THE DIFFERENTIAL DIAGNOSIS OF BURULI ULCER

Bouke de Jong 1, Françoise Portaels 1, Ghislain Sopoh 2, Dissou Affolabi3, Delphin Phanzu4, Anatole Kibadi4, Miriam Eddyani 1

1 Institute of Tropical Medicine, Antwerp, Belgium 2 Centre de Dépistage et de Traitement de l’Ulcère de Buruli, Allada, Benin 3Laboratoire de Référence des Mycobactérie, Cotonou, Benin 4Institut Medical Evangelique, Kimpese, DRC

Outline • Why is the differential diagnosis important? • Different presentations of Buruli ulcer • Other diseases that can be mistaken for BU • Preliminary results on a study on the differential diagnosis of BU

Why study the differential diagnosis? Other diagnoses- other optimal treatment Example • Gram positive infections will respond to rifampicin and streptomycin x 2 months • Can benefit from shorter courses with less side effects – No need for injections, risk of ototoxicity In some countries, BU case notifications 

 clinical expertise 

notifications Case Case

2000 2004 2008 2012 2016  Lab confirmation more important Different forms  different DDx

http://www.who.int/buruli/photos/nonulcerative/en/index.html DDx clinical presentation Nodule: lipoma, sebaceous cyst, furuncle, abscess, onchocerciasis Plaque: leprosy, subcutaneous fungal infections, eczema, psoriasis Edema: bacterial cellulitis, necrotizing fasciitis, actinomycosis, filariasis, erysipelas Ulcer: tropical phagedenic ulcer, ulcers 2nd to venous or arterial insufficiency, cutaneous tuberculosis, necrotizing fasciitis, cutaneous leishmaniasis

The differential diagnosis of Buruli Ulcer Tropical phagedenic ulcer

Pott’s Impetigo, disease pyogranulomatous (TB) Perquis et al., Med Trop, 1966 dermatitis, chronic dermatitis, hidradenitis Kibadi et al., PLoS Negl Trop Dis, 2010 Portaels, Lagarrigue and Buruli Aguiar

ulcer

Malignancies Necrotising fasciitis - Carcinoma Pyoderma - Kaposi sarcoma gangrenosum - Melanoma Mwanatambwe et al., J van der Werf, New Eng J Dermatology, 2002 Med, 2003 Phanzu et al., Am J Trop Med Hyg, 2010 8 Distinguishing features Buruli ulcer Phagedenic ulcers Necrotizing fasciitis Distribution Focal endemic More common in Worldwide regions tropical regions Age Children> adults Children & young All ages adults Location Arms & legs Legs Legs> trunk Presentation Different forms Ulcers Edema, ulcers Smell None Yes Yes Start 2-3 months 2-8 weeks 1-2 days Fever None None High Etiology M. ulcerans polybacterial Gram positive cocci

Phanzu et al 2010

Which lab tests can diagnose BU? • Direct smear examination for AFB • Culture on Lowenstein Jensen slopes • (q)PCR for IS2404 • Histopathology Aims 1. Determine the validity of clinical and microbiological diagnosis 2. Determine the differential diagnoses of BU

Algorithm for improved clinical & microbiological diagnosis of BU

Ghislain Sopoh & Miriam Eddyani Patient recruitment

390 patients with BU-like skin lesions 195 clinically BU • Nodules • Plaques • Oedema • Ulcers 195 clinically not BU

Patient recruitment

Decentralised CDTUB-Allada health posts • Written informed consent

• Clinical and epidemiological documentation 390 patients with BU-like skin lesions

Colonising

2 FNA or 2 swabs

Pathogenic CDTUB Allada: •Culture of general bacteria Regular •Direct smear supervision and examination (ZN, validation of results Gram) by LRM – Dr. Dissou Affolabi INTERPRETATION of BACTERIOLOGY

Cas Type de germes (pour la peau) Quantification des Présence unique ≥ assez nombreux Interprétation de germes d’1 germe polynucléaires (Responsabilité figure dans l’infection) 1 Potentiellement pathogène Nombreux Oui Oui Très probable

