Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Filariasis is caused by nematodes (roundworms) that inhabit the lymphatics and subcutaneous tissues. Three filarial species cause lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Infections are transmitted by mosquito vectors; humans are definitive hosts. Lymphatic filariasis is a major cause of disfigurement and disability in endemic areas, leading to significant economic and psychosocial impact.

The epidemiology, clinical manifestations, and diagnosis of lymphatic filariasis will be reviewed here. The treatment and prevention of lymphatic filariasis (and other filarial infections, including onchocerciasis, loiasis, and mansonellosis) are discussed separately. (See "Lymphatic filariasis: Treatment and prevention" and "Onchocerciasis" and "Loiasis (Loa loa infection)" and "Mansonella infections".)

EPIDEMIOLOGY

Global distribution — W. bancrofti occurs in sub-Saharan Africa, Southeast Asia, the Indian subcontinent, many of the Pacific islands, and focal areas of Latin America and the Caribbean (including Haiti). B. malayi occurs mainly in China, India, Malaysia, the Philippines, Indonesia, and various Pacific islands. B. timori occurs on the Timor Island of Indonesia (figure 1). The WHO maintains an online map depicting the global distribution.

Overall, approximately two-thirds of individuals infected with lymphatic filariasis are in Asia. The epidemiology of lymphatic filariasis is changing due to implementation of a global program of mass drug administration (MDA) to eliminate transmission. Not only has mapping of disease prevalence prior to MDA led to reclassification of some countries (Costa Rica, Suriname, Trinidad and Tobago) as nonendemic, but more than 25 countries have been able to stop MDA due to interruption of transmission and some (Togo, Malawi, Egypt, Yemen, Cambodia, Sri Lanka, Thailand, the Cook Islands, Kiribati, the Marshall Islands, Maldives, Niue, Palau, Tonga, Vanuatu, Vietnam, Wallis and Fortuna, and most recently, Bangladesh) appear to have eliminated transmission entirely [1].

Despite a substantial decrease in cases of lymphatic filariasis worldwide between 2000 and 2018 (from an estimated 199 million to approximately 50 million) [2], infection rates remain high in endemic areas that have not yet implemented MDA. Interruptions and delays in MDA in the context of the coronavirus disease 2019 pandemic have been reported [3] and are likely to further compromise elimination efforts [4]. Finally, residual hotspots of transmission have been identified in several countries, including American Samoa [5] and Ghana [6], after presumed interruption of transmission and cessation of MDA.

Although lymphatic filariasis can be acquired by long-term travelers to endemic areas, this is uncommon. A survey by the GeoSentinel network identified 67 cases of lymphatic filariasis among 43,722 medical encounters of which only 18 were in temporary visitors to endemic areas [7]. The relative infrequency of lymphatic filariasis in travelers has been confirmed in other studies, including a recent 25-year retrospective analysis of patients seen at the Institute for Tropical Medicine in Antwerp, in which lymphatic filariasis was diagnosed in only six patients, of which four were European travelers to endemic areas [8].

More than 90 percent of cases of lymphatic filariasis are due to W. bancrofti, while the remainder is due largely to B. malayi. Estimates suggest that as many as 36 million infected individuals are seriously incapacitated and disfigured by lymphatic filariasis [9]. Moreover, the chronic disability persists even after transmission has been eliminated in the region [10]. One study in India noted that patients with chronic filariasis lose around 29 days of work per year due to complications of infection, highlighting the considerable burden the disease places on individuals and on the community [11]. Another study reported an estimated productivity loss due to lymphatic filariasis of 77 to 100 percent during attacks of acute dermatolymphangioadenitis, 10 to 26 percent for lymphedema, and 15 to 19 percent for hydrocele [12]. In addition, data suggest that the prevalence of depressive illness is high, accounting for an estimated 5.09 million disability-adjusted life years (DALYs) [13].

Lymphatic filariasis is likely first acquired in childhood; it has been suggested that as many as one-third of children are asymptomatically infected before age five [14]. The risk of infection in childhood may be related to the maternal immune response during pregnancy. In one study of 159 Kenyan pregnant women with active Wuchereria infection, neonates lacking filarial-specific T cell responses in cord blood at birth had a 13-fold increased risk of developing childhood infection (compared with uninfected controls) [15].

