Filariasis

Practice Essentials

Filariasis is a disease group caused by filariae that affects humans and animals (ie, nematode parasites of the family Filariidae).^[1] Of the hundreds of described filarial parasites, only 8 species cause natural infections in humans. The World Health Organization (WHO) has identified lymphatic filariasis as a major cause of disability worldwide, with an estimated 40 million individuals affected by the disfiguring features of the disease.^[2]

In lymphatic filariasis, repeated episodes of inflammation and lymphedema lead to lymphatic damage, chronic swelling, and elephantiasis of the legs (see the image below), arms, scrotum, vulva, and breasts.^{[3, 4, 5, 6, 7, 8]}

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Filariasis. Unilateral left lower leg elephantiasis secondary to Wuchereria bancrofti infection in a boy.

Signs and symptoms

Lymphatic filariasis

• Fever
• Inguinal or axillary 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, vulva, and breasts

The following acute syndromes have been described in lymphatic filariasis:

• Acute adenolymphangitis (ADL) - Sudden fever with lymphadenopathy
• Filarial fever - Fever without associated adenitis
• Tropical pulmonary eosinophilia (TPE) - Dry nocturnal cough

Onchocerciasis

The clinical triad of infection in onchocerciasis is as follows:

• Dermatitis - Skin lesions include edema, pruritus, erythema, papules, scablike eruptions, altered pigmentation, and lichenification
• Skin nodules (ie, onchocercomas) - Tend to be common over bony prominences, with anatomic location depending on geographic region of transmission
• Ocular lesions - 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

Loiasis

The diagnostic feature of loiasis is the Calabar swelling, ie, a large, transient area of localized, nonerythematous subcutaneous edema resulting from a hypersensitivity reaction to the parasite. This is most common around the joints. An additional manifestation of loiasis results from migration of the parasite across the conjunctiva, causing discomfort and irritation of the eye.

Mansonelliasis

Mansonella infections are usually asymptomatic. If symptoms are present, they may include fever, pruritus, skin lumps, lymphadenitis, and abdominal pain.

See Clinical Presentation for more detail.

Diagnosis

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.^[9] Wuchereria bancrofti can be detected via by circulating filarial antigen (CFA) 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 O 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 radiography - Diffuse pulmonary infiltrates are visible in patients with TPE
• Ultrasonography - Can be used to demonstrate and monitor lymphatic obstruction of the inguinal and scrotal lymphatics; has also been used to demonstrate the presence of viable worms
• Lymphoscintigraphy^[10]

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

See Workup for more detail.

Management

Antimicrobials used in the treatment of filariasis include the following:

• Diethylcarbamazine (DEC)
• Ivermectin
• Suramin
• Mebendazole
• Flubendazole
• Albendazole
• Doxycycline - Used to target Wolbachia, an endosymbiotic bacteria in multiple filarial species

Surgery

In lymphatic filariasis, large hydroceles and scrotal elephantiasis are manageable with surgical excision. Correcting gross limb elephantiasis with surgery is less successful and may necessitate multiple procedures and skin grafting.

In onchocerciasis, nodulectomy with local anesthetic is a common treatment to reduce skin and eye complications.

See Treatment and Medication for more detail.

• References

Background

Filariasis is a disease group affecting humans and animals, caused by filariae; ie, nematode parasites of the family Filariidae.^[1] Filarial parasites can be classified according to the habitat of the adult worms in the vertebral host, as follows (see Pathophysiology, Etiology, and Workup):

• Cutaneous group - Includes Loa loa, Onchocerca volvulus, and Mansonella streptocerca
• Lymphatic group - Includes Wuchereria bancrofti, Brugia malayi, and Brugia timori
• Body-cavity group - Includes M perstans and M ozzardi^[11]

Of the hundreds of described filarial parasites, only 8 species cause natural infections in humans. The parasites of the cutaneous and lymphatic groups are the most clinically significant. Other species of filariae may cause incomplete infections because they are unable to reach adult maturity in human hosts and therefore cannot produce first-stage larvae, known as microfilariae (eg, Dirofilaria immitis [dog heartworm], Dirofilaria [Nochtiella] repens, and Dirofilaria tenuis [raccoon heartworm]). (See the image below.)

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Filariasis. This figure displays the life cycle of Wuchereria bancrofti in humans and mosquito vectors (ie, Aedes, Anopheles, Culex, Mansonia species)....

