Lemierre syndrome: a needle in a haystack

Abstract

A young woman with no significant past medical history presented with worsening cough, swinging fevers, persistent chest pain and neck tenderness. On examination she was tachycardic, hypotensive, pyrexial and became increasingly confused. Inflammatory markers in her blood were raised, but the chest film showed clear lung fields and urinalysis was negative. The impression was sepsis query source and broad-spectrum intravenous antibiotics were commenced. The patient deteriorated into respiratory failure and was transferred to intensive care. Some days after admission, an anaerobic bacillus, known to cause Lemierre syndrome, was cultured from her blood sample. The patient was treated with organism-sensitive antibiotics and improved over the next few days. She was discharged after further radiological investigations returned normal.

BACKGROUND

Lemierre syndrome is a rare complication of oropharyngeal infections generally affecting young healthy adults. Patients typically present with a sore throat, high fever and neck tenderness. It is predominantly caused by Fusobacterium necrophorum, an anaerobic bacillus.

Lemierre syndrome was common in the pre-antibiotic era and had a high mortality rate. This rate decreased significantly when penicillins were routinely used to treat oropharyngeal infections. However, in recent decades, there has been an increase in reported cases. Treatment consists of a combination of intravenous penicillin and metronidazole. Early initiation of appropriate antibiotics is crucial and directly affects clinical outcome.

The unfamiliarity of clinicians with the classic features of Lemierre syndrome often results in misdiagnosis and sub-optimal treatment. This and the increasing prevalence emphasise the importance of awareness about its distinctive signs and symptoms. In addition there needs to be a high index of suspicion for young adults presenting similarly so these cases can be identified and early treatment initiated.

CASE PRESENTATION

A previously healthy 18-year-old female student presented to the emergency department with a 3-day history of progressively worsening dry cough, swinging fevers and persistent chest pain, which was not relieved by simple analgesia. Two days earlier her general practitioner concluded that she had a viral illness and recommended rest and fluids. Post-admission, she vomited several times and was increasingly disoriented. She had no drug history, no known allergies, had never smoked, and denied any sexual activity.

Basic observations revealed she was tachycardic, hypotensive and pyrexial. On examination she was confused but had no demonstrable focal neurological deficit. There was no rash or lymphadenopathy, but there was tenderness over the right sternocleidomastoid muscle. Oral examination revealed dry mucous membranes and non-suppurative bilateral tonsillar enlargement. The rest of the systemic examination was unremarkable. Initial blood tests revealed a pancytopaenia, hypokalaemia, raised C-reactive protein and D-dimer levels. Urinalysis was negative for human chorionic gonadotrophin, but positive for blood and protein. The initial chest film was unremarkable. The patient’s hypotension worsened despite being given several stat boluses of intravenous colloid. Blood was taken for culture, and intravenous augmentin (1.2 g four times daily) and clarithromycin (500 mg twice daily) were commenced.

The next day the patient deteriorated into type one respiratory failure and was transferred to the intensive care unit. On further examination, there was decreased resonance bilaterally on percussion, right-sided basal crepitations and bronchial breathing around the left axilla. The heterophile antibody, legionella antigen and mycoplasma serology tests were all negative. CT pulmonary angiography excluded pulmonary embolus, but showed bilateral infective nodular infiltrations with a parapneumonic effusion.

Figure 1.

Characteristic radiographic appearance of Fusobacterium necrophorum pulmonary septic embolisation. There are visible round and wedge-shaped opacities, which progress to cavitation.¹

Six days after admission an anaerobic bacillus, later shown to be Fusobacterium necrophorum, was cultured from the blood sample. The diagnosis of Lemierre syndrome was suggested, and treatment was changed to intravenous benzylpenicillin (1.2 g four times daily) and metronidazole (400 mg three times daily). The patient improved and was transferred back to the ward 5 days after intensive care unit admission. Doppler ultrasonography later showed bilateral patency, normal flow and no thrombosis of the jugular or subclavian veins, and the repeat chest film was normal.

The patient received 18 days of intravenous antibiotics in total, and was discharged with a 4-week course of oral amoxicillin (500 mg four times daily) and metronidazole (400 mg three times daily).

OUTCOME AND FOLLOW-UP

The patient returned for a follow-up appointment 4 weeks after discharge. She reported intermittent lethargic periods but felt better overall. Clinical examination was normal and the follow-up chest film showed clear lung fields.

DISCUSSION

What is known today as Lemierre syndrome (also known as postanginal septicaemia) was first described by Courmont and Cade in 1900 as human necrobacillosis.² In 1936 the French clinician André Lemierre (1875–1956) further elucidated the classic clinical features of this illness after reporting on 20 cases of anaerobic septicaemia.³

Lemierre syndrome is a rare complication of acute oropharyngeal infections,⁴ with an estimated incidence of one per million people per annum.⁵ This typically occurs in previously healthy young adults,⁴ particularly males, and is more frequent in the winter.⁶ Patients typically present with non-specific symptoms such as a sore throat, high fevers, neck tenderness and cervical lymphadenopathy.^6,7

