Lemierre syndrome with pulmonary empyema caused by Prevotella intermedia

Abstract

Lemierre syndrome is a rare disease that is most often caused by Fusobacterium necrophorum. We present a case caused by Prevotella intermedia in a young, healthy man, complicated by multiple cavitary lung lesions, loculated pleural effusions requiring chest tube placement and trapezius abscess. Our case highlights (a) P. intermedia as a rare cause of Lemierre syndrome and (b) clinical response to appropriate antimicrobial therapy may be protracted.

Background

Lemierre syndrome, initially described in 1936 by Lemierre,¹ refers to septic thrombophlebitis of the internal jugular vein. The syndrome occurs in healthy young adults with an annual incidence of 3–14 per million people.^{2 3} It commonly starts as an oropharyngeal infection, evolving to a septic picture with subsequent inflammation within the wall of the internal jugular vein, infected thrombus within and septic emboli. Complications include necrotic pulmonary cavitary lesions, pleural effusion/empyema, lung abscesses and septic embolisation to large joints.⁴ Less commonly, soft tissue abscesses, pyomyositis, liver, kidney and central nervous system involvement may be seen.⁵ Diagnosis of Lemierre syndrome is made on typical clinical presentation with the presence of a recent pharyngeal illness complicated by septic emboli and internal jugular vein thrombosis or findings of Fusobacterium necrophorum or other implicated pathogens in blood cultures.⁶ The standard treatment involves antibiotics and abscess drainage.⁷ Mortality rate is high at approximately 10%,^{5 8} especially if the treatment is delayed.

While the most common pathogens are F. necrophorum and other Fusobacterium species, it is less well appreciated that other oropharyngeal bacteria can also cause Lemierre syndrome.^9–11 We present a case of Lemierre syndrome caused by Prevotella intermedia with pulmonary complications with a protracted clinical course despite appropriate antibiotic treatment.

Case presentation

A man in his early 30s with a history of hypertension presented to the emergency department (ED) with a history of 7–10 days of sore throat, shortness of breath, cough and a temperature of 39.4°C. Four days previously, he was evaluated at a walk-in clinic and a rapid antigen throat swab was positive for group A streptococcus for which he was started on cefdinir. He felt progressively weaker with development of left shoulder pain prompting his visit to the ED. On presentation, vital signs showed temperature: 37.8°C, blood pressure: 73/45 mm Hg, heart rate: 116 beats per minute, respiratory rate: 28 breaths per minute and pulse oximeter (SpO₂) 94% (on room air). Physical examination revealed diffuse rhonchi bilaterally, mild tenderness over the left acromion on both active and passive range of motion. Oropharyngeal examination was unremarkable. Cardiovascular examination was unremarkable.

Investigations

On admission, leucocyte count was 23.4 x 10ˆ9/L with neutrophilic pleocytosis (88%); sodium (127 mEq/L), blood urea nitrogen (55 mg/dL), creatinine (1.8 mg/dL), total bilirubin (4.2 mg/dL), alkaline phosphatase (159 U/L), alanine aminotransferase (88 U/L), aspartate aminotransferase (75 U/L), albumin (2.0 g/dL), lactic acid (1.6 mg/dL), C reactive protein (188 mg/dL), erythrocyte sedimentation rate (102 mm/hour), procalcitonin (17.81 ng/mL) (table 1). Coagulation profile showed international normalised ratio of 1.1, and partial thromboplastin time of 34 s. Chest X-ray demonstrated patchy opacities bilaterally in the middle to lower lung zones (figure 1). A left shoulder X-ray demonstrated air in the soft tissue over the left distal clavicle/acromion .

Table 1.

