by author Various diagnostic stratagems

• Hurley DL. Fever in adults. Postgraduate Med 1983; 74: 232–44. • Vickery DM, Quinnell RK. Fever of unknown origin. JAMA 1977; 238: 2183–8. • De Kleijn EMH, Van Lier HJJ, Van Der Meer JWM and the Netherlands FUO study group. Fever of unknown origin (FUO). Medicine 1997; 76: 401–14. • Knockaert DC. Diagnostic strategy for fever of unknown origin in the ultrasonography and computed tomography era. Acta Clin Belg 1992; 47: 100–16. • De Kleijn EMH, Knockaert DC, Van Der Meer JWM. Fever of unknown origin: a new definition and proposal for diagnostic work- up. Eur J Intern Med 2000; 11: 1–3. • Beresford RW, Gosbell IB. Pyrexia of unknown origin: causes, investigation and management. Intern Med J. 2016 Sep;46(9):1011- ESCMID6. eLibrary © by author Sensitivity of tests

ESCMID eLibrary

• 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 by (Baltimore). 2007;86(1):26.author Role of CT-PET

Abnormal FDG- Helpfulness of Mean age Patients with Author / year Number Study design PET/PET-CT FDG-PET/PET- (years) (range) diagnosis n (%) n (%) CT n (%)

Lorenzen 2001 16 42 (17-78) Retrospective 13 (81.3%) 12 (75.0%) 11 (68.8%)

Kjaer 2004 19 49 (27-82) Retrospective 12 (63.2%) 10 (52.6%) 3 (15.8%)

Buysschaert 2004 74 56 (34-68) Prospective 39 (52.7%) 53 (71.6%) 19 (25.7%)

Bleeker-Rovers 2004 35 51 (18-82) Retrospective 19 (54.3%) 15 (48.6%) 13 (37.1%)

Bleeker-Rovers 2007 70 53 (26-87) Prospective 35 (50.0%) 33 (47.1%) 23 (32.9%)

Keidar 2008 48 57 (24-82) Prospective 29 (60.4%) 27 (56.3%) 22 (45.8%)

Balink 2009 68 57 (23-91) Retrospective 44 (64.7%) 41 (60.3%) 38 (55.9%)

Federici 2008 10 51 (25-74) Retrospective 7 (70.0%) 5 (50.0%) 5 (50.0%) Ferda 2009ESCMID48 54 (15-89) Retrospective eLibrary44 (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 . 2011by Dec;80(3):834 -44.author 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

ESCMIDKnockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow eLibrary-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) by 2007; 86:26. author A practical FUO flowchart

History Examination Basic blood tests

Type

Infectious Cancer Inflammatory / Diseases rheumatology

Cross sectional CT PET Auto antibodies imaging

lump Pulmonary ESCMIDlesion eLibrary biopsy Bronchoscopy © by author Cases

ESCMID eLibrary © by author 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 ESCMID localising symptoms of any eLibrary sort © by author 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 39.2oC Examination of chest, abdo, CVS all normal No ESCMID palpable nodes, pharynx eLibrary normal © by author 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.

HIV negative

Blood cultures negative ESCMID eLibrary © by author ESCMID eLibrary © by author Next Steps? 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) ESCMIDOther eLibrary © by author Further results

Chest CT: Unremarkable 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 ESCMIDlymphadenopathy. eLibrary © by author 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 ESCMID eLibrary © by author But over this time…

ESCMID eLibrary © by author 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) ESCMIDOther eLibrary © by author Next Steps

Bone marrow trephine shows normal ANA negative cellularity and grade 2 reticulin. Marrow ANCA negative appears active with myeloid cells showing marked eosinophilia and mildly expanded ENA equivocal erythroid cells. No lymphoma or leukemia infiltration is noted on staining for CD20, CMV IgM borderline CD79a, CD3 & CD5.

ECHO – normal

Patient begins to improve after 8 weeks of fever

Haematology ESCMID arrive – and eLibrary perform a bone marrow © by author ESCMID eLibrary Wreghitt T, Behr S, Hodson J, Irwin D. Feverish granny syndrome. Lancet. 1995 Dec 23-30;346(8991-8992):1716. © by author How was the diagnosis confirmed?

ESCMID eLibrary © by author 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) ESCMID– TPN (Hickman line) from eLibrary 2012 © by author Case 2 - History 2

8 months prior to presentation: • 4 weeks fever, dry cough, headache • Unremarkable examination • Bloods – ESR 112mm/hr – Hb 100g/L – WCC 4.1x109/L (Neuts 2.9, Lymphocytes 0.9) – CRP 52 mg/L – U&E/LFT normal • Blood cultures – 4 sets negative ESCMID– 1x aerobic bottle: GPR  diphtheroideLibrary © by author 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 • ESCMIDBronchoscopy: acellular eLibrary, no organisms grown © by author ESCMID eLibrary © by author 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

At presentation • 5 weeks of intermittent fever, night sweats and ‘generally unwell’ • On examination: – Cachectic – Temperature 37.8oC – Physical examination unremarkable ESCMID– Admitted to hospital eLibrary © by author ESCMID eLibrary © by author Blood Cultures negative ESCMID eLibrary © by author ESCMID eLibrary © by author Case 2 - Next Steps? a) CT chest b) CT PET c) Serum ACE d) Autoantibodies e) Blood cultures (extended incubation) f) ECHO ESCMID eLibrary © by author Multiple small pulmonary nodules, in areas coalescing into focal consolidation. Mediastinal lymphadenopathy. 1cm nodule ESCMID eLibrary © by author Case 2 - Next Steps? a) CT chest b) CT PET c) Serum ACE d) Autoantibodies e) Blood cultures (extended incubation) f) ECHO ESCMID eLibrary © by author ESCMID eLibrary © by author 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) ESCMIDECHO eLibrary © by author 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) ESCMID eLibrary © by author ESCMID eLibrary © by author 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 ESCMID eLibrary © by author ESCMID eLibrary © by author Case 2 - Outcome

Line removed Biopsy deferred Treated with: – amikacin IV – clarithromycin – clofazimine

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 ESCMID localising symptoms of any eLibrary sort © by author 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 37.9oC Examination of chest, abdo, CVS all normal No ESCMID palpable nodes, pharynx eLibrary normal © by author ESCMID eLibrary © by author ESCMID eLibrary © by author 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

A) ECHO? B) More Blood Cultures? C) Further serological tests? D) CT abdo pelvis? E) CT-PET whole body F) Colonoscopy ESCMID eLibrary © by author “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”

Nephrectomy Histology report:

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 ESCMID evidence of recurrence eLibrary at 2 years © by author Summary points

“New” serological tests are available

Immunosuppression broadens the differential

Speak to the laboratory