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Lemierre Syndrome: Often Overlooked
The Journal for Nurse Practitioners 15 (2019) 649e652
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Lemierre Syndrome: Often Overlooked Cinthya Sotelo, DNP, FNP-C a b s t r a c t Keywords: Fusobacterium infections jugular vein Lemierre syndrome pharyngitis thrombophlebitis
Lemierre syndrome is an uncommon, emergent medical condition that is characterized by suppurative thrombophlebitis of the internal jugular vein, usually after a bacterial oropharyngeal infection. Although the incidence had nearly disappeared since the advent of antibiotics, there has been a resurgence of the diagnosis. Fusobacterium necrophorum is the most common causative pathogen, although others have been associated. Lemierre syndrome must be identified early and treated appropriately to reduce patient morbidity and mortality. The nurse practitioner should consider this diagnosis in all young, previously healthy patients who present with worsening sore throat and fever despite treatment with antibiotics. © 2019 Elsevier Inc. All rights reserved.
Background Primary ear, nose, and throat infections are common, and although most are viral in etiology and self-limited, they can be associated with complications, including abscess formation. If the bacterial infection is not treated or contained, rare complications can occur, including thrombophlebitis and septic thrombosis of the head and neck venous system. Lemierre syndrome (LS) is a rare, emergent medical condition that is described as suppurative thrombophlebitis of the internal jugular vein (IJV), usually after a bacterial oropharyngeal infection. LS was first reported by Courmont and Cade in 1900 as a potentially lethal septicemia, which they described as postanginal anaerobic septicemia or necrobacillosis.1 Andre Lemierre, a French microbiologist, further characterized the symptoms based on a review of 20 cases that were identified in 1936.1 He described the disease as a lethal oropharyngeal infection resulting in thrombophlebitis of the internal jugular vein (IJV), bacteremia, and septic embolization.1 He found that this progression of symptoms affected formerly healthy adolescents with a male prevalence and was rapidly fatal within 7 to 15 days.1 This was a clinical picture that was so characteristic he concluded that it was “a syndrome whose diagnosis would be almost impossible to mistake and permits a diagnosis before bacteriological examination, including blood culture.”1 It was not until 1980 that Vogel and Boyer explained a syndrome that they referred to as Lemierre’s postanginal septicemia, based on a trilogy of signs and symptoms.2 Shannon et al were the first authors to reference this syndrome as Lemierre syndrome in 1983.2 LS occurs in approximately 0.8 per million people per year.3 Mortality has significantly improved since the preantibiotic era and is reported at 0% to 18%, higher in untreated cases and cases involving meningitis.3,4 It is more common in men and occurs https://doi.org/10.1016/j.nurpra.2019.06.016 1555-4155/© 2019 Elsevier Inc. All rights reserved.
primarily in young adults in their 20s.3 Small children and the elderly are not completely excluded. Although the incidence of LS had nearly disappeared since the advent of antibiotics in the 1940s, there has been a resurgence of the diagnosis and reported cases over the past 15 to 20 years.2,5,6 This can be attributed to several factors, including practitioner awareness and identification, the use of anti-inflammatory drugs with infection that is not treated with antibiotics, improved radiologic detection methods, and with the inappropriate use of antibiotics, there is also the development of antibiotic resistance to consider. The aim of this report is to present a case of LS that presented to the emergency department (ED) and to discuss the clinical presentation, pathophysiology, risk factors, diagnostic criteria and workup, complications, and available treatments of this oftenoverlooked diagnosis.
Discussion Pathophysiology LS is a critical complication of an acute bacterial or viral oropharyngeal infection that leads to septic thrombophlebitis of the IJV or one of its branches. The spread of infection is precipitated by mucosal damage in which the involved bacteria are allowed to extend into the parapharyngeal space and continue to spread due to the organism’s virulence. After the primary infection of the oropharynx, thrombophlebitis develops from direct extension or by hematogenous or lymphatic spread from peritonsillar vessels.5 This occurs due to several contributing factors, including hemolysin, lipase, and leukotoxin.7 Once thrombophlebitis of the IJV occurs, septic emboli can then allow the hematogenous spread of anaerobic bacteria to other organs.5
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Classic LS encompasses 4 symptoms for proper diagnosis: (1) initial primary oropharyngeal infection; (2) septicemia with a positive blood culture; (3) clinical or radiologic evidence of IJV thrombosis, or both; and (4) involvement of at least one metastatic area.8 Microbiology Fusobacterium necrophorum is the primary causative agent and is found in 90% of cases.3 Its structure varies between bacilli and cocci with filamentous structures.7 It is a strictly anaerobic, nonmotile, nonspore-forming, gram-negative organism appearing in the oropharynx and only appears pathogenic in the environment of a compromised host defense mechanism, as with bacterial or viral pharyngitis.1,9 F necrophorum may take up to 7 days to grow; however, it is not unusual for blood cultures to return negative.3 This should be taken