We posted a poll on twitter on 2/12/24 asking the following question:
- Most respondents chose to anticoagulate.
- The results are in line with real world experience in which 50-60% of patients with Lemierre syndrome are anticoagulated (see metanalyses below).
- However, either answer is acceptable because there is no evidence or consensus to support one option over the other.
- Decision-making may take into account the following considerations/hypotheticals:
- In favor of anticoagulation:
- The clot is comprised of bacteria and fibrin, so anticoagulation has the potential to:
- Prevent propagation of clot.
- Promote recanalization of the vessel.
- The clot is comprised of bacteria and fibrin, so anticoagulation has the potential to:
- In favor of no anticoagulation:
- May cause dispersion of clot-associated bacteria with increased risk of septic emboli.
- Experience with septic thrombophlebitis in other veins/contexts suggests that anticoagulation not necessary.
- Most patients with Lemierre syndrome have thrombocytopenia, increasing the risk of bleeding.
- In favor of anticoagulation:
Below, we will:
- Provide an overview of Lemierre syndrome.
- Review the literature concerning anticoagulation.
The bottom line is that the risks-benefits of anticoagulation in Lemierre syndrome remain unknown!
Description:
- Lemierre syndrome is a rare, but life-threatening:
- Complication of an acute oropharyngeal infection.
- Form of septic thrombophlebitis.
- Classically comprised of:1
- Pharyngeal infection
- Internal jugular vein thrombosis
- Metastatic septic emboli
- Presence of the anaerobic bacterium Fusobacterium necrophorum.
- Uncommon disease in the post-antibiotic era, but may have a high mortality rate if not recognized and treated aggressively.2
History:
- In 1936, Andre Lemierre (1875–1956) reported a series of 20 cases of post-pharyngitis anaerobic sepsis due to an anaerobic Gram-negative rod known as Bacillus funduliformis (later renamed Fusobacterium necrophorum Fusobacterium necrophorum) and complicated by internal jugular vein thrombophlebitis and distant septic emboli.
- In his paper, Lemierre remarked:3
- The disease usually affects young adults or adolescents.
- The most usual initial cause is a tonsillar or peritonsillar abscess.
- “Since the original work of E. Frankel in 1919 German authorities have considered that these septicaemias are the result of a thrombophlebitis of the tonsillar and peritonsillar veins which can spread to the internal jugular vein or even to the facial vein. My own observations agree with this conception.”
- “The post-anginal septicaemias due to anaerobic organisms most frequently seen in Paris are due particularly to the Bacillus funduliformis, described in 1898 by Jean Halle.”
- “B. funduliformis septicaemias… have always been accompanied by the formation of distant metastatic abscesses (most frequent are those in the lungs)… they are in the nature of septic infarcts.”
- “These septicaemias may progress rapidly and end fatally in from 7 to 15 days… of the 20 cases observed by the writer and certain of his colleagues in Paris only two have recovered.”
- Eponym Lemierre syndrome appeared in the 1980s.
Definition:
- Although there is general agreement on the main features of Lemierre syndrome, there is currently no consensus on its definition.4
- Three criteria are historically used to diagnose Lemierre syndrome:5
- Primary site of infection located in the head or neck.6
- Thrombosis or thrombophlebitis of the internal jugular vein or other vein of the head/neck district, or metastatic infectious lesions (sometimes listed as two separate criteria).
- Isolation of F. necrophorum from blood culture or a normally sterile site.
- Several caveats are noteworthy:7
- Cases of thrombosis or septic embolism from Fusobacterium spp. originating from foci outside the head and neck are generally excluded or described as atypical or variant Lemierre syndrome.
- Because thrombosis of the internal jugular vein thrombosis may be missed, and, when present, may resolve over the clinical course, some argue that its demonstration is not required as part of the definition.8
- By the same token, the isolation of Fusobacterium spp. is not considered to be mandatory because the organism is difficult to isolate, cultures may be negative due to empiric antibiotic therapy, and other bacteria seem able to cause Lemierre syndrome.9
- Some have proposed that a history of recent upper respiratory tract infection, evidence of metastatic infectious lesions and evidence of either internal jugular vein thrombophlebitis or isolations of F. necrophorum or Fusobacterium species from blood culture or a normally sterile site is sufficient for diagnosis.10
Epidemiology:
- Most commonly seen among adolescents and young adults.
- 2:1 male: female ratio
- Annual incidence.11
- 0.8 to 3.6 cases/million population overall.
