What is Filariasis

Filariasis refers to parasitic infection caused by filarial parasites or nematodes (roundworms) of the family Filariidae transmitted to humans by blood-sucking insects, such as mosquitoes, blackflies, or midges, acting as biological vectors ¹, ², ³, ⁴, ⁵. Filarial infection is transmitted through the bite of an infected insect as it feeds upon human blood ⁶. Thereafter, parasite larvae mature into adult forms within the host. These adult parasites then multiply, producing microfilariae, which are subsequently ingested by blood-sucking insects along with human blood. These microfilariae undergo subsequent stages of development within the insect’s bodies (see Lymphatic Filariasis Life Cycle below) ⁷, ⁸, ⁹. Of the hundreds of described filarial parasites, only 8 species cause natural infections in humans ¹⁰:

• Onchocerca volvulus causing Onchocerciasis ¹¹, ¹²
• Wuchereria bancrofti causing Bancroftian filariasis (lymphatic filariasis)
• Brugia malayi causing Malayan filariasis (lymphatic filariasis) ¹³, ¹⁴
• Brugia timori causing Malayan filariasis (lymphatic filariasis) ¹³, ¹⁴
• Loa loa causing Loiasis ¹⁵, ¹⁶
• Mansonella species (Dipetalonema spp), Mansonella perstans (Dipetalonema perstans), and Mansonella streptocerca (Dipetalonema streptocerca) causing Mansonelliasis  ¹⁷, ¹⁸, ¹⁹, ²⁰
• Dirofilaria species causing Dirofilariasis ²¹, ²²

The location of these parasites within the human body varies from species to species. Filariasis affects a range of human tissues and often display little or no observable host response throughout their development ²³, ²⁴. An exception occurs when the parasite enters extremely sensitive tissues, such as the conjunctiva ²⁵.

Filariasis can be classified based on the location of the parasite within the human host’s body ⁵, ²⁵, ²⁶, ²⁷:

• Lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, Brugia timori;
• Subcutaneous filariasis: Loa loa, Onchocerca volvulus;
• Serous cavity filariasis: Mansonella spp.

Filariasis signs and symptoms and treatment of filariasis depends on the type of filarial parasitic worm (nematode) infection you have.

Lymphatic filariasis commonly known as elephantiasis is caused by at least three species of nematodes (roundworms) that include Wuchereria bancrofti, Brugia malayi, and Brugia timori, which are transmitted between definitive human hosts by multiple mosquito vectors that include Aedes, Anopheles, Culex, Mansonia, and Ochlerotatus mosquitoes that have varying geographical distributions ²⁸. An estimated 90% of lymphatic filariasis cases are caused by Wuchereria bancrofti also known as Bancroftian filariasis, which are mostly acquired in childhood ²⁹, ³⁰. Brugia malayi and Brugia timori cause about 10% of lymphatic filariasis. Anopheles, Aedes, Culex and Mansonia mosquitoes are the main vectors responsible for filarial parasites transmission to humans. Mosquitoes serve as biological hosts that both develop and transmit the parasite during blood-feeding and establish the infection in humans. People get lymphatic filariasis when bitten by an infectious mosquito carrying the parasite. For the mosquito to become infectious, they must bite, or take a blood meal, from a person already infected with the parasite. About a week or so later, that same mosquito will bite the next person and the parasite may enter through the body through the person’s skin. And the cycle of infection continues (see Lymphatic Filariasis Life Cycle below). Once inside your body, the immature worms make their home in the person’s lymphatic system. They can live for 5 – 7 years there, eventually damaging the lymphatic vessels. In lymphatic filariasis, repeated episodes of inflammation and lymphedema (a chronic swelling of body tissues caused by a problem with the lymphatic system) lead to lymphatic damage, chronic swelling, and elephantiasis of the legs, arms, scrotum, vulva, and breasts ³¹, ³², ³³, ³⁴, ³⁵, ³⁶.

All filarial infections cause some type of skin problems in addition to systemic (affecting the whole body) signs and symptoms. In filariasis or filarial parasite infection, often acquired in childhood, can lead to damage to the lymphatic system, causing lymphedema (a chronic swelling of body tissues caused by a problem with the lymphatic system), fever, pain, and disfigurement, especially in the limbs (elephantiasis) and scrotal swelling or hydrocele (a fluid-filled sac that causes swelling in the scrotum, the pouch that holds the testicles) ²⁹. The legs are involved in most cases, but the lymphedema can also involve the genitals, arms, and breasts. While some filarial parasite infections are asymptomatic, they still cause internal damage and can lead to permanent disability. People affected by lymphatic filariasis are not only physically disabled, but suffer mental, social and financial losses contributing to stigma and poverty.

No form of human filariasis is currently endemic to the United States ³⁷. Wuchereria bancrofti once was prevalent in Charleston, South Carolina, because of the presence of suitable mosquito vectors. Immigrant populations and persons who have traveled long-term to the tropics are potential reservoirs of Wuchereria bancrofti infection. Returning missionaries and overseas workers/volunteers are at particular risk for lymphatic filariasis and onchocerciasis, because of the long pre-patent period and relatively high intensity of exposure required between exposure to infective insect bites and the development of sexually mature adult worms.

Lymphatic filariasis is common in tropical and subtropical regions with an estimated 120 million people in 81 countries being infected and a third of whom have overt clinical disease ³⁸, ³⁹, ⁴⁰. About one-third of those with filariasis reside in India, a third in Africa, and the remainder in the Americas, South-East Asia and the Pacific ⁴¹. It is difficult to estimate prevalence accurately, but according to antigenic studies, prevalence of lymphatic filariasis infection in India (the country with the greatest disease burden) is 5.66% ³⁸.

Filariasis signs and symptoms vary depending on the type of filarial infection, body location and can be acute or chronic in nature. Up to 70% of infected individuals remain asymptomatic. Symptoms usually do not manifest until adolescence or adulthood, when worm burden usually is the highest. Several symptomatic variations have been observed ⁴². Because cases of filariasis in North America and high-income countries are uncommon, physicians initially may miss the diagnosis in these areas. To avoid this pitfall, physicians should obtain and document a thorough travel history from patients with suspicious lesions.

The clinical course of lymphatic filariasis is broadly divided into the following:

• Asymptomatic microfilaremia – Patients with microfilaremia are generally asymptomatic, although those with heavy microfilarial loads may develop acute and chronic inflammatory granulomas secondary to splenic destruction. Passage of cloudy milklike urine may denote chyluria
• Acute phases of adenolymphangitis (ADL) – This refers to the sudden onset of febrile, painful lymphadenopathy. Pathologically, the lymph node is characterized by a retrograde lymphangitis, distinguishing it from bacterial lymphadenitis. Symptoms usually abate within 1 week, but recurrences are possible ⁴³. Signs and symptoms of adenolymphangitis (ADL) include episodic attacks of fever associated with inflammation of the inguinal lymph nodes, testis, and spermatic cord, as well as with lymphedema. Skin exfoliation of the affected body part usually occurs with resolution of an episode.
• Chronic, irreversible lymphedema and hydrocele
  • Lymphedema – the most common presentation that develops over a long period due to chronic lymphatic damage. It characteristically presents with swelling of the limbs either upper or lower depending on the involvement of inguinal or axillary lymphatic vessels. Pitting edema develops in the early stages of the disease, which later progresses into brawny non-pitting type. Elephantiasis is the most severe type of lymphedema characterized by severe swelling of the limbs, genitalia, and breasts. The skin becomes thick and hard, owing to hyperpigmentation and hyperkeratosis.
  • Hydrocele (a fluid-filled sac around a testicle that causes painless swelling of the scrotum) – this is one of the debilitating morbidities associated with chronic lymphatic filariasis. It can be unilateral or bilateral, leading to enlargement of the scrotum. It can be very large, reaching up to 40 cm.

The majority of filarial infections are asymptomatic, showing no external signs of infection while contributing to the transmission of the parasite. These asymptomatic infections still cause damage to the lymphatic system and the kidneys and alter your body’s immune system.

Lymphatic filariasis symptoms predominantly result from the presence of adult worms residing in the lymphatics. They include the following ⁴⁴:

• Fever
• Groin (inguinal) or armpit (axillary) swollen or enlarged lymph nodes (lymphadenopathy)
• Testicular and/or inguinal pain
• Skin exfoliation
• Limb or genital swelling. Repeated episodes of inflammation and lymphedema lead to lymphatic damage, chronic swelling, and elephantiasis of the legs, arms, scrotum (hydrocele), vulva, and breasts.

In general, the diagnostic approach varies by group of filariasis. Traditionally, the diagnosis of filariasis requires demonstrating microfilariae in the peripheral blood or skin. However, circulating filarial antigens (CFA) are now routinely used to diagnose Wuchereria bancrofti infection ⁴⁵. The microfilariae of all species that cause lymphatic filariasis and the microfilariae of Loa loa, Mansonella ozzardi, and Mansonella perstans can be detected on a blood smear ⁴⁶.