Laboratory test results and antibiotics administered by presentation day

	Days from presentation
Investigations/ treatments	0	1	2	3	4				11	Postdischarge (day 7)
Sodium (mEq/L)	127	130	136	135	135				135
BUN (mg/dL)	55	49	30	15	–				–
Creatinine (mg/dL)	1.8	1.3	1.0	0.9	–				–
Total bilirubin (mg/dL)	4.2	2.8	1.5	1.7	1.4				–
ALT (U/L)	88	73	98	226	194				43
AST (U/L)	75	48	56	104	59				23
Procalcitonin (ng/mL)	17.8	7.2		1.3
WCC (×109/L)	23.4	18.5	24.8	25.0	32.7				17.6	13.4
Haemoglobin (g/L)	125	111	106	106	102				88	110
Platelets (×109/L)	121	130	203	388	574				887	1068
Blood culture	2 sets				*	2 sets		†
Chest tube								Placed	Removed
Antibiotics	Cefdinir (−7 to 0) Azithromycin and ceftriaxone (0–2) Ampicillin and sulbactam and vancomycin3				Piperacillin and tazobactam and vancomycin4 5 Piperacillin and tazobactam6 7				Ceftriaxone to postdischarge day 8 Metronidazole to postdischarge day 22

ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, BUN: Blood urea nitrogen, WCC: White cell count

*Anaerobic gram-negative rod (1 bottle from day 0).

†Prevotella intermedia identified.

ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BUN, Blood urea nitrogen; WCC, white cell count.

Figure 1.

(A) Chest X-ray at admission demonstrating patchy opacities bilaterally in the middle to lower lung zones, concerning for pneumonia. (B) Chest X-ray on day 7 demonstrating significant increase in the parenchymal opacification throughout the right lung and associated right pleural effusion, along with cavitary nodules in the left lung, consistent with progression of pneumonia including fungal pneumonia or septic emboli. (C) Chest X-ray, 2 days after chest tube placement, demonstrating interval decrease in right lung opacification. (D) Chest X-ray 1 week after discharge demonstrating overall improvement, but with continued opacification of right lower zone.

On the second day, the SpO₂ dropped to <90% (on room air), requiring supplemental oxygen at 3 L/min, and he was transferred to the intensive care unit. The leucocyte count and alanine/aspartate aminotransferase increased (table 1), prompting additional investigations. A chest/abdomen CT revealed multifocal cavitary pneumonia (figure 2). This prompted an evaluation for Mycobacterium tuberculosis including sputum smears that were negative for acid-fast bacilli. There was a concern for infective endocarditis, and a transthoracic echocardiogram was normal.

Figure 2.

(A) Chest CT scan on day 4 demonstrating multifocal cavitary pneumonia, concerning for septic emboli. (B) Neck CT scan on day 5 demonstrating linear hypodensity filling defect in the left internal jugular vein (arrow), (C) CT scan on day 5 revealing partially visualised peripherally enhancing fluid collection in the left trapezius muscle with associated surrounding inflammatory changes, consistent with abscess.

A single blood culture from admission was positive for an anaerobic gram-negative rod that was later identified as P. intermedia on hospital day 7. The presenting signs and symptoms in the setting of a preceding pharyngeal infection were suggestive of Lemierre syndrome. A neck CT with intravenous contrast revealed a linear hypodensity filling defect in the left internal jugular vein (figure 2), a peripherally enhancing fluid collection (1.4×6.4×1.4 cm) in the left trapezius muscle with surrounding inflammatory changes (figure 2), and collection in subcutaneous soft tissues at the superior aspect of the left distal clavicle. Ultrasound of the fluid collection in the left trapezius muscle showed a small hypoechoic avascular lesion.

On hospital day 4, the patient had decreased breath sounds with increased O₂ requirement, persistent fever and leucocytosis of 32.7 x 10ˆ9/L (table 1). A chest X-ray displayed a significant increase in the parenchymal opacification throughout the right lung with associated right pleural effusion and cavitary nodules in the left lung (figure 1). A right lung ultrasound revealed loculated effusions. Pleural fluid revealed: protein 2.7 g/dL, lactate dehydrogenase 619 U/L and glucose 28 mg/dL, consistent with an exudative process; and microbial culture had no growth.

