The lymphatic system works to transport proteinaceous fluid from the tissues to the venous system. Lymphatic flow is aided by compression from the surrounding musculature and one-way valves within the lymphatic channels. The lymph system parallels the venous system and has many branches, from small lymphatic capillaries to larger lymphatic collecting ducts that drain into the lymph nodes.¹ This system is also important for immune recognition of microbes and microbial products as part of the host response to infection. Inflammation of the lymphatics, or lymphangitis, can result from a variety of conditions, including allergies, insect stings, cancer, and infections.

Infections of the lymphatic system can be broadly grouped into two categories: infections of the lymph nodes or lymphadenitis, and infections of the lymph vessels or lymphangitis. If there is damage to the lymph vessel or surrounding tissues or interruption of the lymphatic flow from intraluminal obstruction, external compression, or surgical removal of lymphatic vessels, lymphedema may occur. As with any static fluid collection, lymphedema is a predisposing factor for subsequent infection.^2,3

Lymphadenitis may occur with or without lymphangitis as a result of hematogenous spread, direct cutaneous inoculation, or extension from a nearby site of infection. A variety of pathogens (bacterial, fungal, mycobacterial, parasitic, and viral) may be the cause lymphadenitis, depending on the site of infection and how the area is drained lymphatically. Because the topic of lymphadenitis is extremely broad, it will not be the focus of this chapter; instead, the concentration will be on lymphangitis.

Lymphangitis most commonly occurs on the upper or lower extremities secondary to direct inoculation but can occur in any part of the body. Normal host tissue via direct inoculation (trauma, insect bite) can be affected, but there is a higher propensity for it to occur in tissue that has suffered lymphatic damage by trauma or as a postsurgical complication, with resulting chronic lymphedema.

A variety of pathogens cause lymphocutaneous syndrome, also known as sporotrichoid lymphangitis or nodular lymphangitis. A pathogen is introduced by cutaneous inoculation or trauma and proceeds to cause infection by spreading up lymphatic channels, often creating nodules along lymphatic vessels with overlying inflammatory changes.^4,5 These pathogens can be grouped according to the timing of incubation into acute and chronic lymphangitis. Acute lymphangitis is mainly caused by bacterial pathogens, most often pyogenic organisms such as Staphylococcus and Streptococcus spp., although any bacterial pathogen infecting the subcutaneous tissues can be implicated in this syndrome. Chronic lymphangitis may be caused by organisms such as Sporothrix schenckii, Nocardia spp., mycobacterial species, endemic fungi, and Leishmania spp. Lymphatic filariasis has both acute and chronic components and is discussed in the section on acute lymphangitis.

Pyogenic Organisms

The most common causes of acute lymphangitis are pyogenic organisms, most commonly Staphylococcus and Streptococcus spp., in conjunction with ongoing skin and soft tissue infection. The infection can occur in normal host tissue without any underlying lymphatic vessel damage but most often occurs in tissue where there has been disruption of the lymphatic system because of surgery or chronic lymphedema from other causes,^2,3 including obesity and edema secondary to congestive heart failure.

Acute lymphangitis is often diagnosed based on the history and physical examination, and the treatment is often empiric unless the patient has a history of exposure, positive blood or wound cultures, or other concurrent symptoms that are telling of the causative pathogen. There are only a few case reports in the literature of acute lymphangitis secondary to Staphylococcus and Streptococcus spp. occurring in hosts without underlying lymphatic damage and independent of a concurrent infection, although this probably occurs more frequently than reported.^6,7,8,9

Any break in the skin can predispose an individual to infection. In some cases, a minor fungal infection of the skin, such as an interdigitial infection with dermatophytes or intertrigo secondary to Candida infection, may be the initial point of entry for Group A streptococci, leading to erysipelas.¹⁰ Recurrent lymphangitis of the leg may be associated with dermatophytosis as well.¹¹ One case series describes a series of three patients with lymphangitis secondary to Staphylococcus aureus associated with possible contact dermatitis.¹²

Any bacterial pathogen capable of causing a skin or soft tissue infection would be expected to cause lymphangitis, but usually the offending organism is not cultured from the tissues, either by aspiration¹³ or punch biopsy.¹⁴ Blood culture results are only positive in 5% of cases.¹⁵ Group A streptococci are thought to be involved most frequently,¹⁶ although one study has shown Group G streptococci to be the most common culprit.¹⁷ Lymphangitis may occur as a constellation of symptoms, as in a case of a finger injury from a computer game resulting in scarlet fever,¹⁸ giving clues to the causative organism. Certainly, any α- or β-hemolytic Streptococcus or Staphylococcus spp., mainly S. aureus, may be involved.

