Lemierre syndrome: Septic thrombophlebitis of the internal jugular vein

INTRODUCTION — Lemierre syndrome refers to septic thrombophlebitis of the internal jugular vein (IJV). The condition typically begins with oropharyngeal infection and frequently involves inflammation within the wall of the vein, infected thrombus within the lumen, surrounding soft tissue inflammation, persistent bacteremia, and septic emboli. Other terms for Lemierre syndrome include postanginal sepsis and necrobacillosis [1,2].

There is no standardized definition of Lemierre syndrome; different criteria have been used in different series [3]. Some series include only cases with the oropharynx as source of infection, while others allow other sources. Some series include only cases due to Fusobacterium species, while others allow other bacteria. Some series include only cases with evidence of septic emboli; other series include cases with positive blood cultures and evidence of septic emboli, even in the absence of IJV thrombosis.

No systematic study of the pathophysiology, management, and outcome of Lemierre syndrome has been performed as this remains a sporadic and relatively rare condition.

EPIDEMIOLOGY — Lemierre syndrome is a rare disease; it occurs most commonly in otherwise healthy young adults [4-6]. In a Danish study from 1998 to 2001, the annual incidence among individuals age 14 to 24, was 14.4 cases per million people; the incidence in the population was 3.6 cases per million people [4]. Some studies suggest Lemierre syndrome might occur more often in men [7,8]. Lemierre syndrome has also been described following solid organ transplantation [9].

MICROBIOLOGY — Lemierre syndrome is usually caused by members of the normal oropharyngeal flora [10]. The most common pathogen is the anaerobe Fusobacterium necrophorum; this pathogen has been isolated in healthy individuals as well as those with jugular vein suppurative thrombophlebitis and tonsillitis [11].

F. necrophorum is an anaerobic nonmotile, filamentous, non-spore forming gram-negative bacillus. It has unique pleomorphic morphology compared with other fusobacteria, with filaments, short rods, and coccoid appearance on Gram stain [12]. It may take ≥5 days for F. necrophorum to grow in culture.

Other pathogens include other Fusobacterium species (eg, Fusobacterium nucleatum) [10] and other organisms such as Enterobacteriaceae [13], Eikenella corrodens [14], Porphyromonas asaccharolytica [15], Bacteroides [16], streptococci including Streptococcus pyogenes and Streptococcus anginosus [17,18]. Rare cases due to Staphylococcus aureus, including methicillin-resistant S. aureus, have been described [19-24].

PATHOGENESIS — In most cases of Lemierre syndrome, primary infection consists of pharyngitis affecting the palatine tonsils or peritonsillar tissue [25]. Less common primary sources of infection include odontogenic infection, mastoiditis, otitis media, sinusitis, and parotitis [5,26].

Primary infection is followed by local invasion to the pharyngeal space and IJV causing septic thrombophlebitis, with an interval of one to three weeks [1]. One case has been described following blunt trauma to the cervical region [19]. The internal carotid artery, also located within the carotid sheath (figure 1), can also be inflamed [27].

How F. necrophorum causes septic thrombophlebitis is not known. Possible mechanisms include hematogenous spread via the tonsillar vein, peritonsillar invasion, or spread to the adjacent lateral pharyngeal space via the lymphatics (figure 1) [1]. Alternatively, alteration of the pharyngeal mucosa in the context of primary bacterial or viral infection may facilitate local invasion of F necrophorum, with direct extension through fascial planes of the neck to the IJV [5].

Several reports have described Lemierre syndrome due to F necrophorum following Epstein-Barr virus infection; the mechanism is uncertain [3,28].

CLINICAL MANIFESTATIONS

Symptoms and signs — Lemierre syndrome is frequently preceded by pharyngitis, usually in association with tonsil or peritonsillar involvement. Other antecedent conditions include mastoiditis, otitis, dental infections, pharyngeal abscesses, or infectious mononucleosis [16]. The interval between antecedent infection and onset of IJV thrombophlebitis is usually one to three weeks [10,16].

Clinical manifestations may include fever (>39°C), rigors, exudative tonsillitis, sore throat, dysphagia, trismus, unilateral neck pain, and tenderness [16]. Respiratory symptoms (reflecting complicating septic pulmonary emboli) may include dyspnea, pleurisy, and/or hemoptysis; these may be present at the time of initial presentation and/or may develop subsequently (see 'Complications' below). Signs of IJV thrombosis include tenderness, swelling, and/or induration over the neck, over the angle of the jaw, or along the sternocleidomastoid muscle [25].

Physical examination of the oropharynx may demonstrate tonsils that are exudative, hyperemic, ulcerated, or normal; notable findings may have resolved by the time septic thrombophlebitis or metastatic complications occur [10,16]. Careful examination of the neck is important because neck swelling can be mistaken for cervical lymph nodes rather than IJV thrombosis; however, a thrombosed IJV is rarely palpable and local signs can be absent. In one review including 109 cases, 47 percent of patients had no significant neck findings on presentation [25].

