This first edition of theWHO guidelines on tularaemia is the WHO GUIDELINES ON TULARAEMIA result of an international collaboration, initiated at a WHO meeting WHO GUIDELINES ON in Bath, UK in 2003. The target audience includes clinicians, laboratory personnel, public health workers, veterinarians, and any other person with an interest in zoonoses. Tularaemia Tularaemia is a bacterial zoonotic disease of the northern hemisphere. The bacterium (Francisella tularensis) is highly virulent for humans and a range of animals such as rodents, hares and rabbits. Humans can infect themselves by direct contact with infected animals, by arthropod bites, by ingestion of contaminated water or food, or by inhalation of infective aerosols. There is no human-to-human transmission. In addition to its natural occurrence, F. tularensis evokes great concern as a potential bioterrorism agent. F. tularensis subspecies tularensis is one of the most infectious pathogens known in human medicine. In order to avoid laboratory-associated infection, safety measures are needed and consequently, clinical laboratories do not generally accept specimens for culture. However, since clinical management of cases depends on early recognition, there is an urgent need for diagnostic services. The book provides background information on the disease, describes the current best practices for its diagnosis and treatment in humans, suggests measures to be taken in case of epidemics and provides guidance on how to handle F. tularensis in the laboratory. ISBN 978 92 4 154737 6 WHO EPIDEMIC AND PANDEMIC ALERT AND RESPONSE WHO Guidelines on Tularaemia EPIDEMIC AND PANDEMIC ALERT AND RESPONSE WHO Library Cataloguing-in-Publication Data WHO Guidelines on Tularaemia. 1.Francisella tularensis – classification. 2.Tularemia – epidemiology. 3.Tularemia – transmission. 4.Tularemia – drug therapy. I.World Health Organization. ISBN 978 92 4 154737 6 (NLM classification: WC 380) © World Health Organization 2007 WHO/CDS/EPR/2007.7 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed in France ACKNOWLEDGMENTS Contents Acknowledgements v Abbreviations vii 1. Introduction 1 2. The infectious agent 3 2.1 Taxonomy 3 2.2 Species and subspecies that differ in virulence and geographical range 4 2.3 Seasonality, age and gender distribution 4 3. Epidemiology 5 3.1 Geographical distribution of tularaemia cases 5 3.2 Vectors 5 3.3 Disease and pathology in animals 8 4. Clinical expression in humans 11 4.1 Source of infection and clinical outcome according to F. tularensis subspecies 11 4.2 Signs and symptoms 12 4.3 Differential diagnoses 17 5. Treatment 21 5.1 Recommendations for treatment and prophylaxis 21 5.2 Antibiotic agents 22 5.3 Antibiotic resistance of F. tularensis 25 6. Laboratory diagnostics and discrimination of subspecies and strains 27 6.1 Case definitions 27 6.2 Diagnostic specimens 27 6.3 Bacteriology 29 6.4 Diagnostic tests 30 6.5 Supplemental characterization 31 6.6 Biosafety considerations 33 7. Surveillance and outbreak management 35 7.1 Surveillance 35 7.2 Surveillance in humans 36 7.3 Surveillance in animals 36 7.4 Outbreak management (humans) 37 8. Considerations for handling F. tularensis 41 8.1 Safety measures in the laboratory 41 8.2 Vaccines and vaccination 43 9. References 47 Annexes 59 A. Diagnostic protocols 61 A.1 Gram stain 61 A.2 Culture on agar 62 A.3 Antigen detection 64 A.4 Molecular detection 70 A.5 Serology 73 A.6 References iii WHO GUIDELINES ON TULARAEMIA B. Tests for supplemental characterization 81 B.1 Antimicrobial susceptibility 81 B.2 Molecular biotyping 82 B.3 References 87 C. Protocols for preparation of selected F. tularensis culture media 89 C.1 Cysteine heart agar base with 9% chocolatized sheep blood (CHAB) 89 C.2 GCII agar with 1% haemoglobin and 1% IsoVitaleX 90 D. Reagent list 93 E. Transport of specimens and cultures of F. tularensis 95 E.1 Shipping F. tularensis 95 E.2 Training 95 E.3 References 96 F. Checklist for outbreak