Upon presentation, the area of inoculation may or may not be evident, but the digits and webbing in between digits must be carefully examined for any breaks in the skin pointing to a possible site of inoculation. Red streaking, a marker of the infection progressing proximally along lymphatic channels, may be evident on the skin. A chain of nodules following the course of the lymphatic vessels will often occur, with or without surrounding inflammatory changes. Draining lymph nodes may be enlarged, painful, or tender, and the patient may complain of systemic symptoms as well.

When skin flora is suspected as the cause of an uncomplicated acute lymphangitis, an antistreptococcal antibiotic is generally recommended. It is necessary to tailor antimicrobial therapy to the resistance profiles of the organisms the patient may be colonized with or that are the most prevalent in the community where the patient resides. Depending on the severity of the infection, the patient’s history, and the resistance profile of the organisms in the patient’s community, an antistaphylococcal antibiotic and coverage for methicillin-resistant S. aureus (MRSA) should also be considered.^19,20 If an exposure is implicated, antibiotic therapy should be directed accordingly. A more comprehensive discussion of the antibiotic therapy of cellulitis and secondary lymphangitis is available in the practice guidelines for skin and soft tissue infections published by the Infectious Diseases Society of America.²¹

Healing may occur with scarring of the lymphatic channels and lymph nodes, resulting in lymphedema or an increase in lymphedema if it was preexisting. This may lead to a spiraling effect because preexisting lymphedema is one of the predisposing risk factors for subsequent occurrence of lymphangitis. Elephantiasis nostras verrucosa is an infrequent clinical entity with skin changes that are characterized by verrucous lesions from chronic nonfilarial lymphedema secondary to infections or other causes.²² Recurrent streptococcal infections may play a role in this condition and may be associated with other infectious complications, such as osteomyelitis of the adjacent bone.²³

It is also important for the physician to evaluate for contributing factors to the episode and attempt to provide therapy for them as well. To treat underlying lymphedema, therapies including leg elevation, exercise, compression devices, massage techniques, and even surgery can be recommended.²⁴ Prophylactic antibiotics can be considered in some patients with recurrent episodes of infection.^25,26 Because many infections arise from breaks in the skin caused by fungal infections in the web spaces of the toes, excellent local skin and foot care practices are important in treating the acute episode as well as preventing any future episodes of infection.²⁷

Other Pathogens

Organisms that cause skin and soft tissue infections may be suspected because of particular exposures. Fresh water exposure may implicate Aeromonas hydrophila or Pseudomonas aeruginosa. Seawater exposure may result in infection with Vibrio vulnificus, and injuries related to handling fish may occur with Streptococcus iniae²⁸ or Erysipelothrix rhusiopathiae exposure.²⁹ Other organisms that have been involved in the setting of animal bites include Pasteurella multocida, Capnocytophaga canimorsus, and Spirillum minus (rat bite fever).²¹ Lymphangitis can also occur in infection with Bartonella henselae infection in cat scratch disease, although lymphadenitis usually predominates.

The genitalia, particularly the penis, can be affected by lymphangitis complicating a number of sexually transmitted infections (STIs), a condition referred to a venereal lymphangitis. This has been seen with syphilis, chlamydia, and even herpes simplex virus.^30,31,32 This usually occurs in concert with other symptoms and signs of the sexually transmitted disease, but occasionally the location alone is the only clinical clue that there is an underlying STI. This is not surprising given the role of lymphatics in the spread of male genital tract infections.³³

Viruses have also been implicated outside of the genitalia. Lymphangitis can be seen accompanying the herpes virus in cases of herpetic whitlow.³⁴ Parvovirus has also been implicated in causing lymphangitis.³⁵

A rare infection recently described in France and South Africa is a rickettsiosis caused by Rickettsia sibirica mongolotimonae that has been characterized by lymphangitis. It is a mild disease, with the lymphangitis usually expanding from an eschar, although lymphangitis without eschar has also been described. This pathogen has been isolated from Hyalomma ticks in Inner Mongolia, but the vector has not been identified in Europe or Africa.³⁶

Lymphatic Filariasis. Acute lymphangitis can also occur as a feature of lymphatic filariasis (LF). This is a rare infection in the United States, but LF is an important cause of disability worldwide. More than 1 billion people living in 83 endemic countries are at risk.³⁷ It is estimated that approximately 120 million people worldwide are affected, and 40 million of those affected have developed incapacitating disabilities or disfigurement from the disease.³⁸ Men make up the largest percent of affected persons,³⁹ and the infection is often acquired in childhood.⁴⁰ In addition to the disfiguration and disability, the disease also has large economic and social consequences.⁴¹

