Lymphatic filariasis is caused by W. bancrofti, B. malayi, or B. timori. The threadlike adult parasites reside in lymphatic channels or lymph nodes, where they may remain viable for more than two decades.
W. bancrofti, the most widely distributed filarial parasite of humans, affects an estimated 110 million people and is found throughout the tropics and subtropics, including Asia and the Pacific Islands, Africa, areas of South America, and the Caribbean basin. Humans are the only definitive host for the parasite. Generally, the subperiodic form is found only in the Pacific Islands; elsewhere, W. bancrofti is nocturnally periodic. (Nocturnally periodic forms of microfilariae are scarce in peripheral blood by day and increase at night, whereas subperiodic forms are present in peripheral blood at all times and reach maximal levels in the afternoon.) Natural vectors for W. bancrofti are Culex fatigans mosquitoes in urban settings and anopheline or aedean mosquitoes in rural areas.
Brugian filariasis due to B. malayi occurs primarily in eastern India, Indonesia, Malaysia, and the Philippines. B. malayi also has two forms distinguished by the periodicity of microfilaremia. The more common nocturnal form is transmitted in areas of coastal rice fields, while the subperiodic form is found in forests. B. malayi naturally infects cats as well as humans. The distribution of B. timori is limited to the islands of southeastern Indonesia.
The principal pathologic changes result from inflammatory damage to the lymphatics, which is typically caused by adult worms and not by microfilariae. Adult worms live in afferent lymphatics or sinuses of lymph nodes and cause lymphatic dilatation and thickening of the vessel walls. The infiltration of plasma cells, eosinophils, and macrophages in and around the infected vessels, along with endothelial and connective tissue proliferation, leads to tortuosity of the lymphatics and damaged or incompetent lymph valves. Lymphedema and chronic stasis changes with hard or brawny edema develop in the overlying skin. These consequences of filarial infection are due both to the direct effects of the worms and to the host's inflammatory response to the parasite. Inflammatory responses are believed to cause the granulomatous and proliferative processes that precede total lymphatic obstruction. It is thought that the lymphatic vessel remains patent as long as the worm remains viable and that the death of the worm leads to enhanced granulomatous reaction and fibrosis. Lymphatic obstruction results, and, despite collateralization of the lymphatics, lymphatic function is compromised.
The most common presentations of the lymphatic filariases are asymptomatic (or subclinical) microfilaremia, hydrocele (Fig. 218-1), acute adenolymphangitis (ADL), and chronic lymphatic disease. In areas where W. bancrofti or B. malayi is endemic, the overwhelming majority of infected individuals have few overt clinical manifestations of filarial infection despite large numbers of circulating microfilariae in the peripheral blood. Although they may be clinically asymptomatic, virtually all persons with W. bancrofti or B. malayi microfilaremia have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria, dilated (and tortuous) lymphatics (visualized by imaging), and—in men with W. bancrofti infection—scrotal lymphangiectasia (detectable by ultrasound). In spite of these findings, the majority of individuals appear to remain clinically asymptomatic for years; in relatively few does the infection progress to either acute or chronic disease.
Hydrocele associated with Wuchereria bancrofti infection.
ADL is characterized by high fever, lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside. Regional lymph nodes are often enlarged, and the entire lymphatic channel can become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis can involve both the upper and lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection. This genital involvement can be manifested by funiculitis, epididymitis, and scrotal pain and tenderness. In endemic areas, another type of acute disease—dermatolymphangioadenitis (DLA)—is recognized as a syndrome that includes high fever, chills, myalgias, and headache. Edematous inflammatory plaques clearly demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation may also be noted. There is often a history of trauma, burns, radiation, insect bites, punctiform lesions, or chemical injury. Entry lesions, especially in the interdigital area, are common. DLA is often diagnosed as cellulitis.