Humans are the only hosts for Bancroftian filariasis; this is an important epidemiologic distinction for goals to suppress and eradicate lymphatic filariasis. In contrast, Brugian filariasis infects humans as well as domestic and wild animals.

Prevalence — The prevalence of microfilaremia in endemic communities increases with age. In endemic areas, most individuals have been exposed by the third or fourth decade of life. The burden of infection with adult worms increases with exposure over time. The adult worm does not replicate within the human host. Therefore, if an individual leaves an endemic area, the adult worm burden cannot increase since exposure to infective larvae has ceased. Mosquito vectors are relatively inefficient transmission vectors of filariasis; therefore, a relatively prolonged stay in an endemic area is usually required for acquisition of infection.

Vectors and life cycle — The mosquito vectors for filariasis vary geographically. Mosquito vectors for Wuchereria include Culex, Anopheles, Aedes, Mansonia, and Coquillitidea; vectors for Brugia are typically Mansonia and Aedes. Both urban and rural transmission of disease occurs. In many tropical and subtropical areas, the prevalence of infection is increasing due to progressive urbanization and increased breeding sites for mosquito vectors.

The life cycle of filariasis begins with introduction of third-stage filarial larvae onto human skin by a mosquito during a blood meal; subsequently, larvae migrate through the bite wound and enter local lymphatic vessels. Over a period of approximately nine months, these larvae develop into mature adult worms (figure 2 and figure 3). Female Wuchereria worms measure 80 to 100 mm in length and 0.24 to 0.30 mm in diameter, and the males measure about 40 mm by 0.1 mm. Female Brugia worms measure 43 to 55 mm in length by 130 to 170 microns in width, and males measure 13 to 23 mm in length by 70 to 80 microns in width.

The adults survive for approximately five years (occasionally up to 12 to 15 years). Male and female worms mate and produce sheathed microfilariae. Wuchereria microfilariae are 244 to 296 microns by 7.5 to 10 microns; Brugia microfilariae are 177 to 230 microns in length and 5 to 7 microns in width. The microfilariae migrate into lymph and enter the blood stream. A mosquito ingests the microfilariae during a blood meal. In the mosquito, the microfilariae develop into third-stage larvae, which can infect another human when the mosquito takes a blood meal, completing the life cycle.

In most of the world, microfilariae are present in the bloodstream only during the evening hours, with peak numbers between approximately 10 pm and 2 am ("nocturnal periodicity"). In the South Pacific, W. bancrofti microfilariae are "subperiodic" (ie, always present in the blood with increased numbers at midday). The periodicity of the microfilariae corresponds to that of the vectors in the different regions.

The interval between acquisition of infective larvae from a mosquito bite and detection of microfilariae in the blood is the prepatent period. In general, this interval is approximately 12 months in duration.

PATHOGENESIS — The pathogenesis and clinical progression of filarial disease is likely influenced by a number of factors, including the extent and duration of exposure to infective insect bites, the quantity of accumulating adult worm antigen in the lymphatics, the host immune response, and the number of secondary bacterial and fungal infections [16-18].

Host immune response — Clinical presentations among exposed individuals depend on several factors, including the host immune response [19,20]; individual variations in immune responses are, in turn, related to host and parasite factors. These include the timing of first exposure to parasites, the specific filarial pathogen involved, the intensity of exposure to infected mosquitoes, prenatal sensitization [21], and other as yet uncharacterized host characteristics [22]. Genetic factors likely influence susceptibility to lymphedema as well as the presence and intensity of microfilaremia [23-26]. Paradoxically, clinical symptoms of lymphedema are often most severe among individuals without detectable microfilaremia, whereas infected individuals with detectable circulating microfilariae are most often asymptomatic [27,28].

Early in infection, filarial antigens provoke Th2-type immune responses, leading to production of cytokines, including interleukins 4, 5 and 13, and resulting in increased levels of eosinophils, immunoglobulin (Ig)E and IgG4. Whether this response is predominantly protective or pathogenic remains controversial [29]. Later in infection, immune responses to parasite antigens are downmodulated with suppression of T lymphocyte proliferation and impaired Th1 and Th2 cytokine production, likely contributing to the chronicity of infection [27]. This immunosuppression is particularly marked in individuals with detectable circulating microfilariae [30] and involves defects in antigen-presenting cell function and increased T regulatory cell numbers and activity. Effects on immune responses to concomitant infections and vaccine responses to irrelevant antigens have also been observed [31,32].