LF is caused by the parasitic worms Wuchereria bancrofti, Burgia malayi, and Burgia timori and is transmitted by several species of mosquitoes, including Anopheles, Aedes, Culex, Mansonia, and Ochlerotatus mosquitoes.⁴² The disease is endemic to Africa, Southeast Asia, the Pacific, and tropical South America. This condition can be seen in the United States as an imported disease. Humans are the only reservoirs for W. bancrofti, although Brugia spp. have been seen to be zoonotic. Whereas W. bancrofti accounts for 90% of all filarial cases in the world,⁴¹ and its distribution reaches across the tropics, B. malayi is found only in South Asia, and B. timori is seen only in Timor and Indonesia.⁴³

After being acquired from an already infected human host, the microfilariae develop through stage 1 and stage 2 larvae into stage three infective larvae, which are injected by the mosquito into the bloodstream of the host.⁴² These larvae grow into adult worms in the lymphatic vessels. These worms can live for 4 to 6 years within human hosts. The parasites intermittently produce microfilariae throughout this time period, infrequently causing systemic symptoms. Most of the time, the hosts are asymptomatic.

Live worms cause local lymphatic dilatation, or lymphangiectasia, thought to be secondary to the parasites themselves as well as local endogenous chemicals and signaling pathways acting on the endothelial cells lining the lymphatics.⁴⁴ Acute filarial lymphangitis (AFL) is seen in endemic areas and occurs not at the initial time of the infection but when an inciting event causes the death of the parasite and the host’s immune system is able to mount an inflammatory reaction against it. The acute response can vary from subclinical, nodular subcutaneous lesions to AFL, acute lymphedema with erythema and pain in the affected limb.⁴⁴ Lymphangitis may also involve the breast and mimic breast cancer. Acute hydroceles and lymphedema have been seen after an episode of AFL thought to be secondary to obstruction of the downstream lymphatic tissue by the inflammatory response against the adult worms.⁴⁵ These lesions can resolve as the inflammatory response resolves after an episode of AFL and do not necessarily mean that the patient will progress to having chronic changes.⁴⁶ After the immune response has degraded the dead worms, the lymphatics have the potential to recannulate, providing for lymphatic flows again, and return to normal tissue.

In endemic areas, LF is often diagnosed on history and physical examination. Detecting subclinical infestation is more difficult and has been the focus of much research because treatment of the asymptomatic infestation may prevent chronic manifestations and therefore morbidity. Microfilariae can be seen on blood smears with or without membrane filtration techniques.⁴⁷ The most opportune time for specimen collection is at night, the time at which the adult female W. bancrofti worms release the microfilariae (nocturnal periodicity). In the South Pacific, however, W. bancrofti has a smaller peak that is maximal during the day, and B. malayi has nocturnal peaks of different amounts. The microfilariae can also be identified in chylous fluid from a hydrocele or in the urine. Peripheral eosinophilia may also be present but is most often seen during episodes of acute inflammation.

Serologic tests (enzyme-linked immunosorbent assay, indirect hemagglutination) have been studied, although these tests are not able to differentiate between past and present infection.³⁹ Antigen testing in the form of an ICT Card Test has become more available and widespread, with sensitivity and specificity of 98.5% and 100%.^47,48 A big advantage to serologic and antigen tests is that they can be used for screening during the daytime, and many studies have shown that despite negative microfilarial blood test results, the antigen will remain positive with ongoing infestation.⁴⁹ Whether that is because of continued disease or infection remains a question, but both scenarios are clinically relevant when the goal is disease eradication as well as surveillance.

Imaging plays a small part in the diagnosis of LF. Ultrasonography of the lymphatic vessels in the groin area can be helpful in documenting the motion of the worms in the lymphatics, also known as the filarial dance sign (FDS).⁵⁰ Lymphoscintigraphy may also be used to examine the lymph vessels in the lower extremities for dilatation.⁵¹

As already discussed, secondary bacterial infections, mainly streptococcal, may contribute significantly to episodes of acute lymphangitis of filarial etiology,⁵² and in some cases, an elevated ASO titer may be sign of this co-infection.⁵³

Chronic Lymphatic Filariasis. Over time, because of repeated infections and resultant damage to the lymphatics and surrounding tissues, the anatomy of the affected area is often not able to return to its pre-infestation state, resulting in chronic LF. Multiple episodes of the acute dermatolymphangioadenitis (ADLA) syndrome may occur, referring to the superinfection and inflammation of the capillary and draining lymphatics as well as regional lymph nodes of the already chronically lymphedematous tissue.^46,54 These recurrent infections may be caused by a variety of organisms⁵⁵ that are thought to be the main reason why even after treatment and the body’s degradation of the parasite and the recannulation of the lymph vessels, the chronic lymphatic damage may result in permanent disfigurement and resulting disability.

Chronic manifestations of the disease include lymphadenopathy, lymphedema, hematuria, hydrocele, chyluria, elephantitis, and tropical pulmonary eosinophilia (TPE).⁴¹ The progressive enlargement of the extremity or genitalia with fibrosis of the subcutaneous tissues and thickening of the skin may occur from prolonged exposure in an endemic area but also from superimposed streptococcal lymphangitis. Sexual disability⁵⁶ as well as depression and social isolation secondary to anatomical disfigurement⁵⁷ are all prevalent throughout endemic areas.