2 Potentiellement pathogène Nombreux Oui Non Probable

3 Potentiellement pathogène Nombreux Non Oui Probable

4 Potentiellement pathogène Nombreux Non Non Assez probable

5 Potentiellement pathogène Peu nombreux Oui Oui Probable

6 Potentiellement pathogène Peu nombreux Oui Non Assez probable

7 Potentiellement pathogène Peu nombreux Non Oui Assez probable

8 Potentiellement pathogène Peu nombreux Non Non Peu probable

9 Peu pathogène Nombreux Oui Oui Probable

10 Peu pathogène Nombreux Oui Non Assez probable

11 Peu pathogène Nombreux Non Oui Assez probable

12 Peu pathogène Nombreux Non Non Peu probable

13 Peu pathogène Peu nombreux Oui Oui Assez probable

14 Peu pathogène Peu nombreux Oui Non Peu probable

15 Peu pathogène Peu nombreux Non Oui Peu probable 20 16 Peu pathogène Peu nombreux Non Non Non probable 390 patients with BU-like skin lesions

2 FNA or 2 swabs

LRM: CDTUB Allada: •PCR M. ulcerans and • Culture of general bacteria general mycobacteria • Direct smear •Direct smear examination (ZN and Gram) examination (auramine) •Culture of mycobacteria 390 patients with CDTUB Allada: BU-like skin lesions • HE • Ziehl-Neelsen • Gram • Grocott 4mm-punch biopsy • PAS Histopathology

Reading in Reading in Parakou Chambéry Interpretation of results Based on all clinical and laboratory information and treatment outcome:

1. confirmed BU – PCR or histo or culture positive 2. possible BU – DSE or clinical diagnosis or treatment response pos or histo doubtful 3. non BU

– Confirmed other etiology vs unclear differential diagnosis

Final diagnosis by clinical expert panel = Composite reference standard First meeting on 26 March 2013 in Geneva

Patient classification

• Patient CDTUB/5/2013 • Patient CDTUB/145/2012 – Clinical Dx: BU cat 3 – Clinical Dx: necrotising fasciitis – DSE: neg – DSE: pos – PCR: pos – PCR: pos – Histo: pos – Histo: compatibe with BU – Bacteriology: sterile culture – Bacteriology: E. coli & P. stuartii, code  Confirmed BU 14, probably not responsible for infection  Confirmed BU

Clinical expert panel T van der Werf, D Phanzu, J Pedrosa, P Johnson, A Kibadi, D Imposo

• Patient CDTUB/121/2012 • Patient CDTUB/66/2012 – Clinical Dx: BU cat 3 – Clinical Dx: necrotising fasciitis – DSE: neg – DSE: neg – PCR: neg – PCR: neg – Histo: neg – Histo: compatibe with BU – Bacteriology: S. aureus , code 8, probably not – Bacteriology: sterile culture responsible for infection  Possible BU  Possible BU  Panel judgement: non BU  Panel judgement: BU

25 Data analysis • Primary analysis: Estimate sensitivities of tests with composite reference standard as gold standard • Secondary analysis: mathematically model contribution of each test

Clinical diagnosis Verification of PCR DSE Histology Culture Number (fictive, BU at first clinical diagnosis as example) consultation by clinician (triage)

+ + + + + + 75 + + + + + + - 3 + + + + + - + 1 + + + + + - - 0 + - + + - + + 13 + + + + - + - 1 + + + + - - + 2 + - - + - - - 20 + … … … … … … … … Patient recruitment in CDTUB-Allada

ABSCESS CERVICAL LYMPHADENITIS ERYSIPELAS 195 clinically BU 89 recruited on 31/05/2013 NECROTIZING FASCIITIS 390 patients with BU-like skin lesions OSTEOMYELITIS • Nodules • Plaques 195 clinically not BU CELULLITIS • Oedema 66 recruited on 31/05/2013 • Ulcers CHRONIC TRAUMATIC WOUND 161 recruited on 31/05/2013 6 clinically MALIGNANT TUMOR undetermined CHRONIC ULCER Thanks to • Didier Agossadou • Ghislain Sopoh • Dissou Affolabi • Luc Brun • Jean-Jacques Roux • Miriam Eddyani, Koen Vandelannoote, Françoise Portaels