Living adult worms in the lymphatics can cause mechanical pathology but do not typically induce an inflammatory response [33]. They may be responsible for the subclinical lymphangiectasia and lymphatic dilatation, both of which can be seen early in infection [34].

Wolbachia — It has been recognized that the lymphatic filarial parasites contain endosymbiotic bacteria Wolbachia [35]. These are Rickettsia-like organisms that appear to be required for homeostasis of the host parasite.

Some of the inflammatory manifestations of lymphatic filariasis that result in progression of clinical disease are likely attributable to immune responses directed at Wolbachia [23,36,37]. Soluble extracts of many filarial species stimulate innate inflammatory responses, which are absent or reduced if the bacteria are absent or have been cleared with antibiotics [38]. In addition, acute and severe inflammatory responses have been observed in individuals with Brugia malayi infection when Wolbachia are released into the blood following death or damage of the worms after antifilarial chemotherapy [39,40].

CLINICAL MANIFESTATIONS — Lymphatic filariasis can be asymptomatic (subclinical) or associated with acute and/or chronic clinical manifestations, including adenolymphangitis, filarial fevers, hydrocele, chronic lymphatic disease, and tropical pulmonary eosinophilia. Most infected residents of endemic areas are asymptomatic. However, subclinical manifestations can be demonstrated in many infected individuals; these include lymphatic dilatation, abnormalities in lymphatic drainage (demonstrable by lymphoscintigraphy), scrotal lymphangiectasia (observed on ultrasound), and microscopic hematuria and/or proteinuria [41]. Nonetheless, estimates suggest that only about one-third of infected individuals in endemic areas will develop clinical manifestations [27]. Travelers to endemic areas rarely develop chronic clinical manifestations but may present with acute symptoms. (See 'Travelers and expatriates' below.)

Eosinophilia is common and may exceed 3000/microL, although the precise frequency of eosinophilia due to filariasis is difficult to determine since other helminth infections frequently coexist among individuals in endemic areas [42]. Other nonspecific laboratory findings include elevated serum immunoglobulin (Ig)E levels and microscopic hematuria and proteinuria. (See 'Renal involvement' below.)

In one large cohort study of HIV infection in Tanzania, the risk of acquiring HIV was increased more than twofold in individuals with lymphatic filariasis (as defined by antigen positivity) [31]. Subsequent data from the same group suggest that this effect is amplified in patients with detectable blood microfilariae [32].

Acute manifestations — Acute manifestations of lymphatic filariasis include acute adenolymphangitis, dermatolymphangioadenitis, filarial fever, and tropical pulmonary eosinophilia.

Acute adenolymphangitis (ADL) — Acute ADL characteristically presents with sudden onset of fever and painful lymphadenopathy. Retrograde lymphangitis (spread of inflammation distally from the lymph node) is frequently observed. ADL is believed to occur because of immune-mediated responses to dying adult worms.

A variety of anatomic sites may be involved; the inguinal lymph nodes and lower extremities are commonly involved sites. In general, acute inflammation tends to resolve after four to seven days. Recurrences typically occur one to four times per year; the number of recurrent events increases with increasing severity of lymphedema [43,44]. In Brugian filariasis, a single focal abscess may form along the inflamed lymphatics and ulcerate.

Acute lymphatic disease can also involve the genitalia; this is the most common manifestation in males with Bancroftian filariasis. Typical symptoms include painful epididymitis associated with fever and malaise.

Acute dermatolymphangioadenitis (DLA) — Acute DLA is a form of acute filarial disease that occurs in endemic areas. Characterized by edematous inflammatory plaques and systemic symptoms (fever, chills, myalgia, headache), DLA is thought to be caused by superficial bacterial infection of damaged skin [45]. A history of local trauma and/or entry lesions, especially in the interdigital area, is common [46], and recurrent episodes have been associated with progression of lymphedema.

Filarial fever — Filarial fever is characterized by acute, self-limited episodes of fever, often in the absence of lymphangitis or lymphadenopathy. Filarial fever may be confused with other causes of fever in the tropics, such as malaria.

Tropical pulmonary eosinophilia — Tropical pulmonary eosinophilia is caused by an immune hyperresponsiveness to microfilariae trapped in the lungs and is characterized by nocturnal wheezing. (See "Tropical pulmonary eosinophilia".)