into consideration, and a high index of suspicion is required for early clinical identification despite diagnostic test results. Other causative organisms include anaerobic streptococci, Bacteroides spp, Prevotella, Peptostreptococcus, Eikenella corrodens, Streptococcus, Porphyromonas, and Proteus.1,3,9 Less common organisms include a-hemolytic and group A b-hemolytic streptococcus, S pneumoniae, and Staphylococcus aureus.1 Antecedent viral infections, including Epstein-Barr virus, can also lead to LS by promoting the pathogenicity of F necrophorum.9 Risk Factors Primary oropharyngeal infections, such as tonsillitis or pharyngitis, are the leading cause of LS. Other less common risk factors include otitis media, occurring with or without mastoiditis, parotitis, odontoid infections, sinusitis, and infected brachial cyst.7,10 Infections related to the gastrointestinal system and female genitourinary system have also been identified.1 Oropharyngeal trauma is also a consideration, but extremely rare.10 The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause the cervical spread of pharyngeal infections; however, their role has not been clearly demonstrated. The use of NSAIDs as part of the treatment regimen for viral or bacterial oropharyngeal infections is common. Although there are no clinical comparative studies, there may be a relationship between the use of NSAIDs and throat infections that may enhance the spread of pathogens.7 Corticosteroid use has also been identified as a stimulating factor that may cause the proliferation of throat infections and cervical cellulitis.7 This is likely related to the immunosuppressive action of corticosteroids. Several decision-making rules, including the McIsaac decision rule and Centor criteria, state that patients with suspected bacterial tonsillitis or pharyngitis ought to receive antibiotics if they meet certain criteria. Although these rules and criteria are clinically useful, the recommended antibiotic therapies only take into consideration the risk of streptococcal infection specifically, but not other pathogens, particularly anaerobes, further enhancing the risk for developing LS.7 Clinical Presentation, Examination Findings, and Diagnostic Evaluation Lemierre classically described a set of presenting signs and symptoms, including pharyngeal inflammation, fever, sore throat, painful swelling of the submandibular glands or the glands of the cervical chain, or both, and abscesses.10 The presenting sore throat can be from a recent viral or bacterial oropharyngeal infection.
Box When to Consider Lemierre Syndrome 1. Otherwise healthy young adult (usually in their 20s) 2. Recent oropharyngeal infection (within 1 week) 3. Persistent/worsening symptoms, bacteremia/sepsis (high fever > 102 F, rigors/chills) 4. Unilateral neck/throat pain and swelling 5. Night sweats 6. Cough
Other associated symptoms and physical examination findings include chills; tender, swollen neck with or without erythema; dysphagia; trismus; abdominal pain; nausea; vomiting; and less commonly, cough.1,3 The complete picture of LS is established in the presence of septic emboli with pulmonary symptoms, including cough, pleuritic chest pain, dyspnea, hemoptysis, or a combination of these.7 Joint pain with or without purulent joint effusion may also be associated.7 More specifically, LS classically occurs in 2 phases with distinct clinical presentations.7 The first phase correlates to the initial oropharyngeal infection, which can present with fever, cervical lymphadenopathy, and may or may not exhibit signs of peritonsillar abscess.7 The second phase correlates to the spread of infection to the parapharyngeal space, with thrombophlebitis of the IJV and sepsis.7 Clinical examination during this phase reveals skin inflammation/induration anterior to the sternocleidomastoid muscle on the same affected side as the oropharyngeal infection.7 The risk for evolving cervical cellulitis, with or without abscess, should also be taken into consideration. The nurse practitioner (NP) should be mindful during this stage in assessing for the extension of any cutaneous inflammation to the suprasternal or supraclavicular region that further raises suspicion for the extension of infection to the anterior mediastinum.7 The presentation of symptoms between each phase could be delayed for approximately 4 to 10 days, but can extend up to 2 weeks.7,10 As a result of this time delay, the patient may not recall the initial oropharyngeal infection, leading to further delay in diagnosis. It is possible for the patient to appear septic without any focused oropharyngeal symptoms because the preceding infection occasionally resolves before presentation. Localized oropharyngeal symptoms can be absent or missed during examination; therefore, a high index of suspicion should be maintained. Differential diagnoses for worsening pharyngitis include nongroup A streptococcus, gonococcal pharyngitis, infectious mononucleosis, human immunodeficiency virus, infection, peritonsillar abscess, and LS.11 Failure of treatment, progression of symptoms, or lack of improvement after 5 days of oral antibiotic therapy warrants a more thorough diagnostic and therapeutic approach and should raise the index of suspicion for the diagnosis of LS.9 Practitioners do not need to alter their approach to simple acute pharyngitis in patients who present as such. However, NPs should reconsider their diagnostic approach in patients who have worsening symptoms and recognize when the diagnosis and treatment of simple acute pharyngitis does not improve after the appropriate course of treatment and expected resolution. Special attention should be given to the following red flag signs that indicate worsening infection or more serious illness: high fever (> 102 F), chills/rigors, night sweats, unilateral neck swelling, and cough (Box).11 A patient who presents with these signs or appears septic should be admitted or sent to the ED for further diagnostic evaluation and management.11
