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The long shadow of Lemierre’s syndrome
Journal of Infection (2017) 74, S47—S53
www.elsevierhealth.com/journals/jinf
The long shadow of Lemierre’s syndrome Joshua Osowicki a,b,c,d,e,*, Sarah Kapur f, Linny Kimly Phuong d,e, Simon Dobson b Group A Streptococcal Research Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, BC Children’s Hospital, Vancouver, British Columbia, Canada c Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia d Infectious Diseases unit, The Royal Children’s Hospital Melbourne, Victoria, Australia e Department of Paediatric Infection and Immunity, Monash Children’s Hospital, Clayton, Australia f Paediatric Infectious Diseases Department, Royal Belfast Hospital for Sick Children, Belfast, UK a
b
Available online 23 June 2017
KEYWORDS Lemierre’s syndrome; Fusobacterium; Septic thrombophlebitis
Summary Lemierre’s syndrome is a rare and feared complication of pharyngitis, occurring most commonly in adolescents and young adults. It is typically defined by the constellation of septic internal jugular vein thrombophlebitis, pulmonary and other septic emboli, and sterilesite infection by Fusobacterium necrophorum. The rarity and severity of Lemierre’s syndrome has made it an attractive subject for case reports but there is a paucity of evidence to inform areas of persistent uncertainty. In recent years, heightened attention and controversy has focused upon speculation that a purported rise in the incidence of Lemierre’s syndrome is due to reduced antibiotic prescribing for respiratory tract infections, that F. necrophorum is an under-appreciated cause of acute tonsillopharyngitis and that testing and targeted treatment would prevent cases of Lemierre’s syndrome. Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association. All rights reserved.
Introduction In 1936 in The Lancet, André Lemierre described the syndrome which would eventually carry his name and concluded that it was, “relatively easy to make a diagnosis on the simple clinical findings…a syndrome so characteristic that a mistake is almost impossible”.1 Although Lemierre broadly addressed “certain septicaemias due to anaerobic organisms” what is best remembered is his illustrative focus on post-anginal septicaemia due to
Bacillus fundiliformis (known today as Fusobacterium necrophorum) in which he described the progression from focal suppurative (peritonsillar) infection to local septic (internal jugular) thrombophlebitis and distant septic (pulmonary) emboli. As familiarity with the most advanced and characteristic elements of Lemierre’s syndrome has diminished in the antibiotic era, it has assumed a classical and almost mythical status, attested to by a proliferation of case reports portraying it as a “forgotten” and “sinister” enigma, contrasting the historical diagnostic confidence
* Corresponding author. The Royal Children’s Hospital Melbourne, 50 Flemington Rd, Victoria, Australia, 3052. Tel.: 61 3 9345 5522. E-mail address: [email protected] (J. Osowicki). 0163-4453/Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association. All rights reserved
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Figure 1 Lemierre’s syndrome — an eponym with many synonyms. The classic syndrome (black text) with variations recognised by André Lemierre in his 1936 paper (grey boxes).
of Lemierre.2,3 Rather than subjecting the syndrome to further review and report, we point instead in this article to previous outstanding reviews4,5 and will concentrate on areas of confusion, contention, and controversy which have emerged in relation to its definition, microbiology, epidemiology, pathogenesis, and management.
Definition The term Lemierre’s (or simply Lemierre) syndrome has been applied broadly and often interchangeably since the 1980s to cases including any one or more of F. necrophorum infection, septic thrombophlebitis, and distant metastatic septic emboli (Figure 1). André Lemierre himself emphasised that the pathway from focal suppurative infection to local thrombophlebitis, generalised sepsis, and distant embolic phenomena could originate: “1) From inflammatory lesions of the nasopharynx, particularly tonsillar and peritonsillar abscesses; 2) From similar lesions of the mouth and jaws; 3) In connexion with otitis media or mastoiditis; 4) From purulent endometritis following parturition; 5) From appendicitis; 6) From infections of the urinary passages”.1 In a meticulous 2007 review of 393 reported cases, including a comprehensive and engaging examination of the historical aspects of Lemierre’s syndrome, Riordan tested various case definitions and arrived at a clinicalmicrobiological hybrid requiring: a history of “anginal illness” within the preceding four weeks or compatible clinical findings and; evidence of remote metastatic lesions and; internal jugular thrombophlebitis or isolation of F. necrophorum or Fusobacterium sp. from blood cultures or other sterile site.4 Though this definition does not fit with Lemierre’s original concept of an ominous pathological sequence common to “certain anaerobic septicaemias”, it conforms (by design) to modern usage. Use of the antiquated
term “anginal illness” was somewhat unfortunate but should be understood to encompass pharyngo-tonsillitis and its attendant local suppurative complications. Taking into account new molecular diagnostic techniques, the final microbiological criteria should be amended to include identification in blood or other sterile site of F. necrophorum or Fusobacterium sp. by culture and/or non-culture-based diagnostics (e.g. polymerase chain reaction, PCR).6−8 This definition notably excludes otogenic Fusobacterium sp. infections, which disproportionately affect young children and can also cause thrombophlebitis and serious intracranial complications.4,9
Epidemiology Efforts to fully appreciate the epidemiology of Lemierre’s syndrome are confounded by its rarity, conflicting definitions, and multiple aliases. Qualified estimates of Lemierre’s syndrome incidence derived from English and Danish retrospective case series from the 1990s were approximately one per million persons per year.10,11 A subsequent prospective study from Denmark reported an annual incidence of 3.6 per million persons per year.12 By any definition and for unexplained reasons, Lemierre’s syndrome predominantly affects young adults. The prospective Danish study found an annual incidence of 14.4 cases per million for persons aged 14−24 years, and in Riordan’s 2007 review of 222 previous cases meeting his restricted case definition, the median age was 19 years and 89% of patients were aged 10 to 35 years.4 Other enigmatic epidemiological observations are a male:female ratio of approximately 2:1 in most series and a concentration of cases in autumn and winter in some series.5 Of greatest epidemiological relevance and resonance is the contention by some authors that the incidence of Lemierre’s syndrome is increasing.10,13,14 Authors of case