Microfilariae are detectable via examination of the following:

• Blood – The microfilariae of all species that cause lymphatic filariasis and the microfilariae of Loa loa, Mansonella ozzardi, and Mansonella perstans are detected in blood. Wuchereria bancrofti can be detected via circulating filarial antigen (CFA) assays. However, assays for circulating parasite antigen of Wuchereria bancrofti are not presently approved by the U.S. Food and Drug Administration (FDA). There are no antigen test for Brugia spp. Serologic enzyme immunoassay tests, including antifilarial IgG1 and IgG4, provide an alternative to microscopic detection of microfilariae for the diagnosis of lymphatic filariasis. Patients with active filarial infection typically have elevated levels of antifilarial IgG4 in the blood and these can be detected using routine assays.
• Urine – If lymphatic filariasis is suspected, urine should be examined macroscopically for chyluria and then concentrated to examine for microfilariae.
• Skin – Onchocerca volvulus and Mansonella streptocerca infections are diagnosed when microfilariae are detected in multiple skin-snip specimens taken from different sites.
• Eye – Microfilariae of Onchocerca volvulus may be detected in the cornea or anterior chamber of the eye using slit-lamp examination.

Useful imaging studies in the evaluation of filariasis include the following:

• Chest X-ray – Diffuse pulmonary infiltrates are visible in patients with tropical pulmonary eosinophilia (TPE)
• Ultrasound – Can be used to demonstrate and monitor lymphatic obstruction of the inguinal and scrotal lymphatics; has been used to demonstrate the presence of viable worms. Careful ultrasound may identify the random movement of adult worms in dilated lymphatics, known as the “filarial dance sign” (FDS). This is particularly useful in a patient with scrotal symptoms and is considered the gold standard investigation for detecting viable adult worms ⁴⁷.
• Lymphoscintigraphy – A nuclear medicine imaging test that maps the lymphatic system by tracking a radioactive tracer injected under the skin, helping to identify the sentinel lymph node in cancer patients or assess lymphatic drainage in conditions like lymphedema ⁴⁸

Histologic findings include the following:

• Lymphatic filariasis – Affected lymph nodes demonstrate fibrosis and lymphatic obstruction with the creation of collateral channels
• Elephantiasis – The skin is characterized by hyperkeratosis, acanthosis, lymph and fatty tissue, loss of elastin fibers, and fibrosis
• Onchocerciasis – Onchocercomas have a central stromal and granulomatous, inflammatory region where the adult worms are found and a peripheral, fibrous section; microfilariae in the skin incite a low-grade inflammatory reaction with loss of elasticity and fibrotic scarring.

Key clinical features that may assist in making a diagnosis of lymphatic filariasis include:

• History of residence in an endemic country for several years;
• Self-limiting nature of attacks, in contrast to bacterial cellulitis, incarcerated hernias or testicular torsion;
• Bilateral symptoms and signs;
• Recurrent episodes;
• Palpable regional masses or lymphadenopathy.

The diagnosis of symptomatic lymphatic filariasis requires strong clinical suspicion. Interestingly, many infected people remain asymptomatic. Risk factors for symptomatic disease include duration and intensity of exposure to vectors, adult worm burden, frequency of secondary infections and the host immune response ⁴⁹.

A blood film and serological evaluation are alternative diagnostic options. In most endemic areas, circulating microfilariae (filarial larvae) exhibit nocturnal periodicity (coinciding with peak feeding of local mosquitos) and are best seen on blood films taken between 10 pm and 4 am. If nocturnal samples are not feasible, then provocation with diethylcarbamazine may enhance microfilarial detection 1–2 hours later. Pacific Island infections (except Papua New Guinea) are subperiodic, with maximal microfilaraemia in the late afternoon, and show unresponsiveness to provocation. Importantly, patients with the chronic manifestations of lymphatic filariasis often have low levels of circulating microfilariae, resulting in lower blood-film sensitivity ⁵⁰.

Diethylcarbamazine citrate (DEC) remains the mainstay of filariasis treatment worldwide, which kills both immature and adult parasitic worms ²⁹. The United States Centers for Disease Control and Prevention (CDC) recommends a single-day or 12-day course of diethylcarbamazine (DEC) at 6 mg/kg/day ⁵¹, ²⁹.

The most common side effects of diethylcarbamazine (DEC) include ⁵¹:

• Dizziness
• Nausea
• Fever
• Headache
• Pain in muscles or joints

Diethylcarbamazine (DEC) has been used globally for more than 50 years. A single combined dose of ivermectin, albendazole, and diethylcarbamazine (DEC) resulted in clearance of microfilaria in 96% of affected patients for up to 3 years and is currently recommended by the World Health Organization (WHO) as triple therapy in areas not endemic with loaisis (Loa loa) ⁵². However, because lymphatic filariasis is rare in the United States, diethylcarbamazine (DEC) is no longer approved by the U.S. Food and Drug Administration (FDA) ⁵¹. Doctors can get diethylcarbamazine (DEC) from CDC, after a confirmed positive lab test.

Diethylcarbamazine (DEC) may not help people who have lymphedema, hydrocele or elephantiasis, as most people with these symptoms no longer have live parasites in their bodies ⁵¹. Your doctor might refer you to a lymphedema therapist to help manage your lymphedema. This includes learning how to keep the affected area clean, exercise, elevation, treatment of wounds and infections, and wearing appropriate footwear. There is limited evidence for the role of doxycycline as some studies advocate the use of doxycycline (200mg/day for 4 to 6 weeks) in adult worm killing and preventing the progression of lymphedema ²⁹. If you have hydrocele (a fluid-filled sac that develops around one or both testicles, causing painless swelling in the scrotum), your doctor might recommend surgery to remove the fluid-filled swelling.

If you also have onchocerciasis or loaisis (Loa loa), also caused by filarial parasitic worms, taking diethylcarbamazine (DEC) might cause life-threatening side effects. Filaricidal action of diethylcarbamazine (DEC) induces an immunological reaction similar to the Mazzotti reaction (a potentially dangerous immune reaction that can occur after treatment for parasitic worm infections, particularly onchocerciasis caused by the rapid death and breakdown of microfilariae or larval worms in the body) seen in onchocerciasis, characterized by headache, joint pain, dizziness, anorexia, malaise, and urticaria ⁵³, ⁵⁴. Doxycycline and ivermectin or albendazole is the recommended combination in individuals with onchocerciasis or loaisis (Loa loa). Doxycycline is preferred in areas co-endemic with Loa loa (loaisis) and has also shown the ability to slow the inflammation and fibrosis that leads to worsening lymphedema. Doxycycline also treats Wolbachia, a genus of symbiotic bacteria that inhabit nematodes ²⁸, ⁴⁹. Filarial nematodes depend on Wolbachia for normal development and fertility ⁵⁵. Doxycycline has been shown to clear filaria of Wolbachia symbionts, leading to microfilarial and macrofilarial death, and thus provides an attractive treatment option ⁵⁶, ⁵⁷, ⁵⁸. Suramin is widely used in onchocerciasis, yet its role remains uncertain in lymphatic filariasis.

Figure 1. Wuchereria bancrofti

Footnote: Microfilaria of Wuchereria bancrofti in thick blood smear stained with Giemsa. Adults of Wuchereria bancrofti are long and threadlike. The males measure up to 40 mm long and females are 80—100 mm long. Adults are found primarily in lymphatic vessels, less commonly in blood vessels.

Figure 2. Brugia malayi

Footnote: Microfilaria of Brugia malayi in a thick blood smear, stained with Giemsa. The tail is tapered, with a significant gap between the terminal and subterminal nuclei. Microfilariae of Brugia malayi are sheathed and in stained blood smears measure 175—230 micrometer (μm). In 2% formalin they are longer, measuring 240—300 micrometer (μm).

Figure 3. Brugia timori

Footnote: Microfilaria of Brugia timori in a thick blood smear, stained with Giemsa and captured at 500x oil magnification. Microfilaria of Brugia timori are sheathed and measure on average 310 micrometer (μm) in stained blood smears and 340 micrometer (μm) in 2% formalin. Microfilaria of Brugia timori differ from Brugia malayi by a having a longer cephalic space, a sheath that does not stain with Giemsa, and a larger number of single-file nuclei towards the tail.

Figure 4. Lymphatic filariasis global distribution

Figure 5. Lymphatic System

Footnotes: The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillary-like channels. Primary lymphatic vessels lack muscular walls and do not have valves. They drain into larger, secondary lymphatic vessels located in the subdermal space. Secondary lymphatic vessels run parallel to the superficial veins and drain into deeper lymphatic vessels located in the subcutaneous fat adjacent to the fascia. Unlike the primary vessels, the secondary and deeper lymphatic vessels have muscular walls and numerous valves to accomplish active and unidirectional lymphatic flow. An intramuscular system of lymphatic vessels that parallels the deep arteries and drains the muscular compartment, joints, and synovium also exists. The superficial and deep lymphatic systems probably function independently, except in abnormal states, although there is evidence that they communicate near lymph nodes ⁶¹. Lymph drains from the lower limbs into the lumbar lymphatic trunk. The lumbar lymphatic trunk joins the intestinal lymphatic trunk and cisterna chyli to form the thoracic duct, which empties into the left subclavian vein. The lymphatic vessels of the left arm drain into the left subclavian lymphatic trunk and then into the left subclavian vein. The lymphatic vessels of the right arm drain into the right subclavian lymphatic trunk and then into the right subclavian vein.