Chronic manifestations — Chronic manifestations of lymphatic filariasis include lymphedema, hydrocele, and renal involvement.

Lymphedema — Lymphedema refers to limb swelling related to chronic inflammation of the lymphatic vessels; it is a common late sequela of filarial infection (picture 1). Involvement of inguinal lymph vessels leads to swelling of the lower limb(s). Involvement of axillary lymph nodes leads to swelling of the upper limb(s); in women, involvement of the breast can also occur. Early in the course of disease, pitting edema develops. Chronic inflammation leads to brawny nonpitting edema and hardening of the tissues, resulting in hyperpigmentation and hyperkeratosis. Severe lymphedema is sometimes referred to as elephantiasis. In Brugian infections, lymphedema is typically restricted to the distal extremities (below the knee or elbow), and genital involvement has not been reported in Brugian filariasis except in areas coendemic for W. bancrofti [47]. (See "Clinical features and diagnosis of peripheral lymphedema".)

Chronic lymphatic disease can also involve the genitalia, resulting in the development of unilateral or bilateral hydrocele(s). Hydroceles can be large (up to or greater than 30 cm in diameter); they are usually painless unless complicated by bacterial infection. Localization of adult worms in the lymphatics of the spermatic cord can lead to palpable thickening of the cord. Lymphatic filariasis of the ovary and mesosalpinx [48] and of the vulva [49] have also been reported.

The differential diagnosis of lymphedema includes malignancy, tuberculosis (and other infectious conditions associated with marked lymphadenopathy), recurrent cellulitis, and primary lymphedema. In patients from the tropics, podoconiosis must also be considered; it is an abnormal inflammatory reaction to mineral particles in certain soils that can result in lymphedema and elephantiasis. Podoconiosis occurs at altitudes higher than those at which mosquitoes can transmit filarial infection (a maximum of about 1500 meters, or 4920 feet) [50]. Loiasis and onchocerciasis can also rarely be associated with lymphedema.

Renal involvement — Intestinal lymph may be intermittently discharged into the renal pelvis, causing lymph fluid to be passed in the urine. This is known as chyluria, and it results in a milky appearance to the urine (picture 2) [51]. Since large amounts of fat and protein can be lost in the urine in individuals with chyluria, this condition can lead to nutritional deficiencies, including anemia and hypoproteinemia.

Individuals with Bancroftian filariasis, especially those who have detectable microfilaremia, can also develop hematuria and proteinuria [52]. The underlying etiology and long-term significance of this finding remain unclear. It may be caused by an immune complex nephritis, but this has not been confirmed.

Travelers and expatriates — While travelers and expatriates usually have insufficient exposure to filariasis to develop the chronic complications of infection observed with high worm burdens, rare cases of recurrent or chronic symptoms have been described [53]. Conversely, these individuals may demonstrate a hypersensitivity reaction to developing larvae, a clinical manifestation that rarely occurs among individuals in endemic areas. This is characterized by a local eosinophilic infiltrate with lymphangitis and lymphadenitis, urticaria, rash, and a peripheral eosinophilia.

DIAGNOSIS — A diagnosis of lymphatic filariasis should be suspected in individuals with relevant epidemiologic exposure who present with typical acute manifestations (fever, acute adenolymphangitis, acute dermatolymphangioadenitis, eosinophilia) or chronic manifestations (lymphedema, chyluria, hydrocele). (See 'Clinical manifestations' above.)

However, symptoms of chronic disease can be subtle, and some affected individuals may be embarrassed to report symptoms due to social stigmata. One study examining case detection strategies in Liberia found that enhanced training of health care workers in the signs of early disease and communication with potentially infected individuals greatly increased the number of cases identified [54].

Definitive diagnosis of lymphatic filariasis can be established by detection of circulating filarial antigen (for W. bancrofti infection only), demonstration of microfilariae or filarial DNA in the blood, or of adult worms in the lymphatics. Rarely, microfilariae and/or adult worms are identified incidentally in tissue biopsies or cytological specimens [55]. Peripheral blood eosinophilia is common and may exceed 3000/microL. The frequency of eosinophilia due to filariasis is difficult to determine since other helminth infections frequently coexist among individuals in endemic areas [42]. Other nonspecific laboratory findings include elevated serum immunoglobulin (Ig)E, microscopic hematuria, and proteinuria. (See 'Renal involvement' above.)