Lemierre’s syndrome reports have understandably taken this as a cue to choose fittingly emotive titles. The case that incidence is rising is well summarized by Riordan.4 It is largely circumstantial and based on relatively low quality evidence, inferring from small case series, microbiological surveys (i.e. frequency of F. necrophorum in blood cultures), trends in numbers of published cases, and anecdote, that Lemierre’s syndrome was relatively common in the pre-antibiotic era, then virtually disappeared, only to reappear and rise in incidence from the 1990s. There are unfortunately no long-term active surveillance data available to settle the matter. Controversy arises because the putative explanations for a possible true increase in Lemierre’s syndrome incidence include reduced antibiotic treatment of respiratory tract infections (RTI), increased use of macrolide antibiotics (not active against F. necrophorum), and fewer tonsillectomy procedures.4,15,16 The first point in particular is an uncomfortable challenge to attitudes in the antimicrobial stewardship era and guideline recommendations restricting antibiotic treatment of sore throat to microbiologicallyconfirmed Group A streptococcal (GAS, Streptococcus pyogenes) pharyngitis and suppurative complications, including Lemierre’s syndrome.17 A case series published by one tertiary referral hospital in Australia attributed an increase in Lemierre’s syndrome cases to reduced prescribing of beta-lactam antibiotics for pharyngitis as part of antimicrobial stewardship efforts.18 Again, the case is circumstantial, based on an apparent temporal association between possibly increasing incidence and antibiotic use trends, and a seductively simple concept of pathogenesis: whatever the cause of sore throat, F. necrophorum cannot enter the bloodstream from the oropharynx if it is preemptively targeted with a suitable antibiotic.15,16 Despite guideline recommendations, prescribing rates in many settings for RTI have remained high and far in excess of GAS pharyngitis rates, though macrolide use has increased.19−22 Gulliford et al. compared practices in the United Kingdom with higher and lower rates of antibiotic prescribing for RTI, capturing 7% of all UK primary care consultations and about 45 million patient years of information, and did not find an increased incidence of Lemierre’s syndrome with lower prescribing rates.23 An association was seen for peritonsillar abscess, another condition in which F necrophorum is implicated. The difference though was only very small, illustrated well by a calculation finding only one additional case per practice (~7000 patients) per decade for every 10% reduction in antibiotic prescribing for RTI.24
Microbiology Lemierre’s syndrome has become almost synonymous in common usage with infection due to F. necrophorum, its most common cause. Observing the frequency with which the organism has been reported in Lemierre’s syndrome, Riordan posed the question, “Is F. necrophorum a sine qua non for Lemierre’s syndrome?”.4 Other organisms reported as a cause of the syndrome (without Fusobacterium sp. identified) include methicillin-susceptible and methicillin-resistant Staphylococcus aureus,25 Staphylococcus epidermidis,26 GAS and other beta haemolytic streptococci,27,28 StreptoStreptococcus constellatus,30 coccus intermedius,29 31 Peptostreptococcus Arcanobacterium haemolyticum,
S49 sp., Prevotella sp.,32 Porphyromonas asaccharolytica,33 Klebsiella pneumoniae,34 Eikenella corrodens, Enterococcus sp., Proteus sp., and Bacteroides sp.4 Answering his own question, Riordan proposed in 2007 that it was “eminently possible” molecular studies would eventually show Fusobacterium sp. to be responsible for “all typical cases of Lemierre’s syndrome”.4 Where identification of Fusobacterium sp. forms part of the case definition, this is obviously a truism. In 1936, Lemierre himself was not nearly as confident that all cases were attributable to Fusobacterium sp.1 Certainly, there are other bacteria causing head and neck infections that are equally capable of causing thrombosis and septic embolism, Staphylococcus aureus being the most obvious example. Head and neck infections arising outside of the oropharynx, or in association with a vascular access device, may also cause internal jugular vein thrombosis and embolism. Many reports have described these cases as “variant”, “atypical” or “Lemierre’s-like” given the different microbiology and pathogenesis. As far as predicting the involvement of Fusobacterium sp. (likely other anaerobic organisms too), a “typical case” might arguably be one with a similarly biphasic course to that observed by Lemierre, with symptoms attributable to thrombophlebitis and/or emboli occurring in the aftermath of a relatively innocuous episode of pharyngitis, often after complete recovery. This is in contrast to the monophasic, progressive, and frequently pyogenic course more often associated with familiar aggressive pathogens such as S. aureus, beta-haemolytic streptococci, and the Streptococcus anginosus group. Sine qua non or not, even where Fusobacterium sp. is the only bacteria identified in a “typical case”, treatment recommendations are for broader coverage of other typical oropharyngeal flora, whether with a single drug (e.g. a carbapenem or beta lactam-beta lactamase inhibitor) or combination therapy (e.g. third-generation cephalosporin + metronidazole).35
Pathogenesis By any definition, Lemierre’s syndrome is a complicated bloodstream infection arising from a polymicrobial mucosal surface. The precise anatomical passage of the responsible pathogen(s) and predisposing conditions are uncertain, though the seeming requirement for the presence of tonsils as a necessary factor for F. necrophorum infection is perhaps a clue.4 Disparate unproven hypotheses and diverse case descriptions favour a multifactorial pathogenesis. Proposed routes of infection are haematogenous, lymphatic, or direct invasion through connective tissue, in association with a discrete abscess or not. Two risqué reports of Lemierre’s syndrome occurring after mucosal trauma during “forceful oral sex” bluntly emphasise the point that mucosal disruption of one kind or another is the basis for pathogen translocation from the oropharynx.36,37 Many authors have noted an association with well-recognised viral and bacterial causes of pharyngitis including Epstein-Barr virus, cytomegalovirus, influenza, GAS, and Mycoplasma pneumoniae.38−44 Some have suggested transient infection-associated mucosal and/or systemic immunosuppression may contribute to the pathogenesis, and cases have been reported with underlying
S50 primary and acquired immunodeficiencies.45−47 Some reports have highlighted a potential role for thrombophilic disorders.4,38,48−50 As with other rare and severe infections striking apparently healthy young people (e.g. toxic shock syndrome), a unitary and unifying explanation of Lemierre’s syndrome pathogenesis seems less likely than a dynamic concept including patient-specific contributions by host, organism, and environmental factors.