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Case Presentation A previously healthy 19-year-old male patient presented to the ED with ongoing fever and sore throat for 6 days despite antibiotic treatment with azithromycin, now with developing palpitations and shortness of breath, vomiting, and dehydration. Upon further questioning, he reported associated headache, neck pain, back pain, and cough. The patient was normotensive, with adequate oxygen saturation, tachycardic, and febrile, with a temperature of 103.1 F. The examination revealed erythematous tonsils with exudate, left tonsillar enlargement, tender bilateral cervical lymphadenopathy, and slight left neck tenderness and swelling. In the ED, diagnostic evaluation should begin with baseline laboratory studies including complete blood count, chemistry panel, C-reactive protein, and blood cultures.12 Laboratory findings vary, but may include an elevated white blood cell count and Creactive protein level, which can assist in differentiating LS from a solitary viral infection.8 A throat swab can be performed, but is usually negative.1 Chest x-ray imaging is commonly done as part of the initial diagnostic evaluation and can show pleural effusion, pulmonary infiltrates, and occasionally, cavitation or empyema.2,8 Radiologic examination of the neck must be done to confirm IJV thrombosis. This can be accomplished through a computed tomography (CT) scan of the neck with intravenous (IV) contrast, magnetic resonance imaging (MRI), or ultrasound. CT scan and MRI are the most commonly used imaging studies to identify thrombosis of the IJV.2,12 CT scan can show distended neck veins with enhancing walls, low attenuation intraluminal filling defects, and swelling of the adjacent soft tissues.1 Doppler ultrasound has been shown to be an accurate method that reveals venous thrombi and shows noncompressible intraluminal low level echoes in the IJV associated with venous distension and absence of flow.7 Contrastenhanced CT scan of the chest is typically done once thrombophlebitis is identified and will give the most information and detect most lung pathologies, including septic emboli, which occur in up to 97% of patients.7,8 CT scan of the head should also be included to rule out any cerebral emboli.12 Diagnostic evaluation in the case patient included laboratory studies that showed a normal white blood cell count with 5% bands, normal chemistries, negative rapid strep throat swab, elevated anti-streptolysin O antibody, and a marginal lactic acid level. Chest X-ray imaging showed borderline cardiomegaly with mild chronic consolidation throughout both lungs, worse at both lung bases, likely due to pulmonary edema. An echocardiogram showed an ejection fraction of 55%. CT scans of the abdomen and chest showed diffuse bilateral airspace opacities, suspicious for pneumonia, as well as trace bilateral effusions. Diagnosis and Management Early detection and treatment is critical to improve outcomes and decrease significant complications.8,9 LS is not often diagnosed until admission and when blood cultures return positive for Fusobacterium spp.5 Blood cultures can take 2 to 7 days for confirmatory results, further delaying the diagnosis.9 Diagnosis is based on 3 criteria: oropharyngeal sepsis, IJV thrombophlebitis, and metastatic infection.3 However, documentation of a thrombus in the IJV continues to be the most reliable way of diagnosing LS aside from blood culture results.5 Aggressive IV antibiotic therapy, supportive care, and adequate fluid resuscitation should be included in the management of patients with LS.1 Initial management should include empiric IV antibiotic therapy against Fusobacterium. This should include a broad-spectrum antibiotic, particularly a b-lactamaseeresistant penicillin, and an antibiotic with good anaerobic coverage.9 Specific
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antibiotics directed against anaerobes include cefoxitin, clindamycin, imipenem, and combination therapy with metronidazole and penicillin.3 The most common causative microbes are typically resistant to macrolides, gentamicin, and quinolones and should therefore be avoided.3 In the era of antibiotic resistance, even more broad-spectrum antibiotic coverage has been suggested to include piperacillin-tazobactam, ticarcillin-clavulanate, or ampicillin-sulbactam.8 Vancomycin can be added if there is a high suspicion for methicillin-resistant Staphylococcus aureus.9 More targeted antibiotic treatment should be initiated once a microbe is confirmed. Treatment with IV antibiotics should continue for 3 to 6 weeks, followed by a continued oral course.5 The use of anticoagulation therapy and whether it impacts thrombosis outcomes in patients remains unclear.10 The American College of Chest Physicians recommends general anticoagulation therapy for an incited thrombotic event for a minimum of 3 months, but this is a general recommendation that is not specific to thrombosis related to LS.10 The risks vs benefits of anticoagulation therapy must be outweighed and include complications of incomplete treatment or bleeding complications, specifically those secondary to disseminated intravascular coagulation.10 Some also suggest the possibility of hematogenous spread of infection with this type of therapy.3 Distinctive findings supporting the use of