Complications — Pulmonary complications are common [3]. Lung lesions commonly present as necrotic cavitary lesions due to septic pulmonary emboli; in two reports, this finding was observed in 97 percent of cases [10,16]. Other forms of pulmonary involvement include infiltrates, pleural effusions or empyema, lung abscesses, pneumothoraces, and necrotizing mediastinitis [25]. In one review including 39 patients with Lemierre syndrome, 51 percent had sterile pleural effusions and 41 percent had lung abscesses; among those with lung abscesses, 25 percent developed an empyema [29].

Hematogenous spread to other sites can occur, with or without septic shock [16,30]. Bacteremia may be transient, so blood cultures may or may not be positive. In a review of 109 cases of Lemierre syndrome, F. necrophorum was isolated from clinical specimens (mostly blood cultures) in 82 percent of cases [25].

After pulmonary involvement, the large joints are the second most common sites affected by septic embolization [1]. In one case series including 40 patients, joint involvement (most commonly knees and hips) was observed in 26 percent of cases; findings ranged from sterile effusions to suppurative arthritis [29]. In another review including 109 patients, joint involvement was observed in 16 percent of cases; the hips, shoulders, and knees were most commonly affected [25].

Other less common presentations of metastatic disease include cutaneous lesions, soft tissue abscesses, pyomyositis, osteomyelitis, splenic and liver abscesses, renal abscesses, endocarditis, pericarditis, and arterial complications (eg, mycotic carotid pseudoaneurysm) [16,30,31].

Involvement of the central nervous system (CNS) has been described but is unusual [1]. Reported CNS complications include meningitis, brain abscesses, subdural empyemas, epidural abscess, septic emboli, and strokes [27]. Cerebral venous thrombosis has also been described; presumably such cases result from retrograde extension of IJV thrombosis.

EVALUATION — Lemierre syndrome should be suspected in young adults with recent pharyngitis who present with fever, a tender/swollen neck, and/or pulmonary manifestations such as septic emboli [25].

The diagnostic evaluation includes obtaining specimens for culture and radiographic imaging of the neck and chest. In addition, further evaluation for complications should be tailored to findings on history and physical examination.

Diagnosis — The diagnosis of Lemierre syndrome may be established in the setting of radiographic imaging demonstrating IJV thrombus, together with culture data demonstrating F. necrophorum or other implicated pathogen. Organisms may be isolated from the throat, the blood, and from metastatic sites of infection. (See 'Microbiology' above.)

In the absence of both of these criteria, a presumptive diagnosis may be made for patients with either definitive radiographic imaging findings or definitive culture results.

Obtaining cultures — The microbiologic diagnosis may be made based on blood culture or throat culture. For patients with metastatic sites of infection who undergo drainage, a microbiologic diagnosis may also be made based on culture of recovered material.

Radiographic imaging — Computed tomography (CT) scan of the neck and chest with contrast allows evaluation of the IJV for filling defects or thrombus; it also facilitates evaluation for lung involvement such as pulmonary emboli and abscesses [10].

Ultrasonography of the neck is an alternative modality for detection of IJV thrombus; it may demonstrate an echogenic region within a dilated IJV or a complex mass of cystic and solid components [10]. However, ultrasonography is less sensitive than CT and is less useful for evaluation of regions deep to the clavicle or mandible [10].

Magnetic resonance imaging of the neck has been used for detection of IJV thrombosis, but experience with this modality for this indication is limited [32]. PET scan use has rarely been reported in diagnosing Lemierre syndrome, identifying complications, and demonstrating the response to therapy [33].

Additional evaluation — Additional evaluation for complications should be tailored to findings on history and physical examination. (See 'Complications' above.)

As examples:

●Patients with joint involvement should undergo evaluation for septic arthritis. (See "Septic arthritis in adults".)

●Patients with headache, neurologic deficits, or meningeal signs should undergo head imaging (preferably magnetic resonance imaging) to evaluate for neurologic complications.

●Patients with abdominal pain or other localizing symptoms should undergo CT of the abdomen and pelvis to evaluate for sites of metastatic infection that may warrant localized drainage.

DIFFERENTIAL DIAGNOSIS

●Right-sided endocarditis – Right-sided endocarditis should be suspected in patients with fever with or without respiratory symptoms (such as cough, chest pain, hemoptysis), in the setting of relevant risk factors (injection drug use, presence of an intravascular device). The diagnosis is established based on clinical manifestations, blood cultures (or other microbiologic data), and echocardiography. (See "Right-sided native valve infective endocarditis".)