Fusobacterium and pharyngitis Many studies have used culture and/or more sensitive molecular methods to characterise the place of Fusobacterium necrophorum in the polymicrobial oropharynx in states of health and disease, including in tonsils removed for infective (e.g. recurrent or chronic tonsillitis) and noninfective indications (e.g. obstructive sleep apnoea).51−53 It has regularly been found as part of the oropharyngeal flora, especially in adolescents and young adults.9,45,47,51 In most but not all studies including asymptomatic controls, Fusobacterium necrophorum has been identified more frequently in symptomatic subjects with pharyngo-tonsillitis (cases), especially in those with chronic and/or recurrent disease.47,54−57 This has been interpreted as evidence of causality by some authors.55,58 Other contributors have argued that oropharyngeal flora may be altered in states of disease (whether viral or bacterial), and proving that F. necrophorum is a cause of pharyngotonsillitis requires a higher level of evidence than this case-control approach.59−61 Evidence of a specific immune response to Fusobacterium sp. in some patients with pharyngitis may be more convincing.62 It is probable that Fusobacterium necrophorum does cause some cases of acute bacterial pharyngotonsillitis, especially in adolescents and young adults.58,63 It is unknown if antibiotic treatment hastens resolutions of symptoms or prevents complications. Linking F. necrophorum pharyngitis and Lemierre’s syndrome, Centor et al. called for a new paradigm in investigation and management of sore throat, estimating that 1 in 400 cases of F. necrophorum pharyngitis is complicated by Lemierre’s syndrome.16 By this estimate, if a highly sensitive and specific diagnostic test were to become available to focus targeted treatment of F. necrophorum, and antibiotic therapy was 100% effective in interrupting the proposed pathogenesis of all Lemierre’s syndrome cases, the number-needed-to-treat (NNT) to prevent a single case would be 400. The true NNT is likely much higher, and not only because there is no commercially available test. The heterogenous features of reported cases of Lemierre’s syndrome suggest that primary progressive F. necrophorum pharyngitis is not the only cause. In a much-publicised 2015 study, Centor et al. compared 312 students attending a student health clinic with acute sore throat to a convenience sample of 180 asymptomatic students.15 Each student was ascribed a Centor score, a clinical decision rule advocated in guidelines for use in deciding which patients with sore throat should have a throat swab to detect GAS (higher score indicates increased likelihood of GAS pharyngitis). All participants had a throat swab tested by molecular methods for F. necrophorum, GAS, group G and C streptococci (GGS/GCS), and Mycoplasma pneumoniae. F. necrophorum was detected
J. Osowicki et al. significantly more often in symptomatic students than in the asymptomatic group (20.5% vs 9.4%). Amongst symptomatic patients, F. necrophorum was detected more frequently than GAS (20.5% vs 10.3%). Detection of GAS, GGS/GCS, and F. necrophorum increased with higher Centor scores. The authors concluded that F. necrophorum was the cause of approximately 11% of acute pharyngitis cases in the age group and setting, and repeated their previous call for reconsideration of recommendations in current pharyngitis guidelines targeting testing and treatment of GAS only. Acknowledging the absence of intervention studies for F. necrophorum pharyngitis they called for “further study and consideration of both testing and treatment” though drew a line short of the level of evidence that would convince their detractors, “We do not believe that one could ethically do a randomized, control trial of antibiotic therapy for F. necrophorum pharyngitis given the potential severity of the Lemierre syndrome”. In a subsequent letter, this was expressed as a recommendation for treatment of adolescents and young adults with GAS-negative acute pharyngitis and a Centor score of 2 or greater with an antibiotic active against F. necrophorum in order to prevent Lemierre’s syndrome, until a molecular test becomes widely available.59,61 In the study by Centor et al., 93/169 (55%) of students with sore throat and Centor score of 2 or greater had no bacterial pathogen identified. Of non-GAS cases with Centor score of 2 or greater, 31/155 (20%) had F. necrophorum detected. Leaving aside acknowledged limitations (no viral studies, frequent isolation of other pathogens), if one were to accept F. necrophorum as the cause of pharyngitis in all of these cases, the NNT to avoid a single Lemierre’s syndrome case with the empiric approach advocated would be at least 2000 if the treatment was 100% effective. The accompanying editorial commentary and subsequent letters highlighted that this approach would significantly increase antibiotic prescribing for sore throat for no proven benefit, even if clinicians only treated the group identified by Centor et al. (i.e.15−30 years of age, Centor score of 2 or greater, and GAS-negative).60,64,65 Given the repeated observation that prescribers do not adhere to the current simpler guidelines and prescribe antibiotics far more frequently than recommended for sore throat, and usually with inappropriately broadspectrum antibiotics, it is likely that such a recommendation would lead to more antibiotic use for sore throat in other groups too.20,22,66 Conversely, economic modeling has been used to show cost-effectiveness for targeted treatment of F. necrophorum in young adults in Denmark (i.e. positive throat swab) if the incidence of Lemierre’s syndrome were to be reduced by only 20−25%.67 The claim that a randomised controlled trial would not be ethical is dubious. Testing and treatment of Fusobacterium-positive pharyngitis is not standard of care anywhere and the option of empiric treatment without a test would lead to an unacceptable increase in use of antibiotics for pharyngitis. A RCT would offer testing and treatment to individuals who would not usually be provided with either. Using a similar diagnostic approach as in the study by Centor et al, detection of F. necrophorum could be followed by specific targeted therapy (i.e. metronidazole) or placebo (where GAS was also detected a macrolide could be used as a placebo for F. necrophorum). While the rarity of Lemierre’s syndrome clearly makes it a poor primary
Lemierre’s syndrome outcome, if treatment significantly hastened resolution of symptoms, F. necrophorum would be firmly established as a cause of acute tonsillopharyngitis, there would be a market for a testing platform, and subsequent surveillance may show an impact on Lemierre’s syndrome incidence.
Diagnosis and management Patients with Lemierre’s syndrome have disparate presenting complaints. The road to diagnosis can be tortuous, and is often prompted by identification of F. necrophorum in blood cultures or unexpected imaging findings consistent with septic emboli. Some cases will be missing obvious clinical, microbiological and radiological features and early multidisciplinary involvement to guide investigations and interventions is advisable, including infectious diseases, microbiology, radiology, haematology, surgery, and often intensive care teams. The diagnosis is frequently made with Doppler ultrasound of the internal jugular vein, blood cultures, and chest imaging. Sometimes, more sensitive and/or invasive techniques such as CT, MRI, sampling of embolic foci, and use of 16S rRNA sequencing in culturenegative cases are required, and can help to define the extent of disease and guide management.5,46 There are no intervention studies to inform management of Lemierre’s syndrome. Recommendations are based on historical practice and in vitro microbiology studies, supported by limited data from observational studies and case reports. The key components of management are antibiotic therapy and drainage of collections at the primary and secondary (embolic) sites of infection. Indications for anticoagulation are uncertain and internal jugular vein surgery (ligation or excision) is now rarely performed.68−70 Anticoagulation use has been controversial but may be more common than in the past despite there having been no prospective study of its efficacy, as suggested by 46% of reported cases in a 2016 systematic review of 137 cases from “the past 5 years” receiving anticoagulation compared to 23% of cases in Riordan’s 2007 review of 393 cases.4,71−73 These ancillary interventions are applied most often in severe, progressive, or refractory cases with persistent sepsis, ongoing septic emboli, and extensive and/or progressive thrombosis.4,5,47,74 The advent of antibiotics has seen the mortality of Lemierre’s syndrome fall from at least 90% to 5%.5 F. necrophorum isolates show in vitro susceptibility to to metronidazole, clindamycin, beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations, and carbapenems.4,5,75 Most isolates are susceptible to penicillin, though resistant betalactamase producing strains are well described and preclude penicillin monotherapy for serious invasive infections.76 F. necrophorum is intrinsically resistant to fluoroquinolones and aminoglycosides. Resistance to macrolides is common. Except for the newer glycylcycline antibiotic tigecycline, tetracyclines have poor activity. Metronidazole is considered the treatment of choice for Fusobacterium sp. infections. It is active against all isolates, has excellent tissue penetration (including CSF), high intracellular levels and high oral bioavailability. Penicillin and clindamycin treatment failure have been reported despite in vitro susceptibility, with subsequent successful salvage therapy with metronidazole.77 Carbapenems and
S51 metronidazole have also been shown to have greater in vitro bactericidal activity than alternative agents. Oral streptococci are usually targeted in combinations (e.g. ceftriaxone + metronidazole) or monotherapy (e.g. a carbapenem or BL/BLI) due to concern for polymicrobial translocation from the oropharynx.35 As for other infections with endovascular and/or necrotic foci, response to appropriate antibiotic treatment may be slow and fever often persists for more than 7 days.5,77 Total duration of treatment and timing of switch from intravenous to oral antibiotics should be individualised, depending on severity, response to treatment, and metastatic sites of infection. Duration is typically in the range of 3−6 weeks, and early switch from intravenous antibiotics to an oral regimen (ideally including metronidazole) should be considered following clinical improvement.