Differential diagnosis

Infective endocarditis was initially considered given concern for septic pulmonary emboli. However, the cardiovascular examination was unremarkable, and only two minor clinical criteria (fever, positive blood culture that does not meet major clinical criterion) of the modified Duke criteria were met. Additionally, the transthoracic echocardiography showed no vegetations.

Treatment

The patient received various antibiotics including ceftriaxone, azithromycin, ampicillin and sulbactam, piperacillin and sulbactam, vancomycin, and metronidazole (table 1). When the diagnosis of Lemierre syndrome was deemed the most consistent with the clinical course, antimicrobial therapy was simplified to intravenous ceftriaxone and oral metronidazole. Repeat blood cultures had no growth after 5 days of incubation. He was discharged home with plans to complete 4 weeks of intravenous ceftriaxone and 6 weeks of oral metronidazole.

After the discovery of the loculated right pleural effusion, a chest tube was placed on hospital day 7. Following multiple intrapleural fibrinolytic treatment with alteplase and dornase alfa, the right chest tube drained 1700 mL over 18 hours, and a subsequent chest X-ray demonstrated decreased opacification in the right lung (figure 1).

A chest CT showed slight improvement in a few of the cavitated lung nodules and decreased right pleural effusion, and the chest tube was removed after 4 days.

Due to left shoulder pain, and finding of left trapezius muscle fluid collection, there were multiple attempts to aspirate the fluid; however, no fluid was obtained.

Outcome and follow-up

One week after hospital discharge, the patient was seen as an outpatient. He continued to show clinical improvement. His leucocyte count had decreased to 13.4 x 10ˆ9/L, and haemoglobin increased from 88 to 110 g/L (8.8 to 11.0 g/dL). The chest X-ray showed improvement (figure 1), but there was persistent right lower zone effusion. No further intravenous antibiotics were given, and metronidazole was continued for an additional 2 weeks.

Discussion

We describe a case of Lemierre syndrome caused by P. intermedia complicated by multiple cavitary lung lesions, loculated pleural effusions/empyema requiring chest tube placement, likely trapezius abscess requiring a prolonged hospital stay.

Lemierre syndrome typically develops following pharyngitis and is often monomicrobial, but less commonly can develop from otogenic or odontogenic infections.^{12 13} The mechanisms and risk factors for the progression of disease to Lemierre syndrome are unknown. Potential explanations of internal jugular vein involvement include haematogenous spread via the tonsillar vein or spread to the lateral pharyngeal space via lymphatics. Alternative explanations include local invasion with direct extension to the internal jugular vein in the setting of mucosal damage. Gram-negative bacteria may also have prothrombotic properties¹⁴ and could lead to septic thrombophlebitis elsewhere, including in the dura, pelvis and portal vein.¹⁵

Internal jugular thrombophlebitis is often unilateral, but bilateral involvement has also been described¹⁶ and pulmonary complications are attributed to septic emboli. Lemierre syndrome is most commonly caused by F. necrophorum, an obligate anaerobic gram-negative bacillus that is part of the normal flora of oral cavity, gastrointestinal and female genital tract. It is recognised as a cause of pharyngitis in older adolescents and adults up to 30 years of age with symptoms indistinguishable from group A Streptococcus. Other causative bacteria include other Fusobacterium species (eg, Bacteroides species, non-group A streptococci and Prevotella species).⁶ P. intermedia is also a gram-negative obligate anaerobic bacterium found in oral mucosa and it often identified in periodontal diseases.¹⁷ There are few published reports of P. intermedia causing Lemierre syndrome. In a recent meta-analysis of 394 patients with Lemierre syndrome, blood culture identified P. intermedia only in 0.5% of patients as the culprit organism, while F. necrophorum was identified in 33.2%, and no organism was identified in 7.4%.¹⁰ In another report, Prevotella was identified in a case of Lemierre syndrome complicated with cavernous sinus thrombosis.¹⁸ In some cases of Lemierre syndrome, the infection can be polymicrobial. Identification of Prevotella is classically by phenotypic and biochemical assays which have a long turn-around time. Nucleic acid testing (PCR) is more reliable but expensive. Matrix-assisted laser desorption ionisation time of flight mass spectrometry has also been used.¹⁹ In our patient, after the identification of gram-negative bacteria in the blood cultures, P. intermedia was identified with the RapID ANA II system (Thermo Fisher Scientific), an identification system based on enzyme technology that is used for identification of medically important anaerobic bacteria.

