Suppurative phlebitis, or venous infection, is a clinical condition that is often associated with thrombosis of the involved section of the vein, bacteremia, and metastatic abscesses. The infection is intravascular, so the associated bacteremia is often continuous, as is also seen in endocarditis, infections of arterial prostheses, and catheter sepsis. Naturally occurring suppurative phlebitis is an uncommon disease. Cases typically arise from an antecedent infection in close anatomic proximity to the primarily affected vessel. Nosocomial cases caused by instrumentation of the venous system also occur. Suppurative phlebitis can cause significant systemic complications and mortality if not recognized and treated promptly and appropriately.

Naturally occurring suppurative thrombophlebitis occurs when an infection spreads to involve an adjacent venous structure or when a venous thrombosis becomes secondarily infected. Although any vein may potentially be involved, several clinical syndromes involving deep veins are well described. Perhaps the most well-known syndrome involving thrombophlebitis is Lemierre’s syndrome, defined as postanginal sepsis with thrombophlebitis of the internal jugular vein. Lemierre first described the syndrome in 1936, and it remains a significant clinical entity today.¹ Pylephlebitis, first described in 1926 by Kramer and Robinson, is suppurative thrombophlebitis of the portal vein.² It is most commonly caused by complicated intraabdominal infections. The mesenteric vessels may also be involved. The most frequently associated infections leading to pylephlebitis include diverticulitis³ and appendicitis,^4,5 although it has also been described as a complication of choledocholithiasis,⁶ pyelonephritis,² and Crohn’s disease.^7,8 Other peritoneal sites of suppurative phlebitis include the pelvic veins after pelvic infection, which often occurs in the postpartum period.^9,10 Suppurative thrombophlebitis of the veins of the head and neck is well described with cases having been reported to involve the ophthalmic vein,¹¹ lateral venous sinuses^12,13 and cavernous sinus^14,15 after episodes of sinusitis or otitis media.^16,17

Suppurative phlebitis occurs through two main mechanisms. In some cases, established venous thromboses become infected by circulating bacteria in the blood, with ensuing infection of the venous wall. In most cases, infection is caused by spread of bacteria from adjacent infected tissue to the affected vein. In Lemierre’s syndrome, for example, the precipitating infection is often in the oropharynx. Mucosal damage from bacterial or viral pharyngitis or odontogenic infection results in invasion of bacteria into the lateral pharyngeal space with subsequent development of phlebitis of the internal jugular vein.¹⁸ Invasion of the retropharyngeal soft tissue may lead to phlebitis and thrombosis of the tonsillar veins with propagation to the internal jugular vein.¹⁹ Thrombophlebitis of the portal, mesenteric, or pelvic veins occurs in much the same manner. Inflammation of infected tissue adjacent to a deep blood vessel allows progression of infection to the vessel wall with subsequent propagation of infection and metastatic infection from that site.

In addition to the direct bacterial infection of the venous wall, the concordant inflammation may lead to endothelial damage and a hypercoagulable state, promoting formation of thrombosis.²⁰

After the onset of infectious thrombophlebitis, bacteremia ensues. Without prompt treatment, the infected thrombosis may propagate to involve additional vessels and causing further local tissue inflammation and damage. Additionally, septic emboli may cause metastatic foci of infection in other tissues. Lemierre’s syndrome frequently leads to pulmonary septic emboli and occasionally causes empyema.²¹ Some reports cite up to a 95% incidence of pulmonary involvement in patients with Lemierre’s disease.²² Thrombophlebitis of the portal system occasionally results in metastatic hepatic and splenic abscesses.^8,23

Disease may progress rapidly, and patients may quickly develop septic shock. Without appropriate antibiotics, mortality approaches 100%. This was seen in the preantibiotic era, when the first cases of Lemierre’s syndrome and pylephlebitis were almost uniformly fatal.²⁴ With the advent of antibiotics, mortality has decreased tremendously. A recent prospective study in Denmark of Fusobacterium necrophorum bacteremia complicating Lemierre’s syndrome identified a 9% mortality among 58 cases diagnosed over a 3-year period,²⁵ in agreement with other published reports of modern-day mortality rates ranging between 4% and 18%.²⁴