Conclusions Due to its rarity and severity, Lemierre’s syndrome is regarded as an enigmatic clinical phenomenon. Prompt diagnosis and appropriate treatment in individual cases relies upon awareness of the unusual pattern of clinical features and a low-threshold for suspicion. Important questions remain as to whether or not Lemierre’s syndrome is increasing in incidence as well as the role of F. necrophorum in acute tonsillopharyngitis. Answers to these questions might be found in strengthened surveillance efforts and a RCT of testing and treatment for F. necrophorum-positive tonsillopharyngitis.
Conflict of interest The authors have no conflicts of interest to report.
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30. Shimada M, Morinaga Y, Kitazaki T, Fukuda M, Hashiguchi K, Yanagihara K, et al. A severe case of Lemierre Syndrome with Streptococcus constellatus Infection. Jpn J Infect Dis 2014;67(6):488−9. 31. Ji YQ, Wang J, Kong LQ, Juggessur-Mungur KS, Wu TH, Zhang ZH. Lemierre syndrome caused by Arcanobacterium haemolyticum. Chin Med J (Engl) 2013;126(2):391−2. 32. 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. 33. Takeda K, Kenzaka T, Morita Y, Kuroki S, Kajii E. A rare case of Lemierre`s syndrome caused by Porphyromonas asaccharolytica. Infection 2013;41(4):889−92. 34. 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(8):260−6. 35. Gilbert DN, Chambers HF, Eliopoulis GM, Saag MS, Pavia AT. The Sanford Guide to Antimicrobial Therapy 2016. 46st ed. Sperryville, VA: Antimicrobial Therapy, Inc; 2016. 36. Dellamonica P, Bernard E. ‘Deep throat’ cellulitis. J Infect 1999;38(2):134. 37. Takenouchi S, Kunieda T, Yamada R, Yamakita N. Lemierre syndrome caused by oral sex. J Formos Med Assoc 2014;113(10):762−3. 38. Holm K, Svensson PJ, Rasmussen M. Invasive Fusobacterium necrophorum infections and Lemierre’s syndrome: the role of thrombophilia and EBV. Eur J Clin Microbiol Infect Dis 2015;34(11):2199−207. 39. Klein NC, Petelin A, Cunha BA. Mycoplasma pneumoniae preceding Lemierre’s syndrome due to Fusobacterium nucleatum complicated by acute Epstein-Barr virus (EBV) infectious mononucleosis in an immunocompetent host. Heart Lung 2013;42(1):74−6. 40. Porquet-Bordes V, Guillet E, Cammas B, Runel-Belliard C. [Lemierre syndrome and influenza A (H1N1)]. Arch Pediatr 2011;18(4):413−5. 41. Chacko EM, Krilov LR, Patten W, Lee PJ. Lemierre’s and Lemierre’s-like syndromes in association with infectious mononucleosis. J Laryngol Otol 2010;124(12):1257−62. 42. Dalamaga M, Karmaniolas K, Chavelas C, Liatis S, Matekovits H, Migdalis I. Fusobacterium necrophorum septicemia following Epstein-Barr virus infectious mononucleosis. Anaerobe 2003;9(6):285. 43. Stenfors LE, Bye HM, Räisänen S, Myklebust R. Bacterial penetration into tonsillar surface epithelium during infectious mononucleosis. J Laryngol Otol 2000;114(11):848−52. 44. Dagan R, Powell KR. Postanginal sepsis following infectious mononucleosis. Arch Intern Med 1987;147(9):1581−3. 45. Kjærulff AMG, Thomsen MK, Ovesen T, Klug TE. Clinical and biochemical characteristics of patients with Fusobacterium necrophorum-positive acute tonsillitis. Eur Arch Otorhinolaryngol 2015;272(6):1457−63. 46. Bailhache M, Mariani-Kurkdjian P, Lehours P, Sarlangue J, Pillet P, Bingen E, et al. Fusobacterium invasive infections in children: a retrospective study in two French tertiary care centres. Eur J Clin Microbiol Infect Dis 2013;32(8):1041−7. 47. Brazier JS. Human infections with Fusobacterium necrophorum. Anaerobe 2006;12(4):165−72. 48. Hlibczuk V. Lemierre’s syndrome complicating bacterial pharyngitis in a patient with undiagnosed factor XII deficiency. J Emerg Med 2007;32(4):365−9. 49. Schmid T, Miskin H, Schlesinger Y, Argaman Z, Kleid D. Respiratory failure and hypercoagulability in a toddler with Lemierre’s syndrome. Pediatrics 2005;115(5):e620−2. 50. Goldenberg NA, Knapp-Clevenger R, Hays T, MancoJohnson MJ. Lemierre’s and Lemierre’s-like syndromes in children: survival and thromboembolic outcomes. Pediatrics
Lemierre’s syndrome 2005;116(4):e543−8. 51. Björk H, Bieber L, Hedin K, Sundqvist M. Tonsillar colonisation of Fusobacterium necrophorum in patients subjected to tonsillectomy. BMC Infectious Diseases 2015;15:264. 52. Klug TE, Henriksen J-J, Fuursted K, Ovesen T. Similar recovery rates of Fusobacterium necrophorum from recurrently infected and non-infected tonsils. Dan Med Bull 2011;58(7):A4295−A. 53. Klug TE, Henriksen JJ, Fuursted K, Ovesen T. Significant pathogens in peritonsillar abscesses. Eur J Clin Microbiol Infect Dis 2011;30(5):619−27. 54. Jensen A, Hansen TM, Bank S, Kristensen LH, Prag J. Fusobacterium necrophorum tonsillitis: an important cause of tonsillitis in adolescents and young adults. Clin Microbiol Infect 2015;21(3):266.e1−3. 55. Eaton C, Swindells J. The significance and epidemiology of Fusobacterium necrophorum in sore throats. J Infect 2014;69(2):194−6. 56. Batty A, Wren MW, Gal M. Fusobacterium necrophorum as the cause of recurrent sore throat: comparison of isolates from persistent sore throat syndrome and Lemierre’s disease. J Infect 2005;51(4):299−306. 