investigation 99 F.1 Preparations 99 F.2 Outbreak investigation in the field 100 F.3 Example for a tularaemia outbreak, Kosovo (Serbia) 101 G. Protocols for trapping and sampling small mammals 105 G.1 Trapping of small mammals 105 G.2 Protocols for collecting diagnostic samples from small mammals 105 G.3 References 107 Index 109 List of figures 3.1 Geographical distribution of tularaemia 6 4.1 Primary ulcer in a case of tularaemia 16 4.2 Lymph node enlargement 16 4.3 Hilar enlargement 16 4.4 Extended right-sided consolidation 16 5.1 Distribution of MIC values for six quinolones 26 A.1 F. tularensis on CHAB agar after 48 h incubation 63 A.2 Isolate of F. tularensis stained by the direct fluorescence method 65 A.3 Slide agglutination for F. tularensis 67 E.1 Flowchart for the classification of infectious substances and patient specimens 96 List of tables 3.1 Animals found to be infected with F. tularensis 10 4.1 Clinical forms of tularaemia 13 4.2 Differential diagnosis by route of acquisition 18 5.1 Minimum inhibitory concentrations (MICs) 22 6.1 Discriminating characteristics of Francisella species and subspecies 33 6.2 Polymerase chain reaction (PCR) methods to discriminate F. tularensis subspecies 33 C.1 Chemically-defined enrichment supplement for F. tularensis 91 D.1 Diagnostic reagents for F. tularensis 93 iv ACKNOWLEDGMENTS Acknowledgements Chief Editor Arne Tärnvik, Umeå University, Umeå, Sweden Secretariat Regula Leuenberger, World Health Organization, Geneva, Switzerland Chairs Roland Grunow, Robert Koch Institute, Berlin, Germany Jeannine Petersen, Centers for Disease Control and Prevention, Fort Collins, CO, USA Anders Sjöstedt, Umeå University, Umeå, Sweden Richard W. Titball, Defence Science and Technology Laboratory, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom Other contributors Pedro Anda, Instituto de Salud Carlos III, Madrid, Spain Tina Broman, Swedish Defence Research Agency, Umeå, Sweden May Chu, World Health Organization, Geneva, Switzerland Karen Elkins, Food and Drug Administration, Rockville Pike, MD, USA Mats Forsman, Swedish Defence Research Agency, Umeå, Sweden Anders Johansson, Umeå University, Umeå, Sweden Michael Kosoy, Centers for Disease Control and Prevention, Fort Collins, CO, USA Gérard Krause, Robert Koch Institute, Berlin, Germany Francis E. Nano, University of Victoria, Victoria, BC, Canada Andrew Pearson, Health Protection Agency, London, United Kingdom Note: All the contributors listed above are members of the informal WHO working group on tularaemia, established at the WHO meeting Improving public health preparedness for and response to the threat of epidemics: tularaemia network, Bath, United Kingdom, 14–15 September 2003 (document: WHO/CDS/CSR/LYO/2004.6).1 The authors wish to express their gratitude for the intellectual contributions and expert advice provided throughout the process of compiling these guidelines. Special support was given at all stages by May Chu, World Health Organization. At various stages, the following col­ leagues were involved: Alim Aikimbayev, Almaty, Kazakhstan; Karen Elkins, Rockville Pike, MD, USA; Art Friedlander, Frederick, MD, USA; Tatiana A. Gremyakova, Moscow, Russian Federation; Alec Macela, Hradec Kralove, Czech Republic; Paul Mead, Fort Collins, CO, USA; Irina Meschcheryakova, Moscow, Russian Federation; Torsten Mörner, Uppsala, Sweden; Marty Schreifer, Fort Collins, CO, USA; Martin Wale, Nottingham, United Kingdom. 1 All external experts/contributors have signed declarations of interest in accordance with WHO policy and no conflict of interests were declared. The declarations of interest are available on request. v WHO GUIDELINES ON TULARAEMIA Expert review of the document was performed by Alim Aikimbayev, Pedro Anda, Erik Bäck, Tina Broman, Mats Forsman, Tatiana A. Gremyakova, Zdenek Hubálek, Richard F. Jacobs, Anders Johansson, Aynur Karadenizli, Gérard Krause, Michael Kosoy, Alec Macela, Gunnar Sandström, and Sam R. Telford.