Comprehensive Overview of Lemierre's Syndrome

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine

and I'm Rahul Damania from Cleveland Clinic Children’s Hospital and we are two Pediatric ICU physicians passionate about all things MED-ED in the PICU. PICU Doc on Call focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode an 18 -year old with sore throat, and unilateral L-sided neck pain for ~2 weeks.

Here's the case presented by Rahul:

An 18-year-old female presents to the ED with cough, fever, fatigue, sore throat, and unilateral L-sided neck pain for ~2 weeks. The patient also has been having non-specific chest pain, weight loss, and decreased appetite for ~ 1 month.

Patient has no recent travel h/o, no h/o of vaping or illicit drug use, and there were no sick contacts at home. Vitals revealed an HR 105, BP 116/66, Temp 38.3, and respiratory rate 35, She was 65 Kg and SPO2 on 2L NC was 100%. Physical exam was negative except (L) neck tender to palpation. There was no goiter, lymphadenopathy or hepatosplenomegaly.

An initial chest x-ray was significant for possible multi-lobar pneumonia versus metastases. A Chest CT revealed multifocal septic emboli in the lungs. Echo did not show any gross vegetation. She has no rash or any trauma to the neck or difficulty swallowing, no oral ulcers, joint pain, or diarrhea. She had no recent dental work or drinking of unpasteurized milk or eating raw fish or meat. She was admitted to the PICU as she had hypotension requiring fluid boluses, and lab works significant for hyponatremia, rhabdomyolysis, worsening AKI, elevated ferritin, and elevated D-dimer. Her serum uric acid was 9.9, LDH = 230 (normal) ,ESR 78 (normal = 20 or less). Her serum lactate and serum troponin and BNP were all normal. Pertinently, US neck revealed an occlusive thrombus in the (L) IJ vein (done so as to avoid contrast in face of AKI), and blood cultures sent.

To summarize key elements from this case, this 18-year-old female presents with

• fever +cough+sore throat
• Fatigue + Weight loss
• (L) neck pain
• Hypotension with abnormal labs including a concerning WBC with (L) shift, anemia, AKI, elevated uric acid, and ESR
• Chest CT with possible pulmonary emboli
• US showing occlusion.
• All of which brings up a concern for possible malignancy or pulmonary emboli from a septic focus in the neck and a possible diagnosis of Lemierre syndrome
• This episode will be organized…
• Definition
• Diagnosis (physical, laboratory)
• Management
• Rahul: What is the definition of Lemierre’s syndrome?
• Lemierre’s syndrome, also known as post-anginal septicemia or necrobacillosis, is characterized by bacteremia, internal jugular vein thrombophlebitis, and metastatic septic emboli secondary to acute pharyngeal infections. All of which are seen in our above case presentation. Previously called as the forgotten disease as its incidence was decreasing due to the increasing use of antibiotics especially penicillin for URI. However, recently there is an increase in Lemierre’s disease cases with decreased use of antibiotics due to antibiotic stewardship. The recent increase in Lemierre disease due to decreased antibiotic use has not been proven and remain controversial.
• Rahul what are some of the causative organisms of Lemierre syndrome?
• The most common causative agent of Lemierre’s syndrome is Fusobacterium necrophorum, followed by Fusobacterium nucleatum and anaerobic bacteria such as streptococci, staphylococci, and Klebsiella pneumoniae.
• Rahul: Can you tell our listeners about the pathophysiology of Lemierre’s syndrome?
• Lemierre syndrome can occur in health adults (more common in males in the age group of 14-24 years). Risk factors include immunocompromised patients, organisms, and environmental conditions. Lipopolysaccharides in F. necrophorum have endotoxic properties and are important virulence factors. The causative bacteria invade the pharyngeal mucosa previously weakened by preceding viral or bacterial pharyngitis, and lateral pharyngeal space, resulting in subsequent internal jugular vein septic thrombophlebitis and metastatic infections.
• Pneumonia or pleural empyema is the most common metastatic infection in Lemierre’s syndrome. Septic syndrome co-occurring with ear, neck and pulmonary empyema is a rare emerging medical condition. Proposed routes of infection are direct invasion and lymphatic or hematogenous spread to the connective tissue and associated clinical abscess formation or distant septic embolic metastasis.
• Once infection has reached the IJV, hematogenous spread to other sites can occur, causing various complications and ultimately death due to septic shock if antibiotics are delayed.
• The lungs are most commonly affected in up to 85% of cases. Lung lesions commonly appear as necrotic cavitary lesions but can also present as infiltrates, pleural effusions, empyema, lung abscesses, and necrotizing mediastinitis. Epidural and brain abscesses have been as complications of Lemierre’s syndrome and presumably result from the retrograde intracranial extension of IJV thrombosis. Less common infections include: soft tissue abscesses, pyomyositis, splenic and liver abscesses, osteomyelitis, endocarditis, pericarditis, renal abscess, and brain abscess.
• Atypical Lemierre’s syndrome involves thrombophlebitis of vessels other than the IJ. It may also involve bacteria other than Fusobacterium necrophorum or F. nucleatum.
• To summarize, In Lemierre syndrome the disease course is usually rapid and irreversible; therefore, timely diagnosis and prompt antibiotic therapy is important. Lemierre syndrome must be suspected in any patient with acute tonsillo-pharyngitis with persistent neck pain and septic syndrome. Septic pelvic thrombophlebitis complicated by multiple septic emboli after intrauterine device insertion has been reported in adults.