57. Batty A, Wren MWD. Prevalence of Fusobacterium necrophorum and other upper respiratory tract pathogens isolated from throat swabs. Br J Biomed Sci 2005;62(2):66−70. 58. 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. 59. Centor RM, Atkinson TP, Waites KB. Fusobacterium-Positive and Streptococcal-Positive Pharyngitis. Ann Intern Med 2015;162(12):877−8. 60. Linder JA. Sore throat: avoid overcomplicating the uncomplicated. Ann Intern Med 2015;162(4):311−2. 61. Centor RM, Atkinson TP, Estrada C, Waites KB. Sore Throat: Avoid Overcomplicating the Uncomplicated. Ann Intern Med 2015;162(12):878. 62. Klug TE, Henriksen JJ, Rusan M, Fuursted K, Krogfelt KA, Ovesen T, et al. Antibody development to Fusobacterium necrophorum in patients with peritonsillar abscess. Eur J Clin Microbiol Infect Dis 2014;33(10):1733−9. 63. Klug TE, Rusan M, Fuursted K, Ovesen T, Jorgensen AW. A systematic review of Fusobacterium necrophorum-positive acute tonsillitis: prevalence, methods of detection, patient characteristics, and the usefulness of the Centor score. Eur J Clin Microbiol Infect Dis 2016;35(12):1903−1912. 64. Linder JA. Sore Throat: Avoid Overcomplicating the Uncomplicated. Ann Intern Med 2015;162(12):878−9. 65. Matthys J, De Meyere M, De Sutter A. Fusobacterium-Positive
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and Streptococcal-Positive Pharyngitis. Ann Intern Med 2015;162(12):876. Hersh AL, Fleming-Dutra KE, Shapiro DJ, Hyun DY, Hicks LA, Outpatient Antibiotic Use Target-Setting W. Frequency of First-line Antibiotic Selection Among US Ambulatory Care Visits for Otitis Media, Sinusitis, and Pharyngitis. JAMA Intern Med 2016;176(12):1870−2. Bank S, Christensen K, Kristensen LH, Prag J. A costeffectiveness analysis of identifying Fusobacterium necrophorum in throat swabs followed by antibiotic treatment to reduce the incidence of Lemierre’s syndrome and peritonsillar abscesses. Eur J Clin Microbiol Infect Dis 2013;32(1):71−8. Karkos PD, Asrani S, Karkos CD, Leong SC, Theochari EG, Alexopoulou TD, et al. Lemierre’s syndrome: A systematic review. Laryngoscope 2009;119(8):1552−9. Wang D, Price AK, Leitch KK, Salvadori M, Singh RN, Kornecki A, et al. Lemierre’s syndrome with septic shock caused by Fusobacterium necrophorum. Anaesth Intensive Care 2007;35(5):796−801. Escher R, Haltmeier S, von Steiger N, Dutly AE, Arnold A, Kickuth R, et al. Advanced Lemierre syndrome requiring surgery. Infection 2008;36(5):495−6. Johannesen KM, Bodtger U. Lemierre’s syndrome: current perspectives on diagnosis and management. Infect Drug Resist 2016;9:221−7. Agrafiotis M, Moulara E, Chloros D, Tsara V. Lemierre syndrome and the role of modern antibiotics and therapeutic anticoagulation in its treatment. Am J Emerg Med 2015;33(5):733.e3−4. Phan T, So TY. Use of anticoagulation therapy for jugular vein thrombus in pediatric patients with Lemierre’s syndrome. Int J Clin Pharm 2012;34(6):818−21. 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(6): 458−65. Yusuf E, Halewyck S, Wybo I, Pierard D, Gordts F. Fusobacterium necrophorum and other Fusobacterium spp. isolated from head and neck infections: A 10-year epidemiology study in an academic hospital. Anaerobe 2015;34:120−4. Brook I. Infections caused by beta-lactamase-producing Fusobacterium spp. in children. Pediatr Infect Dis J 1993;12(6):532−3. DeGaffe GH, Murphy JR, Butler IJ, Shelburne J, Heresi GP. Severe narrowing of left cavernous carotid artery associated with Fusobacterium necrophorum infection. Anaerobe 2013;22:118−20.
www.elsevierhealth.com/journals/jinf
The long shadow of Lemierre’s syndrome Joshua Osowicki a,b,c,d,e,*, Sarah Kapur f, Linny Kimly Phuong d,e, Simon Dobson b Group A Streptococcal Research Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, BC Children’s Hospital, Vancouver, British Columbia, Canada c Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia d Infectious Diseases unit, The Royal Children’s Hospital Melbourne, Victoria, Australia e Department of Paediatric Infection and Immunity, Monash Children’s Hospital, Clayton, Australia f Paediatric Infectious Diseases Department, Royal Belfast Hospital for Sick Children, Belfast, UK a
b
Available online 23 June 2017
KEYWORDS Lemierre’s syndrome; Fusobacterium; Septic thrombophlebitis
Summary Lemierre’s syndrome is a rare and feared complication of pharyngitis, occurring most commonly in adolescents and young adults. It is typically defined by the constellation of septic internal jugular vein thrombophlebitis, pulmonary and other septic emboli, and sterilesite infection by Fusobacterium necrophorum. The rarity and severity of Lemierre’s syndrome has made it an attractive subject for case reports but there is a paucity of evidence to inform areas of persistent uncertainty. In recent years, heightened attention and controversy has focused upon speculation that a purported rise in the incidence of Lemierre’s syndrome is due to reduced antibiotic prescribing for respiratory tract infections, that F. necrophorum is an under-appreciated cause of acute tonsillopharyngitis and that testing and targeted treatment would prevent cases of Lemierre’s syndrome. Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association. All rights reserved.
