Lemierre's Syndrome: The Forgotten Thrombophlebitis

Fusobacterium necrophorum Sepsis from Oropharyngeal Infection - A Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Background: Lemierre's syndrome, once termed "the forgotten disease," has re-emerged as a significant clinical entity in the post-antibiotic era. This syndrome represents a constellation of oropharyngeal infection, internal jugular vein thrombophlebitis, and metastatic septic emboli, predominantly caused by Fusobacterium necrophorum.

Methods: This comprehensive review synthesizes current literature on pathophysiology, clinical presentation, diagnostic approaches, and management strategies for Lemierre's syndrome, with emphasis on critical care considerations.

Results: The syndrome predominantly affects previously healthy adolescents and young adults, with mortality rates ranging from 5-15% in contemporary series. Early recognition and aggressive antimicrobial therapy combined with anticoagulation consideration remain cornerstones of management.

Conclusions: Lemierre's syndrome requires high clinical suspicion for timely diagnosis. Critical care physicians must be aware of its protean manifestations and potential for rapid clinical deterioration.

Keywords: Lemierre's syndrome, Fusobacterium necrophorum, jugular vein thrombosis, septic emboli, critical care

Introduction

André Lemierre first described the syndrome bearing his name in 1936 as "anaerobic postanginal sepsis," characterizing it as an illness of "such constant symptoms and such a grave prognosis that it seems to me to be worthy of a special description."¹ The syndrome was later termed "the forgotten disease" due to its apparent disappearance following widespread antibiotic use.² However, the past three decades have witnessed a concerning resurgence, with reported incidence rates of 0.8-3.6 per million population annually.³⁻⁴

Lemierre's syndrome represents a unique clinical entity characterized by the classic triad of:

Primary oropharyngeal infection (typically pharyngotonsillitis)
Internal jugular vein (IJV) thrombophlebitis
Metastatic septic emboli to distant organs

Pathophysiology

Microbiology and Virulence Factors

Fusobacterium necrophorum, a gram-negative, strictly anaerobic, non-spore-forming rod, is the causative organism in 82-90% of cases.⁵ This organism exhibits several virulence factors that contribute to its pathogenicity:

Endotoxin production: Lipopolysaccharide components trigger inflammatory cascades
Hemagglutinin: Facilitates platelet aggregation and thrombosis
Leukocidin: Causes neutrophil destruction and tissue necrosis
Hemolysin: Promotes tissue invasion and vascular damage

Other implicated organisms include Fusobacterium nucleatum, Bacteroides species, Peptostreptococcus species, and rarely, Arcanobacterium haemolyticum.⁶

Pathogenetic Sequence

The pathogenesis follows a predictable sequence:

Primary infection: Typically begins as pharyngotonsillitis or peritonsillar abscess
Local invasion: Bacterial spread to parapharyngeal space
Vascular invasion: Penetration into carotid sheath and IJV
Thrombophlebitis: Septic thrombosis of IJV with potential extension to sigmoid and lateral sinuses
Metastatic seeding: Hematogenous dissemination causing septic emboli

Clinical Presentation

Demographics

Lemierre's syndrome predominantly affects previously healthy adolescents and young adults (median age 16-20 years), with a slight male predominance (1.2-1.5:1).⁷ The syndrome rarely occurs in children under 10 years or adults over 40 years.

Clinical Course

The illness typically follows a biphasic pattern:

Phase 1 (Days 1-5): Primary oropharyngeal infection

Acute pharyngotonsillitis (90-95% of cases)
Fever, sore throat, odynophagia
Often misdiagnosed as viral pharyngitis or infectious mononucleosis

Phase 2 (Days 5-10): Systemic complications

High-grade fever with rigors
Neck pain and swelling (50-80% of cases)
Signs of sepsis and multiorgan dysfunction

Physical Examination Findings

Classic Signs:

Unilateral neck pain and tenderness along the sternocleidomastoid muscle
Induration and swelling of the neck ("bull neck" appearance)
Trismus (limited jaw opening)
Muffled voice or "hot potato" voice

Metastatic Complications:

Pulmonary emboli (75-85% of cases): Pleuritic chest pain, dyspnea, hemoptysis
Joint involvement (15-30%): Septic arthritis, typically large joints
Hepatic abscesses (5-15%): Right upper quadrant pain, hepatomegaly
Intracranial complications (5-10%): Meningitis, brain abscess, cavernous sinus thrombosis