- 4.4 cases/million population aged 14 to 25 years (Denmark, 1998–2001).
- 16 cases/million population aged 15 to 19 years (Sweden, 2017).
- Incidence rates appear to be increasing, possibly owing to:12
- Increased reporting.
- Better identification of cases with:
- Improvement of anaerobic blood culture techniques.
- More advanced imaging techniques for the detection of IJV thrombophlebitis.
- Reduced antibiotic use in primary practice for patients with sore throats (because of concerns about development of antibiotic resistance).
- Increasing antibiotic resistance.
- Fewer tonsillectomies.
Pathogenesis:
- Causative organism:
- Causative bacteria invade the pharyngeal mucosa, which is weakened by preceding viral or bacterial pharyngitis, and lateral pharyngeal space, resulting in subsequent internal jugular vein septic thrombophlebitis and metastatic infections.
- Once the infection is established, it is hypothesized that F. necrophorum may spread to the internal jugular vein via:15
- The tonsillar vein.
- The lymphatic system.
- Direct invasion and attachment of peritonsillar abscesses onto veins found in the loose connective tissue of the pharynx.
- Pathogenesis of venous thrombosis in Lemierre syndrome may involve:16
- Endothelial dysfunction caused by inflammatory factors from the local infection.
- Hemagglutinin which promotes platelet aggregation.
- Direct activation of the contact system.
- The venous thrombi may have evolved as a means to insulate bacteria from immune cells while promoting a locally anaerobic environment.
- The release of heparinase may precipitate septic embolization.
- The increased incidence in adolescents and young adults is thought to be due to involution of tonsillar tissue, predisposing this age group to infections in tonsillar crypts.17
Clinical Presentation:
- The signs and symptoms of Lemierre syndrome generally appear in two stages:18
- The first stage is the primary infection, usually presenting as acute pharyngitis with:
- Sore throat
- Fever
- The second stage consists of internal jugular vein thrombophlebitis and sepsis:
- Usually occurs several days after the primary infection.
- Patients typically present to hospital acutely unwell with sepsis.
- The primary infection may already have resolved or the symptoms are masked by the acute illness.
- Internal jugular vein thrombophlebitis may manifest with symptoms of ipsilateral neck pain and headache and clinical signs of swelling along the sternocleidomastoid muscle:
- Neck mass 23%
- Neck pain 20%
- Evidence of metastatic lesions to end organs including the lungs, joints, brain, and liver (> 80% of patients):
- Pulmonary (most common organ involved):
- Complications include:
- Pneumonia
- Empyema
- Lung abscesses
- Pleural effusions
- Septic pulmonary emboli
- Presentation includes:
- Pleuritic chest pain
- Shortness of breath
- Cough
- Hemoptysis
- Complications include:
- Joints:
- Typically manifests as septic arthritis which presents with pain in the affected joint.
- Hip, knee, and shoulder were among the commonly affected joints.
- May also lead to osteomyelitis of the adjacent bone.
- Central nervous system
- Complications include:
- Meningitis
- Encephalitis
- Cavernous sinus thrombosis
- Cerebral abscess
- Cerebral infarction
- Complications include:
- Pulmonary (most common organ involved):
- The disease course is usually rapid and irreversible; therefore, timely diagnosis and prompt antibiotic therapy is important.
- In a study of 447 with Lemierre syndrome:
- The first stage is the primary infection, usually presenting as acute pharyngitis with:
Treatment other than anticoagulation:
- All patients require prompt antibiotic therapy; according to Up-to-Date (accessed 2/12/24):
- Empiric antibiotic regimens include:
- Piperacillin-tazobactam (3.375 g intravenously [IV] every six hours).
- A carbapenem such as imipenem (500 mg IV every 6 hours) OR meropenem (1 g IV every 8 hours) OR ertapenem (1 g IV every 24 hours).
- Ceftriaxone (2 g IV every 24 hours) plus metronidazole (500 mg IV every 8 hours).
- Antibiotics should be tailored accordingly to culture and susceptibility data when available.
- Empiric antibiotic regimens include:
- Surgical treatment is often necessary, and internal vein ligation is rarely performed in cases with septic embolization refractory to medical therapy.19
Anticoagulation:
- There is no current consensus on the role of anticoagulation and its effect on vessel recanalization in this syndrome:20
- Evidence regarding risk-benefits is scant.
- Clinical practice guideline recommendations do not exist.
- Recommendations are based on expert opinion.