Figure 6. Lymphedema

Footnotes: The lymphatic vessels normally maintain normal interstitial pressures by removing the excess interstitial fluid that results from the imbalance between the intravascular fluid that enters from the arterioles and exits into the venules. Large proteins and cells that cannot exit the interstitial space through the venules leave the interstitial fluid through the lymphatic vessels. As the lymph moves through the lymphatic vessels, it passes through lymph nodes and eventually into one of two lymphatic ducts that empty into a large vein near the heart. In lymphedema, the flow of lymph through the lymphatic vessels is disrupted or blocked. This leads to increased interstitial pressure and an accumulation of interstitial fluid, large proteins, and cellular debris in the interstitial space, which induces inflammation. The inflammation may cause further damage to the lymphatic vessels. The macrophages and lymphocytes release inflammatory markers, which causes fibrosis, fat cell hypertrophy, and the classical sign of swelling. Lymphedema may be caused by cancer or cancer treatment.

Figure 7. Lymphatic filariasis

Footnotes: (A) A patient with elephantiasis of the left leg. (B) A Haitian Woman suffering from lymphatic filariasis presenting with bilateral lymphedema.

What is elephantiasis?

Elephantiasis also known as lymphatic filariasis, is a filarial parasitic infection (filarial worms) transmitted by mosquitoes that blocks your lymphatic system, causing severe swelling and thickening of the skin, often in the limbs, breasts, or genitals ⁶⁴, ⁶⁵, ²⁹. People with elephantiasis may also develop inflammation, swelling and fever. Symptoms can take years to appear, even if the infection was acquired in childhood. The condition is a major cause of disability and poverty in tropical and subtropical regions of Africa, Asia, and South America. Diagnosis involves a blood test, and treatment includes antiparasitic medication to kill the worms and supportive care like compression to manage lymphedema. Without treatment, elephantiasis can cause health complications.

What causes filariasis?

Filariasis refers to parasitic infection caused by filarial parasites or nematodes (roundworms) of the family Filariidae transmitted to humans by blood-sucking insects, such as mosquitoes, blackflies, or midges, acting as biological vectors ¹, ², ³. Filarial infection is transmitted through the bite of an infected insect as it feeds upon human blood ⁶. Thereafter, parasite larvae mature into adult forms within the host. These adult parasites then multiply, producing microfilariae, which are subsequently ingested by blood-sucking insects along with human blood. These microfilariae undergo subsequent stages of development within the insect’s bodies (see Lymphatic Filariasis Life Cycle below) ⁷, ⁸, ⁹.

Of the hundreds of described filarial parasites, only 8 species cause natural infections in humans ¹⁰:

• Onchocerca volvulus causing Onchocerciasis ¹¹, ¹²
• Wuchereria bancrofti causing Bancroftian filariasis (lymphatic filariasis)
• Brugia malayi causing Malayan filariasis (lymphatic filariasis) ¹³, ¹⁴
• Brugia timori causing Malayan filariasis (lymphatic filariasis) ¹³, ¹⁴
• Loa loa causing Loiasis ¹⁵, ¹⁶
• Mansonella species (Dipetalonema spp), Mansonella perstans (Dipetalonema perstans), and Mansonella streptocerca (Dipetalonema streptocerca) causing Mansonelliasis  ¹⁷, ¹⁸, ¹⁹, ²⁰
• Dirofilaria species causing Dirofilariasis ²¹, ²²

The location of these parasites within the human body varies from species to species. Filariasis affects a range of human tissues and often display little or no observable host response throughout their development ²³, ²⁴. An exception occurs when the parasite enters extremely sensitive tissues, such as the conjunctiva ²⁵.

Filariasis can be classified based on the location of the parasite within the human host’s body ⁵, ²⁵, ²⁶, ²⁷:

• Lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, Brugia timori;
• Subcutaneous filariasis: Loa loa, Onchocerca volvulus;
• Serous cavity filariasis: Mansonella spp.

Filariasis signs and symptoms and treatment of filariasis depends on the type of filarial parasitic worm (nematode) infection you have.

Filariasis is predominantly a disease of tropical countries and affects the lives of millions of people. Filariasis is spread from host-to-host via the bites of certain flies and mosquitoes that act as vectors for the parasites. For example the filarial nematode Onchocerca volvulus enters the skin from the bite of an infected blackfly (Simulium species). The nematode is in its third larval stage before it moults to its fourth larval stage in 4-6 weeks. Then after some months it moults again to become a juvenile adult that matures and mates after about a year to produce microfilariae. These adult worms live and mate encased in fibrous nodules just below the skin surface and can live there for up to 10-15 years.

It has been discovered that a type of Rickettsia (Wolbachia spp.) has a symbiotic relationship with filarial nematodes. The bacteria initiates the filarial disease process with a severe adverse inflammatory reaction.

Table 1. Filariasis

What causes lymphatic filariasis?

Lymphatic filariasis is caused by infection with parasites classified as nematodes (roundworms) of the family Filariodidea. There are 3 types of these thread-like filarial worms:

• Wuchereria bancrofti, which is responsible for 90% of lymphatic filariasis cases.
• Brugia malayi, which causes most of the remainder of lymphatic filariasis cases.
• Brugia timori, which also causes the lymphatic filariasis.

The majority of Wuchereria bancrofti infections occur in South and Southeast Asia, as well as sub-Saharan Africa. Central and South America and the Pacific islands are endemic regions. Brugia malayi has been reported in South and Southeast Asia, India, Indonesia, Thailand, Vietnam, Malaysia, and the Philippines. In contrast, Brugia timori is restricted to eastern Indonesia and East Timor ⁶⁷.

Adult worms nest in the lymphatic vessels and disrupt the normal function of the lymphatic system. The worms can live for approximately 6–8 years and, during their life time, produce millions of microfilariae (immature larvae) that circulate in the blood (see Lymphatic Filariasis Life Cycle below). Mosquitoes are infected with microfilariae by ingesting blood when biting an infected host. Microfilariae mature into infective larvae within the mosquito. When infected mosquitoes bite people, mature parasite larvae are deposited on the skin, from where they can enter the body. The larvae then migrate to the lymphatic vessels where they develop into adult worms, thus continuing a cycle of transmission.

Lymphatic filariasis is transmitted by 5 different types of mosquitoes including Aedes, Anopheles, Culex, Mansonia, and Ochlerotatus ²⁸. For example by the Culex mosquito, widespread across urban and semi-urban areas, Anopheles, mainly found in rural areas, and Aedes, mainly in endemic islands in the Pacific ⁶⁸. The typical vector for Brugia malayi and Brugia timori filariasis are mosquito species in the genera Mansonia and Aedes ³⁰. Wuchereria bancrofti is transmitted by many different mosquito genera/species, depending on geographical distribution. Among them are Aedes spp., Anopheles spp., Culex spp., Mansonia spp., and Coquillettida juxtamansonia ³⁰.

Acute lymphatic filariasis is related to larval molting and adult maturation to fifth-stage larvae. Adult worms are found in lymph nodes and lymphatic vessels distal to the nodes. Females measure 80-100 mm in length and males are 40 mm.

The most commonly affected nodes are in the femoral and epitrochlear regions. Abscess formation may occur at the nodes or anywhere along the distal vessel. Infection with Brugia timori appears to result in more abscesses than infection with Brugia malayi or Wuchereria bancrofti ⁶⁹.

Cellular invasion with plasma cells, eosinophils, and macrophages, together with hyperplasia of the lymphatic endothelium, occurs with repeated inflammatory episodes ⁶⁹. The consequence is lymphatic damage and chronic leakage of protein-rich lymph in the tissues, thickening and verrucous changes of the skin, and chronic streptococcal and fungal infections, all of which contribute to the appearance of elephantiasis. The skin of individuals with elephantiasis is characterized by hyperkeratosis, acanthosis, lymph and fatty tissue, loss of elastin fibers, and fibrosis.

Brugia malayi elephantiasis is more likely to affect the upper and lower limbs, with genital pathology and chyluria being rare. Secondary bacterial infection in elephantiasis can result in blindness.

The exact mechanism behind the lymphatic damage involves a complex interplay of lymphangiectasia and inflammatory reactions triggered by the dying worms. Adult filarial worms usually reside in the afferent, efferent, and hilar lymphatics, causing blockage and subclinical lymphangiectasia. Moreover, lymphatic damage also results from the host’s immune response to the parasite’s endosymbiont Wolbachia. Antigens released by the dying worms trigger inflammatory reactions causing lymphatic damage.