In general, suppurative thrombophlebitis is an uncommon condition. Adults are affected more often than children, mostly because many of the antecedent infections leading to this condition occur in adulthood. Lemierre’s syndrome typically affects previously healthy young adults. In five series of more than 200 patients, the average age of patients was 18 to 20 years, although there are case reports of patients of all ages.¹⁹

The most common locations of suppurative phlebitis are the superficial veins of the extremities because they may be infected from unintentional or intentional trauma, such as occurs with intravenous (IV) drug use (IVDU). Suppurative phlebitis of the internal jugular veins, or Lemierre’s syndrome, remains very rare, with an incidence of approximately one case per million persons per year. Likewise, the incidence of pelvic septic thrombophlebitis in one study was one in 3000 deliveries (one in 9000 after vaginal delivery; one in 800 after cesarean section). Pylephlebitis was estimated to occur in 0.4% of patients with appendicitis before the advent of antibiotics but is now recognized very rarely.⁵ A retrospective review of computed tomography (CT) scans performed on 138 consecutive cases of diverticulitis found pylephlebitis in only one case (0.7%).²⁶

In a review from Egypt, lateral sinus thrombophlebitis was the most common intracranial complication among 442 patients with acute or chronic suppurative otitis media, affecting 120 patients (29%) at some point of their illness, with no predilection to the patient’s age.¹⁶ Cavernous sinus thrombosis, presenting as an orbital syndrome in patients with sinusitis, particularly ethmoid sinusitis, is also a rare infection.

Many typical symptoms of patients with suppurative thrombophlebitis are nonlocalizing. Approximately 80% of patients have fever and may have other constitutional symptoms such as rigors or drenching sweats. Patients may also present in septic shock. Many patients also have tenderness or pain localizing to the affected site. Patients may also present with secondary signs of infection such as shortness of breath or mental status changes. These may occur in instances of septic emboli to distal sites such as the lungs or the brain.

More specific findings may be present in instances of particular vessel involvement. Superficial suppurative thrombophlebitis can complicate skin and soft tissue infections, and a palpable and tender cord is often apparent in presentation. It may be difficult to distinguish bland thrombophlebitis from septic thrombophlebitis without expressing pus from or aspirating the involved segment of vein, but the diagnosis should certainly be considered in a patient with a palpable cord and bacteremia without another evident source of infection.

Patients with suppurative thrombophlebitis of the internal jugular vein often have a history of antecedent oropharyngeal or otic infection that may or may not be clinically apparent at the time of presentation. Some patients may have exudative pharyngitis, tonsillar or retropharyngeal abscess, or otitis media on examination. Half of these patients present with neck swelling and tenderness and cervical lymphadenopathy and may have other suggestive symptoms, including trismus, torticollis, dysphagia, or dysarthria.¹⁸

Although Lemierre’s syndrome may extend to involve communicating intracranial vessels, suppurative phlebitis of intracranial veins most typically occurs after infection of the sinuses or auditory canal. It may also complicate other intracranial infections, including bacterial meningitis, epidural abscess, or subdural empyema. Intracranial suppurative phlebitis is often characterized by headache, focal neurologic findings, and seizures. Patients with lateral sinus thrombophlebitis and cavernous sinus thrombophlebitis often have evidence of chronic otitis media on examination. Patients present with proptosis, chemosis, oculomotor paralysis, or isolated cranial nerve palsies. Patients with recent acute sinusitis also have the potential to develop cavernous sinus thrombosis or orbital vein thrombophlebitis. Cavernous sinus thrombosis caused by sinusitis can be distinguished clinically from orbital cellulitis by loss of papillary responses to light caused by cranial nerve III palsy.

Pylephlebitis usually develops after a clinically apparent intraperitoneal infection. Patients often have fever and abdominal pain related to the primary infection, so mesenteric or portal vessel involvement may not be recognized immediately unless suspicion is high. Patients with septic pelvic thrombophlebitis often have had recent delivery or gynecologic surgery. Pelvic thrombophlebitis may complicate postpartum infections or other pelvic infections, in some cases unrelated to medical therapy. In fact, cases caused by vaginal delivery outnumber those complicating c-section, abortion, or gynecologic surgery.

