Lemierre Syndrome

Etiology

Lemierre syndrome originates as a complication of bacterial throat infections. The most commonly responsible bacteria are Fusobacterium necrophorum, an obligate anaerobic, gram-negative bacilli, and Fusobacterium nucleatum. These bacteria can cause invasive disease secondary to multiple virulence factors, including endotoxins and exotoxins. Other organisms, such as Streptococcus species., Bacteroides species., Staphylococcus aureus, Klebsiella pneumoniae, and others have also been reported in other case studies.[4][5][6]

F. necrophorum is part of the normal bacterial flora in the pharynx, gastrointestinal tract, and female genital tract. In addition to primary infection, it is postulated that other etiologies of oropharyngeal infections can lead to conditions that are conducive to fusobacterial growth. These can be viral infections, eg, acute Epstein Barr, or bacterial infections, eg, streptococcal infection. Conditions conducive to anaerobic growth, such as a peritonsillar abscess, allow growth and penetration of the surrounding tissues by F. necrophorum. Extension of the infection from the oropharynx into the lateral pharyngeal space results in the seeding of the internal jugular vein, septic thrombophlebitis, and subsequent access to the venous system, resulting in septicemia and septic emboli.[7][8]

Epidemiology

The highest reported incidence of Lemierre syndrome was prior to the antibiotic era. With the widespread use of penicillin in the 1960s and 1970s, the incidence of LS declined sharply. Since the late 1970s, there has been a steady rise in reported cases, which may be due to the decreased use of empiric antibiotics in oropharyngeal infections. It is still a rare syndrome with an estimated worldwide incidence of 1/1,000,000. LS typically affects young, previously healthy adolescents and young adults. The median age of patients with LS is between 19 to 22 years of age, depending on the study with a 2:1 male-to-female ratio. Approximately 90% of the patients who develop LS are between 10 and 35.

Pathophysiology

Lemierre syndrome begins as a localized oropharyngeal infection. It is not known definitively whether F. necrophorum acts predominantly as a primary or secondary pathogen in the initial stages of LS. In addition to direct infection, it is postulated that mucosal damage of the pharynx caused by other bacterial or viral infections leads to conditions conducive to a fusobacterial superinfection. The infection then spreads into the lateral pharyngeal space and soft tissues of the neck. Venous thrombosis is initiated locally in the peritonsillar veins and then extends to the internal jugular veins. F. necrophorum has been shown to aggregate human platelets in vitro, subsequently precipitating intravascular coagulation. When combined with venous stasis from extrinsic compression and intrinsic vessel occlusion secondary to inflammation and edema, this leads to the development of septic thrombosis of the internal jugular vein. The release of septic emboli into the systemic circulation results in the widespread dissemination of F. necrophorum into the lung, pleura, joints, bones, muscles, spleen, liver, kidney, and other endpoints of circulation. Direct extension or propagation of thrombus can result in central nervous system abscess formation as well as cavernous sinus thrombosis.

History and Physical

The presentation and clinical progression of Lemierre disease can usually be divided into 3 main phases. These phases may also serve to diagnose the syndrome.

Oropharyngeal Infection

The clinical features of Lemierre syndrome begin with an oropharyngeal infection with subsequent febrile episodes and rigors anywhere from 4 to 7 days after the initial illness. Early diagnosis can be challenging as the symptoms are non-specific and usually attributable to self-limited pharyngeal infections. Over two-thirds of patients recount a pharyngeal infection at the onset of the illness, but rarely the illness has been described in the setting of parotitis, otitis media, mastoiditis, sinusitis, and dental infections. Patients with confirmed Epstein-Barr infections may also develop LS, and seropositive patients with mononucleosis can suffer diagnostic delays when LS is not considered an alternative diagnosis. The persistence of fever and worsening clinical status at 1 week can be an important clinical clue.

