Lemierre Syndrome: Clinical Update and Protocol for a Systematic Review and Individual Patient Data Meta-analysis

Clara Sacco; Federica Zane; Serena Granziera; Karin Holm; Dina Creemers-Schild; Michel-André Hotz; Elena Turpini; Adele Valentini; Christian Righini; Petros D. Karkos; Peter Verhamme; Marcello Di Nisio; Stavros Konstantinides; Alessandro Pecci; Stefano Barco; on behalf of the Lemierre Study Group

doi:10.1055/s-0038-1654720

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 2019; 39(01): 076-086
DOI: 10.1055/s-0038-1654720

Review Article

Georg Thieme Verlag KG Stuttgart · New York

Lemierre Syndrome: Clinical Update and Protocol for a Systematic Review and Individual Patient Data Meta-analysis

Autor*innen

Clara Sacco

¹Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
Federica Zane

¹Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
Serena Granziera

²Department of Medicine (DIMED), Geriatric Clinic, University of Padua, Padua, Italy

³Department of Physical and Rehabilitation Medicine, “Villa Salus” Hospital, Mestre, Italy
Karin Holm

⁴Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
Dina Creemers-Schild

⁵Department of Internal Medicine, Langeland Hospital, Zoetermeer, The Netherlands
Michel-André Hotz

⁶Department of ENT, Head and Neck Surgery, Inselspital (University Hospital of Bern), University of Bern, Bern, Switzerland
Elena Turpini

⁷Department of Radiology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
Adele Valentini

⁷Department of Radiology, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
Christian Righini

⁸Department of Otolaryngology–Head and Neck Surgery, Grenoble University Hospital, Grenoble, France
Petros D. Karkos

⁹Department of Otolaryngology–Head and Neck Surgery, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
Peter Verhamme

¹⁰Department of Vascular Medicine and Haemostasis, University Hospitals Leuven, Leuven, Belgium
Marcello Di Nisio

¹¹Department of Medicine and Ageing Sciences, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
Stavros Konstantinides

¹²Center for Thrombosis and Haemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

¹³Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
Alessandro Pecci

¹Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
Stefano Barco

¹²Center for Thrombosis and Haemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

on behalf of the Lemierre Study Group

Abstract

Lemierre syndrome usually affects otherwise healthy adolescents or young adults and occurs at an overall rate of 1 to 10 cases per million person-years with an estimated fatality rate of 4 to 9%. Diagnostic criteria remain debated and include acute neck/head bacterial infection (often tonsillitis caused by anaerobes at high potential for sepsis and vascular invasion, notably Fusobacterium necrophorum) complicated by local vein thrombosis, usually involving the internal jugular vein, and systemic septic embolism. Medical treatment is based on antibiotic therapy with anaerobic coverage, anticoagulant drugs and supportive care in case of sepsis. Surgical procedures can be required, including drainage of the abscesses, tissue debridement and jugular vein ligation. Evidence for clinical management is extremely poor in the absence of any adequately sized study with clinical outcomes. In this article, we illustrate two cases of Lemierre syndrome not caused by Fusobacterium necrophorum and provide a clinically oriented discussion on the main issues on epidemiology, pathophysiology and management strategies of this disorder. Finally, we summarize the study protocol of a proposed systematic review and individual patient data meta-analysis of the literature. Our ongoing work aims to investigate the risk of new thromboembolic events, major bleeding or death in patients diagnosed with Lemierre syndrome, and to better elucidate the role of anticoagulant therapy in this setting. This effort represents the starting point for an evidence-based treatment of Lemierre syndrome built on multinational interdisciplinary collaborative studies.