anticoagulation therapy include thrombus extension into the cavernous sinus, lack of improved condition after adequate antibiotic therapy for 2 to 3 days, or coexisting hypercoagulable disorder.3 If the decision is made to proceed with anticoagulants, the ideal method should be bridge therapy with heparin, followed by warfarin, for 3 months.9 Follow-up CT scans are recommended at 1- to 2-month intervals to reevaluate for thrombus progression, occurrence of septic emboli, and continued need for anticoagulation.9 Surgical management with IJV ligation or resection is rarely indicated but may be needed if septic emboli persist despite antibiotic treatment.3 Other complications requiring surgery include loculated empyemas, brain abscesses, pulmonary abscesses, and retropharyngeal abscesses.9 Overall, a trial of appropriate antibiotics, with possible anticoagulation, is the first-line treatment, followed with consideration for surgery if there is no clinical improvement or if complications develop.9 The patient in the presented case was admitted to the intensive care unit on broad-spectrum IV antibiotics, including vancomycin, piperacillin/tazobactam, metronidazole, and levofloxacin, pending final blood culture results and further specialty consultations. Further testing, including a CT scan of the neck with IV contrast, revealed a nonocclusive thrombus within the high left IJV, and blood cultures were positive for F necrophorum, consistent with LS. Targeted antibiotic therapy was then initiated with imipenem and metronidazole, and the patient was also prescribed heparin. CT scan of the chest without IV contrast was repeated to evaluate the patient’s worsening respiratory condition and revealed bilateral multilobar septic emboli and pneumonia as well as bilateral consolidation, small bilateral pleural effusions, and reactive lymph nodes at the left lower neck and bilateral mediastinum. The patient required mechanical ventilation, with persistent intermittent fever and worsening condition that demanded a higher level of care, at which time he was transferred to a tertiary care center. Complications The most common complications of LS involve metastatic infections of the lung and include empyema, pneumatoceles, pulmonary embolism, and pneumothorax.8 Infections of the skin and soft tissue, as well as the bones and joints, are the second most occurring areas of infection and include septic arthritis and
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osteomyelitis.3 Rarer areas of metastatic infection include abscess of the liver and spleen, adult respiratory distress syndrome, acute renal failure, meningitis, carotid thrombosis, endocarditis and pericarditis, mediastinal infection with pericardial tamponade, disseminated intravascular coagulation, and thrombocytopenia.1,3,8 If the initial infection is not adequately managed with antibiotic therapy, septicemia can occur and ultimately result in multisystem organ dysfunction, potential end-organ damage/failure, or death.10 Conclusion LS is a rare, emergent medical condition that should be identified and treated early to reduce patient morbidity and mortality. The diagnosis should be considered by the NP in all young, previously healthy patients who present to the ED with worsening sore throat, fever, and overall condition despite treatment with oral antibiotics. Initial empiric IV antibiotic treatment should be targeted at anaerobes, specifically those that are susceptible to Fusobacterium spp. The use of anticoagulants remains unclear and controversial. Although LS is rare, it is still present, and the NP should continue to maintain a high index of suspicion. References 1. Murthy KA, Thippeswamy T, Kiran HS. The ‘forgotten disease’ (or the never known). J Assoc Physicians India. 2013;61(10):754-757. 2. Alfreijat M. A case of Lemierre’s syndrome with a brief literature review. J Infect Public Health. 2016;9(5):681-683. https://doi.org/10.1016/j.jiph.2016.01.006.
3. Bahall M, Giddings S, Bahall K. Lemierre’s syndrome: forgotten, but not absent. BMJ Case Rep. 2017;2017: bcr2017221203. Published 2017 Aug 7. https://doi. org/10.1136/bcr-2017-221203. 4. Johannesen K, Bodtger U, Heltberg O. Lemierre’s syndrome: the forgotten disease. J Thromb. 2013;37(3):246-248. https://doi.org/10.1007/s11239-0130931-y. 5. Gupta N, Kralovic SM, McGraw D. Lemierre syndrome: not so forgotten! Am J Crit Care. 2014;23(2):176-169, https://doi.org/10.4037/ajcc2014975. 6. Karkos PD, Asrani S, Karkos CD, et al. Lemierre’s syndrome: a systematic review. Laryngoscope. 2009;119(8):1552-1559. 7. Righini CA, Karkas A, Tourniaire R, et al. Lemierre syndrome: study of 11 cases and literature review. Head Neck. 2014;36(7):1044-1051. https://doi.org/ 10.1002/hed.23410. 8. Murray M, Stevens T, Herford A, Roberts J. Lemierre syndrome: two cases requiring surgical intervention. J Oral Maxillofac Surg. 2013;71(2):310-315. https://doi.org/10.1016/j.joms.2012.05.012. 9. Wong AP, Duggins ML, Neil T. Internal jugular vein septic thrombophlebitis (Lemierre Syndrome) as a complication of pharyngitis. J Am Board Fam Med. 2015;28(3):425-430. https://doi.org/10.3122/jabfm.2015.03.140131. 10. Cupit-Link M, Nageswara Rao A, Warad DM, Rodriguez V. Lemierre syndrome: a retrospective study of the role of anticoagulation and thrombosis outcomes. Acta Haematol. 2016;137(2):59-65. https://doi.org/10.1159/000452855. 11. Centor RM, Samlowski R. Avoiding sore throat morbidity and mortality: when is it not “just a sore throat? Am Fam Physician. 2011;83(1):26-28. 12. Schubert AD, Hots M, Caversaccio MD, Arnold A. Septic thrombosis of the internal jugular vein: Lemierre’s syndrome revisited. Laryngoscope. 2015;125(4):863-868.