Clinical progression of the disease varies in individuals depending on the host’s immune response. Chronicity of the infection has been attributed to the suppression of Th1 and Th2 immune responses. The asymptomatic carrier state has links to the synergistic interplay between poly-specific natural IgG4 and anti-filarial IgG4 in blocking the pathogenesis ⁷⁰, ⁷¹, ⁷². Genetic predisposition to lymphedema and prenatal exposure in endemic areas also play a vital role.

What causes lymphedema?

Brugia malayi life cycle

During a blood meal, an infected mosquito typically Mansonia species and Aedes species introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound (number 1). They develop into adults that commonly reside in the lymphatics (number 2). The adult worms outwardly resemble those of Wuchereria bancrofti but are smaller. Female worms measure 43 to 55 mm in length by 130 to 170 μm in width, and males measure 13 to 23 mm in length by 70 to 80 μm in width. Adults produce microfilariae, measuring 177 to 230 μm in length and 5 to 7 μm in width, which are sheathed and have nocturnal periodicity (in some regions Brugia malayi may be sub-periodic, and note that microfilariae are usually not produced in Brugia pahangi infections). The microfilariae migrate into lymph and enter the blood stream reaching the peripheral blood (number 3). A mosquito ingests the microfilariae during a blood meal (number 4). After ingestion, the microfilariae lose their sheaths and work their way through the wall of the proventriculus and cardiac portion of the midgut to reach the thoracic muscles (number 5). There the microfilariae develop into first-stage larvae (number 6) and subsequently into third-stage larvae (number 7). The third-stage larvae migrate through the hemocoel to the mosquito’s proboscis (number 8) and can infect another human when the mosquito takes a blood meal (number 1).

Figure 9. Brugia malayi life cycle

Filariasis Prevention

The best way to prevent filariasis is by preventing spread of the parasites by vector control. This means eliminating or controlling infected flies and mosquitoes. Research is underway to find a biological agent that will eliminate the vector and is inexpensive, non-toxic to humans and deployable on a large scale. It is important to take steps to avoid mosquito bites even if you are taking medications as an added layer to prevent filariasis.

Elimination of lymphatic filariasis is possible by stopping the spread of the infection through preventive drug therapy. The World Health Organization (WHO) recommended preventive drug strategy for lymphatic filariasis elimination using mass drug administration (MDA) ⁸⁴. Mass drug administration (MDA) involves administering an annual dose of medicines to the entire at-risk population. The medicines used have a limited effect on adult parasites but effectively reduce the density of larval worms in the body (microfilariae in the bloodstream) and prevent the spread of parasites to mosquitoes ⁸⁴. It is worth noting that mass drug administration (MDA) does not cure filarial infections, but it can reduce or interrupt transmission of new infections by clearing larval parasites from human blood so that they are not available for mosquitoes, which are the vectors (intermediate hosts) ⁸⁵ .

The mass drug administration (MDA) regimen recommended depends on the co-endemicity of lymphatic filariasis with other filarial diseases. WHO recommends the following mass drug administration (MDA) regimens ⁸⁴:

• Albendazole (400 mg) alone twice per year for areas co-endemic with loiasis;
• Ivermectin (200 mcg/kg) and albendazole (400 mg) in countries with onchocerciasis;
• Diethylcarbamazine citrate (DEC) (6 mg/kg) and albendazole (400 mg) in countries without onchocerciasis; and
• Ivermectin (200 mcg/kg) together with diethylcarbamazine citrate (DEC) (6 mg/kg) and albendazole (400 mg) in countries without onchocerciasis and where other programmatic conditions are met.

The impact of mass drug administration (MDA) depends on the efficacy of the regimen and the coverage (proportion of total population ingesting the medicines). Mass drug administration (MDA) with the 2-medicine regimens have interrupted the transmission cycle when conducted annually for at least 4–6 years with effective coverage of the total population at risk. Salt fortified with diethylcarbamazine citrate (DEC) has also been used in a few unique settings to interrupt the transmission cycle.

Mosquito control

Mosquito control is a supplemental strategy supported by WHO. It is used to reduce transmission of lymphatic filariasis and other mosquito-borne infections. Depending on the parasite-vector species, measures such as insecticide-treated nets, indoor residual spraying or personal protection measures may help protect people from infection. The use of insecticide-treated nets in areas where Anopheles is the primary vector for filariasis enhances the impact on transmission during and after mass drug administration (MDA). Historically, mosquito control has in select settings contributed to the elimination of lymphatic filariasis in the absence of large-scale preventive drug therapy.

Preventing Mosquito Bites

Mosquitoes bite day and night. They spread parasites through bites that can make you sick. Take steps to protect yourself and your family from mosquito bites that can make you sick.

• Use Environmental Protection Agency (EPA)-registered insect repellents.
  • Tips for babies and children:
    • Dress your child in clothing that covers arms and legs.
    • Cover strollers and baby carriers with mosquito netting.
  • When using insect repellent on your child:
    • Always follow label instructions.
    • Do not use products containing oil of lemon eucalyptus (OLE) [a plant-derived ingredient] or para-menthane-diol (PMD) on children under 3 years old.
    • Do not apply repellent to a child’s hands, eyes, mouth, cuts, or irritated skin.
    • Adults: Apply repellent onto your hands and then apply to a child’s face.
  • Tips for everyone:
    • Always follow the product label instructions.
    • Reapply repellent as directed.
    • Do not apply repellent on the skin under clothing.
    • If you are using sunscreen, apply sunscreen first and insect repellent second.
• Wear loose-fitting, long-sleeved shirts and pants.
• Wear clothing and gear treated with permethrin. Permethrin is an insecticide that kills or repels mosquitoes.
  • Permethrin-treated clothing provides protection after multiple washings.
  • Do not use permethrin products directly on skin.
• Control mosquitoes indoors and outdoors. Stop mosquitoes from laying eggs in or near water.
  • Check for water-holding containers both indoors and outdoors.
  • Once a week, empty and scrub, turn over, cover, or throw out items that hold water, such as tires, buckets, toys, pools, birdbaths, flowerpot saucers, or trash containers.

Filariasis signs and symptoms

Filariasis signs and symptoms vary depending on the type of filarial infection, body location and can be acute or chronic in nature. Up to 70% of infected individuals remain asymptomatic. Symptoms usually do not manifest until adolescence or adulthood, when worm burden usually is the highest. Several symptomatic variations have been observed ⁴². Because cases of filariasis in North America and high-income countries are uncommon, physicians initially may miss the diagnosis in these areas. To avoid this pitfall, physicians should obtain and document a thorough travel history from patients with suspicious lesions.

Lymphatic filariasis signs and symptoms

Lymphatic filariasis can be caused by either Wuchereria bancrofti (Bancroftian filariasis), Brugia malayi (Malayan filariasis) or Brugia timori (Malayan filariasis).

The clinical course of lymphatic filariasis is broadly divided into the following:

• Asymptomatic microfilaremia – Patients with microfilaremia are generally asymptomatic, although those with heavy microfilarial loads may develop acute and chronic inflammatory granulomas secondary to splenic destruction. Passage of cloudy milklike urine may denote chyluria
• Acute phases of adenolymphangitis (ADL) – This refers to the sudden onset of febrile, painful lymphadenopathy. Pathologically, the lymph node is characterized by a retrograde lymphangitis, distinguishing it from bacterial lymphadenitis. Symptoms usually abate within 1 week, but recurrences are possible ⁴³. Signs and symptoms of adenolymphangitis (ADL) include episodic attacks of fever associated with inflammation of the inguinal lymph nodes, testis, and spermatic cord, as well as with lymphedema. Skin exfoliation of the affected body part usually occurs with resolution of an episode.
• Chronic, irreversible lymphedema and hydrocele
  • Lymphedema – the most common presentation that develops over a long period due to chronic lymphatic damage. It characteristically presents with swelling of the limbs either upper or lower depending on the involvement of inguinal or axillary lymphatic vessels. Pitting edema develops in the early stages of the disease, which later progresses into brawny non-pitting type. Elephantiasis is the most severe type of lymphedema characterized by severe swelling of the limbs, genitalia, and breasts. The skin becomes thick and hard, owing to hyperpigmentation and hyperkeratosis.
  • Hydrocele (a fluid-filled sac around a testicle that causes painless swelling of the scrotum) – this is one of the debilitating morbidities associated with chronic lymphatic filariasis. It can be unilateral or bilateral, leading to enlargement of the scrotum. It can be very large, reaching up to 40 cm.

Lymphatic filariasis is a long-lasting, chronic, and persistent disease, with the majority of infected individuals remaining asymptomatic, showing no external signs of infection while contributing to the transmission of the parasite. These asymptomatic infections still cause damage to the lymphatic system and the kidneys and alter your body’s immune system.