Zusammenfassung

Das Lemierre-Syndrom betrifft normalerweise gesunde Jugendliche oder junge Erwachsene und tritt mit einer Gesamttodesrate von 1 bis 10 Fällen pro Million Personenjahre mit einer geschätzten Sterblichkeitsrate von 4 bis 9% auf. Diagnostische Kriterien bleiben umstritten und umfassen akute Kopf-Hals-Bakterieninfektionen (häufig Tonsillitis durch Anaerobier mit hohem Sepsis-und Gefäßinvasionspotenzial, insbesondere Fusobacterium necrophorum), kompliziert durch lokale Venenthrombose, die gewöhnlich die Vena jugularis interna involviert, und systemische septische Embolie. Die medizinische Behandlung basiert auf einer Antibiotikatherapie mit anaerober Abdeckung, Antikoagulanzien, und unterstützender Behandlung bei Sepsis. Chirurgische Maßnahmen können erforderlich sein, einschließlich der Drainage der Abszesse, Gewebedebridement und Jugularvenenligatur. Die Evidenz für das klinische Management ist in Ermangelung einer ausreichend bemessenen Studie mit klinischen Ergebnissen äußerst schlecht. In diesem Artikel illustrieren wir zwei Fälle von Lemierre-Syndrom, die nicht durch Fusobacterium necrophorum verursacht wurden und bieten eine klinisch orientierte Diskussion über die Hauptprobleme der Epidemiologie, Pathophysiologie und Managementstrategien dieser Erkrankung. Abschließend fassen wir das Studienprotokoll einer vorgeschlagenen systematischen Übersichtsarbeit und einer individuellen Patientendaten-Metaanalyse der Literatur zusammen. Unsere laufende Arbeit zielt darauf ab, das Risiko neuer thromboembolischer Ereignisse, schwerer Blutungen oder Todesfälle bei Patienten mit Lemierre-Syndrom zu untersuchen und die Rolle der Antikoagulanzien-Therapie in diesem Zusammenhang besser zu klären. Diese Bemühungen bilden den Ausgangspunkt für eine evidenzbasierte Behandlung des Lemierre-Syndroms, welche auf multinationalen interdisziplinären kollaborativen Studien aufbaut.

Keywords

Lemierre syndrome - venous thromboembolism - bacterial infection - anticoagulant treatment - Fusobacterium necrophorum

Schlüsselwörter

Lemierre-Syndrom - Venöse Thromboembolie - bakterielle Infektion - Antikoagulanz - Fusobacterium necrophorum