Cinthya Sotelo, DNP, FNP-BC, is an assistant professor in the Patricia A. Chin School of Nursing at California State University, Los Angeles. She can be contacted at cvasqu36@ calstatela.edu. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Lemierre Syndrome: Often Overlooked Cinthya Sotelo, DNP, FNP-C a b s t r a c t Keywords: Fusobacterium infections jugular vein Lemierre syndrome pharyngitis thrombophlebitis
Lemierre syndrome is an uncommon, emergent medical condition that is characterized by suppurative thrombophlebitis of the internal jugular vein, usually after a bacterial oropharyngeal infection. Although the incidence had nearly disappeared since the advent of antibiotics, there has been a resurgence of the diagnosis. Fusobacterium necrophorum is the most common causative pathogen, although others have been associated. Lemierre syndrome must be identified early and treated appropriately to reduce patient morbidity and mortality. The nurse practitioner should consider this diagnosis in all young, previously healthy patients who present with worsening sore throat and fever despite treatment with antibiotics. © 2019 Elsevier Inc. All rights reserved.
Background Primary ear, nose, and throat infections are common, and although most are viral in etiology and self-limited, they can be associated with complications, including abscess formation. If the bacterial infection is not treated or contained, rare complications can occur, including thrombophlebitis and septic thrombosis of the head and neck venous system. Lemierre syndrome (LS) is a rare, emergent medical condition that is described as suppurative thrombophlebitis of the internal jugular vein (IJV), usually after a bacterial oropharyngeal infection. LS was first reported by Courmont and Cade in 1900 as a potentially lethal septicemia, which they described as postanginal anaerobic septicemia or necrobacillosis.1 Andre Lemierre, a French microbiologist, further characterized the symptoms based on a review of 20 cases that were identified in 1936.1 He described the disease as a lethal oropharyngeal infection resulting in thrombophlebitis of the internal jugular vein (IJV), bacteremia, and septic embolization.1 He found that this progression of symptoms affected formerly healthy adolescents with a male prevalence and was rapidly fatal within 7 to 15 days.1 This was a clinical picture that was so characteristic he concluded that it was “a syndrome whose diagnosis would be almost impossible to mistake and permits a diagnosis before bacteriological examination, including blood culture.”1 It was not until 1980 that Vogel and Boyer explained a syndrome that they referred to as Lemierre’s postanginal septicemia, based on a trilogy of signs and symptoms.2 Shannon et al were the first authors to reference this syndrome as Lemierre syndrome in 1983.2 LS occurs in approximately 0.8 per million people per year.3 Mortality has significantly improved since the preantibiotic era and is reported at 0% to 18%, higher in untreated cases and cases involving meningitis.3,4 It is more common in men and occurs https://doi.org/10.1016/j.nurpra.2019.06.016 1555-4155/© 2019 Elsevier Inc. All rights reserved.
primarily in young adults in their 20s.3 Small children and the elderly are not completely excluded. Although the incidence of LS had nearly disappeared since the advent of antibiotics in the 1940s, there has been a resurgence of the diagnosis and reported cases over the past 15 to 20 years.2,5,6 This can be attributed to several factors, including practitioner awareness and identification, the use of anti-inflammatory drugs with infection that is not treated with antibiotics, improved radiologic detection methods, and with the inappropriate use of antibiotics, there is also the development of antibiotic resistance to consider. The aim of this report is to present a case of LS that presented to the emergency department (ED) and to discuss the clinical presentation, pathophysiology, risk factors, diagnostic criteria and workup, complications, and available treatments of this oftenoverlooked diagnosis.
Discussion Pathophysiology LS is a critical complication of an acute bacterial or viral oropharyngeal infection that leads to septic thrombophlebitis of the IJV or one of its branches. The spread of infection is precipitated by mucosal damage in which the involved bacteria are allowed to extend into the parapharyngeal space and continue to spread due to the organism’s virulence. After the primary infection of the oropharynx, thrombophlebitis develops from direct extension or by hematogenous or lymphatic spread from peritonsillar vessels.5 This occurs due to several contributing factors, including hemolysin, lipase, and leukotoxin.7 Once thrombophlebitis of the IJV occurs, septic emboli can then allow the hematogenous spread of anaerobic bacteria to other organs.5
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Classic LS encompasses 4 symptoms for proper diagnosis: (1) initial primary oropharyngeal infection; (2) septicemia with a positive blood culture; (3) clinical or radiologic evidence of IJV thrombosis, or both; and (4) involvement of at least one metastatic area.8 Microbiology Fusobacterium necrophorum is the primary causative agent and is found in 90% of cases.3 Its structure varies between bacilli and cocci with filamentous structures.7 It is a strictly anaerobic, nonmotile, nonspore-forming, gram-negative organism appearing in the oropharynx and only appears pathogenic in the environment of a compromised host defense mechanism, as with bacterial or viral pharyngitis.1,9 F necrophorum may take up to 7 days to grow; however, it is not unusual for blood cultures to return negative.3 This should be taken into consideration, and a