Infections caused by anaerobic bacteria are common, and may be serious and life-threatening. Anaerobes predominant in the bacterial flora of normal human skin and mucous membranes, and are a common cause of bacterial infections of endogenous origin. Infections due to anaerobes can evolve all body systems and sites. The predominate ones include: abdominal, pelvic, respiratory, and skin and soft tissues infections. Because of their fastidious nature, they are difficult to isolate and are often overlooked. Failure to direct therapy against these organisms often leads to clinical failures. Their isolation requires appropriate methods of collection, transportation and cultivation of specimens. Treatment of anaerobic bacterial infection is complicated by the slow growth of these organisms, which makes diagnosis in the laboratory only possible after several days, by their often polymicrobial nature and by the growing resistance of anaerobic bacteria to antimicrobial agents.

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Lemierre's Syndrome

  

           Lemierre’s Syndrome, also known as necrobacillosis or postanginal sepsis, is characterized by an oropharyngeal infection followed by internal jugular vein septic thrombophlebitis and metastatic infections, most often to the lungs and joints.  It is typically seen in otherwise healthy young adults and adolescents. The syndrome is most commonly associated with the anaerobic gram-negative rod, Fusobacterium necrophorum.  It was first  reported by several authors in the early 1900’s[1,2,3], and was best described by Lemierre in 1936 [4], as a rapidly progressive infection that is usually fatal within 7-15 days [4,5].  The reports of infection decreased  in the 1960’s through the early 1970’s[5], probably due to the wide use of antibiotics for pharyngitis. Recently, reports of cases have again become more common. 

 Even though mortality decreased to 4-12% with appropriate antibiotics, delay in initiating appropriate therapy has been associated with increased mortality [9]. It remains therefore important to be aware of this classic syndrome so that its clinical presentation can be recognize and appropriate therapy is initiated early.
   

 Microbiology           
Fusobacterium necrophorum is the most common pathogen isolated for patients with Lemierre’s, occurring in 70% of cases over the last decade. Other organisms that have been reported as a cause of Lemierre’s Syndrome, either isolated with or without F.necrophorum, include F. nucleatumStreptococcus spp, Peptosterptococcus spp, Eikenella corrodensBacteroides spp, , Peptostreptococcus spp., Bacteroides spp.,  Streptococcus milleri, Group F StreptococcusHaemophilus aphrophilus, and Gemella morbillorum.[J17]


Patogenesis

F. necrophorum possesses several unique virulence factors. These include lipopolysaccharide endotoxin which has been shown to be lethal in animal models, [5] and exotoxins, such as leukocidin, hemolysin, lipase, and cytoplasmic toxin.[13] The key virulence factor in the ability of F. necrophorum to cause the internal jugular vein thrombosis characteristic of Lemierre’s Syndrome.  Human platelet aggregation has been demonstrated from broth cultures and washed cells when exposed to the surface of 13 of the 16 virulent A type strains of Fusobacterium necrophorum, but with none of the avirulent B or AB biotypes. [32]  Thrombosis has also been demonstrated in animal models .  Kanoe, et al, demonstrated the formation of thrombi in mesenteric microcirculation of guinea pigs after they were inoculated with F. necrophorum.[40]

It has been hypothesized that alterations in the pharyngeal mucosa where F. necrophorum  reside, are required for the development of infection. Such changes could be secondary to a primary viral throat infection, such as infectious mononucleosis, or to cigarette smoking. [17] 


Right external jugular vein thrombophlebitis (Panel A, arrows). Chest computed tomographic imaging  shows bilateral pleural effusion and multiple areas of consolidation with cavitation. (NEJM 2004; 350:e14)


Diagnosis


  Postanginal sepsis or necrobacillosis has a very typical clinical presentation. It almost always occurs in otherwise healthy adolescents or young adults, although a few cases have been reported in young children. [5, 9,10,11]   The patients initially develop an oropharyngeal infection, most commonly pharyngitis or exudative tonsillitis, but the syndrome has followed mastoiditis, otitis, dental infections, and parapharyngeal abscesses [12,13,14, 22].  Less frequent causes include surgery ( e.g. tonsillectomy) or trauma. [15,16]  All the signs and symptoms of the initial oropharyngeal infection may have resolved by the time the internal jugular vein thrombosis and metastatic infections develop. [4, 5, 16]

 The time interval between the onset of the initial oropharyngeal infection and the emergence of internal jugular vein thrombophlebitis and associated septicemia is generally less than a week, but may be up to 3 weeks [9].  As the infection progresses and internal jugular vein thrombophlebitis develops, high spiking fevers, and toxicity appears.[5, 11]   Patients may have trismus and swelling and tenderness along the sternocleidomastoid muscle at the angle of the jaw.  These findings may be associated with [5, 16]  Local findings may be minimal when the infection involves the posterior compartment of the lateral pharyngeal space. [17

 The internal jugular vein thrombophlebitis generates septic emboli, that mimics endocarditis. Patients may present with pulmonary involvement that can include dyspnea, pleuritic chest pain, and occasionally hemoptysis. [5]  Chest x-ray can show bilateral nodular infiltrates,  pleural effusions and cavitary lesions.[16] CT can demonstrate intravascular thrombus; but is  less sensitive than high resolution ultrasonography for identifying small mural thrombi.12 Radionuclide gallium scans can localize the source of infection. However, inability to document a thrombus should not delay initiation of appropriate antibiotic therapy for anaerobic sepsisSevere respiratory compromise requiring mechanical ventilation, and adult respiratory distress syndrome, empyema, and lung abscess have all been observed.[16,18]