Circulating antigen detection — Circulating filarial antigen (CFA) assays have been developed for diagnosis of W. bancrofti infections but are not yet available for Brugian filariasis. These tests detect antigens released by adult filarial worms, so they may be positive even in amicrofilaremic individuals [56]. In addition, antigen levels remain stable during the day and night, so these tests can be performed at any time.

Commercially available CFA tests for specific detection of W. bancrofti include an Og4C3 monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA), which gives a quantitative result that correlates with adult worm burden (TropBio ELISA) [57], and immunochromatographic technique (ICT) tests available through the World Health Organization (WHO): a card-based assay (BinaxNOW Filariasis ICT) that provides qualitative or semi-quantitative results [58,59] and a test strip (Alere Filariasis Test Strip) [60] that provides qualitative results but appears to be more sensitive than the ICT card test. All of these assays have better sensitivity than microscopy for diagnosis of lymphatic filariasis [61,62].

In one study of 282 microfilaremic individuals in Brazil, the sensitivity of the Og4C3 at microfilarial densities of <1, 1 to 30, and >30 microfilariae per mL of blood was 72, 98, and 100 percent, respectively [63]. Among individuals with ultrasound or biopsy evidence of infection and no detectable microfilariae, 67 percent had a positive test. In another study of 674 individuals from rural areas of Papua New Guinea, the Og4C3 CFA test detected twice as many cases as blood smear evaluation [64].

False-positive W. bancrofti antigen test results are common in patients with large numbers of circulating Loa loa microfilariae [65,66]. In addition, a negative antigen test cannot exclude filarial infection as a cause of chronic pathology since filarial antigens eventually become undetectable in treated or "burned out" infection, even in the setting of lymphatic damage. Although the quantitative Og4C3 ELISA may be of some use in following patients after treatment since antigen levels typically decline with treatment [62,67,68], it remains unclear whether a persistently positive antigen test should prompt additional therapy.

Blood smears — Examination of blood smears for microfilariae should be performed in all individuals in whom the diagnosis of filariasis is suspected, if circulating antigen testing is not available or Brugian filariasis is a consideration based on the exposure history.

Both Bancroftian and Brugian filariasis tend to demonstrate nocturnal periodicity; the greatest number of microfilariae can be found in blood between 10:00 PM and 2:00 AM, which is the peak biting time of the mosquito vectors. Thus, ideally, blood should be drawn during this window. In the South Pacific, W. bancrofti microfilariae may be present even during daytime hours (subperiodic) [69]; there are also some subperiodic variants of Brugian filariasis [70].

Microfilariae stain with Wright or Giemsa stains. Microfilarial levels in infected individuals from endemic areas can exceed 10,000 microfilariae per mL of blood, although lower levels are more common. As a result, infection may be missed on a routine thick smear, which typically contains approximately 20 microL of blood. Concentration techniques, including Nuclepore filtration and Knott's concentration (sedimentation in 2 percent formalin), are more sensitive as they facilitate examination of larger quantities of blood [71].

The three filarial species that cause lymphatic filariasis can be differentiated from each other and from other filarial nematodes by their morphologic characteristics (picture 3 and picture 4 and picture 5). W. bancrofti and both Brugia species have an acellular sheath that stains and is visible on light microscopy. B. malayi has terminal and subterminal nuclei in its tail; W. bancrofti has no nuclei in its tail.

Polymerase chain reaction — Species-specific polymerase chain reaction techniques have been used as research tools to detect filarial infection in humans and to assess prevalence of microfilarial infection among mosquitoes, although they are not commercially available [72,73].

Antifilarial antibody tests — Serologic tests for filarial antibodies that detect elevated levels of IgG and IgG4 are available from the Laboratory of Parasitic Diseases at the National Institutes of Health (301-496-5398), the United States Centers for Disease Control and Prevention (404-718-4100), and several commercial laboratories. Most of these assays are based on crude antigen mixtures; therefore, they do not differentiate between the various types of filarial infections and often cross-react with antigens from other helminths. Furthermore, since antibody tests cannot distinguish between active infection and past infection or exposure, they are useful primarily in detecting infection in travelers from nonendemic areas and have little predictive value in long-term residents of endemic areas. Although a negative test can help exclude recent infection, patients with chronic manifestations of lymphatic filariasis can become antibody negative over time.