- Expert opinion:
- In favor of using anticoagulation:
- Carlson et al favored initial heparinization followed by warfarin for 6 months based on positive experience with heparin in septic pelvic thrombophlebitis.
- Valerio et al wrote on behalf of the Bacteria-Associated Thrombosis, Thrombophlebitis and LEmierre syndrome (BATTLE) registry: “It is hard to find a rationale to depart from international guidelines suggesting in-hospital thromboprophylaxis for bedridden patient with an acute inflammatory disease and recommending routine anticoagulant treatment of acute venous thromboembolism. Any deviation from this approach should, in our opinion, represent an exception and be decided on an individual level basis until higher-level clinical evidence becomes available.”21
- In a meta-analysis of 712 cases of Lemierre syndrome, the authors concluded that “It is our opinion that the latter would also apply to Lemierre syndrome and that routine anticoagulant treatment should be considered in patients without contraindications.”22
- In favor of not treating with anticoagulation:
- Karkos et al concluded in 2004 after treating a case and performing a brief literature review that there is no evidence for a beneficial effect of anticoagulant therapy.23
- Up-to-Date writes: “In general, we suggest not treating most patients with anticoagulation. We pursue anticoagulation in the setting of progression of thrombosis or continued fever or bacteremia after five to seven days of appropriate antimicrobial therapy (with drainage of purulent collections as appropriate), given potential concern for retrograde progression into the cavernous or other sinus.
- In favor of using anticoagulation:
- Primary data:
- Retrospective study of 18 pediatric and adult patients with Lemierre syndrome:
- 6 of the patients weeks were anticoagulated for at least 4 weeks (median 23.1 weeks, range 6.9–32.9 weeks).
- Six patients were in the pediatric age group (<18 years).
- All patients had improvement in their thrombi by 3 months.
- All patients had improvement in their thrombi by three months, with:
- Of the 12 nonanticoagulated patients:
- Complete resolution in 9
- Partial resolution in 3
- Of the 6 anticoagulated patients:
- Complete thrombus resolution in 2
- Partial resolution in 4
- Of the 12 nonanticoagulated patients:
- No patient developed recurrent thrombosis or progression during the follow-up period, regardless of anticoagulation status.
- Conclusions: “Our study suggests that anticoagulation in LS may not affect thrombosis outcomes.”
- Retrospective study of 11 pediatric patients with Lemierre syndrome and thrombosis:
- All 11 patients were anticoagulated with low molecular weight heparin (LMWH) for an average duration of 105.8 days.
- In total, 10 of the 11 patients had partial or complete resolution of the thrombus within a median of 3.4 months.
- No control non-anticoagulated group was analyzed
- Conclusions: Benefit of anticoagulation might outweigh the low risks given their observation of no adverse effects from anticoagulation.
- Meta-analysis of 712 cases of Lemierre syndrome:
- Median age was 21 years; 41% were female.
- At diagnosis:
- Acute thrombosis of head/neck veins was detected in 84% of patients.
- Septic embolism in 82% of patients.
- Both in 80% of patients.
- The location of thrombosis was in:
- Jugular vein in 74%.
- Cerebral vein(s) in 20%.
- Any vein in the head or neck in 84%.
- Septic embolism was seen in 82%, mainly to the lungs.
- All patients were treated with antibiotics.
- 56% of patients received anticoagulation, mostly with LMWH.
- 20% of patients were transitioned to vitamin K antagonists and were anticoagulated for a median of 84 days.
- 17.2% of patients suffered from at least one early complication (in-hospital or within 30 days), including:
- New or recurrent venous thromboembolism (5.2% of patients after a median of 4 days from diagnosis).
- New or worsening (peripheral) septic lesions (11.7% of patients after a median of 4 days from diagnosis).
- Major bleeding (2.9%).
- Death (4%).
- The rate of new or recurrent venous thromboembolism and new or worsening (peripheral) septic lesions was:
- Lower in patients who received anticoagulation (OR: 0.59;0.36–0.94).
- Higher in those with initial intracranial involvement (OR: 2.35; 1.45–3.80).
- Patients who developed early thromboembolic complications:
- Received less often anticoagulant therapy 42%; vs 54%).
- Were more likely to have intracranial involvement at diagnosis (39% vs. 24%).
- Underwent more surgical procedures (78% vs. 49%).
- Were administered more frequently four or more antibiotics (43% vs. 26%).
- Major bleeding:
- Occurred in 2.9% overall.