●Catheter-associated septic thrombophlebitis – Catheter-associated septic thrombophlebitis should be suspected in patients with catheter-related bloodstream infection and persistent bacteremia after 72 hours of appropriate therapy. Complications include septic pulmonary emboli and secondary pneumonia; these may also be presenting manifestations of the infection. The presence of venous thrombosis may be established via duplex ultrasonography; the microbiologic diagnosis may be based on blood culture. (See "Intravascular non-hemodialysis catheter-related infection: Clinical manifestations and diagnosis", section on 'Complications'.)

●Malignancy – Bilateral internal jugular venous thrombosis has been associated with underlying malignancy; screening for malignancy should be considered in such cases [34]. (See "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for breast cancer: Strategies and recommendations".)

TREATMENT — The principles of treatment include appropriate antibiotic therapy as well as consideration regarding the need for surgical intervention and anticoagulation.

Antibiotics

Empiric therapy — Empiric therapy for classic Lemierre syndrome (jugular vein suppurative thrombophlebitis with an oropharyngeal source) should target F. necrophorum and oral streptococci.

The regimen should consist of an antibiotic regimen that is resistant to beta-lactamase, since F. necrophorum beta-lactamase production and treatment failure with penicillin has been reported [10,35].

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)

We do not favor use of empiric ampicillin-sulbactam because resistance rates are higher than for piperacillin-tazobactam or carbapenems [36,37]. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Beta-lactamase inhibitor combinations'.)

For patients with hemodynamic instability or other findings suggestive of severe disease, or risk factors for methicillin-resistant S. aureus (MRSA) infection (table 1), we include vancomycin for empiric coverage of MRSA (table 2).

For patients with known or suspected central nervous system (CNS) involvement, a broad-spectrum regimen with favorable CNS penetration should be used, such as vancomycin (table 2), ceftriaxone (2 g IV every 12 hours), and metronidazole (500 mg IV every 8 hours).

Tailoring therapy — Antibiotics should be tailored accordingly to culture and susceptibility data when available.

If cultures grow F. necrophorum, the antibiotic regimen can be narrowed to metronidazole monotherapy once there are signs of clinical improvement. Antimicrobial resistance among F. necrophorum is rare. In one review including 100 F. necrophorum isolates, all were susceptible to metronidazole, clindamycin, imipenem, amoxicillin-clavulanate, and cefoxitin; penicillin resistance was observed in 2 percent of strains [7]. However, other authors note that up to 10 percent of isolates are resistant to clindamycin [38].

The duration of antibiotic therapy should be guided by clinical circumstances. In general, we favor an antibiotic duration of at least four weeks, including at least two weeks of intravenous therapy [4]. In the setting of complications (such as pulmonary abscesses, septic arthritis, etc), the duration of antibiotic therapy should be adjusted accordingly. (See related topics.)

The clinical response to treatment may be slow, even with appropriate antimicrobial therapy. In two studies, the mean time to defervescence was eight to nine days [39,40]. This may be because of limited antibiotic penetration into fibrin clot and/or necrotic abscesses [12,41].

In the setting of persistent bacteremia or clinical worsening despite appropriate antimicrobial therapy, our approach is as follows:

●Perform repeat computed tomography imaging to evaluate for extension of thrombus or other complications.

●Pursue formal antimicrobial susceptibility testing.

●Add empiric metronidazole (500 mg IV every 8 hours) if not already part of the antibiotic regimen, to optimize targeted anaerobic therapy.

●Ensure patients with purulent fluid collections undergo drainage. (See 'Interventional procedures' below.)

●Evaluate indications for anticoagulation. (See 'Anticoagulation' below.)

Once the infection has been controlled (based on clinical circumstances, including resolution of fever and completion of drainage or debridement if necessary), and two weeks of intravenous therapy have been completed, antibiotic therapy can be completed orally. Oral options for treatment of F. necrophorum infection include metronidazole (500 mg orally three times daily), amoxicillin-clavulanic acid (875/125 mg orally twice daily), or clindamycin (450 mg orally three times daily).

Anticoagulation — It is uncertain whether anticoagulation may reduce propagation of thrombus or septic embolic events originating from IJV thrombosis; data are limited to case reports [34,42].

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.

When anticoagulation is used, the optimal duration is uncertain. It is reasonable to discontinue anticoagulation once the patient has improved clinically and imaging suggests that thrombus extension has ceased. Anticoagulation for longer than six weeks may be appropriate for patients with embolic disease or underlying prothrombotic risk factors; we typically consult with a hematologist regarding the optimal duration.

Thrombolytic therapy is an additional option when thrombosis progresses [34], but there is minimal experience with this treatment in Lemierre syndrome and no conclusive evidence of efficacy.

Interventional procedures — The need for interventional procedures should be guided by clinical circumstances. As examples, patients with purulent fluid collections should undergo drainage, patients with empyema should undergo chest tube drainage, and patients with necrotic tissue should undergo debridement [1].