Pradip: What are some of the clinical manifestations of Lemierre Syndrome?

In any patient deep neck infections, subsequent septicemia, thrombophlebitis of the IJV, and metastatic infections (ascending or descending septic emboli) should arouse suspicion for Lemierre's syndrome. In any ill-appearing patient with acute tonsillopharyngitis (throat pain, dysphagia, productive cough) with high fevers, malaise, and neck pain with tenderness should lead to the suspicion of Lemierres syndrome. Patients can also develop trismus. Most young people present with pharyngitis initially, but the old-aged group present with distant complications, such as empyema or brain abscess. Persistent headache with focal neurological signs should alert the clinician of Sagittal sinus venous thrombosis, brain abscess or meningitis.

If you had to work up this patient with Lemierre syndrome what would be your diagnostic approach?

• A good history and physical exam is very important. Any ill-appearing patient with sore throat, high fever, neck pain +tenderness should prompt further evaluation of Lemierre syndrome.
• CBC with differential, blood cultures (aerobic and anaerobic), CRP, CMP, DIC panel should be sent.
• Contrast-enhanced computed tomography (CT) of the neck is the imaging of choice as it detects vascular thrombosis of the IJV and other complications such as pulmonary emboli, empyema, osteomyelitis, and brain or epidural abscess. CT shows intra-luminal filling defects, thrombosis, and enhancement of the IJV along with soft tissue swelling.
• Doppler ultrasonography although less sensitive than CT can be used especially if contrast cannot be used due to AKI (as in our case above). US will show an echogenic region within a dilated IJV or a complex mass of cystic and solid components. US can also detect clots in blood vessels. Magnetic resonance imaging has been used in specific cases to detect IJV thrombosis especially when CNS complication such as brain abscess is suspected.
• An echocardiogram would be helpful to evaluate for intra-cardiac vegetations given septic emboli in the lungs were seen in our patient.

If our history, physical, and diagnostic investigation led us to Lemierre syndrome as our diagnosis what would be your general management of framework?

• The ill-appearing patient should be admitted to the PICU as the patient will require prompt attention to airway, breathing, and hemodynamics. Adequate IV access should be obtained as these patients can become hemodynamically unstable from sepsis.
• A multidisciplinary team approach involving the PCCM, infectious disease, hematologists, and ENT physicians is warranted. After appropriate cultures are obtained - Metronidazole and beta-lactamase inhibiting agents like piperacillin-tazobactam. Ceftriaxone or a carbapenem. Metronidazole is bactericidal; it shows excellent penetration into most tissues including the cerebrospinal fluid.
• If IJV suppuration is due to an infected CVL and not a complication of pharyngitis- consideration should be given to the initiation of vancomycin.
• Antibiotic therapy should be continued for at least 3-6 weeks. Once the infection is controlled, therapy can be completed orally. The initial clinical response may be slow as Lemierre syndrome is an endovascular infection and antibiotics may have difficulty penetrating the fibrin clot. Pleural effusion or abscess drainage may be required in selected cases.
• Another important aspect of therapy is the use of anticoagulant therapy with heparin. Anticoagulation plays a part in preventing septic embolic events originating from IJV thrombosis. We typically start low molecular weight heparin such as Lovenox 1mg/kg sc BID with a goal heparin assay of 0.5-1 (done 4 hours after 2nd or 3rd dose). Lovenox dose needs adjustment in AKI.
• Fusobacterium necrophorum is intrinsically resistant to macrolides, fluoroquinolones, tetracyclines, and aminoglycosides. Fusobacterium necrophorum is resistant to Pn G due to the production of penicillinase.

Rahul, what are some clinical pearls or pitfalls to avoid?

• Suspect Lemierre syndrome in any ill-appearing patient presenting with high fevers, sore throat, and neck pain with tenderness.
• Once septic thrombophlebitis has occurred, complications should be evaluated including descending or ascending infections, such as pneumonia, empyema, or brain abscess.
• CT scan of the neck with IV contrast is the study of choice
• Initiate antibiotics early after a blood culture with metronidazole and a beta-lactamase inhibiting antibiotics such as ceftriaxone, piperacillin-tazobactam, or carbapenem such as meropenem
• anticoagulation therapy with low molecular weight heparin should be considered in consultation with hematology.

This concludes our episode on Lemierre syndrome. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. Stay tuned for our next episode! Thank you!

References

• Fuhrman & Zimmerman - Textbook of Pediatric Critical Care Chapter 107: Franzon D et al. Bacterial and Fungal Infections. page 1265
• Reference 1: Lee WS, Jean SS, Chen FL, Hsieh SM, Hsueh PR. Lemierre's syndrome: A forgotten and re-emerging infection. J Microbiol Immunol Infect. 2020 Aug;53(4):513-517. doi: 10.1016/j.jmii.2020.03.027. Epub 2020 Apr 4. PMID: 32303484.
• Reference 2: Walkty A, Embil J. Lemierre's Syndrome. N Engl J Med. 2019 Mar 21;380(12):e16. doi: 10.1056/NEJMicm1808378. PMID: 30893539.