Infection Extension to the Parapharyngeal Space of the Neck with Thrombophlebitis of the Internal Jugular Vein

Neck tenderness and swelling may be an early clinical sign that pharyngitis has extended beyond the oropharynx. Unilateral tenderness and swelling at the mandibular angle, known as the “cord sign,” indicates internal jugular thrombosis but is only present in 25% to 45% of cases. A focused exam of the neck, including the suprasternal and supraclavicular regions, for signs of cutaneous cellulitis should also be performed and can indicate an extension of the infection to cervical veins and the mediastinal structures.

Septic Emboli

Once F. necrophorum has invaded the cervical veins, septic emboli occur. The most frequently affected organ is the lungs (85%), but joints, liver, kidney, brain, bones, heart, and meninges can all be involved. Bacteremia is associated with fever, lethargy, or shock, as well as end-organ damage. Septic shock occurs in approximately 7% of cases. Acute respiratory distress syndrome requiring mechanical ventilation may affect up to 10% of patient presentations.

Evaluation

The diagnosis of Lemierre syndrome is primarily clinical, but adjunctive testing can be helpful. Comprehensive laboratory evaluation is indicated in patients presenting with concern for sepsis or with systemic inflammatory response syndrome (SIRS) criteria. Some of the more frequent laboratory abnormalities include leukocytosis, mild to severe renal impairment, abnormal liver function tests including elevated bilirubin, thrombocytopenia, as well as other evidence of disseminated intravascular coagulation. Blood cultures should be collected, and growth typically occurs over 2 to 7 days and shows Fusobacterium species in over 70% of cases. Blood cultures may be negative in LS due to the difficulties that can be associated with culturing anaerobic organisms.

The lungs are the most common site of metastatic infection, and imaging should include a chest radiograph to evaluate for septic emboli and other pulmonary complications, including pulmonary effusions, lung abscesses, and empyema. Additional sites of bacterial metastasis may result in septic arthritis, osteomyelitis, meningitis, pericarditis, and hepatic abscesses. Other imaging modalities used to evaluate for septic thrombosis of the internal jugular vein may include ultrasound, CT of the neck with contrast, and magnetic resonance imaging (MRI). MRV has the highest sensitivity (97%) for detecting internal jugular thrombosis, while CT is usually the most available and widely used clinically. Ultrasound can be a useful modality given its comparatively lower cost and lack of radiation risk, but the low echogenicity of fresh clots combined with anatomic constraints of the lower neck may result in lower sensitivity for the detection of acute thrombosis.

Treatment / Management

The mainstay of treatment for Lemierre syndrome is antibiotic therapy. A beta-lactamase-resistant beta-lactam antibiotic is recommended as an empiric therapy due to case reports of treatment failures with penicillin secondary to beta-lactamase-producing F. necrophorum. Antibiotics should be tailored to the culture results and susceptibility data when available. Alternative options include clindamycin or metronidazole for patients with significant clinical allergy to beta-lactams. Antibiotic therapy is continued for 6 weeks in most patients to achieve appropriate penetration into fibrin clots.

Surgical management may be necessary in cases of abscess formation, respiratory distress secondary to pulmonary thrombosis, metastasis, and in patients with extension of thrombus into the mediastinum or cerebrum. Surgical incision and drainage of the abscess at affected sites may be indicated to control infection.

Anticoagulation therapy in Lemierre syndrome is controversial. Uncomplicated LS without evidence of extensive clot burden resolves with appropriate antibiotic therapy and supportive care and does not require anticoagulation. There are no controlled trials to validate the practice, but anticoagulation is usually recommended when the thrombus extends into the cerebral sinuses, for large or bilateral clot burden, or when a patient fails to improve in the first 72 hours with appropriate antibiotic and/or surgical therapy.

Differential Diagnosis

The differential diagnosis for early LS is broad and consists of all causes of oropharyngeal infections, both viral and bacterial. Advanced LS can mimic any cause of systemic bacteremia with or without septic emboli.

Prognosis

Advanced Lemierre syndrome is a life-threatening condition. Even with appropriate antibiotics and therapy, mortality has been reported to be between 5% and 18%. Hospital admission usually requires intensive care unit (ICU) status, and the average length of stay in the hospital is approximately 3 weeks. Septic emboli and end-organ effects can result in long-term morbidity.