Filariasis has a significant economic and psychosocial impact in endemic areas, disfiguring and/or incapacitating more than 40 million individuals.^[2] With a strong association with mental illness, depression with filariasis is believed to account for 5.09 million disability-adjusted life years (DALYs).^[12] (See Epidemiology, Prognosis, Clinical Presentation, and Treatment.)

Filariae have a specific geographic distribution. For example, W bancrofti is found in sub-Saharan Africa, Southeast Asia, India, and the Pacific Islands. B malayi is found in similar locations but not in sub-Saharan Africa. B timori occurs on Timor Island, in Indonesia. (See Epidemiology.)

In endemic areas, the prevalence of microfilaremia increases with age, as adult worms are gradually acquired over years. Lymphatic filariasis is first contracted in childhood, and most individuals in endemic areas have been exposed by the third or fourth decade of life. (See Pathophysiology and Etiology.)^[13]

As with most helminths, adult filarial parasites replicate in a definitive host. The adult worm burden in an individual cannot increase unless the host is exposed to additional microfilaria. Infected individuals cannot sustain higher levels of parasitemia once they leave the endemic area.

Because the mosquito vector is inefficient, a relatively prolonged stay in an endemic area is usually required to acquire the infection. Disorganized urbanization is adding to the vector population and hence to the increased incidence and prevalence of such diseases in low-income countries.

Patient education

Patients should learn to protect against insect vectors and to refrain from self-treatment regimens, especially with diethylcarbamazine (DEC), since this drug can lead to meningoencephalopathy. (See Treatment and Medication.)

• References

Pathophysiology

The filarial life cycle, like that of all nematodes, consists of 5 developmental (larval) stages in a vertebral host and an arthropod intermediate host and vector. Adult female worms produce thousands of first-stage larvae, or microfilariae, which are ingested by a feeding insect vector. Some microfilariae have a unique daily circadian periodicity in the peripheral circulation. The arthropod vectors (mosquitoes and flies) also have a circadian rhythm in which they obtain blood meals. The highest concentration of microfilariae usually occurs when the local vector is feeding most actively.^[14]

Microfilariae undergo two developmental changes in the insect. Third-stage larvae then are inoculated back into the vertebral host during the act of feeding for the final two stages of development. These larvae travel through the dermis and enter regional lymphatic vessels. During the next 9 months, the larvae develop into mature worms (20-100 mm in length). An average parasite can survive for about 5 years.

The pre-patent period is defined as the interval between a vector bite and the appearance of microfilariae in blood, with an estimated duration of about 12 months.

The following factors affect the pathogenesis of filariasis:

• The quantity of accumulating adult worm antigen in the lymphatics^{[15, 16]}
• The duration and level of exposure to infective insect bites^[17]
• The number of secondary bacterial and fungal infections^[15]
• The degree of host immune response^[18]

Filarial infection generates significant inflammatory immune responses that participate in the development of symptomatic lymphatic obstruction. Increased levels of immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) secondary to antigenic (from dead worms) stimulation of Th2-type immune response have been demonstrated.^[19]

Studies indicate that there is a familial tendency to lymphatic obstruction. This provides support for the hypothesis that host genes influence lymphedema susceptibility.^[20] Studies also suggest that microfilaremia may be increased in individuals with low levels of mannose-binding lectin, suggesting a genetic predisposition.^[8] Furthermore, a propensity to develop chronic disease has been demonstrated in patients with polymorphisms of endothelin-1 and tumor necrosis factor receptor II.^[21]

Prenatal exposure seems to be an important determinant in conferring greater immune tolerance to parasite antigen.^[22] Thus, individuals from endemic areas are often asymptomatic until late in the disease when they have high worm burden, whereas nonimmune expatriates tend to have brisk immune responses and more severe early clinical symptoms, even in light infections.

Studies have shown that lymphatic filarial parasites contain rickettsia-like Wolbachia endosymbiotic bacteria.^[23] This association has been recognized as contributing to the inflammatory reaction seen in filariasis.

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Etiology

Lymphatic filariasis

Mosquitoes of the genera Aedes, Anopheles, Culex, or Mansonia are the intermediate hosts and vectors of all species that cause lymphatic filariasis.^[24]

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 B timori appears to result in more abscesses than infection with B malayi or W bancrofti. (See the image below.)