Our patient’s presenting signs and symptoms were consistent with Lemierre syndrome. Severe clinical symptoms including hypotension, fever, hypoxia and leucocytosis prompted evaluation with neck CT, confirming the diagnosis. In patients with Lemierre syndrome, pulmonary complications due to septic emboli including effusions (51%) and empyema (25%) are common5 9 20 21 as seen in our patient who developed multiple necrotic cavitary lung lesions. Our patient had good dentition and had several less commonly seen complications including air in soft tissue and abscess in trapezius muscle, that may be related to Lemierre syndrome.^{22 23} Given that our patient was first diagnosed with group A streptococcus pharyngitis and later developed trapezius abscess, direct extension to the surrounding tissues in the setting of mucosal damage followed by haematogenous spread seems most likely. It is unclear what predisposing features are present in patients with Lemierre syndrome. It is possible that a preceding viral infection (eg, Epstein-Barr virus, cytomegalovirus) or bacterial pharyngitis (eg, group A Strep) may induce initial mucosal damage that may predispose to superinfection with anaerobes.

The mainstay of treatment for Lemierre syndrome is antibiotic therapy for at least 4 weeks, including at least 2 weeks of intravenous treatment, guided by clinical findings.⁷ The appropriate treatment regimens include a beta-lactamase resistant beta-lactam (such as piperacillin and tazobactam), a carbapenem (such as imipenem) or ceftriaxone and metronidazole. The use of ampicillin and sulbactam is often discouraged due to higher resistance compared with piperacillin and tazobactam or carbapenems.^{24 25} In our patient, following the findings on neck CT scan and finding of anaerobic gram-negative bacteraemia, ampicillin and sulbactam was switched to piperacillin and tazobactam.

Clinical and laboratory response to appropriate antibiotics may be protracted, with several studies indicating that defervescence may require more than a week.^{26 27} Our patient presented to the hospital more than 1 week after onset of symptoms. He was started on appropriate antibiotics on hospital days 3–4 and required 9 days of appropriate intravenous treatment before he could be discharged. Our patient continued to have pleural effusion in the right lower lung zone at follow-up (figure 1). Persistent pleural effusions can be seen in Lemierre syndrome and may require decortication.²⁸

The role of anticoagulation in Lemierre syndrome is controversial. Uncomplicated disease without extensive clot burden resolves with appropriate antibiotics and supportive care and does not require anticoagulation. Although there are no clinical trials given the rarity of this disease, anticoagulation is often reserved for patients with extensive clot burden, thrombus extension into cerebral sinuses or patients who have continued fever or bacteraemia, or progression of thrombosis despite appropriate antimicrobial therapy.²⁹

In conclusion, we present a case of Lemierre syndrome caused by P. intermedia complicated by multiple cavitary lung lesions, loculated pleural effusions requiring chest tube placement and trapezius abscess. Lemierre syndrome was more common in the preantibiotic era, so it is often classified as a forgotten disease as clinicians are less familiar with its manifestations. However, the emergence of antibiotic resistance has led to a re-emergence of cases.⁴ In otherwise healthy young adults presenting with atypical pneumonia and multifocal findings consistent with septic emboli, clinicians should have high suspicion for Lemierre syndrome, especially in the setting of preceding pharyngeal infections.

Learning points.

• Lemierre syndrome can develop due to Prevotella intermedia, an oral commensal anaerobic gram-negative bacterium.

• In otherwise healthy young adults with unusual pneumonia, clinicians should have a high suspicion for Lemierre syndrome, especially in the setting of a preceding pharyngeal infection.

• Clinical complications particularly pulmonary empyema may require surgical management.

• Clinical and laboratory response to appropriate antimicrobial therapy may be protracted in Lemierre syndrome.

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