If lymphatic damage progresses, transient lymphedema can develop into lymphatic obstruction and the permanent changes associated with elephantiasis (Fig. 218-2). Brawny edema follows early pitting edema, and thickening of the subcutaneous tissues and hyperkeratosis occur. Fissuring of the skin develops, as do hyperplastic changes. Superinfection of these poorly vascularized tissues becomes a problem. In bancroftian filariasis, in which genital involvement is common, hydroceles may develop (Fig. 218-1); in advanced stages, this condition may evolve into scrotal lymphedema and scrotal elephantiasis. Furthermore, if there is obstruction of the retroperitoneal lymphatics, increased renal lymphatic pressure leads to rupture of the renal lymphatics and the development of chyluria, which is usually intermittent and most prominent in the morning.
Elephantiasis of the lower extremity associated with Wuchereria bancrofti infection.
The clinical manifestations of filarial infections in travelers or transmigrants who have recently entered an endemic region are distinctive. Given a sufficient number of bites by infected vectors, usually over a 3- to 6-month period, recently exposed patients can develop acute lymphatic or scrotal inflammation with or without urticaria and localized angioedema. Lymphadenitis of epitrochlear, axillary, femoral, or inguinal lymph nodes is often followed by retrogradely evolving lymphangitis. Acute attacks are short-lived and are not usually accompanied by fever. With prolonged exposure to infected mosquitoes, these attacks, if untreated, become more severe and lead to permanent lymphatic inflammation and obstruction.
A definitive diagnosis can be made only by detection of the parasites and hence can be difficult. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Microfilariae can be found in blood, in hydrocele fluid, or (occasionally) in other body fluids. Such fluids can be examined microscopically, either directly or—for greater sensitivity—after concentration of the parasites by the passage of fluid through a polycarbonate cylindrical-pore filter (pore size, 3 μm) or by the centrifugation of fluid fixed in 2% formalin (Knott's concentration technique). The timing of blood collection is critical and should be based on the periodicity of the microfilariae in the endemic region involved. Many infected individuals do not have microfilaremia, and definitive diagnosis in such cases can be difficult. Assays for circulating antigens of W. bancrofti permit the diagnosis of microfilaremic and cryptic (amicrofilaremic) infection. Two tests are commercially available: an enzyme-linked immunosorbent assay (ELISA) and a rapid-format immunochromatographic card test. Both assays have sensitivities of 93–100% and specificities approaching 100%. There are currently no tests for circulating antigens in brugian filariasis.
Polymerase chain reaction (PCR)-based assays for DNA of W. bancrofti and B. malayi in blood have been developed. A number of studies indicate that the sensitivity of this diagnostic method is equivalent to or greater than that of parasitologic methods.
In cases of suspected lymphatic filariasis, examination of the scrotum, the lymph nodes, or (in female patients) the breast by means of high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics. Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of men infected with W. bancrofti. Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the filaria dance sign). Radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaremic persons and those with clinical manifestations of lymphatic pathology. While of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection; it is principally a research tool, although it has been used more widely for assessment of lymphedema of any cause. Eosinophilia and elevated serum concentrations of IgE and antifilarial antibody support the diagnosis of lymphatic filariasis. There is, however, extensive cross-reactivity between filarial antigens and antigens of other helminths, including the common intestinal roundworms; thus, interpretations of serologic findings can be difficult. In addition, residents of endemic areas can become sensitized to filarial antigens (and thus be serologically positive) through exposure to infected mosquitoes without having patent filarial infections.
The ADL associated with lymphatic filariasis must be distinguished from thrombophlebitis, infection, and trauma. Retrograde evolution is a characteristic feature that helps distinguish filarial lymphangitis from ascending bacterial lymphangitis. Chronic filarial lymphedema must also be distinguished from the lymphedema of malignancy, postoperative scarring, trauma, chronic edematous states, and congenital lymphatic system abnormalities.
Treatment: Lymphatic Filariasis
With newer definitions of clinical syndromes in lymphatic filariasis and new tools to assess clinical status (e.g., ultrasound, lymphoscintigraphy, circulating filarial antigen assays, PCR), approaches to treatment based on infection status can be considered.