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Filarial abscess scar on the left upper thigh in a young male who is positive for Wuchereria bancrofti microfilariae

Cellular invasion with plasma cells, eosinophils, and macrophages, together with hyperplasia of the lymphatic endothelium, occurs with repeated inflammatory episodes. 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, which all 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.)

B 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.

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 syndromes are as follows:

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

Onchocerciasis

O volvulus microfilariae from the skin are ingested by the Simulium species of blackflies. 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.^[25]

Loiasis

Mango flies or deerflies of Chrysops genus transmit loiasis. Response to L loa infection appears to differ between residents and nonresidents in endemic areas. Nonresidents with infection 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. (See the image below.)^[26]

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Filariasis. Microfilariae of Loa loa detected in skin snips.

L loa meningoencephalopathy

Meningoencephalopathy is a severe and often fatal complication of infection. This syndrome is usually related to diethylcarbamazine (DEC) administration in individuals with high-density microfilaremia but it may occur without drug therapy.^[27]

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 may also be observed.

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Epidemiology

Occurrence in the United States

No form of human filariasis is currently endemic to the United States. W bancrofti was once 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 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.

Two cases of ocular onchocerciasis have been reported in the United States^[28] as has a single case of a spinal mass in a toddler due to Onchocerca lupi infection.^[29]

Global occurrence

Lymphatic filariasis affects more than 120 million people worldwide and is found throughout the tropics and subtropics. In 1997, the World Health Organization (WHO) initiated the Global Program to Eliminate Lymphatic Filariasis (GPELF) with a goal to globally eliminate lymphatic filariasis as a public health problem by 2020.^{[2, 30]} This initiative utilizes mass drug administration (MDA) in 60 countries. The goal is to reduce prevalence levels to a point at which transmission is no longer sustainable. This program has led to a prevalence reduction in 15 countries so far.^[2]

At least 37 million people are infected with O volvulus globally. The vast majority of cases (99%) occur in sub-Saharan Africa.^[31] Onchocerciasis is the second leading infectious cause of blindness worldwide. Approximately half a million people are affected.^[32] In 2016, Abu-Hamed, Sudan, became the first region to eliminate the disease under a mass treatment program with ivermectin.^[33] Today, continued efforts to reduce disease prevalence are conducted via guidance by the WHO and the Non-Governmental Development Organizations Coordination Group for Onchocerciasis Control.

Prevalence rates of L loa range from 3-13 million people worldwide.^[34] Loiasis remains of particular interest when initiating MDA programs for lymphatic filariasis because the drugs commonly used in these regimens (DEC) may have adverse effects in patients with high-density Loa loa infection.

Sex- and age-related demographics

Both sexes are equally susceptible to filariasis. Because of different local and cultural practices, however, as well as differences in exposure to insect vectors, one sex or the other may be exposed to infection more often.

Individuals of all ages are susceptible to infection and are potentially microfilaremic. Microfilaremia rates increase with age through childhood and early adulthood, although clinical infection may not be apparent. The manifestation of acute and chronic filariasis usually occurs only after years of repeated and intense exposure to infected vectors in endemic areas.

• References

Prognosis

The prognosis in filariasis is good if infection is recognized and treated early. Filarial diseases are rarely fatal, but the consequences of infection can cause significant personal and socioeconomic hardship for those who are affected.

The morbidity of human filariasis results mainly from the host reaction to microfilariae or developing adult worms in different areas of the body. Long-term disability may result from chronic lymphatic damage or blindness, depending on the infectious filarial organism.

• References

History

Symptoms of filariasis are dependent on species and body type 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 is usually the highest. Several symptomatic variations have been observed.^[35]

Because cases of filariasis in North America and high-income countries are uncommon, physicians may initially 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

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)
• Chronic, irreversible lymphedema

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

• Fever
• Inguinal or axillary lymphadenopathy
• Testicular and/or inguinal pain
• Skin exfoliation
• Limb or genital swelling

The following acute syndromes have been described in filariasis:

• Acute adenolymphangitis (ADL) - Sudden fever with lymphadenopathy
• Filarial fever - Fever without associated adenitis
• Tropical pulmonary eosinophilia (TPE) - Dry nocturnal cough

Acute 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.^[36]

Signs and symptoms of 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.

Tropical pulmonary eosinophilia

TPE is a form of occult filariasis. Presenting symptoms include a dry, paroxysmal nocturnal cough; wheezing; dyspnea; anorexia; malaise; and weight loss.