Lymphatic filariasis can manifest in a wide range of clinical signs, including lymphedema of the legs, lymphangitis, elephantiasis, and, uniquely in Wuchereria bancrofti (Bancroftian filariasis)-infected individuals, hydrocele (a fluid-filled sac around a testicle that causes painless swelling of the scrotum) ⁸⁶. Asymptomatic infections are characterized by the presence of several regulatory immune processes driven by living parasites that promote their long-term survival ⁸⁷, ⁸⁸, ⁸⁹, ⁹⁰. The precise mechanisms by which lymphatic filariasis clinical disease manifests remain uncertain, although it is likely to be associated with the host’s inflammatory response to dead or dying adult parasites. The parasites’ death results in inflammation of lymphatic vessels and lymph nodes, which may cause pain and swelling in the affected area ⁸⁶, ⁹¹. The susceptibility to infection, host response, and the risk of developing pathological features are familial and probably related to host genetic predisposition ⁹², ⁹³, ⁹⁴.

Lymphatic filariasis symptoms predominantly result from the presence of adult worms residing in the lymphatics. They include the following ⁴⁴:

• Fever
• Groin (inguinal) or armpit (axillary) swollen or enlarged lymph nodes (lymphadenopathy)
• Testicular and/or inguinal pain
• Skin exfoliation
• Limb or genital swelling. Repeated episodes of inflammation and lymphedema lead to lymphatic damage, chronic swelling, and elephantiasis of the legs, arms, scrotum (hydrocele), vulva, and breasts

The following acute syndromes have been described in lymphatic filariasis ²:

• Acute adenolymphangitis (ADL) – repeated bouts of lymphangitis causing lymphedema.
• Filariatic fever – manifests with lymphangitis and lymphadenitis with nonspecific symptoms, including headache, fever, chills, and general malaise.
• Filarial abscess – may form, causing localized swelling and pain until rupture, which results in the discharge of dead adult worms. Granulomatous reactions can lead to lumps in subcutaneous tissues ⁴⁴.
• Tropical pulmonary eosinophilia (TPE). Tropical pulmonary eosinophilia (TPE) is an immune response or hypersensitivity lung reaction to filarial parasites, primarily from Wuchereria bancrofti and Brugia malayi, and is marked by peripheral hypereosinophilia (high eosinophil count) and eosinophilic pulmonary infiltrate causing pulmonary restrictive lung disease, wheezing, shortness of breath, dry paroxysmal nocturnal cough, chest pain, anorexia, malaise, weight loss, splenomegaly, and bloody sputum ⁹⁵. The syndrome, often seen in tropical regions most frequently in South and Southeast Asia, but increasingly in travelers, is typically misdiagnosed as asthma and is effectively treated with diethylcarbamazine (DEC) ⁴⁴. Without treatment, tropical pulmonary eosinophilia (TPE) can lead to interstitial lung disease and other complications.

Acute episodes of local inflammation involving skin, lymph nodes and lymphatic vessels often accompany chronic lymphoedema or elephantiasis. Some of these episodes are caused by the body’s immune response to the parasite. Most are the result of secondary bacterial skin infection where normal defenses have been partially lost due to underlying lymphatic damage. These acute attacks are debilitating, may last for weeks and are the primary cause of lost wages among people suffering with lymphatic filariasis.

When lymphatic filariasis develops into chronic conditions due to dysfunction of lymphatic vessels it leads to lymphoedema (tissue swelling) or elephantiasis (skin/tissue thickening) of limbs and hydrocele (scrotal swelling).

The most obvious symptom of lymphatic filariasis is elephantiasis. This is a condition where the limbs swell to the point that they resemble an elephant’s foreleg in size, texture and color and the skin may become thick and pitted and secondary infection are frequent due to lymphatic dysfunction. The thickening of the skin and swelling of underlying tissues (edema) is caused by parasites lodged in the lymphatic system, a network of channels, nodes and organs that maintain proper fluid levels in the body. Elephantiasis appears to be due an immune response to the dead and dying worms in the lymphatic system. Mainly limbs, breasts and genital organs are affected. Without treatment continued lymphatic damage will lead to irreversible elephantiasis. Such body deformities often lead to social stigma and sub-optimal mental health, loss of income-earning opportunities and increased medical expenses for patients and their caretakers. The socioeconomic burdens of isolation and poverty are immense.

Occult filariasis

Occult filariasis denotes filarial infection in which microfilariae are not observed in the blood but may be found in other body fluids and/or tissues.

The occult lymphatic filariasis syndromes are as follows:

• Tropical pulmonary eosinophilia (TPE) – Symptoms result from allergic and inflammatory reactions elicited by the microfilariae and parasite antigens of Wuchereria bancrofti and Brugia malayi  that the lungs clear from the bloodstream
• Dirofilaria immitis or Dirofilaria repens infection (Dirofilariasis) – Human infection with Dirofilaria immitis may result in pulmonary lesions of immature Dirofilaria worms in the lung periphery; if Dirofilaria immitis larvae lodge in branches of the pulmonary arteries, they can cause pulmonary infarcts
• Filarial arthritis
• Filarial breast abscess
• Filarial-associated immune-complex glomerulonephritis

Subcutaneous Filariasis

Subcutaneous filariasis is primarily characterised by cutaneous (skin) and subcutaneous symptoms resulting from nematode infections, including those caused by Onchocerca volvulus, Loa loa, and Mansonella ozzardi ⁹⁶.

Onchocerca volvulus (onchocerciasis) is predominantly impacting sub-Saharan Africa, Yemen, and regions of Central and South America ⁹⁷, ⁹⁸. Loa loa (Loiasis) primarily affects rural populations in Central and West Africa, with over 20 million patients chronically infected in regions with medium to high transmission rates ⁹⁹, while Mansonella ozzardi, one of three species in the genus Mansonella (the others being Mansonella perstans and Mansonella streptocerca) causing mansonellosis ¹⁰⁰, is common across the neotropical region from southern Mexico to northwestern Argentina ²⁰.

Subcutaneous filariasis symptoms include the appearance of papules, nodules, and scratches on the skin surface, which becomes dry and thickened, often accompanied by changes in skin pigmentation and intense itch ¹⁰¹.

Onchocerciasis

Onchocerca volvulus microfilariae from the skin are ingested by the Simulium species of blackflies. Onchocercal dermatitis is the most common sign and symptom of onchocerciasis. The skin becomes very itchy and a red spotty rash is often present. Scratching often leads to bleeding, ulcers and secondary infections. The lower trunk, pelvis, buttocks, thighs and legs appear to be the most affected. Microfilariae are the main cause of Onchocercal dermatitis.

In addition to onchodermatitis, nodules containing adult worms called onchoceromas develop just below the skin surface. These nodules can be up to several centimetres in diameter and are usually firm, flattened or bean-shaped, movable and non-tender. They most often occur over bony parts of the body such as the skull, ribs, scapulae, elbows, and knees.

If left untreated, onchoceriasis can lead to chronic skin changes. Skin loses its elasticity and layers of the skin start to die and form scar tissue. This very thin wrinkled skin results in an elephant-skin appearance that later turns into something like lizard skin.

Chronic onchocerciasis cases are hyper-responsive to parasite antigen, have increased eosinophilia, and result in the presence of high levels of serum IgE. Patterns of onchocercal eye disease also are associated with parasite strain differences at the DNA level ¹⁰².

Eye lesions are usually related to the duration and severity of infection and are caused by an abnormal host immune response to microfilariae; loss of visual acuity may occur.

Common eye findings in onchocerciasis include the following ¹⁰³:

• Punctate keratitis
• Pannus formation
• Corneal fibrosis
• Iridocyclitis
• Glaucoma
• Choroiditis
• Optic atrophy

Loiasis

Mango flies or deerflies of Chrysops genus transmit Loa loa infection also known as African eye worm or Loiasis. Response to Loa loa infection appears to differ between residents and nonresidents in endemic areas. Nonresidents with Loa loa infection (Loiasis) appear to be more prone to symptoms than residents despite lower levels of microfilaremia. Eosinophil, serum IgE, and antibody levels are also higher in nonresidents with infection ¹⁰⁴. Loa loa infection or Loiasis, is currently not recognized by the World Health Organisation (WHO) as one of the key neglected tropical diseases. The typical clinical manifestation of loiasis, occurring in approximately 80% of individuals, is the migration of the adult parasite under the sclera or subconjunctival eyelid tissue ¹⁰⁵.

The initial bite from a redfly infected with the Loa loa parasite causes redness, swelling and itching. As the parasite moults to larval stage 4 it causes red urticarial papules (itchy red spots) in the skin of the affected area. Then over the next 3 months or more as it develops into the adult form, patients may experience pain and numbness of the affected area, temporary swelling of a limb, itchiness and occasionally hives.

The diagnostic feature of loiasis is the Calabar swelling, a large transient area of localized, nonerythematous subcutaneous edema. This is most common observed around joints.

Peripheral nerve involvement in loiasis also has been described ¹⁰⁶. Microfilaremia tends to be asymptomatic. Occasionally, the worm is observed migrating through subconjunctival or other tissues.

Meningoencephalopathy is a severe and often fatal complication of Loa loa infection. This syndrome is usually related to diethylcarbamazine (DEC) administration in individuals with high-density microfilaremia but it may occur without drug therapy ¹⁰⁷. Diethylcarbamazine (DEC) causes a large influx of microfilariae into the cerebrospinal fluid, leading to capillary obstruction, cerebral edema, hypoxia, and coma. Localized necrotizing granulomas are also present, in response to microfilariae. Endomyocardial fibrosis, nephritic syndrome, and venous thrombosis also may be observed.