Radilogical study of pulmonary lower lobes opacification in a patient with Lemierre's Syndrome

                              




                           CT scan of neck showing the gas filled abscess (White arrow)

    
                                 


Clotted off jugular vein (red arrow). Normal appearing jugular vein is indicated by the blue arrow


Septic arthritis of the large joints, including the knee, hip, shoulder, ankle, and sternoclavicular joint, have decreased in frequency since the advent of antibiotics.[5]  Osteomyelitis, soft tissue abscesses, cutaneous pustular lesions are common, and    meningitis, pyomyositis, renal involvement, and acute abdomen  are rare. [5, 17, 20] 

Hepatic and splenic abscesses are rare.[5,17]  Hyperbilirubinemia and jaundice with eleveted liver enzymes can be present in up to half of the patients.[9]  The the jaundice may be due to the toxicity of circulating bacterial products such as the lipopolysaccharide endotoxin produced by F. necrophorum.[5]

Of the 53 cases published in the last decade only 23 had a documented thrombosis of  the internal jugular vein and metastatic infections, but all of the patients had an antecedent oropharyngeal infection and either a positive culture for F. necrophorum, a documented internal jugular vein thrombophlebitis, or metastatic infections.

              F. necrophorum was isolated from either blood or abscess cultures in 68% of the cases, and was the only isolate in 60% of the cases.  These numbers are similar to those seen in the earlier reviews. [5]   F. nucleatum was found in 4%, and Fusobacterium spp. not further speciated were seen in another 18%.  The remaining 8% of the cases were from species other than Fusobacterium
            
            F. necrophorum is often isolated from the blood, parapharyngeal abscess, or metastatic infection site and its recovery is a valuable clue to the diagnosis.  Diagnosis of  Lemierre’s Syndrome, requires the presence of both metastatic infection and internal jugular vein thrombosis. The diagnosis of thrombophlebitis is often made presumptively, and only 25% of the reported cases were actually documented to have thrombophlebitis either surgically or radiographically. [9] The imaging method of choice is contrast-enhanced CT is because it is more sensitive than other methods and enables the discovery of additional pathologies such as pulmonary emboli, soft tissue abscesses, osteomyelitis, and septic arthritis.[8, 23, 24, 25]  It can identify low attenuation intraluminal filling defects, distended veins with enhancing walls, and localized soft tissue edema. [22]  High resolution computed tomography (HRCT) can complement  helical CT in establishing the diagnosis of septic pulmonary emboli. [30]

            Doppler Ultrasonography can evaluate jugular thrombosis and is generally less expensive and less invasive than CT and can demonstrate thrombosis in instances that  CT did not.[7]  However, it does not provides goog imaging beneath the clavicle and under the mandible and may not pick up a fresh thrombus due to low echogenicity. Doppler ultrasound can provides a clearer demonstration of the extent of the thrombus. [30] 

 Magnetic resonance imaging (MRI) has been suggested as the diagnostic procedure of choice [25], because of its increased sensitivity, greater soft-tissue contrast, and avoidance of intravenous contrast and radiation. Magnetic resonance angiography (MRA) was successfully used to identify a thrombus that was not detected on CT [8], but it has not yet been clearly shown to be generally superior to CT and is much more expensive. [22] Other techniques that are considered  less useful include gallium scan, conventional retrograde angiography, and scintigraphic venography with Tc-99m. [9,26]

Management
            There are four facets of therapy for Lemierre’s Syndrome.  The most important are administration of appropriate antibiotic therapy and surgical drainage of purulent fluid collections.    Anticoagulation is controversial, and internal jugular vein ligation is typically saved for severe cases.

            Antibiotic therapy should be directed at the eradication of  anaerobic bacteria in general and against F. necrophorum specifically.  Penicillin has often been recommended in the past, because Fusobacterium was very susceptible to it.  However, because of the increased recovery of beta-lactamase producting F. necrophorum isolates [27,31],  as well as documented failures [29], penicillin is no longer considered appropriate therapy.  Effective antibiotics include clindamycin, metronidazole, the combination of a penicillin plus a beta lactamase inhibitor (i.e. ticarcillin-clavulanate, ampicillin-sulbactam), chloramphenicol, or the carbapenems. The course of antibiotics should be prolonged, for at least 6 weeks. In  reviews of the literature the length of antibiotic treatment ranged from 7-128 days ( median of 41 days ) of therapy.[9]  Delay  in initiating antibiotic treatment is associated with worse outcomes, and increased mortality. [9]

            The use of anticoagulation is controversial, as there are no controlled trials assessing it's value in internal jugular vein thrombophlebitis.  Josey and Staggers found that the addition of intravenous heparin was associated with a more rapid resolution of septic pelvic thrombophlebitis. [29]   Some suggested that anticoagulation be reserved for patients with clinical evidence of internal jugular vein thrombosis propagating retrograde toward the cavernous sinus. [22]  When used, anticoagulation is generally recommended for 3 months.

            Internal jugular vein ligation was often used in the pre-antibiotic era.  However, ligation or excision is generally now recommended only in advanced clinical disease with persistent fevers, repeated septic emboli, or uncontrolled sepsis. [22] 



REFERENCES

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