Symptoms of TPE are usually due to the inflammatory response to the infection. Characteristically, peripheral blood eosinophilia and abnormal findings on chest radiography are observed. TPE is usually related to W bancrofti or B malayi infection.

Onchocerciasis

Onchocerciasis is also known as “hanging groins, leopard skin, river blindness, or sowda.” Symptoms result from the presence of microfilariae in the skin and eyes and include pruritus, subcutaneous nodules (onchocercomas), lymphadenitis, and blindness.

Patients with onchocerciasis may report impaired visual acuity due to corneal fibrosis. Epilepsy has been associated with onchocerciasis in some studies.^[37]

Loiasis

The symptoms of L loa infection are usually confined to subcutaneous swellings on the extremities, localized pain, pruritus, and urticaria. The lesions, known as Calabar swellings, result from a local hypersensitivity reaction to the parasite and are named after the Nigerian city in which they were discovered.

Rare manifestations of infection include the following:

• Arthritis
• Breast calcification
• Meningoencephalopathy
• Endomyocardial fibrosis
• Peripheral neuropathy
• Pleural effusions
• Retinopathy

M ozzardi, M perstans, and M streptocerca infection

Mansonella infections are usually asymptomatic. If symptoms are present, they may include fever, pruritus, skin lumps, lymphadenitis, and abdominal pain.

Dirofilaria infection

The genus Dirofilaria is classified under the family of Filariidae and is commonly known as the parasitic cause of “heart worm” in dogs, cats, and other mammals. Clinical manifestations of the disease in humans are rare but may include the following:

• Symptoms of D immitis infection involve the respiratory system and include chest discomfort, cough, fever, and hemoptysis.
• Symptoms of D repens infection usually include a lump in the subcutaneous tissue, submucosa, or eyelid.

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Physical Examination

Signs of filariasis present on examination are species-dependent and may be acute or chronic in nature.

Lymphatic filariasis

In lymphatic filariasis, repeated episodes of inflammation and lymphedema lead to lymphatic damage, chronic swelling, and elephantiasis of the legs, arms, scrotum, vulva, and breasts. (See the images below.)^{[3, 4, 5, 6, 7, 8]}

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Lymphatic filariasis resulting from Wuchereria bancrofti infection may result in limb lymphedema, inguinal lymphadenopathy, and hydrocele. Photograph ....

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Filariasis. Unilateral left lower leg elephantiasis secondary to Wuchereria bancrofti infection in a boy.

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Filariasis. This is a close-up view of the unilateral lower leg elephantiasis shown in the previous image. Note the lymphedema and typical skin appear....

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Filariasis. Lateral view of the right outer aspect of a leg affected by elephantiasis secondary to Wuchereria bancrofti infection.

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Filariasis. Inner aspect of the lower leg of the male patient in the previous image, showing gross elephantiasis secondary to Wuchereria bancrofti inf....

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Filariasis. Unilateral left hydrocele and testicular enlargement secondary to Wuchereria bancrofti infection in a man who also was positive for microf....

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Filariasis. Bilateral hydrocele, testicular enlargement, and inguinal lymphadenopathy secondary to Wuchereria bancrofti infection.

The WHO grading system defines the severity of edema. The stages range from 1-7, and, as the stage increases, so does the extent of edema and risk for secondary infection.^[38]

Hydrocele is the most common manifestation of chronic W bancrofti infection in males in endemic areas but is rare with B malayi and B timori infection.

Chyluria also may be present in chronically infected persons. Since large amounts of fat and protein are lost in the urine, these conditions can lead to nutritional deficiencies.

Tropical pulmonary eosinophilia

Scattered wheezes and crackles occur in both lung fields. Lymphadenopathy and hepatomegaly may be present.

Onchocerciasis

The clinical manifestations of infection include dermatitis, skin nodules, and ocular lesions, as follows:

• Dermatitis - Skin lesions include edema, pruritus, erythema, papules, scablike eruptions, altered pigmentation, and lichenification
• Skin nodules (ie, onchocercomas) - Skin nodules tend to be common over bony prominences (see the image below)
•  

  

   
• Ocular lesions - 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:

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

Loiasis

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

Peripheral nerve involvement in loiasis has also been described.^[39] Microfilaremia tends to be asymptomatic. Occasionally, the worm is observed migrating through subconjunctival or other tissues.

M ozzardi, M perstans, and M streptocerca infection

Subcutaneous or conjunctival nodules and lymphadenopathy may be detected in symptomatic persons.