Diagnostic Approach

Laboratory Investigations

Essential Laboratory Tests:

Complete blood count: Leukocytosis with left shift (>15,000/μL in 80-90% of cases)
Inflammatory markers: Elevated C-reactive protein (typically >200 mg/L), erythrocyte sedimentation rate
Liver function tests: Often elevated transaminases
Coagulation studies: May show consumptive coagulopathy
Blood cultures: Positive in 60-80% of cases (may require prolonged incubation)
D-dimer: Typically markedly elevated

🔑 Clinical Pearl: Blood cultures may be negative in up to 40% of cases due to the fastidious nature of F. necrophorum. Consider requesting anaerobic cultures with extended incubation periods.

Imaging Studies

Contrast-Enhanced CT of Neck and Chest:

Neck: IJV thrombosis appears as filling defect or rim enhancement
Chest: Multiple cavitary lesions ("cannonball" lesions) in 75-85% of cases

Doppler Ultrasonography:

Non-invasive assessment of IJV patency
May miss early or partial thrombosis
Operator-dependent technique

Magnetic Resonance Venography (MRV):

Gold standard for vascular imaging
Superior soft tissue resolution
Can assess intracranial extension

🔑 Clinical Pearl: CT with contrast is the initial imaging modality of choice. Look for the "target sign" - rim enhancement around a hypodense IJV thrombus.

Differential Diagnosis

The differential diagnosis is broad and includes:

Infectious:

Infectious mononucleosis (Epstein-Barr virus, cytomegalovirus)
Bacterial pharyngitis (Group A Streptococcus)
Parapharyngeal abscess
Ludwig's angina

Malignant:

Lymphoma (Hodgkin's and non-Hodgkin's)
Nasopharyngeal carcinoma
Rhabdomyosarcoma

Vascular:

Primary thrombophlebitis
Superior vena cava syndrome
Carotid artery dissection

Management

Antimicrobial Therapy

First-line Treatment: High-dose penicillin remains the antibiotic of choice for F. necrophorum:

Penicillin G: 18-24 million units IV daily (divided q4h) for adults
Duration: Minimum 2-3 weeks IV followed by 2-4 weeks oral therapy

Alternative Regimens:

Clindamycin: 600-900 mg IV q8h (excellent anaerobic coverage)
Metronidazole + Penicillin: 500 mg IV q8h + standard penicillin dosing
Ampicillin-sulbactam: 3g IV q6h
Piperacillin-tazobactam: 4.5g IV q8h

🔑 Clinical Pearl: Clindamycin may be superior to penicillin due to its anti-toxin effects and better tissue penetration. Consider it as first-line in severe cases.

Anticoagulation Therapy

The role of anticoagulation remains controversial with no randomized controlled trials available.

Indications for Anticoagulation:

Extensive thrombosis involving multiple vessels
Propagating thrombus despite adequate antibiotics
Embolic complications
No absolute contraindications

Anticoagulation Protocol:

Heparin: Initial bolus 80 units/kg, followed by 18 units/kg/hr
Target aPTT: 60-80 seconds
Duration: 3-6 months (individualized based on thrombus extent)
Transition: To warfarin (INR 2.0-3.0) or direct oral anticoagulants

⚠️ Oyster: Anticoagulation may increase bleeding risk, particularly with hepatic involvement. Carefully weigh risks and benefits in each case.

Surgical Intervention

Indications for Surgery:

Drainage of parapharyngeal or retropharyngeal abscesses
IJV ligation (rarely required)
Management of metastatic complications (hepatic abscess drainage, empyema)

🔑 Hack: Early ENT consultation is crucial. Urgent surgical drainage may be life-saving in cases with airway compromise.

Critical Care Management

Sepsis Resuscitation:

Aggressive fluid resuscitation following Surviving Sepsis Campaign guidelines
Vasopressor support (norepinephrine first-line)
Early goal-directed therapy

Respiratory Support:

High index of suspicion for pulmonary emboli
May require mechanical ventilation for ARDS
Consider ECMO in refractory cases

Monitoring and Complications:

Serial echocardiography for endocarditis evaluation
Neurological monitoring for intracranial complications
Renal function monitoring for sepsis-associated AKI

Prognosis and Outcomes

Historical vs. Contemporary Mortality

The mortality rate has significantly improved from the pre-antibiotic era:

Pre-antibiotic era: 90% mortality
Contemporary series: 5-15% mortality⁸⁻⁹

Prognostic Factors

Poor Prognostic Indicators:

Delayed diagnosis (>7 days from symptom onset)
Multiorgan involvement
Intracranial complications
Age >40 years
Immunocompromised state

🔑 Clinical Pearl: Early recognition and treatment within 48-72 hours of IJV thrombosis significantly improves outcomes.