Introduction In 1936 in The Lancet, André Lemierre described the syndrome which would eventually carry his name and concluded that it was, “relatively easy to make a diagnosis on the simple clinical findings…a syndrome so characteristic that a mistake is almost impossible”.1 Although Lemierre broadly addressed “certain septicaemias due to anaerobic organisms” what is best remembered is his illustrative focus on post-anginal septicaemia due to
Bacillus fundiliformis (known today as Fusobacterium necrophorum) in which he described the progression from focal suppurative (peritonsillar) infection to local septic (internal jugular) thrombophlebitis and distant septic (pulmonary) emboli. As familiarity with the most advanced and characteristic elements of Lemierre’s syndrome has diminished in the antibiotic era, it has assumed a classical and almost mythical status, attested to by a proliferation of case reports portraying it as a “forgotten” and “sinister” enigma, contrasting the historical diagnostic confidence
* Corresponding author. The Royal Children’s Hospital Melbourne, 50 Flemington Rd, Victoria, Australia, 3052. Tel.: 61 3 9345 5522. E-mail address: [email protected] (J. Osowicki). 0163-4453/Crown Copyright © 2017 Published by Elsevier Ltd on behalf of the British Infection Association. All rights reserved
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Figure 1 Lemierre’s syndrome — an eponym with many synonyms. The classic syndrome (black text) with variations recognised by André Lemierre in his 1936 paper (grey boxes).
of Lemierre.2,3 Rather than subjecting the syndrome to further review and report, we point instead in this article to previous outstanding reviews4,5 and will concentrate on areas of confusion, contention, and controversy which have emerged in relation to its definition, microbiology, epidemiology, pathogenesis, and management.
Definition The term Lemierre’s (or simply Lemierre) syndrome has been applied broadly and often interchangeably since the 1980s to cases including any one or more of F. necrophorum infection, septic thrombophlebitis, and distant metastatic septic emboli (Figure 1). André Lemierre himself emphasised that the pathway from focal suppurative infection to local thrombophlebitis, generalised sepsis, and distant embolic phenomena could originate: “1) From inflammatory lesions of the nasopharynx, particularly tonsillar and peritonsillar abscesses; 2) From similar lesions of the mouth and jaws; 3) In connexion with otitis media or mastoiditis; 4) From purulent endometritis following parturition; 5) From appendicitis; 6) From infections of the urinary passages”.1 In a meticulous 2007 review of 393 reported cases, including a comprehensive and engaging examination of the historical aspects of Lemierre’s syndrome, Riordan tested various case definitions and arrived at a clinicalmicrobiological hybrid requiring: a history of “anginal illness” within the preceding four weeks or compatible clinical findings and; evidence of remote metastatic lesions and; internal jugular thrombophlebitis or isolation of F. necrophorum or Fusobacterium sp. from blood cultures or other sterile site.4 Though this definition does not fit with Lemierre’s original concept of an ominous pathological sequence common to “certain anaerobic septicaemias”, it conforms (by design) to modern usage. Use of the antiquated
term “anginal illness” was somewhat unfortunate but should be understood to encompass pharyngo-tonsillitis and its attendant local suppurative complications. Taking into account new molecular diagnostic techniques, the final microbiological criteria should be amended to include identification in blood or other sterile site of F. necrophorum or Fusobacterium sp. by culture and/or non-culture-based diagnostics (e.g. polymerase chain reaction, PCR).6−8 This definition notably excludes otogenic Fusobacterium sp. infections, which disproportionately affect young children and can also cause thrombophlebitis and serious intracranial complications.4,9
Epidemiology Efforts to fully appreciate the epidemiology of Lemierre’s syndrome are confounded by its rarity, conflicting definitions, and multiple aliases. Qualified estimates of Lemierre’s syndrome incidence derived from English and Danish retrospective case series from the 1990s were approximately one per million persons per year.10,11 A subsequent prospective study from Denmark reported an annual incidence of 3.6 per million persons per year.12 By any definition and for unexplained reasons, Lemierre’s syndrome predominantly affects young adults. The prospective Danish study found an annual incidence of 14.4 cases per million for persons aged 14−24 years, and in Riordan’s 2007 review of 222 previous cases meeting his restricted case definition, the median age was 19 years and 89% of patients were aged 10 to 35 years.4 Other enigmatic epidemiological observations are a male:female ratio of approximately 2:1 in most series and a concentration of cases in autumn and winter in some series.5 Of greatest epidemiological relevance and resonance is the contention by some authors that the incidence of Lemierre’s syndrome is increasing.10,13,14 Authors of case
Lemierre’s syndrome reports have understandably taken this as a cue to choose fittingly emotive titles. The case that incidence is rising is well summarized by Riordan.4 It is largely circumstantial and based on relatively low quality evidence, inferring from small case series, microbiological surveys (i.e. frequency of F. necrophorum in blood cultures), trends in numbers of published cases, and anecdote, that Lemierre’s syndrome was relatively common in the pre-antibiotic era, then virtually disappeared, only to reappear and rise in incidence from the 1990s. There are unfortunately no long-term active surveillance data available to settle the matter. Controversy arises because the putative explanations for a possible true increase in Lemierre’s syndrome incidence include reduced antibiotic treatment of respiratory tract infections (RTI), increased use of macrolide antibiotics (not active against F. necrophorum), and fewer tonsillectomy procedures.4,15,16 The first point in particular is an uncomfortable challenge to attitudes in the antimicrobial stewardship era and guideline recommendations restricting antibiotic treatment of sore throat to microbiologicallyconfirmed Group A streptococcal (GAS, Streptococcus pyogenes) pharyngitis and suppurative complications, including Lemierre’s syndrome.17 A case series published by one tertiary referral hospital in Australia attributed an increase in Lemierre’s syndrome cases to reduced prescribing of beta-lactam antibiotics for pharyngitis as part of antimicrobial stewardship efforts.18 Again, the case is circumstantial, based on an apparent temporal association between possibly increasing incidence and antibiotic use trends, and a seductively simple concept of pathogenesis: whatever the cause of sore throat, F. necrophorum cannot enter the bloodstream from the oropharynx if it is preemptively targeted with a suitable antibiotic.15,16 Despite guideline recommendations, prescribing rates in many settings for RTI have remained high and far in excess of GAS pharyngitis rates, though macrolide use has increased.19−22 Gulliford et al. compared practices in the United Kingdom with higher and lower rates of antibiotic prescribing for RTI, capturing 7% of all UK primary care consultations and about 45 million patient years of information, and did not find an increased incidence of Lemierre’s syndrome with lower prescribing rates.23 An association was seen for peritonsillar abscess, another condition in which F necrophorum is implicated. The difference though was only very small, illustrated well by a calculation finding only one additional case per practice (~7000 patients) per decade for every 10% reduction in antibiotic prescribing for RTI.24