Dirofilaria infection

These infections are characterized as follows:

• D repens infection - May result in painless subcutaneous, submucosal, or eyelid lumps
• D immitis infection - Reduced localized air entry on chest auscultation may be detected

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Approach Considerations

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 W bancrofti infection. The microfilariae of all species that cause lymphatic filariasis and the microfilariae of L loa, M ozzardi, and M perstans can be detected on a blood smear.^[9] Broadly, the diagnostic approach varies by group of filariasis.

Lymphatic filariasis

Microfilariae on blood smear examination: Draw blood at night, when levels of parasitemia are generally highest. The three lymphatic filarial species can also be distinguished based on their morphologic characteristics on light microscopy.

Circulating filarial antigen (CFA) detection: These assays are regularly available for only W bancrofti detection in lymphatic filariasis.

Adult worms can be seen in the lymphatics.

Additional testing in lymphatic filariasis includes PCR and serology. PCR is not widely available and is mostly used in a research setting. Serology testing for filarial antibodies cannot distinguish between past and present infection and are not typically specific for filarial infections; however, specificity can be improved via assays based on certain recombinant antigens, such as Wb123 in W bancrofti.^[41]

Cutaneous filariasis

Definitive diagnosis of O volvulus and M streptocerca infections occurs when microfilariae are detected in multiple skin snip specimens taken from different body sites. In addition, microfilariae of O volvulus may be detected in the cornea or anterior chamber of the eye, using slit-lamp examination. O volvulus may also be detected with antigen testing, although this is not regularly available.^[42] 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 of 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

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

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Detection of Microfilariae in Blood

The microfilariae of all species that cause lymphatic filariasis and the microfilariae of L loa, M ozzardi, and M perstans are detected in blood. (See the image below.)

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Filariasis. Microfilariae of Mansonella perstans in peripheral blood.

Species that cause lymphatic filariasis have microfilarial levels that tend to peak at night, so it is recommended to collect samples between 10:00 pm and 2:00 am. For loiasis, microfilariae levels peak between 10 am and 2 pm. Capillary finger-prick or venous blood is used for thick blood films. Venous blood also can be concentrated or passed through a Nuclepore filter before being examined microscopically to improve sensitivity.^[43] The organism species can be determined based on the microscopic appearance. W bancrofti and Brugia species have an acellular sheath. W bancrofti has no nuclei in its tail, whereas B malayi has terminal and subterminal nuclei. (See the image below.)

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Filariasis. Appearance of microfilariae after concentration of venous blood with a Nuclepore filter.

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Filariasis. Microfilaria of Wuchereria bancrofti in a peripheral blood smear.

Microfilariae may be absent in the following cases:

• Patients with ADL or late chronic lymphatic disease
• Typically, patients with loiasis, unless the infection has been present for many years

Detection of filarial antigen

The presence of circulating filarial antigens in the peripheral blood, with or without microfilariae, is diagnostic of filarial infection and is useful in monitoring response to therapy. Commercial kits are available for W bancrofti to test venous blood and can be quantitative (Og4C3 monoclonal antibody-based ELISA) or qualitative (immunochromatographic). These assays have all demonstrated superior sensitivity over microscopy.^[44]

Detection of filarial antibodies

The use of recombinant antigens for the diagnosis of certain filarial species has improved sensitivity and specificity of these tests over the years. For W bancrofti, an IgG4 assay has been developed for the recombinant antigen Wb123 and demonstrates superior sensitivity and specificity in the diagnosis of bancroftian filariasis.^[41] In addition, ICD card tests for IgG4 antibodies against recombinant antigen Ov-16 in onchocerciasis have improved the sensitivity and specificity of serologic testing in these cases.^[45]

Serum immunoglobulin concentrations: Elevated serum IgE and IgG4 occur with active filarial disease. A multiplex bead assay to monitor serial levels of serum antibody during treatment has been proposed.^[46]

Complete blood cell count

Eosinophilia is marked in all forms of patent filarial infection.

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Detection of Microfilariae in the Skin, Eye, and Urine

Skin

O volvulus and M streptocerca infections are diagnosed when microfilariae are detected in multiple skin snip specimens from different body sites.

Preferred skin snip sites vary regionally. In suspected cases of African onchocerciasis, the recommended sites for skin snips are the gluteal and thigh regions. For American onchocerciasis, the scapula and iliac crest areas are preferred.