For patients with uncontrolled sepsis or ongoing septic emboli despite appropriate antibiotic therapy and anticoagulation, ligation or excision of the IJV has been described [10,25,39,43]. This approach should be viewed as a last resort. In one review including more than 390 patients with Lemierre syndrome between 1990 and 2017, only 10 were treated with IJV ligation or excision [43].

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Lemierre syndrome refers to septic thrombophlebitis of the internal jugular vein (IJV). It is a rare disease that occurs most commonly in otherwise healthy young adults. The condition typically begins with oropharyngeal infection and frequently involves inflammation within the wall of the vein, infected thrombus within the lumen, inflammation of surrounding soft tissues, persistent bacteremia, and septic emboli. (See 'Introduction' above and 'Epidemiology' above.)

●Microbiology – Lemierre syndrome is usually caused by oropharyngeal flora; the most common pathogens are the anaerobe Fusobacterium necrophorum and oral streptococci. Rare cases due to Staphylococcus aureus have been described. (See 'Microbiology' above.)

●Clinical manifestations

•Symptoms and signs – Clinical manifestations may include fever, rigors, exudative tonsillitis, sore throat, dysphagia, trismus, unilateral neck pain, and tenderness. Signs of IJV thrombosis include tenderness, swelling, and/or induration over the neck, over the angle of the jaw, or along the sternocleidomastoid muscle. Physical examination of the oropharynx may demonstrate tonsils that are exudative, hyperemic, ulcerated, or normal; findings may have resolved by the time septic thrombophlebitis or metastatic complications occur. (See 'Symptoms and signs' above.)

•Complications – Complications arise in the setting of hematogenous spread of infection. Pulmonary complications are common; symptoms including dyspnea, pleurisy, and/or hemoptysis are common. Lung lesions commonly present as necrotic cavitary lesions due to septic pulmonary emboli. The large joints are the second most commonly affected site of metastatic infection. Involvement of the central nervous system (CNS) has been described but is uncommon. Cerebral venous thrombosis has also been described; presumably such cases result from retrograde extension of IJV thrombosis. (See 'Complications' above.)

●Evaluation – Lemierre syndrome should be suspected in young adults with recent pharyngitis who present with fever, a tender/swollen neck, and/or pulmonary manifestations such as septic emboli. The diagnostic evaluation includes obtaining specimens for culture and radiographic imaging of the neck and chest. In addition, further evaluation for complications should be tailored to findings on history and physical examination. (See 'Evaluation' above.)

●Management

•Antibiotic therapy – Empiric antibiotic therapy for classic Lemierre syndrome (jugular vein suppurative thrombophlebitis with an oropharyngeal source) should target F. necrophorum and oral streptococci using combination therapy. Antibiotics should be tailored accordingly to culture and susceptibility data when available.

-We suggest an antibiotic regimen that is resistant to beta-lactamase (Grade 2C); F. necrophorum beta-lactamase production and treatment failure with penicillin has been reported. Empiric antibiotic regimens include piperacillin-tazobactam, a carbapenem, or ceftriaxone plus metronidazole. (See 'Empiric therapy' above.)

-For patients with hemodynamic instability or other findings suggestive of severe disease, or risk factors for methicillin-resistant S. aureus (MRSA) infection (table 1), we include vancomycin for empiric coverage of MRSA (table 2). For patients with known or suspected CNS involvement, we use a broad-spectrum regimen with favorable CNS penetration such as vancomycin, ceftriaxone (2 g intravenously [IV] every 12 hours), and metronidazole (500 mg IV every 8 hours).

•Duration – We suggest an antibiotic duration of at least four weeks, including at least two weeks of intravenous therapy (Grade 2C). In the setting of complications (such as pulmonary abscesses, septic arthritis, etc), the duration of antibiotic therapy should be adjusted accordingly. (See 'Tailoring therapy' above.)

•Refractory disease – The clinical response to treatment may be slow, even with appropriate antimicrobial therapy. In the setting of persistent bacteremia or clinical worsening despite appropriate antimicrobial therapy, we perform repeat computed tomography imaging to evaluate for extension of thrombus or other complications. We also pursue formal antimicrobial susceptibility testing, add empiric metronidazole (if not already part of the antibiotic regimen) to optimize targeted anaerobic therapy, and ensure patients with purulent fluid collections undergo drainage. (See 'Tailoring therapy' above and 'Interventional procedures' above.)

•Anticoagulation – We suggest not treating most patients with anticoagulation (Grade 2C). Exceptions include patients with evidence of progression of thrombosis or continued fever or bacteremia despite appropriate antibiotic therapy (See 'Tailoring therapy' above and 'Interventional procedures' above and 'Anticoagulation' above.)