Long-term Sequelae

Most patients recover completely with appropriate treatment. However, potential long-term complications include:

Chronic IJV occlusion (5-10% of cases)
Post-thrombotic syndrome
Recurrent pulmonary emboli
Chronic pain syndromes

Prevention and Public Health Considerations

Risk Factor Modification

Prompt treatment of pharyngotonsillitis in adolescents
Avoid inappropriate antibiotic use that may mask early symptoms
Consider Lemierre's syndrome in differential diagnosis of prolonged pharyngitis

Emerging Resistance Patterns

Recent studies suggest increasing resistance to metronidazole in some F. necrophorum isolates, emphasizing the importance of antimicrobial susceptibility testing when possible.¹⁰

Future Directions

Research Priorities

Randomized controlled trials for anticoagulation therapy
Novel diagnostic biomarkers for early detection
Optimal duration of antibiotic therapy
Role of adjunctive therapies (hyperbaric oxygen, immunoglobulin)

Diagnostic Innovations

Point-of-care PCR testing for F. necrophorum
Advanced imaging techniques (4D flow MRI)
Biomarker panels for risk stratification

Case Vignettes

Case 1: Classic Presentation

A 19-year-old previously healthy male presents with 3 days of severe sore throat followed by high fever, rigors, and right-sided neck pain. Physical examination reveals trismus, right neck swelling, and tenderness along the sternocleidomastoid muscle. CT neck shows right IJV thrombosis with surrounding inflammation. Blood cultures grow F. necrophorum. Patient responds well to IV penicillin and anticoagulation.

Case 2: Delayed Recognition

A 17-year-old female treated for "viral pharyngitis" presents 10 days later with septic shock and bilateral pulmonary nodules. Despite initial negative blood cultures, high clinical suspicion leads to targeted therapy for Lemierre's syndrome. CT imaging confirms IJV thrombosis and multiple pulmonary abscesses. Extended anaerobic cultures eventually confirm F. necrophorum.

Conclusion

Lemierre's syndrome remains a challenging diagnosis that requires high clinical suspicion, particularly in young adults with pharyngitis followed by systemic complications. The syndrome's resurgence in the post-antibiotic era underscores the importance of maintaining awareness of this "forgotten" disease. Key factors for success include:

Early recognition: Consider Lemierre's syndrome in young patients with pharyngitis and systemic symptoms
Appropriate imaging: Contrast-enhanced CT of neck and chest should be performed urgently
Targeted therapy: High-dose penicillin or clindamycin with consideration for anticoagulation
Multidisciplinary care: Early involvement of ENT, infectious disease, and critical care specialists

Critical care physicians must maintain vigilance for this potentially lethal but treatable condition. With appropriate recognition and management, the prognosis remains favorable in the majority of cases.

References

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Karkos PD, Asrani S, Karkos CD, et al. Lemierre's syndrome: A systematic review. Laryngoscope. 2009;119(8):1552-1559.
Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre's syndrome. Clin Microbiol Rev. 2007;20(4):622-659.
Eilbert W, Singla N. Lemierre's syndrome. Int J Emerg Med. 2013;6:40.
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):458-465.
Golpe R, Marín B, Alonso M. Lemierre's syndrome (necrobacillosis). Postgrad Med J. 1999;75(881):141-144.
Ramirez S, Hild TG, Rudolph CN, et al. Increased diagnosis of Lemierre syndrome and other Fusobacterium necrophorum infections at a Children's Hospital. Pediatrics. 2003;112(5):e380-e385.
Screaton NJ, Ravenel JG, Lehner PJ, et al. Lemierre syndrome: forgotten but not extinct--report of four cases. Radiology. 1999;213(2):369-374.
Jensen A, Hagelskjær Kristensen L, Prag J. Detection of Fusobacterium necrophorum subsp. funduliforme in tonsillitis in young adults by real-time PCR. Clin Microbiol Infect. 2007;13(7):695-701.

Wednesday, September 17, 2025