Volltext

Referenzen

References
1 Lemierre A. On certain septicaemias due to anaerobic organisms. Lancet 1936; 1: 701-703
2 Shannon GW, Ellis CV, Stepp WP. Oropharyngeal bacteroides melaninogenicus infection with septicemia: Lemierre's syndrome. J Fam Pract 1983; 16 (01) 159-160 , 163, 166
3 Karkos PD, Asrani S, Karkos CD. , et al. Lemierre's syndrome: a systematic review. Laryngoscope 2009; 119 (08) 1552-1559
4 Syed MI, Baring D, Murray C. In reference to Lemierre's syndrome: a systematic review. Laryngoscope 2010; 120 (01) 215-216 , author reply 216
5 Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre's syndrome. Clin Microbiol Rev 2007; 20 (04) 622-659
6 Holm K, Svensson PJ, Rasmussen M. Invasive Fusobacterium necrophorum infections and Lemièrre's syndrome: the role of thrombophilia and EBV. Eur J Clin Microbiol Infect Dis 2015; 34 (11) 2199-2207
7 Wani P, Antony N, Wardi M, Rodriguez-Castro CE, Teleb M. The forgotten one: Lemierre's syndrome due to Gram-negative rods Prevotella bacteremia. Am J Case Rep 2016; 17: 18-22
8 Huits RM, van Assen S, Wildeboer-Veloo AC, Verschuuren EA, Koeter GH. Prevotella bivia necrobacillosis following infectious mononucleosis. J Infect 2006; 53 (02) e59-e63
9 Chuncharunee A, Khawcharoenporn T. Lemierre's syndrome caused by Klebsiella pneumoniae in a diabetic patient: a case report and review of the literature. Hawaii J Med Public Health 2015; 74 (08) 260-266
10 Garbati MA, Ahsan AM, Hakawi AM. Lemierre's syndrome due to Klebsiella pneumoniae in a 63-year-old man with diabetes: a case report. J Med Case Reports 2012; 6: 97
11 Lee WS, Wang FD, Shieh YH, Teng SO, Ou TY. Lemierre syndrome complicating multiple brain abscesses caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae cured by fosfomycin and meropenem combination therapy. J Microbiol Immunol Infect 2012; 45 (01) 72-74
12 Tsai YJ, Lin YC, Harnnd DJ, Chiang RP, Wu HM. A Lemierre syndrome variant caused by Klebsiella pneumoniae. J Formos Med Assoc 2012; 111 (07) 403-405
13 Osman M, Hasan S, Bachuwa G. Oesophageal cancer presenting as Lemierre's syndrome caused by Streptococcus anginosus . BMJ Case Rep 2017; 2017: bcr-2017-bcr-219661
14 Alberio L, Lämmle B. Images in clinical medicine. Capnocytophaga canimorsus sepsis. N Engl J Med 1998; 339 (25) 1827
15 Kleinjan A, Di Nisio M, Beyer-Westendorf J. , et al. Safety and feasibility of a diagnostic algorithm combining clinical probability, D-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study. Ann Intern Med 2014; 160 (07) 451-457
16 Pijl JP, Glaudemans AWJM, Slart RHJA, Kwee TC. FDG-PET/CT as a new method for diagnosis and whole-body evaluation of Lemierre syndrome. Clin Nucl Med 2017; 42 (08) e377-e380
17 Aliyu SH, Yong PF, Newport MJ. , et al. Molecular diagnosis of Fusobacterium necrophorum infection (Lemierre's syndrome). Eur J Clin Microbiol Infect Dis 2005; 24 (03) 226-229
18 Weesner CL, Cisek JE. Lemierre syndrome: the forgotten disease. Ann Emerg Med 1993; 22 (02) 256-258
19 Hagelskjaer Kristensen L, Prag J. Lemierre's syndrome and other disseminated Fusobacterium necrophorum infections in Denmark: a prospective epidemiological and clinical survey. Eur J Clin Microbiol Infect Dis 2008; 27 (09) 779-789
20 Hagelskjaer LH, Prag J, Malczynski J, Kristensen JH. Incidence and clinical epidemiology of necrobacillosis, including Lemierre's syndrome, in Denmark 1990-1995. Eur J Clin Microbiol Infect Dis 1998; 17 (08) 561-565
21 Jones JW, Riordan T, Morgan MS. Investigation of postanginal sepsis and Lemierre's syndrome in the South West Peninsula. Commun Dis Public Health 2001; 4 (04) 278-281
22 Bank S, Jensen A, Nielsen HM, Kristensen LH, Voldstedlund M, Prag J. Fusobacterium necrophorum findings in Denmark from 2010 to 2014 using data from the Danish microbiology database. APMIS 2016; 124 (12) 1087-1092
23 Brazier JS, Hall V, Yusuf E, Duerden BI. Fusobacterium necrophorum infections in England and Wales 1990-2000. J Med Microbiol 2002; 51 (03) 269-272
24 Leugers CM, Clover R. Lemierre syndrome: postanginal sepsis. J Am Board Fam Pract 1995; 8 (05) 384-391
25 Armstrong AW, Spooner K, Sanders JW. Lemierre's syndrome. Curr Infect Dis Rep 2000; 2 (02) 168-173
26 Chirinos JA, Lichtstein DM, Garcia J, Tamariz LJ. The evolution of Lemierre syndrome: report of 2 cases and review of the literature. Medicine (Baltimore) 2002; 81 (06) 458-465
27 Schmidt M, Horvath-Puho E, Thomsen RW, Smeeth L, Sørensen HT. Acute infections and venous thromboembolism. J Intern Med 2012; 271 (06) 608-618
28 Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367 (9516): 1075-1079
29 Holm K, Frick IM, Björck L, Rasmussen M. Activation of the contact system at the surface of Fusobacterium necrophorum represents a possible virulence mechanism in Lemièrre's syndrome. Infect Immun 2011; 79 (08) 3284-3290
30 Holm K, Rasmussen M. Binding and activation of plasminogen at the surface of Fusobacterium necrophorum. Microb Pathog 2013; 59-60: 29-32
31 Kumar A, Menon S, Nagaraja TG, Narayanan S. Identification of an outer membrane protein of Fusobacterium necrophorum subsp. necrophorum that binds with high affinity to bovine endothelial cells. Vet Microbiol 2015; 176 (1-2): 196-201