high index of suspicion is required for early clinical identification despite diagnostic test results. Other causative organisms include anaerobic streptococci, Bacteroides spp, Prevotella, Peptostreptococcus, Eikenella corrodens, Streptococcus, Porphyromonas, and Proteus.1,3,9 Less common organisms include a-hemolytic and group A b-hemolytic streptococcus, S pneumoniae, and Staphylococcus aureus.1 Antecedent viral infections, including Epstein-Barr virus, can also lead to LS by promoting the pathogenicity of F necrophorum.9 Risk Factors Primary oropharyngeal infections, such as tonsillitis or pharyngitis, are the leading cause of LS. Other less common risk factors include otitis media, occurring with or without mastoiditis, parotitis, odontoid infections, sinusitis, and infected brachial cyst.7,10 Infections related to the gastrointestinal system and female genitourinary system have also been identified.1 Oropharyngeal trauma is also a consideration, but extremely rare.10 The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause the cervical spread of pharyngeal infections; however, their role has not been clearly demonstrated. The use of NSAIDs as part of the treatment regimen for viral or bacterial oropharyngeal infections is common. Although there are no clinical comparative studies, there may be a relationship between the use of NSAIDs and throat infections that may enhance the spread of pathogens.7 Corticosteroid use has also been identified as a stimulating factor that may cause the proliferation of throat infections and cervical cellulitis.7 This is likely related to the immunosuppressive action of corticosteroids. Several decision-making rules, including the McIsaac decision rule and Centor criteria, state that patients with suspected bacterial tonsillitis or pharyngitis ought to receive antibiotics if they meet certain criteria. Although these rules and criteria are clinically useful, the recommended antibiotic therapies only take into consideration the risk of streptococcal infection specifically, but not other pathogens, particularly anaerobes, further enhancing the risk for developing LS.7 Clinical Presentation, Examination Findings, and Diagnostic Evaluation Lemierre classically described a set of presenting signs and symptoms, including pharyngeal inflammation, fever, sore throat, painful swelling of the submandibular glands or the glands of the cervical chain, or both, and abscesses.10 The presenting sore throat can be from a recent viral or bacterial oropharyngeal infection.
Box When to Consider Lemierre Syndrome 1. Otherwise healthy young adult (usually in their 20s) 2. Recent oropharyngeal infection (within 1 week) 3. Persistent/worsening symptoms, bacteremia/sepsis (high fever > 102 F, rigors/chills) 4. Unilateral neck/throat pain and swelling 5. Night sweats 6. Cough
Other associated symptoms and physical examination findings include chills; tender, swollen neck with or without erythema; dysphagia; trismus; abdominal pain; nausea; vomiting; and less commonly, cough.1,3 The complete picture of LS is established in the presence of septic emboli with pulmonary symptoms, including cough, pleuritic chest pain, dyspnea, hemoptysis, or a combination of these.7 Joint pain with or without purulent joint effusion may also be associated.7 More specifically, LS classically occurs in 2 phases with distinct clinical presentations.7 The first phase correlates to the initial oropharyngeal infection, which can present with fever, cervical lymphadenopathy, and may or may not exhibit signs of peritonsillar abscess.7 The second phase correlates to the spread of infection to the parapharyngeal space, with thrombophlebitis of the IJV and sepsis.7 Clinical examination during this phase reveals skin inflammation/induration anterior to the sternocleidomastoid muscle on the same affected side as the oropharyngeal infection.7 The risk for evolving cervical cellulitis, with or without abscess, should also be taken into consideration. The nurse practitioner (NP) should be mindful during this stage in assessing for the extension of any cutaneous inflammation to the suprasternal or supraclavicular region that further raises suspicion for the extension of infection to the anterior mediastinum.7 The presentation of symptoms between each phase could be delayed for approximately 4 to 10 days, but can extend up to 2 weeks.7,10 As a result of this time delay, the patient may not recall the initial oropharyngeal infection, leading to further delay in diagnosis. It is possible for the patient to appear septic without any focused oropharyngeal symptoms because the preceding infection occasionally resolves before presentation. Localized oropharyngeal symptoms can be absent or missed during examination; therefore, a high index of suspicion should be maintained. Differential diagnoses for worsening pharyngitis include nongroup A streptococcus, gonococcal pharyngitis, infectious mononucleosis, human immunodeficiency virus, infection, peritonsillar abscess, and LS.11 Failure of treatment, progression of symptoms, or lack of improvement after 5 days of oral antibiotic therapy warrants a more thorough diagnostic and therapeutic approach and should raise the index of suspicion for the diagnosis of LS.9 Practitioners do not need to alter their approach to simple acute pharyngitis in patients who present as such. However, NPs should reconsider their diagnostic approach in patients who have worsening symptoms and recognize when the diagnosis and treatment of simple acute pharyngitis does not improve after the appropriate course of treatment and expected resolution. Special attention should be given to the following red flag signs that indicate worsening infection or more serious illness: high fever (> 102 F), chills/rigors, night sweats, unilateral neck swelling, and cough (Box).11 A patient who presents with these signs or appears septic should be admitted or sent to the ED for further diagnostic evaluation and management.11