Diethylcarbamazine [(DEC), 6 mg/kg daily for 12 days], which has both macro- and microfilaricidal properties, remains the drug of choice for the treatment of active lymphatic filariasis (defined by microfilaremia, antigen positivity, or adult worms on ultrasound), although albendazole (400 mg twice daily for 21 days) has also demonstrated macrofilaricidal efficacy. A 4- to 6-week course of doxycycline (targeting the intracellular Wolbachia) also has significant macrofilaricidal activity, as has DEC/albendazole used daily for 7 days. The addition of DEC to a 3-week course of doxycycline has recently been shown to be efficacious in lymphatic filariasis.
Regimens that combine single doses of albendazole (400 mg) with either DEC (6 mg/kg) or ivermectin (200 μg/kg) all have a sustained microfilaricidal effect and are the mainstay of programs for the eradication of lymphatic filariasis in Africa (albendazole/ivermectin) and elsewhere (albendazole/DEC) (see “Prevention and Control,” below).
As has already been mentioned, a growing body of evidence indicates that, although they may be asymptomatic, virtually all persons with W. bancrofti or B. malayi microfilaremia have some degree of subclinical disease (hematuria, proteinuria, abnormalities on lymphoscintigraphy). Thus, early treatment of asymptomatic persons is recommended to prevent further lymphatic damage. For ADL, supportive treatment (including the administration of antipyretics and analgesics) is recommended, as is antibiotic therapy if secondary bacterial infection is likely. Similarly, because lymphatic disease is associated with the presence of adult worms, treatment with DEC is recommended for microfilaria-negative carriers of adult worms.
In persons with chronic manifestations of lymphatic filariasis, treatment regimens that emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy have gained wide acceptance for morbidity control. These regimens are similar to those recommended for lymphedema of most nonfilarial causes and known by a variety of names, including complex decongestive physiotherapy and complex lymphedema therapy. Hydroceles (Fig. 218-1) can be managed surgically. With chronic manifestations of lymphatic filariasis, drug treatment should be reserved for individuals with evidence of active infection.
Side effects of DEC treatment include fever, chills, arthralgias, headaches, nausea, and vomiting. Both the development and the severity of these reactions are directly related to the number of microfilariae circulating in the bloodstream. The adverse reactions may represent either an acute hypersensitivity reaction to the antigens being released by dead and dying parasites or an inflammatory reaction induced by the intracellular Wolbachia endosymbionts freed from their intracellular niche.
Ivermectin has a side effect profile similar to that of DEC when used in lymphatic filariasis. In patients infected with L. loa, who have high levels of Loa microfilaremia, DEC—like ivermectin (see “Loiasis,” below)—can elicit severe encephalopathic complications. When used in single-dose regimens for the treatment of lymphatic filariasis, albendazole is associated with relatively few side effects.
To protect themselves against filarial infection, individuals must avoid contact with infected mosquitoes by using personal protective measures including bed nets, particularly those impregnated with insecticides such as permethrin. Community-based intervention is the current approach to elimination of lymphatic filariasis as a public health problem. The underlying tenet of this approach is that mass annual distribution of antimicrofilarial chemotherapy—albendazole with either DEC (for all areas except those where onchocerciasis is coendemic; see section on onchocerciasis treatment, below) or ivermectin—will profoundly suppress microfilaremia. If the suppression is sustained, then transmission can be interrupted.
Created by the World Health Organization in 1997, the Global Programme to Eliminate Lymphatic Filariasis is based on mass administration of single annual doses of DEC plus albendazole in non-African regions and of albendazole plus ivermectin in Africa. Available information at the end of 2008 indicated that >695 million persons in 51 countries had thus far participated. Not only has lymphatic filariasis been eliminated in some defined areas, but collateral benefits—avoidance of disability and treatment of intestinal helminths and other conditions (e.g., scabies and louse infestation)—have also been noted. The strategy of the global program is being refined, and attempts are being made to integrate this effort with other mass-treatment strategies (e.g., deworming programs, malaria control, and trachoma control).