In addition, the patient may have local complications, such as septic arthritis, subperiosteal abscesses, or osteomyelitis caused by direct extension from septic phlebitis in nearby veins.

The causative organisms of naturally occurring suppurative thrombophlebitis are many and varied. In general, the anatomic location of the underlying infection leading to thrombophlebitis dictates the most likely organisms present.

Internal Jugular Septic Thrombophlebitis

Historically, Lemierre’s syndrome was considered to have been solely caused by F. necrophorum, an obligate anaerobic, gram-negative rod that is part of the normal oral flora.²⁷ Although F. necrophorum does cause the majority of cases of internal jugular suppurative phlebitis, other organisms may cause co-infection or may cause the syndrome without Fusobacterium present. In a review of five studies involving more than 200 patients with internal jugular suppurative phlebitis, F. necrophorum was identified in 152 (69%) of cases and Fusobacterium spp. in 38 (17%). In 18 (8%) cases, aerobic or anaerobic bacteria was identified as the causative organism, and in 14 (6%) cases, culture results were negative. In 26 (12%) cases, an additional co-infecting organism was identified with F. necrophorum. Polymicrobial infection usually consists of non-Fusobacterium normal oral flora such as Streptococcus spp., Prevotella spp., and Haemophilus spp.

The most commonly isolated organism in individuals with pylephlebitis is Bacteroides fragilis. Other causative organisms are also normal colonic flora and include Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter spp., and more rarely streptococci and anaerobes such as Clostridium spp.^3,28

Superficial thrombophlebitis is often caused by cutaneous trauma, such as occurs with IVDU, and the infecting organism is typically normal skin flora. In a study of 36 cases of suppurative thrombophlebitis among IV drug users in Switzerland, the causative organisms in 53% were Staphylococcus aureus, Streptococcus pyogenes in 19%, and Streptococcus spp. in 19%.²⁹

Candidal infections do occasionally cause suppurative thrombophlebitis, but almost all cases are secondary to indwelling peripheral or central venous catheters (CVCs) and are not naturally occurring. The other rare fungal suppurative phlebitis that occurs is cavernous sinus thrombosis caused by molds, either Aspergillus or related molds or the agents of zygomycosis.^30,31,32 These infections usually occur in immunocompromised patients, including those with neutropenia, immunosuppression for transplantation, or the neutrophil dysfunction that occurs with diabetic ketoacidosis. In these cases, the occlusion of the cavernous sinus is often from the proliferation of hyphae rather than a thrombosis.

The diagnosis of suppurative phlebitis relies heavily on radiologic findings. Suggestive findings include air within the lumen or wall of the involved vessel or inflammation of the vessel wall.³³ Based on the anatomic location of the venous infection, ultrasonography, CT, and magnetic resonance imaging (MRI) are all diagnostic options. All of these tests have different advantages and disadvantages that must be weighed on an individual patient basis.

Ultrasonography can be used in many situations. It is inexpensive, can be done quickly, and does not involve exposure to radiation or contrast. The use of Doppler ultrasonography allows additional assessment of vessel blood flow and patency. A primary flaw in ultrasonography is that it is operator dependent. An inexperienced technician may miss subtle findings that could aid in diagnosis. In Lemierre’s syndrome, ultrasonography may identify thrombosis of the internal or external jugular vein. However, ultrasonography is limited in internal jugular suppurative thrombophlebitis by not being able to reliably visualize disease below the clavicle and at the skull base and cervical spaces below the hyoid bone.³³ It may therefore miss thrombophlebitis in these areas or may not be able to thoroughly diagnose the extent of thrombosis proximally or distally.

The utility of ultrasonography in patients with pylephlebitis lies in its ability to show portal vein thrombosis. Ultrasonography is less sensitive, however, for detecting thrombosis in the splenic and mesenteric veins.³⁴ Ultrasonography, however, may not identify the underlying condition, such as appendicitis or diverticulitis, leading to pyelophlebitis.