Mansonelliasis

Mansonella ozzardi infection can manifest as a skin rash, headache, fever, itching, lymphoedema (e.g., swelling of the arms or legs), and joint pain ¹⁰⁸. Most patients infected with Mansonella perstans (Mansonellosis) do not experience any symptoms. Newcomers to an endemic area who become infected appear to experience more symptoms than local inhabitants. Symptoms include swelling of the arms, shoulders, and face; abdominal pain; itchiness; fatigue; and joint pain.

The most common symptom of a patient infected with Mansonella streptocerca (streptocerciasis) is chronic itching dermatitis that is often confined to one part of the torso. Constant scratching may thicken the skin.

Dirofilariasis

Humans are poor hosts for this filarial parasite (Dirofilaria immitis, Dirofilaria repens, and Dirofilaria tenuis) as the worm usually dies before reaching sexual maturity. However in recent years there has been a reported increase in the number of human dirofilariasis cases. The head, neck, breasts, arms, legs and scrotum are most commonly affected. A flesh-colored to red inflamed tender nodule develops. This can be painful and cause burning and itching.

Human infections with Dirofilaria immitis can result in areas of inflammation induced by dying adult worms in pulmonary arteries that appear as coin lesions on chest x-rays. Coin lesions can also be caused by cancer and other serious diseases, and a coin lesion discovered accidentally on chest x-ray usually leads to an invasive procedure to learn the cause. Most human cases of pulmonary dirofilariasis are diagnosed from samples taken during these procedures. Most reported cases of Dirofilaria immitis infection in humans have been in persons with no symptoms. People with symptoms can have cough (including coughing up blood), chest pain, fever, and pleural effusion (excess fluid between the tissues that line the lungs and the chest cavity). Rarely, Dirofilaria immitis worms have been found in humans at outside the lungs, including the brain, eye, and testicle. When Dirofilaria repens and Dirofilaria tenuis infection is reported in humans, it is generally as the cause of nodules under the skin, but on occasion, worms are found in the conjunctiva.

Filariasis Complications

The chronic manifestations of lymphedema and/or hydrocele will develop in approximately 30% of people infected ¹⁰⁹. Lymphedema mostly affects the legs, but can also occur in the arms, breasts, and genitalia. Most people develop these symptoms years after the initial infection has cleared.

Filarial hydrocele is thought to be the consequence of lymphatic damage caused by adult worms. Chyluria, which results from rupture of dilated lymphatics into the renal pelvis, can occur as a manifestation of bancroftian filariasis. Microscopic hematuria and proteinuria are also found in lymphatic filariasis patients.

Recurrent secondary bacterial infections of the affected extremity, characterized by severe pain, fever and chills, hasten the progression of lymphedema to its advanced stage, known as elephantiasis.

Another complication of lymphatic filariasis is tropical pulmonary eosinophilia (TPE) syndrome, a potentially serious, progressive lung disease characterized by fever and non-productive, nocturnal cough, wheezing, or both. Symptoms result from immune hyper-responsiveness to microfilariae in the pulmonary capillaries. Signs include marked eosinophilia, high serum immunoglobulin E (IgE) concentrations, and positive antifilarial antibodies. Peripheral microfilaremia is absent in patients with tropical pulmonary eosinophilia (TPE). Most cases of tropical pulmonary eosinophilia (TPE) have been reported in long-term residents from Asia, with men ages 20 – 40 most commonly affected.

Filariasis diagnosis

In general, the diagnostic approach varies by group of filariasis. Traditionally, the diagnosis of filariasis requires demonstrating microfilariae in the peripheral blood or skin. However, circulating filarial antigens (CFA) are now routinely used to diagnose Wuchereria bancrofti infection ⁴⁵. The microfilariae of all species that cause lymphatic filariasis and the microfilariae of Loa loa, Mansonella ozzardi, and Mansonella perstans can be detected on a blood smear ⁴⁶.

Microfilariae are detectable via examination of the following:

• Blood – The microfilariae of all species that cause lymphatic filariasis and the microfilariae of Loa loa, Mansonella ozzardi, and Mansonella perstans are detected in blood. Wuchereria bancrofti can be detected via circulating filarial antigen (CFA) assays. However, assays for circulating parasite antigen of Wuchereria bancrofti are not presently approved by the U.S. Food and Drug Administration (FDA). There are no antigen test for Brugia spp. Serologic enzyme immunoassay tests, including antifilarial IgG1 and IgG4, provide an alternative to microscopic detection of microfilariae for the diagnosis of lymphatic filariasis. Patients with active filarial infection typically have elevated levels of antifilarial IgG4 in the blood and these can be detected using routine assays.
• Urine – If lymphatic filariasis is suspected, urine should be examined macroscopically for chyluria and then concentrated to examine for microfilariae.
• Skin – Onchocerca volvulus and Mansonella streptocerca infections are diagnosed when microfilariae are detected in multiple skin-snip specimens taken from different sites.
• Eye – Microfilariae of Onchocerca volvulus may be detected in the cornea or anterior chamber of the eye using slit-lamp examination.

Useful imaging studies in the evaluation of filariasis include the following:

• Chest X-ray – Diffuse pulmonary infiltrates are visible in patients with tropical pulmonary eosinophilia (TPE)
• Ultrasound – Can be used to demonstrate and monitor lymphatic obstruction of the inguinal and scrotal lymphatics; has been used to demonstrate the presence of viable worms. Careful ultrasound may identify the random movement of adult worms in dilated lymphatics, known as the “filarial dance sign” (FDS). This is particularly useful in a patient with scrotal symptoms and is considered the gold standard investigation for detecting viable adult worms ⁴⁷.
• Lymphoscintigraphy – A nuclear medicine imaging test that maps the lymphatic system by tracking a radioactive tracer injected under the skin, helping to identify the sentinel lymph node in cancer patients or assess lymphatic drainage in conditions like lymphedema ⁴⁸

Histologic findings include the following:

• Lymphatic filariasis – Affected lymph nodes demonstrate fibrosis and lymphatic obstruction with the creation of collateral channels
• Elephantiasis – The skin is characterized by hyperkeratosis, acanthosis, lymph and fatty tissue, loss of elastin fibers, and fibrosis
• Onchocerciasis – Onchocercomas have a central stromal and granulomatous, inflammatory region where the adult worms are found and a peripheral, fibrous section; microfilariae in the skin incite a low-grade inflammatory reaction with loss of elasticity and fibrotic scarring.

Key clinical features that may assist in making a diagnosis of lymphatic filariasis include:

• History of residence in an endemic country for several years;
• Self-limiting nature of attacks, in contrast to bacterial cellulitis, incarcerated hernias or testicular torsion;
• Bilateral symptoms and signs;
• Recurrent episodes;
• Palpable regional masses or lymphadenopathy.

The diagnosis of symptomatic lymphatic filariasis requires strong clinical suspicion. Interestingly, many infected people remain asymptomatic. Risk factors for symptomatic disease include duration and intensity of exposure to vectors, adult worm burden, frequency of secondary infections and the host immune response ⁴⁹.

A blood film and serological evaluation are alternative diagnostic options. In most endemic areas, circulating microfilariae (filarial larvae) exhibit nocturnal periodicity (coinciding with peak feeding of local mosquitos) and are best seen on blood films taken between 10 pm and 4 am. If nocturnal samples are not feasible, then provocation with diethylcarbamazine may enhance microfilarial detection 1–2 hours later. Pacific Island infections (except Papua New Guinea) are subperiodic, with maximal microfilaraemia in the late afternoon, and show unresponsiveness to provocation. Importantly, patients with the chronic manifestations of lymphatic filariasis often have low levels of circulating microfilariae, resulting in lower blood-film sensitivity ⁵⁰.

Lymphatic filariasis diagnosis

Microfilariae on blood smear examination: Draw blood at night, when levels of parasitemia are generally highest (most often at night between 10 PM – 2 AM). The three lymphatic filarial species can also be distinguished based on their morphologic characteristics on light microscopy.

Microscopy: Lymphatic filariasis is usually identified by the finding of microfilaria in peripheral blood smears (thick or thin) stained with Giemsa or hematoxylin-and-eosin and subsequent morphologic species identification. For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lysed in 2% formalin (Knott’s technique), or filtration through a polycarbonate membrane. Microfilariae of Wuchereria bancrofti and Brugia malayi or Brugia timori species exhibit a nocturnal periodicity and an accurate diagnosis is best achieved on blood collected at night. Wuchereria bancrofti that are sub-periodic may be encountered in some regions of the Pacific Islands, eastern Malaysia, and Vietnam. Sub-periodic Brugia malayi also occurs in parts of Malaysia. Adult worms can be seen in the lymphatics. Adults of both species may be identified in biopsy specimens of lymphatic tissue.