Microbiology Lemierre’s syndrome has become almost synonymous in common usage with infection due to F. necrophorum, its most common cause. Observing the frequency with which the organism has been reported in Lemierre’s syndrome, Riordan posed the question, “Is F. necrophorum a sine qua non for Lemierre’s syndrome?”.4 Other organisms reported as a cause of the syndrome (without Fusobacterium sp. identified) include methicillin-susceptible and methicillin-resistant Staphylococcus aureus,25 Staphylococcus epidermidis,26 GAS and other beta haemolytic streptococci,27,28 StreptoStreptococcus constellatus,30 coccus intermedius,29 31 Peptostreptococcus Arcanobacterium haemolyticum,
S49 sp., Prevotella sp.,32 Porphyromonas asaccharolytica,33 Klebsiella pneumoniae,34 Eikenella corrodens, Enterococcus sp., Proteus sp., and Bacteroides sp.4 Answering his own question, Riordan proposed in 2007 that it was “eminently possible” molecular studies would eventually show Fusobacterium sp. to be responsible for “all typical cases of Lemierre’s syndrome”.4 Where identification of Fusobacterium sp. forms part of the case definition, this is obviously a truism. In 1936, Lemierre himself was not nearly as confident that all cases were attributable to Fusobacterium sp.1 Certainly, there are other bacteria causing head and neck infections that are equally capable of causing thrombosis and septic embolism, Staphylococcus aureus being the most obvious example. Head and neck infections arising outside of the oropharynx, or in association with a vascular access device, may also cause internal jugular vein thrombosis and embolism. Many reports have described these cases as “variant”, “atypical” or “Lemierre’s-like” given the different microbiology and pathogenesis. As far as predicting the involvement of Fusobacterium sp. (likely other anaerobic organisms too), a “typical case” might arguably be one with a similarly biphasic course to that observed by Lemierre, with symptoms attributable to thrombophlebitis and/or emboli occurring in the aftermath of a relatively innocuous episode of pharyngitis, often after complete recovery. This is in contrast to the monophasic, progressive, and frequently pyogenic course more often associated with familiar aggressive pathogens such as S. aureus, beta-haemolytic streptococci, and the Streptococcus anginosus group. Sine qua non or not, even where Fusobacterium sp. is the only bacteria identified in a “typical case”, treatment recommendations are for broader coverage of other typical oropharyngeal flora, whether with a single drug (e.g. a carbapenem or beta lactam-beta lactamase inhibitor) or combination therapy (e.g. third-generation cephalosporin + metronidazole).35
Pathogenesis By any definition, Lemierre’s syndrome is a complicated bloodstream infection arising from a polymicrobial mucosal surface. The precise anatomical passage of the responsible pathogen(s) and predisposing conditions are uncertain, though the seeming requirement for the presence of tonsils as a necessary factor for F. necrophorum infection is perhaps a clue.4 Disparate unproven hypotheses and diverse case descriptions favour a multifactorial pathogenesis. Proposed routes of infection are haematogenous, lymphatic, or direct invasion through connective tissue, in association with a discrete abscess or not. Two risqué reports of Lemierre’s syndrome occurring after mucosal trauma during “forceful oral sex” bluntly emphasise the point that mucosal disruption of one kind or another is the basis for pathogen translocation from the oropharynx.36,37 Many authors have noted an association with well-recognised viral and bacterial causes of pharyngitis including Epstein-Barr virus, cytomegalovirus, influenza, GAS, and Mycoplasma pneumoniae.38−44 Some have suggested transient infection-associated mucosal and/or systemic immunosuppression may contribute to the pathogenesis, and cases have been reported with underlying
S50 primary and acquired immunodeficiencies.45−47 Some reports have highlighted a potential role for thrombophilic disorders.4,38,48−50 As with other rare and severe infections striking apparently healthy young people (e.g. toxic shock syndrome), a unitary and unifying explanation of Lemierre’s syndrome pathogenesis seems less likely than a dynamic concept including patient-specific contributions by host, organism, and environmental factors.
Fusobacterium and pharyngitis Many studies have used culture and/or more sensitive molecular methods to characterise the place of Fusobacterium necrophorum in the polymicrobial oropharynx in states of health and disease, including in tonsils removed for infective (e.g. recurrent or chronic tonsillitis) and noninfective indications (e.g. obstructive sleep apnoea).51−53 It has regularly been found as part of the oropharyngeal flora, especially in adolescents and young adults.9,45,47,51 In most but not all studies including asymptomatic controls, Fusobacterium necrophorum has been identified more frequently in symptomatic subjects with pharyngo-tonsillitis (cases), especially in those with chronic and/or recurrent disease.47,54−57 This has been interpreted as evidence of causality by some authors.55,58 Other contributors have argued that oropharyngeal flora may be altered in states of disease (whether viral or bacterial), and proving that F. necrophorum is a cause of pharyngotonsillitis requires a higher level of evidence than this case-control approach.59−61 Evidence of a specific immune response to Fusobacterium sp. in some patients with pharyngitis may be more convincing.62 It is probable that Fusobacterium necrophorum does cause some cases of acute bacterial pharyngotonsillitis, especially in adolescents and young adults.58,63 It is unknown if antibiotic treatment hastens resolutions of symptoms or prevents complications. Linking F. necrophorum pharyngitis and Lemierre’s syndrome, Centor et al. called for a new paradigm in investigation and management of sore throat, estimating that 1 in 400 cases of F. necrophorum pharyngitis is complicated by Lemierre’s syndrome.16 By this estimate, if a highly sensitive and specific diagnostic test were to become available to focus targeted treatment of F. necrophorum, and antibiotic therapy was 100% effective in interrupting the proposed pathogenesis of all Lemierre’s syndrome cases, the number-needed-to-treat (NNT) to prevent a single case would be 400. The true NNT is likely much higher, and not only because there is no commercially available test. The heterogenous features of reported cases of Lemierre’s syndrome suggest that primary progressive F. necrophorum pharyngitis is not the only cause. In a much-publicised 2015 study, Centor et al. compared 312 students attending a student health clinic with acute sore throat to a convenience sample of 180 asymptomatic students.15 Each student was ascribed a Centor score, a clinical decision rule advocated in guidelines for use in deciding which patients with sore throat should have a throat swab to detect GAS (higher score indicates increased likelihood of GAS pharyngitis). All participants had a throat swab tested by molecular methods for F. necrophorum, GAS, group G and C streptococci (GGS/GCS), and Mycoplasma pneumoniae. F. necrophorum was detected