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Case Presentation A previously healthy 19-year-old male patient presented to the ED with ongoing fever and sore throat for 6 days despite antibiotic treatment with azithromycin, now with developing palpitations and shortness of breath, vomiting, and dehydration. Upon further questioning, he reported associated headache, neck pain, back pain, and cough. The patient was normotensive, with adequate oxygen saturation, tachycardic, and febrile, with a temperature of 103.1 F. The examination revealed erythematous tonsils with exudate, left tonsillar enlargement, tender bilateral cervical lymphadenopathy, and slight left neck tenderness and swelling. In the ED, diagnostic evaluation should begin with baseline laboratory studies including complete blood count, chemistry panel, C-reactive protein, and blood cultures.12 Laboratory findings vary, but may include an elevated white blood cell count and Creactive protein level, which can assist in differentiating LS from a solitary viral infection.8 A throat swab can be performed, but is usually negative.1 Chest x-ray imaging is commonly done as part of the initial diagnostic evaluation and can show pleural effusion, pulmonary infiltrates, and occasionally, cavitation or empyema.2,8 Radiologic examination of the neck must be done to confirm IJV thrombosis. This can be accomplished through a computed tomography (CT) scan of the neck with intravenous (IV) contrast, magnetic resonance imaging (MRI), or ultrasound. CT scan and MRI are the most commonly used imaging studies to identify thrombosis of the IJV.2,12 CT scan can show distended neck veins with enhancing walls, low attenuation intraluminal filling defects, and swelling of the adjacent soft tissues.1 Doppler ultrasound has been shown to be an accurate method that reveals venous thrombi and shows noncompressible intraluminal low level echoes in the IJV associated with venous distension and absence of flow.7 Contrastenhanced CT scan of the chest is typically done once thrombophlebitis is identified and will give the most information and detect most lung pathologies, including septic emboli, which occur in up to 97% of patients.7,8 CT scan of the head should also be included to rule out any cerebral emboli.12 Diagnostic evaluation in the case patient included laboratory studies that showed a normal white blood cell count with 5% bands, normal chemistries, negative rapid strep throat swab, elevated anti-streptolysin O antibody, and a marginal lactic acid level. Chest X-ray imaging showed borderline cardiomegaly with mild chronic consolidation throughout both lungs, worse at both lung bases, likely due to pulmonary edema. An echocardiogram showed an ejection fraction of 55%. CT scans of the abdomen and chest showed diffuse bilateral airspace opacities, suspicious for pneumonia, as well as trace bilateral effusions. Diagnosis and Management Early detection and treatment is critical to improve outcomes and decrease significant complications.8,9 LS is not often diagnosed until admission and when blood cultures return positive for Fusobacterium spp.5 Blood cultures can take 2 to 7 days for confirmatory results, further delaying the diagnosis.9 Diagnosis is based on 3 criteria: oropharyngeal sepsis, IJV thrombophlebitis, and metastatic infection.3 However, documentation of a thrombus in the IJV continues to be the most reliable way of diagnosing LS aside from blood culture results.5 Aggressive IV antibiotic therapy, supportive care, and adequate fluid resuscitation should be included in the management of patients with LS.1 Initial management should include empiric IV antibiotic therapy against Fusobacterium. This should include a broad-spectrum antibiotic, particularly a b-lactamaseeresistant penicillin, and an antibiotic with good anaerobic coverage.9 Specific
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antibiotics directed against anaerobes include cefoxitin, clindamycin, imipenem, and combination therapy with metronidazole and penicillin.3 The most common causative microbes are typically resistant to macrolides, gentamicin, and quinolones and should therefore be avoided.3 In the era of antibiotic resistance, even more broad-spectrum antibiotic coverage has been suggested to include piperacillin-tazobactam, ticarcillin-clavulanate, or ampicillin-sulbactam.8 Vancomycin can be added if there is a high suspicion for methicillin-resistant Staphylococcus aureus.9 More targeted antibiotic treatment should be initiated once a microbe is confirmed. Treatment with IV antibiotics should continue for 3 to 6 weeks, followed by a continued oral course.5 The use of anticoagulation therapy and whether it impacts thrombosis outcomes in patients remains unclear.10 The American College of Chest Physicians recommends general anticoagulation therapy for an incited thrombotic event for a minimum of 3 months, but this is a general recommendation that is not specific to thrombosis related to LS.10 The risks vs benefits of anticoagulation therapy must be outweighed and include complications of incomplete treatment or bleeding complications, specifically those secondary to disseminated intravascular coagulation.10 Some also suggest the possibility of hematogenous spread of infection with this type of therapy.3 Distinctive findings supporting the use of anticoagulation therapy include thrombus extension into the cavernous sinus, lack of improved condition after adequate antibiotic therapy for 2 to 3 days, or coexisting