Circulating filarial antigen (CFA) detection: Antigen detection using an immunoassay for circulating filarial antigens are available for only Wuchereria bancrofti detection in lymphatic filariasis. Unlike microfilariae with nocturnal periodicity, filarial antigens can be detected in blood samples collected at any time of day. A rapid format immunochromatographic test has been shown to be a useful and sensitive tool for the detection of Wuchereria bancrofti antigen and is being used widely by lymphatic filariasis elimination programs. Currently, this test is not licensed for use in the United States and cannot be used for patient diagnosis.

Additional testing in lymphatic filariasis includes polymerase chain reaction (PCR) and antibody detection. Polymerase Chain Reaction (PCR) is not widely available and is mostly used in a research setting. Serologic enzyme immunoassay tests, including antifilarial IgG1 and IgG4, provide an alternative to microscopic detection of microfilariae for the diagnosis of lymphatic filariasis. Patients with active filarial infection typically have elevated levels of antifilarial IgG4 in the blood and these can be detected using routine assays. However, antibody detection for filarial antibodies cannot distinguish between past and present infection and are not typically specific for filarial infections. Specificity can be improved via IgG4 assays based on certain recombinant antigens, such as Wb123 in Wuchereria bancrofti ¹¹⁰.

The Brugia Rapid (Reszon Diagnostics International Sdn. Bhd., Selangor, Malaysia) is a rapid strip test operating on the principle of immunochromatographic technology ¹¹¹. The Brugia Rapid test is based on the specific reaction of a recombinant BmR1 protein produced in Escherichia coli with antiparasitic antibodies found in the patient’s serum. The antibodies react with the BmR1 antigen, which then binds to monoclonal anti-human IgG4 antibodies linked to colloidal gold ¹¹². The IgG4 enzyme-linked immunosorbent assay (ELISA), utilizing the BmR1 antigen, demonstrated a specificity rate of 95.6% and a sensitivity rate of 96% ¹¹³. For the Brugia Rapid test, the results indicated 97% sensitivity and 99% specificity ¹¹¹. Furthermore, a second validation study was conducted. The sensitivity of the strip test was found to be 93%. In the field study, compared to microscopic examination of thick blood smears, the sensitivity of the test was 87% and the specificity was 100%. The rapid strip test was therefore a useful diagnostic tool for filariasis in Brugia malayi endemic areas ¹¹⁴. Other studies have also demonstrated the high sensitivity and specificity of the test in detecting infection with the parasite ¹¹⁵, ¹¹⁶, ¹¹⁷, ¹¹⁸. Based on the detection of specific IgG4 antibodies against recombinant BmR1 antigens, a Brugia Rapid test is commercially available from Reszon Diagnostics International Sdn. Bhd., Selangor, Malaysia. The WHO, in its Global Programme to Eliminate Lymphatic Filariasis, recommends the Brugia Rapid test for the detection of Brugia malayi invasion ¹¹⁹. However, it should be noted that Brugia Rapid tests, which detect IgG4 antibodies specific to filaria, may generate false-positive results in patients who have been previously infected and have undergone treatment. This is because individuals affected by lymphatic filariasis may retain B-cell memory, leading to the detection of antibodies for some time after the elimination of the parasite. Currently, there is a lack of a commercial test for the detection of Brugia malayi antigens, which highlights the need for further research to improve the diagnosis of lymphatic filariasis ¹²⁰.

Cutaneous filariasis diagnosis

Definitive diagnosis of Onchocerca volvulus (onchocerciasis) and Mansonella streptocerca (streptocerciasis) infections occurs when microfilariae are detected in multiple skin snip specimens taken from different body sites. In addition, microfilariae of Onchocerca volvulus may be detected in the cornea or anterior chamber of the eye, using slit-lamp examination. Onchocerca volvulus may also be detected with antigen testing, although this is not regularly available ¹²¹. Additional testing with serology and PCR have similar application in these cases, as noted above. Of note, the Mazzoti test (detailed below) should not be routinely used in the diagnosis of onchocerciasis owing to its risk for severe adverse reactions.

Loa loa infection can be definitively diagnosed by observing microfilariae on blood smear examination or by detecting migrating adult worms in the subcutaneous tissue or conjunctiva. For travelers to endemic areas, serology can be useful to detect exposure to Loa loa. Sensitivity and specificity of such testing varies depending on the assay used.

Body cavity filariasis diagnosis

Mansonella ozzardi and Mansonella perstans infections can be definitively diagnosed by observing microfilariae on blood smear examination. Additional testing with serology and polymerase chain reaction (PCR) have similar application in these cases, as described above.

Filariasis Differential Diagnosis

Filariasis differential diagnosis includes ²⁵, ⁷⁸:

• Several zoonotic filariasis, including Onchocerca, Dirofilaria, Brugia, Dipetalonema, Loaina, Meningonema
• Lymphoma
• Allergic bronchopulmonary aspergillosis
• Systemic vasculitis
• Chronic eosinophilic pneumonia
• Idiopathic hypereosinophilic syndrome
• Acute poststreptococcal glomerulonephritis
• Testicular neoplasms
• Congenital abnormalities of lymphatics
• Pelvic cancer
• Damage to the lymph system secondary to surgery or radiation.

Differential diagnoses of lymphatic filariasis include the following ¹²²:

• Bacterial or fungal lymphadenitis – Sporotrichosis resulting from Sporothrix schenckii infection
• Recurrent streptococcal lymphadenitis
• Congenital or hereditary lymphedema – Milroy syndrome
• Nonfilarial elephantiasis
• Congenital hydrocele
• Epididymal cysts
• Carcinoma of the testis and/or scrotum
• Lymphosarcoma

Differential diagnoses of occult filariasis include the following:

• Asthma
• Septic arthritis
• Bacterial breast abscess
• Idiopathic or poststreptococcal glomerulonephritis

Other differential diagnoses of filariasis include the following:

• Onchocerciasis – Vitiligo, trachoma, lepromatous leprosy
• Loiasis – Hereditary and/or localized idiopathic angioedema

Filariasis treatment

Diethylcarbamazine citrate (DEC) remains the mainstay of filariasis treatment worldwide, which kills both immature and adult parasitic worms ²⁹. The United States Centers for Disease Control and Prevention (CDC) recommends a single-day or 12-day course of diethylcarbamazine (DEC) at 6 mg/kg/day ⁵¹, ²⁹.

The most common side effects of diethylcarbamazine (DEC) include ⁵¹:

• Dizziness
• Nausea
• Fever
• Headache
• Pain in muscles or joints

Diethylcarbamazine (DEC) has been used globally for more than 50 years. A single combined dose of ivermectin, albendazole, and diethylcarbamazine (DEC) resulted in clearance of microfilaria in 96% of affected patients for up to 3 years and is currently recommended by the World Health Organization (WHO) as triple therapy in areas not endemic with loaisis (Loa loa) ⁵². However, because lymphatic filariasis is rare in the United States, diethylcarbamazine (DEC) is no longer approved by the U.S. Food and Drug Administration (FDA) ⁵¹. Doctors can get diethylcarbamazine (DEC) from CDC, after a confirmed positive lab test.

Diethylcarbamazine (DEC) may not help people who have lymphedema, hydrocele or elephantiasis, as most people with these symptoms no longer have live parasites in their bodies ⁵¹. Your doctor might refer you to a lymphedema therapist to help manage your lymphedema. This includes learning how to keep the affected area clean, exercise, elevation, treatment of wounds and infections, and wearing appropriate footwear. There is limited evidence for the role of doxycycline as some studies advocate the use of doxycycline (200mg/day for 4 to 6 weeks) in adult worm killing and preventing the progression of lymphedema ²⁹. If you have hydrocele (a fluid-filled sac that develops around one or both testicles, causing painless swelling in the scrotum), your doctor might recommend surgery to remove the fluid-filled swelling.

If you also have onchocerciasis or loaisis (Loa loa), also caused by filarial parasitic worms, taking diethylcarbamazine (DEC) might cause life-threatening side effects. Filaricidal action of diethylcarbamazine (DEC) induces an immunological reaction similar to the Mazzotti reaction (a potentially dangerous immune reaction that can occur after treatment for parasitic worm infections, particularly onchocerciasis caused by the rapid death and breakdown of microfilariae or larval worms in the body) seen in onchocerciasis, characterized by headache, joint pain, dizziness, anorexia, malaise, and urticaria ⁵³, ⁵⁴. Doxycycline and ivermectin or albendazole is the recommended combination in individuals with onchocerciasis or loaisis (Loa loa). Doxycycline is preferred in areas co-endemic with Loa loa (loaisis) and has also shown the ability to slow the inflammation and fibrosis that leads to worsening lymphedema. Doxycycline also treats Wolbachia, a genus of symbiotic bacteria that inhabit nematodes ²⁸, ⁴⁹. Filarial nematodes depend on Wolbachia for normal development and fertility ⁵⁵. Doxycycline has been shown to clear filaria of Wolbachia symbionts, leading to microfilarial and macrofilarial death, and thus provides an attractive treatment option ⁵⁶, ⁵⁷, ⁵⁸. Suramin is widely used in onchocerciasis, yet its role remains uncertain in lymphatic filariasis.