Several assays based on recombinant antigens appear to have enhanced specificity [74]. These include three rapid IgG4 antibody detection tests: (1) BRUGIArapid, which is specific for the Brugia antigen BmR1, (2) PanLF Rapid, which combines Brugia Rapid with a test for BmSXP that detects infection with both Brugia species and W. bancrofti, and (3) SD Bioline Onchocerciasis/LF IgG4 Rapid Test, which combines IgG4 antibody detection tests for Wb123 and Ov16, sensitive and specific markers of early infection with W. bancrofti and Onchocerca volvulus, respectively [75].

Imaging — Ultrasound and lymphoscintigraphic techniques can be used to detect the presence of adult worms in lymphatic vessels. Living worms tend to be in continuous motion, which can be detected on ultrasound; this has been described as the "filarial dance" sign. Lymphatics containing worms can be distinguished from blood vessels by irregular movement on Doppler evaluation (movie 1) [76]. In some cases, worms can be visualized in the breast lymphatics [77]. Detection of motion on ultrasound has also been used to monitor the effectiveness of therapy [78,79]. Calcified (dead) worms are sometimes identified on routine mammography and can be confused with malignancy [80].

Previously, contrast lymphangiography was used to visualize lymphatic vessels. However, this procedure can damage vessels, so it has largely been replaced by lymphoscintigraphy. Lymphoscintigraphy is a useful tool for assessing the extent of lymphatic damage [41]. Adult worms may be directly visible within the lymphatics, and massive lymphatic dilation may be observed surrounding and beyond the adult worms. Lymphatic abnormalities can be detected by lymphoscintigraphy early in disease prior to the development of clinical symptoms. More recently, studies in Bangladesh using infrared imaging suggest that this modality may be useful as a noninvasive point-of-care tool for the detection of subclinical lymphedema in areas endemic for lymphatic filariasis [81].

Evaluating for coinfection — In patients from areas where onchocerciasis or loiasis is endemic (figure 1), evaluation for these infections should be pursued prior to treatment [82]. Administration of diethylcarbamazine (DEC) for treatment of lymphatic filariasis can provoke a severe inflammatory reaction in patients with onchocerciasis. Potentially fatal encephalopathy has been reported following DEC or ivermectin administration in patients coinfected with L. loa who have high microfilarial loads. (See "Lymphatic filariasis: Treatment and prevention", section on 'Diethylcarbamazine' and "Onchocerciasis", section on 'Loa loa coinfection' and "Loiasis (Loa loa infection)", section on 'Other tests'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of lymphatic filariasis includes:

●Loiasis – Loiasis is a parasitic infection caused by the filarial nematode L. loa. Clinical manifestations include transient localized subcutaneous swellings (known as Calabar swellings) and migration of the worm across the subconjunctiva of the eye. Calabar swellings involving the distal limbs can persist for months. False-positive antigen tests for W. bancrofti in the setting of L. loa microfilaremia may complicate the diagnosis of occult W. bancrofti in coinfected patients [65,83,84]. The diagnosis is established by identifying a migrating adult worm in the subcutaneous tissue or conjunctiva or by detecting microfilariae in a blood smear. (See "Loiasis (Loa loa infection)".)

●Onchocerciasis – Onchocerciasis is a parasitic infection caused by the filarial nematode Onchocerca volvulus. Clinical manifestations of onchocerciasis include eye involvement, subcutaneous nodules, skin involvement, and systemic manifestations. A manifestation of skin disease includes "hanging groin," which occurs as result of atrophy affecting the skin of the groin and anterior thigh. Inguinal lymph nodes enlarge in a sling of atrophic skin on the medial thigh; as the nodes shrink and become fibrotic, they leave redundant folds of loose skin. (See "Onchocerciasis".)

●Lymphedema – The differential diagnosis of lymphedema includes malignancy, tuberculosis, recurrent cellulitis, podoconiosis, and primary lymphedema. The approach to lymphedema is discussed further separately. (See "Clinical features and diagnosis of peripheral lymphedema".)

●Bacterial lymphangitis – Bacterial lymphangitis generally develops in the setting of streptococcal or staphylococcal infection. It consists of erythematous, tender streaks extending proximally with involvement of regional lymph nodes, whereas filarial lymphangitis occurs in a retrograde progression with distal spread away from lymph nodes (where the parasites reside). (See "Lymphangitis".)