hypercoagulable disorder.3 If the decision is made to proceed with anticoagulants, the ideal method should be bridge therapy with heparin, followed by warfarin, for 3 months.9 Follow-up CT scans are recommended at 1- to 2-month intervals to reevaluate for thrombus progression, occurrence of septic emboli, and continued need for anticoagulation.9 Surgical management with IJV ligation or resection is rarely indicated but may be needed if septic emboli persist despite antibiotic treatment.3 Other complications requiring surgery include loculated empyemas, brain abscesses, pulmonary abscesses, and retropharyngeal abscesses.9 Overall, a trial of appropriate antibiotics, with possible anticoagulation, is the first-line treatment, followed with consideration for surgery if there is no clinical improvement or if complications develop.9 The patient in the presented case was admitted to the intensive care unit on broad-spectrum IV antibiotics, including vancomycin, piperacillin/tazobactam, metronidazole, and levofloxacin, pending final blood culture results and further specialty consultations. Further testing, including a CT scan of the neck with IV contrast, revealed a nonocclusive thrombus within the high left IJV, and blood cultures were positive for F necrophorum, consistent with LS. Targeted antibiotic therapy was then initiated with imipenem and metronidazole, and the patient was also prescribed heparin. CT scan of the chest without IV contrast was repeated to evaluate the patient’s worsening respiratory condition and revealed bilateral multilobar septic emboli and pneumonia as well as bilateral consolidation, small bilateral pleural effusions, and reactive lymph nodes at the left lower neck and bilateral mediastinum. The patient required mechanical ventilation, with persistent intermittent fever and worsening condition that demanded a higher level of care, at which time he was transferred to a tertiary care center. Complications The most common complications of LS involve metastatic infections of the lung and include empyema, pneumatoceles, pulmonary embolism, and pneumothorax.8 Infections of the skin and soft tissue, as well as the bones and joints, are the second most occurring areas of infection and include septic arthritis and
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osteomyelitis.3 Rarer areas of metastatic infection include abscess of the liver and spleen, adult respiratory distress syndrome, acute renal failure, meningitis, carotid thrombosis, endocarditis and pericarditis, mediastinal infection with pericardial tamponade, disseminated intravascular coagulation, and thrombocytopenia.1,3,8 If the initial infection is not adequately managed with antibiotic therapy, septicemia can occur and ultimately result in multisystem organ dysfunction, potential end-organ damage/failure, or death.10 Conclusion LS is a rare, emergent medical condition that should be identified and treated early to reduce patient morbidity and mortality. The diagnosis should be considered by the NP in all young, previously healthy patients who present to the ED with worsening sore throat, fever, and overall condition despite treatment with oral antibiotics. Initial empiric IV antibiotic treatment should be targeted at anaerobes, specifically those that are susceptible to Fusobacterium spp. The use of anticoagulants remains unclear and controversial. Although LS is rare, it is still present, and the NP should continue to maintain a high index of suspicion. References 1. Murthy KA, Thippeswamy T, Kiran HS. The ‘forgotten disease’ (or the never known). J Assoc Physicians India. 2013;61(10):754-757. 2. Alfreijat M. A case of Lemierre’s syndrome with a brief literature review. J Infect Public Health. 2016;9(5):681-683. https://doi.org/10.1016/j.jiph.2016.01.006.
3. Bahall M, Giddings S, Bahall K. Lemierre’s syndrome: forgotten, but not absent. BMJ Case Rep. 2017;2017: bcr2017221203. Published 2017 Aug 7. https://doi. org/10.1136/bcr-2017-221203. 4. Johannesen K, Bodtger U, Heltberg O. Lemierre’s syndrome: the forgotten disease. J Thromb. 2013;37(3):246-248. https://doi.org/10.1007/s11239-0130931-y. 5. Gupta N, Kralovic SM, McGraw D. Lemierre syndrome: not so forgotten! Am J Crit Care. 2014;23(2):176-169, https://doi.org/10.4037/ajcc2014975. 6. Karkos PD, Asrani S, Karkos CD, et al. Lemierre’s syndrome: a systematic review. Laryngoscope. 2009;119(8):1552-1559. 7. Righini CA, Karkas A, Tourniaire R, et al. Lemierre syndrome: study of 11 cases and literature review. Head Neck. 2014;36(7):1044-1051. https://doi.org/ 10.1002/hed.23410. 8. Murray M, Stevens T, Herford A, Roberts J. Lemierre syndrome: two cases requiring surgical intervention. J Oral Maxillofac Surg. 2013;71(2):310-315. https://doi.org/10.1016/j.joms.2012.05.012. 9. Wong AP, Duggins ML, Neil T. Internal jugular vein septic thrombophlebitis (Lemierre Syndrome) as a complication of pharyngitis. J Am Board Fam Med. 2015;28(3):425-430. https://doi.org/10.3122/jabfm.2015.03.140131. 10. Cupit-Link M, Nageswara Rao A, Warad DM, Rodriguez V. Lemierre syndrome: a retrospective study of the role of anticoagulation and thrombosis outcomes. Acta Haematol. 2016;137(2):59-65. https://doi.org/10.1159/000452855. 11. Centor RM, Samlowski R. Avoiding sore throat morbidity and mortality: when is it not “just a sore throat? Am Fam Physician. 2011;83(1):26-28. 12. Schubert AD, Hots M, Caversaccio MD, Arnold A. Septic thrombosis of the internal jugular vein: Lemierre’s syndrome revisited. Laryngoscope. 2015;125(4):863-868.
Cinthya Sotelo, DNP, FNP-BC, is an assistant professor in the Patricia A. Chin School of Nursing at California State University, Los Angeles. She can be contacted at cvasqu36@ calstatela.edu. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.