Multiple clinical trials have demonstrated doxycycline’s efficacy in reducing adult worm viability (as measured by scrotal ultrasound), circulating antigenemia (a marker of adult worm burden) and microfilaremia ⁵⁶, ⁵⁷, ⁵⁸. The degree of reduction of adult worm viability with doxycycline (75%–92%) appears to be far greater than that with any of the commonly used antifilarial agents. Furthermore, doxycycline has significant effects on disease progression, bringing about improvement in lymphatic function, hydrocoele size, lymphoedema, circulating levels of lymphangiogenic factors and rates of lymphangitis ⁵⁶. The extent to which doxycycline’s effects are mediated through activity against secondary bacterial pathogens has not been evaluated.

The optimal dose and duration for doxycycline therapy is unclear, but studies using 200 mg daily for at least 6 weeks have shown the best results ⁵⁶, ⁵⁸. Whether doxycycline should be used in conjunction with ivermectin, albendazole or diethylcarbamazine remains unknown. These additional drugs increase adverse events; however, few trials have compared combination regimens to doxycycline alone  ⁵⁷. Overall, the evidence suggests that in non-endemic settings doxycycline is the treatment of choice for symptomatic lymphatic filariasis. All patients in this series demonstrated a good clinical response to doxycycline.

Table 2. Filariasis treatment options

Lymphatic filariasis treatment

The usual treatment for lymphatic filariasis is a drug called diethylcarbamazine (DEC), which kills both immature and adult parasitic worms. Your doctor may recommend either a single-day treatment or taking the drug for 12 days.

The most common side effects of diethylcarbamazine (DEC) include ⁵¹:

• Dizziness
• Nausea
• Fever
• Headache
• Pain in muscles or joints

Diethylcarbamazine (DEC) has been used globally for more than 50 years. However, because lymphatic filariasis is rare in the United States, the drug is no longer approved by the U.S. Food and Drug Administration (FDA). Your doctor can get this drug from CDC, after a confirmed positive lab test.

Diethylcarbamazine (DEC) may not help people who have lymphedema or elephantiasis, as most people with these symptoms no longer have live parasites in their bodies. Your healthcare provider might refer you to a lymphedema therapist to help manage your condition. This includes learning how to keep the affected area clean, exercise, elevation, treatment of wounds and infections, and using appropriate footwear. If you have hydrocele, your doctor might recommend surgery to remove the fluid-filled swelling.

If you also have onchocerciasis or loaisis (Loa loa), also caused by filarial parasitic worms, taking diethylcarbamazine (DEC) might cause life-threatening side effects. Filaricidal action of diethylcarbamazine (DEC) induces an immunological reaction similar to the Mazzotti reaction (a potentially dangerous immune reaction that can occur after treatment for parasitic worm infections, particularly onchocerciasis caused by the rapid death and breakdown of microfilariae or larval worms in the body) seen in onchocerciasis, characterized by headache, joint pain, dizziness, anorexia, malaise, and urticaria ⁵³, ⁵⁴. Doxycycline and ivermectin or albendazole is the recommended combination in individuals with onchocerciasis or loaisis (Loa loa). Suramin is widely used in onchocerciasis, yet its role remains uncertain in lymphatic filariasis.

Lymphedema treatment

Lymphedema can progress due to repeated attacks of adenolymphangitis (ADL), even in the absence of lymphatic filariasis. Adenolymphangitis (ADL) refers to acute, recurrent, painful, and inflammatory episodes of lymphatic filariasis characterized by fever, limb swelling, and lymph node or lymph vessel inflammation, which are often the first signs of lymphatic filariasis and lead to lymphedema. Though the precise cause remains unclear, adenolymphangitis (ADL) episodes are thought to be triggered by secondary bacterial or fungal infections accessing the lymphatic system, which is already compromised by the underlying parasitic worms. Basic hygiene interventions are shown to reduce adenolymphangitis (ADL) episodes, which contribute to the progression of lymphedema and the loss of the patient’s ability to perform daily tasks

Common treatments for early-stage or mild lymphedema include ⁷⁸, ¹²³, ⁴⁴:

• Elevation of affected area to allow gravity to help drain extra fluid.
• Exercises and movements that promote fluid drainage and improve range of motion.
• Skin and nail care to prevent cuts or injuries to the skin around the affected area, which can make lymphedema worse or lead to cellulitis.
• Antibiotic and antifungal creams to prevent flares of lymphangitis
• Manual lymphatic drainage (MLD) is a type of gentle massage that helps move lymph fluid out of the swollen area. A trained therapist does this and might teach you how to do self manual lymphatic drainage (MLD) at home.
• Compression garments are special sleeves or stockings to prevent fluid build-up. A prescription from your doctor is needed. They are fitted to you by a professional and apply different amounts of pressure in different areas. Never wear a compression garment that hasn’t been fitted for you. This can trigger lymphedema or make it worse.
• Promote fluid circulation. Body areas that have damaged or missing lymph nodes can’t move and drain lymph fluid through the area as well. But there are things you can do to promote drainage of lymph fluid:
  • Don’t wear tight clothing, jewelry, or other items that constrict or squeeze the affected area.
  • Wearing comfortable shoes
  • If you wear a compression garment, wear it as directed. These garments apply measured and specific amounts of pressure to different areas and are not the same as tight clothing.
  • Don’t wear a compression garment that doesn’t fit or that you’ve grown out of. Get re-fitted for a garment every few months.
  • Avoid having blood pressure measurements taken on the affected arm, when possible.
  • Ask your doctor or therapist what exercises are good for your type and area of lymphedema.
  • Raising the affected arm or leg (above the level of your heart if possible) can improve swelling.
  • If you have lymphedema in your lower body, avoid crossing your legs.
  • Ask how to do manual lymph drainage (MLD) on yourself.
  • Note any changes in size, shape, or color of the affected area. Compare to the non-affected side if possible. Tell your doctor right away if you notice any changes.
  • Drinking plenty of fluids each day is important for everyone at every age. Drinking enough water helps the body filter and get rid of excess fluid and waste products. Researchers recently studied how people cope with lymphedema. One part of the study looked at their eating and drinking habits. The researchers found:
    • About 1 in 3 study participants reported that increasing their daily water intake was helpful for their symptoms.
    • About 1 in 4 study participants rated decreased alcohol intake as very helpful in controlling symptoms.
    • Water is usually the best choice for daily hydration. In addition to water, choosing unsweetened, low-fat beverages can support fluid intake. Water is also found in many foods, such as vegetables, fruits, broths and soups.

Treating moderate lymphedema

Complete decongestive therapy (CDT) is the combination of manual lymphatic drainage (MLD), compression therapy, skin care, exercises, and elevation. Complete decongestive therapy (CDT) is often used to manage mild to moderate lymphedema.

Treating severe lymphedema

For severe lymphedema, intermittent pneumatic compression (IPC) might be added to the treatment plan. Intermittent pneumatic compression (IPC) is a type of compression therapy where a sleeve or stocking is applied to the affected areas and inflated like a blood pressure cuff. It applies specific amounts of pressure to move fluid out of the area. Intermittent pneumatic compression (IPC) might also be used for less severe cases of lymphedema if a person can’t wear compression garments or can’t do manual self-lymphatic drainage.

Surgery might be an option if lymphedema is severe and hasn’t improved with other treatments.

• Liposuction removes extra fat that can develop in areas of lymphedema.
• Lympho-venous or lymphatic bypass takes lymph vessels and attaches them to small veins to improve drainage.
• Vascularized lymph node transfer (VLNT) takes healthy lymph nodes from another part of the body and places them in the area with lymphedema.

Surgical treatments

Surgical treatments exist for the debulking of skin and creating lymphovenous anastomosis to improve drainage. Topical coumarin and flavonoids were shown to be effective in reducing lymphedema. It is thought that increased macrophage activity leads to the reuptake of proteinaceous material ⁷⁸.

A case report documented the success of ablative carbon dioxide laser treatment of skin lesions and lymphocutaneous fistulas, which resulted in significant improvement of skin lesions. It works by causing thermal damage to the dermis, resulting in the remodeling of superficial tissue and dermal tightening. This was done in a patient with non-filarial elephantiasis but could have an application in filarial disease ¹²⁴.

Filariasis prognosis

Filariasis prognosis is good if filariasis is recognized early and treated in a timely fashion to prevent deformity ²⁹, ², ¹²⁵. Filariasis responds to 5 annual doses of diethylcarbamazine (DEC) with or without ivermectin or albendazole. However, those having chronic lymphatic damage in the form of lymphedema or elephantiasis will respond poorly. Elephantiasis is the most severe form and is due to many years of acute on chronic superimposed infections. There is some ability to treat lymphedema, but it is difficult to manage once reaching advanced stages of the disease. These chronic forms have a poor prognosis. Patients with hydrocele might respond to surgery, but recurrence is common. Long-term disability may result from chronic lymphatic damage or blindness, depending on the infectious filarial organism. Lymphedema or elephantiasis is debilitating rendering the person incapable of performing daily activities.

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