Ultrasonography is also of limited utility in pelvic vein suppurative thrombophlebitis. A report of three cases of postpartum ovarian vein thrombophlebitis (PPOVT) showed that only one case (33%) was correctly identified at the time of initial ultrasound examination.⁸ Although other studies have shown that Doppler ultrasonography may identify decreased or absent flow within the ovarian vein or inferior vena cava (IVC), the ovarian vein is long with a tortuous course and may be obstructed from adequate visualization by overlying bowel. The anatomy pelvis also may lead to confusion of PPOVT with hydroureter, lymphadenopathy, dilated fallopian tube, or thrombosis of the inferior mesenteric vein.⁸ Therefore, the authors concluded that ultrasonography may be better used in this setting as a test used to document response to antibiotic and anticoagulant therapy.

In cases of superficial superficial suppurative thrombophlebitis, ultrasonography can typically identify venous thrombosis and may be able to identify any adjacent soft tissue infection if radiographic examinations are thought to be needed to establish diagnosis or better evaluate the extent of disease.

CT and MRI are both excellent methods of diagnosing suppurative thrombophlebitis. The main advantage of these modalities lies in their ability to show much more detail of the affected vessel and surrounding tissue. CT and MRI can both show the entire extent of thrombophlebitis along with extension into other vessels. In CT images, affected vessels are often distended with partially or fully occlusive thrombus, a thickened enhancing vessel wall, and surrounding soft tissue inflammation.²¹ MR also shows venous thrombosis and adjacent soft tissue abnormalities very well. Both modalities can show surrounding tissue in greater detail, often allowing for identification of the precipitating infectious site. Additionally, both CT and MRI are able to detect clinically relevant embolic phenomena resulting from the primary suppurative phlebitis, such as pulmonary septic emboli and hepatic, splenic, and brain abscesses. The main drawbacks of CT are its expense and the exposure of the patient to radiation and contrast dye. The main drawbacks of MRI are expense and the long duration of the studies. Overall, CT and MR studies are generally more useful for deep vein infections and when the primary site of infection is unknown.

In addition to diagnostic imaging, aerobic and anaerobic blood cultures should be obtained. Given that this infection is endovascular, blood cultures are generally high yield and can help to tailor antibiotics appropriately. Whenever possible, the first set of blood cultures should be drawn before initiation of antibiotics to improve the likelihood of identifying a causative organism. In Lemierre’s syndrome, blood cultures are positive in 60% to 100% of cases and in more than 35% of cases of septic pelvic thrombophlebitis. Studies of superficial thrombophlebitis have shown positive cultures in more than 80% of patients.

Laboratory tests in patients with suppurative thrombophlebitis are often abnormal and suggestive of infection but are nonspecific. Patients commonly have elevated white blood cell counts with a prominent left shift, and the C-reactive protein level is elevated.

Therapy

The severity of suppurative phlebitis and the fulminant course of disease require early intervention. Empiric antibiotics are imperative to successful therapy, and a delay in initiation of antibiotics has been shown to result in higher patient mortality.³⁵ Initial antibiotic therapy should be broad spectrum to cover aerobic gram-positive and -negative organisms as well as anaerobic bacteria. Appropriate antibiotics may include a third- or fourth-generation cephalosporins such as ceftazidime or cefepime, a β-lactamase–resistant penicillin such as ampicillin–sulbactam or piperacillin–tazobactam, or a carbapenem.³⁶ In cases of methicillin-resistant S. aureus (MRSA may be the infecting organism, such as in superficial thrombophlebitis), vancomycin, daptomycin, or linezolid may be of benefit. Metronidazole or clindamycin may be added for additional anaerobic coverage. Empiric antifungal coverage is not indicated unless a compelling history is obtained because fungal suppurative phlebitis is rare and is almost always associated with an indwelling catheter. Generally, most recommendations for the duration of antibiotic therapy are for 4 to 6 weeks of IV antibiotics and follow published guidelines for endovascular infections such as endocarditis. However, at least one recent study in large vein septic thrombophlebitis among IV drug abusers showed that IV therapy that lasts more than 7 days but fewer than 28 days and followed by oral antibiotics is likely to be effective in these cases.¹⁶ In complicated cases, antibiotic use may have to be prolonged, with the duration determined by clinical information such as findings on repeat radiographic imaging.