●Nonfilarial hydrocele – A hydrocele is a collection of fluid between the parietal and visceral layers of the tunica vaginalis, the tissue layer that surrounds the testis and spermatic cord (figure 4). Chronic lymphatic disease due to filariasis can be associated with unilateral or bilateral hydrocele; in some cases, these can be very large. Filarial hydrocele is clinically indistinguishable from nonfilarial hydrocele, especially in the early stages.

SUMMARY

●Filariasis is caused by nematodes (roundworms) that inhabit the lymphatics and subcutaneous tissues. Three species cause lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Infection is transmitted by mosquito vectors; humans are definitive hosts. Lymphatic filariasis is a major cause of disfigurement and disability in endemic areas, leading to significant economic and psychosocial impact. (See 'Introduction' above.)

●W. bancrofti occurs in sub-Saharan Africa, Southeast Asia, the Indian subcontinent, many of the Pacific islands, and focal areas of Latin America. B. malayi occurs mainly in China, India, Malaysia, the Philippines, Indonesia, and various Pacific islands. B. timori occurs on the Timor Island of Indonesia. Despite the success of mass drug administration programs in reducing transmission in many endemic areas, the worldwide prevalence of infection in 2018 was estimated to be more than 50 million people. More than 90 percent of these infections are due to W. bancrofti; most of the remainder is due to B. malayi. Acquisition of infection by travelers is rare. (See 'Epidemiology' above.)

●The life cycle of filariasis begins with introduction of larvae onto human skin by a mosquito during a blood meal; these gain entry via the bite wound and enter local lymphatic vessels (figure 2 and figure 3). The larvae develop into mature adult worms, which mate and produce sheathed microfilariae with nocturnal periodicity. A mosquito ingests the microfilariae during a blood meal; these develop into larvae, which can infect another human when the mosquito takes a subsequent blood meal, completing the life cycle. (See 'Vectors and life cycle' above.)

●The pathogenesis and clinical progression of filarial disease is likely influenced by several factors, including the extent and duration of exposure to infective insect bites, the quantity of accumulating adult worm antigen in the lymphatics, the host immune response, and the number of secondary bacterial and fungal infections. (See 'Pathogenesis' above.)

●In endemic areas, acute manifestations of lymphatic filariasis include acute adenolymphangitis, acute dermatolymphangioadenitis, filarial fever, and tropical pulmonary eosinophilia. Chronic manifestations of lymphatic filariasis include lymphedema, hydrocele, and renal involvement. Depression is common in the setting of chronic lymphedema. (See 'Clinical manifestations' above.)

●While travelers and expatriates usually have insufficient exposure to filariasis to develop the chronic complications of infection observed with high worm burdens, rare cases of recurrent or chronic symptoms have been described. Conversely, these individuals may demonstrate a hypersensitivity reaction to developing larvae, which rarely occurs among individuals in endemic areas. This is characterized by a local eosinophilic infiltrate with lymphangitis and lymphadenitis, urticaria, rash, and a peripheral eosinophilia. (See 'Travelers and expatriates' above.)

●The diagnosis of lymphatic filariasis is based upon clinical and epidemiologic clues together with laboratory evaluation. The best laboratory tool for diagnosis of W. bancrofti infection is antigen testing, although false positives may occur in patients with Loa loa; examination of blood smears is a less sensitive but acceptable alternative in settings where antigen testing is not available. Definitive diagnosis of Brugian filariasis requires blood smear examination; serology can be helpful in appropriate clinical settings. Ultrasound can also be a useful diagnostic tool. Eosinophilia is common and may exceed 3000/microL. (See 'Diagnosis' above.)

●W. bancrofti, B. malayi, and B. timori can be differentiated from each other and from other filarial nematodes on blood smear by their morphologic characteristics (picture 3 and picture 4 and picture 5). W. bancrofti and both Brugia species have acellular sheath stains and are visible on light microscopy. B. malayi has terminal and subterminal nuclei in its tail; W. bancrofti has no nuclei in its tail. (See 'Blood smears' above.)

●In patients who have resided in areas where onchocerciasis or loiasis is endemic (figure 1), evaluation for these infections should be pursued prior to treatment. Administration of diethylcarbamazine (DEC) for treatment of lymphatic filariasis in the setting of onchocerciasis or loiasis coinfection can induce severe inflammatory reactions. (See 'Evaluating for coinfection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Karin Leder, who contributed to earlier versions of this topic review.