Treatment There has been a significant amount of research done looking at diethylcarbamazine (DEC), albendazole, and ivermectin alone, in combination, and at various dosing schedules for the prevention and treatment of filarial disease. All three agents have activity against microfilariae, but DEC alone causes death of the adult worms. Single- to triple-dose regimens of DEC have been shown to reduce the microfilarial burden transiently.⁵⁸ One study looked at DEC and albendazole alone and in combination as one-time doses for the treatment of W. bancrofti and did not find any differences in efficacy.⁵⁹

DEC causes an intense inflammatory reaction in the eyes of patients with onchocerciasis. Because of this, in areas where patients are possibly co-infected with Onchocerca volvulus spp. and W. bancrofti, DEC is not used, and ivermectin and albendazole are used in combination instead. In non-onchocerciasis countries, DEC and albendazole are administered for mass drug administration (MDA).

Attention has recently been on the treatment of patients with the endosymbiotic bacteria Wolbachia spp. with doxycycline because Wolbachia organisms are needed for worm survival.^60,61 After treatment with doxycycline to eliminate Wolbachia spp., patients have decreased levels of vascular endothelial growth factors (VEGFs). These growth factors are involved in lymphangiogenesis and ultimately can improve lymphatic disease, including lymph vessel dilatation.⁶¹ Because of the cost, doxycycline is not an alternative for MDA and is not recommended for people who are continuing to reside in at-risk areas because treatment would most likely need to be repeated as rates of re-infection are high.⁶⁰ Rifampicin has also shown to have some antifilarial effect.⁶²

In the case of both chronic and acute LF, an aggressive foot or local wound care regimen should be encouraged. Techniques to improve lymphedema, as described above, including massage and elevation of the affected limb with bandaging or use of compression devices when able, should be used. Regular footwear use should also be encouraged when indicated. Foot care programs have been shown to be a sustainable and cost-effective way to improve disability caused by LF.^63,64

Some nations, including Japan, have been successful at eradicating the disease through MDA programs, public health education, and vector control.⁶⁵ The Global Programme to Eliminate Lymphatic Filariasis hopes to replicate these achievements globally⁶⁶ and has had great success over the first 8 years of the program with MDA efforts in endemic countries.⁶⁷

In addition to chronic lymphangitis caused by filariasis, chronic lymphangitis may occur from a variety of other infections, particularly fungal and mycobacterial infections. Chronic lymphangitis caused by these pathogens, also known as the lymphocutaneous syndrome or nodular lymphangitis, differs from acute lymphangitis in clinical presentation and microbiologic etiologies. Lymphocutaneous syndrome is characterized by subcutaneous infection that spreads along the lymphatic system. The most common cause is Sporothrix schenckii infection. In fact, the clinical presentation of nodular lymphangitis is often referred to as sporotrichoid, even when it is not caused by Sporothrix infection. Other causes of this syndrome include atypical mycobacterium, especially Mycobacterium marinum, Nocardia spp., leishmaniasis, and endemic fungi. The epidemiology, clinical course, and treatment of patients with chronic lymphangitis are specific to the unique microorganisms that cause the disease.

Sporothrix

The most common microorganism that causes lymphocutaneous syndrome is S. schenckii. This organism was first discovered by a medical student at Johns Hopkins in 1896. Since that time, it has been found sporadically throughout the world, occasionally causing epidemics. It is a dimorphic fungus that exists as a mold at room temperature and a yeast above 37°C. Although it has a worldwide distribution, it is more prevalent in warm, humid environments. Sporothrix spp. is endemic to Mexico, Costa Rica, Guatemala, Columbia, Brazil, Uruguay, South Africa, India, and Japan. It is hyperendemic in Abancay in the Peruvian Andes, where there was an incidence as high as 60 in 100,000 people per year in 1996.⁶⁸ Sporothrix infection has also occurred in epidemic form throughout the world. The largest epidemic was in the South African gold mines, where more than 3000 workers were affected between 1941 and 1944.⁶⁹ This outbreak was traced back to contaminated wood that was used in supporting the mine shafts. Although most epidemics are traced back to an environmental source such as sphagnum moss^70,71 or moldy hay,⁶⁸ more recently there have been outbreaks in Brazil thought to be secondary to zoonotic transmission from housecats.⁷³

Epidemiologic studies have found adults to be at highest risk for the disease, except in certain areas of Peru, where a majority of cases are in children younger than age 14 years.⁷⁴ Children are more likely to get facial lesions.⁷⁵ There is a male predominance in some countries and a female predominance in others, thought to be secondary to gender roles regarding farming and gardening.^75,76,77