32 Liesenborghs L, Verhamme P, Vanassche T. Staphylococcus aureus, master manipulator of the human hemostatic system. J Thromb Haemost 2018; 16 (03) 441-454
33 Peetermans M, Vanassche T, Liesenborghs L, Lijnen RH, Verhamme P. Bacterial pathogens activate plasminogen to breach tissue barriers and escape from innate immunity. Crit Rev Microbiol 2016; 42 (06) 866-882
34 Holm K, Bank S, Nielsen H, Kristensen LH, Prag J, Jensen A. The role of Fusobacterium necrophorum in pharyngotonsillitis - a review. Anaerobe 2016; 42: 89-97
35 Rusan M, Klug TE, Ovesen T. An overview of the microbiology of acute ear, nose and throat infections requiring hospitalisation. Eur J Clin Microbiol Infect Dis 2009; 28 (03) 243-251
36 Trotter C, Borrow R, Andrews N, Miller E. Seroprevalence of meningococcal serogroup C bactericidal antibody in England and Wales in the pre-vaccination era. Vaccine 2003; 21 (11-12): 1094-1098
37 Friberg N, Carlson P, Kentala E. , et al. Factor H binding as a complement evasion mechanism for an anaerobic pathogen, Fusobacterium necrophorum. J Immunol 2008; 181 (12) 8624-8632
38 Holm K, Collin M, Hagelskjær-Kristensen L, Jensen A, Rasmussen M. Three variants of the leukotoxin gene in human isolates of Fusobacterium necrophorum subspecies funduliforme. Anaerobe 2017; 45: 129-132
39 Tadepalli S, Stewart GC, Nagaraja TG, Narayanan SK. Human Fusobacterium necrophorum strains have a leukotoxin gene and exhibit leukotoxic activity. J Med Microbiol 2008; 57 (Pt 2): 225-231
40 Narayanan SK, Nagaraja TG, Chengappa MM, Stewart GC. Leukotoxins of gram-negative bacteria. Vet Microbiol 2002; 84 (04) 337-356
41 Hedin K, Bieber L, Lindh M, Sundqvist M. The aetiology of pharyngotonsillitis in adolescents and adults - Fusobacterium necrophorum is commonly found. Clin Microbiol Infect 2015; 21 (03) 263.e1-263.e7
42 Bondy P, Grant T. Lemierre's syndrome: what are the roles for anticoagulation and long-term antibiotic therapy?. Ann Otol Rhinol Laryngol 2008; 117 (09) 679-683
43 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369 (09) 840-851
44 Levy MM, Dellinger RP, Townsend SR. , et al; Surviving Sepsis Campaign. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010; 38 (02) 367-374
45 Ferrer R, Artigas A, Levy MM. , et al; Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 2008; 299 (19) 2294-2303
46 Seymour CW, Gesten F, Prescott HC. , et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017; 376 (23) 2235-2244
47 Cupit-Link MC, Nageswara Rao A, Warad DM, Rodriguez V. Lemierre syndrome: a retrospective study of the role of anticoagulation and thrombosis outcomes. Acta Haematol 2017; 137 (02) 59-65
48 Vanassche T, Peetermans WE, Herregods MC, Herijgers P, Verhamme P. Anti-thrombotic therapy in infective endocarditis. Expert Rev Cardiovasc Ther 2011; 9 (09) 1203-1219
49 Halton JML, Picard AC, Harper R. , et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of dabigatran etexilate oral liquid formulation in infants with venous thromboembolism. Thromb Haemost 2017; 117 (11) 2168-2175
50 Young G, Yee DL, O'Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer 2011; 57 (06) 1049-1054
51 Willmann S, Becker C, Burghaus R. , et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 89-102
52 Malec L, Young G. Treatment of venous thromboembolism in pediatric patients. Front Pediatr 2017; 5: 26
53 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149 (02) 315-352
54 Redford MR, Ellis R, Rees CJ. Fusobacterium necrophorum infection associated with portal vein thrombosis. J Med Microbiol 2005; 54 (Pt 10): 993-995
55 Schulman S, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
56 Jackson D, Daly J, Saltman DC. Aggregating case reports: a way for the future of evidence-based health care?. Clin Case Rep 2014; 2 (02) 23-24
57 Vazquez FJ, Paulin P, Rodriguez P, Lubertino M, Gándara E. The outcome of pulmonary vein thrombosis in non-surgical patients. A systematic review and case report. Thromb Haemost 2015; 113 (05) 1151-1154
58 Khalil N, Nicotra A, Rakowicz W. Treatment for meralgia paraesthetica. Cochrane Database Syst Rev 2012; 12: CD004159
59 Buonfrate D, Requena-Mendez A, Angheben A. , et al. Severe strongyloidiasis: a systematic review of case reports. BMC Infect Dis 2013; 13: 78
60 Cardona Zorrilla AF, Reveiz Herault L, Casasbuenas A, Aponte DM, Ramos PL. Systematic review of case reports concerning adults suffering from neutropenic enterocolitis. Clin Transl Oncol 2006; 8 (01) 31-38
61 George JN, Raskob GE, Shah SR. , et al. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 1998; 129 (11) 886-890
62 Abdel-Wahab N, Lopez-Olivo MA, Pinto-Patarroyo GP, Suarez-Almazor ME. Systematic review of case reports of antiphospholipid syndrome following infection. Lupus 2016; 25 (14) 1520-1531
63 Stewart LA, Clarke M, Rovers M. , et al; PRISMA-IPD Development Group. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA 2015; 313 (16) 1657-1665

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