The predominant causative organism is F necrophorum, an anaerobic Gram-negative bacillus that comprises part of the normal oropharyngeal, gastrointestinal and female genital tract flora.⁴ However, other causative organisms have been identified including Eikenella corrodens, Bacteroides sp and Streptococcus sp.⁸

Classic features of Lemierre syndrome include: (1) a primary oropharyngeal infection (the majority of reported cases begin as such, but other foci have been described in the sinuses, ears and teeth)⁹; (2) a secondary anaerobic septicaemia, confirmed by positive blood culture; (3) radiological or clinical evidence of venous thrombophlebitis; and (4) septic dissemination to other organs.^4,10,11

Pulmonary lesions (emboli, infarcts, abscesses, effusions) are the commonest result of septic dissemination,⁷ followed in descending frequency by jaundice, septic arthritis, renal failure, meningitis, osteomyelitis and disseminated intravascular coagulopathy.¹²

Lemierre syndrome was common in the pre-antibiotic era; with mortality rates as high as 90%,³ the prognosis was exceedingly poor. Death usually resulted within days of symptom onset because of rapidly worsening septicaemia and infectious embolisation.¹³

Lemierre syndrome was seldom reported between the 1960s and 1980s, a period when penicillins were commonly used to treat oropharyngeal infections. However there has been a stark increase in the number of reported cases since 1990.¹⁴ Some suggest the increase in incidence is a result of increasingly limited treatment of oropharyngeal infections with penicillins⁶ and improved anaerobic diagnostic techniques.^1,15

Despite the characteristic features of Lemierre syndrome, it is often not considered as a differential diagnosis until a known causative organism is cultured. The differential diagnoses for identical or similar presentations include: infectious mononucleosis, atypical pneumonia, aspiration pneumonia, viral pharyngitis, acute bacterial pneumonia and leptospirosis.¹

Despite the distinctive clinical picture, the pathophysiology of the illness is yet to be fully understood.^16,17 One explanation of the pathogenicity of F necrophorum is its ability to produce toxins including lipopolysaccharide endotoxin, haemolysin, coagulase, leucocidin and platelet aggregating factor.⁷ These toxins cause microabscess formation,¹⁷ within which the organism multiplies and spreads.¹⁸ This initially causes tonsillar vein thrombophlebitis¹⁹ before moving centrally to involve the jugular venous system,¹⁵ most commonly the internal jugular vein. The toxins also cause fibrin and platelet aggregation, further promoting intravascular inflammation and coagulation.

In the pre-antibiotic era, internal jugular vein ligation was the treatment of choice for Lemierre syndrome.²⁰ These days high-dose intravenous antibiotics, specifically combinations of penicillins and metronidazole, are the first-line treatment²¹ especially in extremely septic or haemodynamically unstable patients.⁷ Ligation is now only necessary if severe sepsis persists despite aggressive antibiotic therapy.^7,20 Mortality is high without antibiotic therapy, with the estimated mortality rate of untreated patients between 30% and 90%.¹⁵ Even when treated, irrespective of sepsis severity, mortality ranges from 0 to 18%.¹ There is some evidence that delaying appropriate antibiotic therapy, even by a few days, affects outcome.¹² However full recovery is expected when treated appropriately.⁵

The role of anticoagulation remains controversial, not least because it poses the risk of infection spread. Some reports have shown clinical improvement post-anticoagulation,^22,23 but many maintain that because most patients do well despite not being anticoagulated, it is rarely indicated.^1,24 This risk of furthering sepsis is such that some suggest anticoagulation should only be used in the context where there is thrombosis retrograde to the cavernous sinus.^7,15,25,26

Cases of Lemierre syndrome have decreased since the discovery of antibiotics; however there has been a resurgence of reports in recent years. This increasing prevalence combined with the unfamiliarity of clinicians with its classic features¹ often results in misdiagnosis and sub-optimal treatment of this potentially fatal illness. Therefore there needs to be a high index of suspicion so these cases can be identified and early treatment initiated.

An obvious dilemma is presented. On one hand, it is inappropriate and unnecessary to treat every case of oropharyngeal infection with antibiotics because of medication side-effects and the possibility of promoting antibiotic resistance.¹ However, treatment with antibiotics is vital in the case of Lemierre syndrome. It is practically impossible to identify every single patient who could be presenting with early signs of F necrophorum infection; however, it is important for clinicians to be aware of the distinctive signs and symptoms.

LEARNING POINTS

• Lemierre syndrome is a rare complication of acute oropharyngeal infections, typically affecting previously healthy young adults. (Estimated incidence: one per million people per annum.)

• The classic features of Lemierre syndrome include: (a) a primary oropharyngeal infection; (b) a secondary anaerobic septicaemia, confirmed by positive blood culture; (c) radiological or clinical evidence of venous thrombophlebitis (usually the internal jugular vein); (d) septic dissemination to other organs.

• Delaying appropriate treatment can significantly affect outcome. High-dose intravenous antibiotic administration, specifically a combination of penicillin and metronidazole, is the treatment of choice.

• The increasing prevalence of Lemierre syndrome and unfamiliarity with its features often results in misdiagnosis. It is therefore important for clinicians to be aware of the signs and symptoms and have a high index of suspicion concerning similar presentations.