J. Osowicki et al. significantly more often in symptomatic students than in the asymptomatic group (20.5% vs 9.4%). Amongst symptomatic patients, F. necrophorum was detected more frequently than GAS (20.5% vs 10.3%). Detection of GAS, GGS/GCS, and F. necrophorum increased with higher Centor scores. The authors concluded that F. necrophorum was the cause of approximately 11% of acute pharyngitis cases in the age group and setting, and repeated their previous call for reconsideration of recommendations in current pharyngitis guidelines targeting testing and treatment of GAS only. Acknowledging the absence of intervention studies for F. necrophorum pharyngitis they called for “further study and consideration of both testing and treatment” though drew a line short of the level of evidence that would convince their detractors, “We do not believe that one could ethically do a randomized, control trial of antibiotic therapy for F. necrophorum pharyngitis given the potential severity of the Lemierre syndrome”. In a subsequent letter, this was expressed as a recommendation for treatment of adolescents and young adults with GAS-negative acute pharyngitis and a Centor score of 2 or greater with an antibiotic active against F. necrophorum in order to prevent Lemierre’s syndrome, until a molecular test becomes widely available.59,61 In the study by Centor et al., 93/169 (55%) of students with sore throat and Centor score of 2 or greater had no bacterial pathogen identified. Of non-GAS cases with Centor score of 2 or greater, 31/155 (20%) had F. necrophorum detected. Leaving aside acknowledged limitations (no viral studies, frequent isolation of other pathogens), if one were to accept F. necrophorum as the cause of pharyngitis in all of these cases, the NNT to avoid a single Lemierre’s syndrome case with the empiric approach advocated would be at least 2000 if the treatment was 100% effective. The accompanying editorial commentary and subsequent letters highlighted that this approach would significantly increase antibiotic prescribing for sore throat for no proven benefit, even if clinicians only treated the group identified by Centor et al. (i.e.15−30 years of age, Centor score of 2 or greater, and GAS-negative).60,64,65 Given the repeated observation that prescribers do not adhere to the current simpler guidelines and prescribe antibiotics far more frequently than recommended for sore throat, and usually with inappropriately broadspectrum antibiotics, it is likely that such a recommendation would lead to more antibiotic use for sore throat in other groups too.20,22,66 Conversely, economic modeling has been used to show cost-effectiveness for targeted treatment of F. necrophorum in young adults in Denmark (i.e. positive throat swab) if the incidence of Lemierre’s syndrome were to be reduced by only 20−25%.67 The claim that a randomised controlled trial would not be ethical is dubious. Testing and treatment of Fusobacterium-positive pharyngitis is not standard of care anywhere and the option of empiric treatment without a test would lead to an unacceptable increase in use of antibiotics for pharyngitis. A RCT would offer testing and treatment to individuals who would not usually be provided with either. Using a similar diagnostic approach as in the study by Centor et al, detection of F. necrophorum could be followed by specific targeted therapy (i.e. metronidazole) or placebo (where GAS was also detected a macrolide could be used as a placebo for F. necrophorum). While the rarity of Lemierre’s syndrome clearly makes it a poor primary
Lemierre’s syndrome outcome, if treatment significantly hastened resolution of symptoms, F. necrophorum would be firmly established as a cause of acute tonsillopharyngitis, there would be a market for a testing platform, and subsequent surveillance may show an impact on Lemierre’s syndrome incidence.
Diagnosis and management Patients with Lemierre’s syndrome have disparate presenting complaints. The road to diagnosis can be tortuous, and is often prompted by identification of F. necrophorum in blood cultures or unexpected imaging findings consistent with septic emboli. Some cases will be missing obvious clinical, microbiological and radiological features and early multidisciplinary involvement to guide investigations and interventions is advisable, including infectious diseases, microbiology, radiology, haematology, surgery, and often intensive care teams. The diagnosis is frequently made with Doppler ultrasound of the internal jugular vein, blood cultures, and chest imaging. Sometimes, more sensitive and/or invasive techniques such as CT, MRI, sampling of embolic foci, and use of 16S rRNA sequencing in culturenegative cases are required, and can help to define the extent of disease and guide management.5,46 There are no intervention studies to inform management of Lemierre’s syndrome. Recommendations are based on historical practice and in vitro microbiology studies, supported by limited data from observational studies and case reports. The key components of management are antibiotic therapy and drainage of collections at the primary and secondary (embolic) sites of infection. Indications for anticoagulation are uncertain and internal jugular vein surgery (ligation or excision) is now rarely performed.68−70 Anticoagulation use has been controversial but may be more common than in the past despite there having been no prospective study of its efficacy, as suggested by 46% of reported cases in a 2016 systematic review of 137 cases from “the past 5 years” receiving anticoagulation compared to 23% of cases in Riordan’s 2007 review of 393 cases.4,71−73 These ancillary interventions are applied most often in severe, progressive, or refractory cases with persistent sepsis, ongoing septic emboli, and extensive and/or progressive thrombosis.4,5,47,74 The advent of antibiotics has seen the mortality of Lemierre’s syndrome fall from at least 90% to 5%.5 F. necrophorum isolates show in vitro susceptibility to to metronidazole, clindamycin, beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations, and carbapenems.4,5,75 Most isolates are susceptible to penicillin, though resistant betalactamase producing strains are well described and preclude penicillin monotherapy for serious invasive infections.76 F. necrophorum is intrinsically resistant to fluoroquinolones and aminoglycosides. Resistance to macrolides is common. Except for the newer glycylcycline antibiotic tigecycline, tetracyclines have poor activity. Metronidazole is considered the treatment of choice for Fusobacterium sp. infections. It is active against all isolates, has excellent tissue penetration (including CSF), high intracellular levels and high oral bioavailability. Penicillin and clindamycin treatment failure have been reported despite in vitro susceptibility, with subsequent successful salvage therapy with metronidazole.77 Carbapenems and
S51 metronidazole have also been shown to have greater in vitro bactericidal activity than alternative agents. Oral streptococci are usually targeted in combinations (e.g. ceftriaxone + metronidazole) or monotherapy (e.g. a carbapenem or BL/BLI) due to concern for polymicrobial translocation from the oropharynx.35 As for other infections with endovascular and/or necrotic foci, response to appropriate antibiotic treatment may be slow and fever often persists for more than 7 days.5,77 Total duration of treatment and timing of switch from intravenous to oral antibiotics should be individualised, depending on severity, response to treatment, and metastatic sites of infection. Duration is typically in the range of 3−6 weeks, and early switch from intravenous antibiotics to an oral regimen (ideally including metronidazole) should be considered following clinical improvement.
Conclusions Due to its rarity and severity, Lemierre’s syndrome is regarded as an enigmatic clinical phenomenon. Prompt diagnosis and appropriate treatment in individual cases relies upon awareness of the unusual pattern of clinical features and a low-threshold for suspicion. Important questions remain as to whether or not Lemierre’s syndrome is increasing in incidence as well as the role of F. necrophorum in acute tonsillopharyngitis. Answers to these questions might be found in strengthened surveillance efforts and a RCT of testing and treatment for F. necrophorum-positive tonsillopharyngitis.
Conflict of interest The authors have no conflicts of interest to report.
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