- Noted in 2.8% that received anticoagulation and in 3.1% that did not.
- Mortality was 4%.
- Conclusions: “We found that, beyond the serious initial thromboembolic manifestations of the disorder, the rates of new or recurrent thromboembolic complications and septic lesions remain high despite hospitalization...the role of anticoagulant treatment for Lemierre syndrome has long been debated. We showed not only that initial thromboembolic manifestations involve multiple sites and often extend to the cerebral veins, but also that the risk of new complications persists throughout hospitalization… the interpretation of these results must be very cautious and primarily oriented to generate hypotheses. International guidelines on venous thromboembolism prevention and treatment unanimously recommend that all hospitalized patients with an acute medical illness undergo routine risk assessment to decide on thromboprophylaxis and stipulate that therapeutic-dose anticoagulation is indicated in the presence of an objectively diagnosed acute venous thromboembolic event, provided that no major bleeding risk factors exist. It is our opinion that the latter would also apply to Lemierre syndrome and that routine anticoagulant treatment should be considered in patients without contraindications.”
- Retrospective study of 18 pediatric and adult patients with Lemierre syndrome:
- Meta-analysis of 394 patients with a diagnosis of Lemierre syndrome reported between 1980 and 2017:
- Meta-analysis was conducted on:
- 194 of these patients to examine the effect of anticoagulation on mortality.
- 50 patients to examine the effect of anti coagulation on vessel recanalization on follow-up imaging.
- OR for anticoagulation and mortality was 0.6, while the OR for anticoagulation and vessel recanalization was 1.6. Neither relationship was statistically significant, showing no effect on mortality or vessel recanalization with anticoagulation
- Review of the literature revealed anticoagulant use in 63.4% of patients anticoagulated overall since 1980.
- A search of the literature did not reveal any studies that systematically examined the relationship between mortality and anticoagulation.
- Conclusions: “The present meta-analysis examined 394 patients presented in the literature between 1980 and 2017 with a diagnosis of Lemierre syndrome. A meta-analysis of the effect of anticoagulation on vessel recanalization and mortality failed to show a statistically significant benefit for either outcome. Aggressive IV antibiotic therapy combined with surgical intervention when indicated appeared to be the mainstay of treatment in Lemierre syndrome, with a low mortality rate overall with or without anticoagulation.”
- Meta-analysis was conducted on:
- Post hoc observational and population-based study of 82 patients:
- All patients diagnosed invasive infections with F. necrophorum in Sweden from January 1, 2010, to December 31, 2017.
- 82 patients were included.
- Jugular vein thrombosis was identified in 62% of patients.
- Presence or absence of jugular vein thrombosis had no effect on:
- Age of presentation
- Presence of comorbidities
- Duration of symptoms on presentation
- Presence of Lemierre-associated complications, except for typical pulmonary septic emboli, which were more commonly identified in patients with jugular thrombosis.
- Most patients with Lemierre syndrome presented with thrombocytopenia; platelet counts were lower among patients with jugular vein thrombosis.
- All patients with Lemierre syndrome received effective antibiotics on admission.
- In patients with Lemierre syndrome with jugular vein thrombosis:
- 40% were not treated with anticoagulation therapy
- 60% were treated with anticoagulation therapy:
- 33% received therapeutic doses
- 27% received prophylactic doses
- Patients with jugular vein thrombosis had a longer time to defervescence and yet, not significantly, more often required intensive care unit (ICU) admission.
- Sequelae and mortality at 30 days were similar independent of presence of jugular vein thrombosis.
- Conclusions: “Speculatively, as septic thrombophlebitis in Lemierre’s syndrome consists of infected debris, it is not clear that nonseptic and septic venous thromboembolism should be considered equal in terms of treatment, and fears have been raised of facilitating spread of infection through anticoagulation therapy. On the other hand, in an impressive recent large compilation of previously published cases of Lemierre’s syndrome it was suggested that anticoagulant therapy may reduce new in-hospital peripheral septic lesions [refers to above meta-analysis]… to settle the question of the role of anticoagulation therapy in Lemierre’s syndrome, a multinational prospective randomized trial is likely required.”
Prognosis:
- This is reflected by the in-hospital mortality of 4.0% and long-term sequelae in 12%
- Fatal outcome was common in the pre-antibiotic era.
- In the original series described by Lemierre, 18 out of 20 patients died
- fatality rates, with estimates over the last 20 years stable around 5%
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