Mazzotti test

Owing to the risk of severe adverse reactions, the Mazzotti test is not regularly used in the diagnosis of onchocerciasis, especially in individuals with a high disease burden. In certain cases, the test may allow for a presumptive diagnosis of cutaneous filariasis when skin snips are negative for microfilariae. To perform the test, a single dose (50-100 mg) of DEC is given, and, if the patient is infected, he or she will experience an intense pruritic rash with fever and edema. Steroids may be necessary to control this inflammatory reaction. Alternatively, a patch test with 10% DEC solution can be placed on the skin, resulting in a more localized reaction.

Eye

Microfilariae of O volvulus may be detected in the cornea or anterior chamber of the eye using slit-lamp examination.

Urine examination and microscopy

Microfilariae may also be observed in chylous urine and hydrocele fluid. If lymphatic filariasis is suspected, urine should be examined macroscopically for chyluria and then concentrated to examine for microfilariae.

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Imaging Studies

The following imaging studies can be used in the evaluation of filariasis:

• Chest radiography - Diffuse pulmonary infiltrates are visible in patients with tropical pulmonary eosinophilia (TPE)
• Ultrasonography - Can be used to demonstrate and monitor lymphatic obstruction of the inguinal and scrotal lymphatics
• Lymphoscintigraphy^[10]

Ultrasonography has also been used to demonstrate the presence of viable worms, which are seen to be in continuous motion (ie, "filarial dance" sign). This imaging characteristic has been used to monitor the effectiveness of treatment.^[47] In addition, deep onchocercomas and vitreous changes in the eye can sometimes be detected with ultrasonography.

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Biopsy

Biopsy specimens should be obtained only in patients with cutaneous filariasis, as excising nodes may further impede lymphatic drainage in patients with lymphatic filariasis. Adult worms of O volvulus and L loa are found in the nodules and fibrotic tissue of the skin. L loa worms occasionally can be dissected from the conjunctiva of the eye or bridge of the nose as they migrate through subcutaneous tissue.

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Histologic Findings

Lymphatic filariasis

Affected lymph nodes demonstrate fibrosis and lymphatic obstruction with the creation of collateral channels. The skin of individuals with elephantiasis is characterized by hyperkeratosis, acanthosis, lymph and fatty tissue, loss of elastin fibers, and fibrosis. (See the image below.)

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Filariasis. Adult worms of Wuchereria bancrofti in cross section isolated from a testicular lump.

Onchocerciasis

Two areas are evident in onchocercomas: (1) a central stromal and granulomatous, inflammatory region where the adult worms are found and (2) a peripheral, fibrous section. Microfilariae in the skin incite a low-grade inflammatory reaction with loss of elasticity and fibrotic scarring. (See the image below.)

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Filariasis. Adult Onchocerca volvulus contained within onchocercomas of the skin.

• References

Approach Considerations

Medical Management

The medical management of a filarial infection should be specific and based on the microfilariae isolated or antigenemia detected. Specific attention should be paid to the presence of coinfection with multiple filarial organisms, as this will alter the treatment regimen.

Mass drug administration (MDA) reduces the transmission of filarial infection and disease morbidity by decreasing the burden of microfilaremia, resulting in suboptimal levels for transmission by disease vectors.^{[48, 49, 50, 51, 52, 53]} The effects of mass treatment on filariasis have reportedly been sustained for up to 6 years.^{[54, 55, 56, 57]}

In 1997, the World Health Organization (WHO) initiated the Global Program to Eliminate Lymphatic Filariasis (GPELF) with a goal to globally eliminate lymphatic filariasis as a public health problem by 2020.^{[2, 30]} This initiative utilizes mass drug administration (MDA) in 60 countries at risk to reduce prevalence levels to a point at which transmission is no longer sustainable. The effort has led to a prevalence reduction in 15 countries thus far.^[2] Overall, MDA strategies have differed both in their drug regimen and frequency. Traditionally, annual mass treatment with albendazole plus ivermectin or DEC has been used to interrupt the transmission of W bancrofti.

One study evaluated the effect of higher dose and increased frequency (twice yearly) of albendazole plus ivermectin therapy for W bancrofti. It found that it resulted in complete microfilarial clearance, as well as a more sustained clearance than that resulting from standard-dose albendazole-ivermectin treatment.^[58] Another study demonstrated that a 3-drug regimen (DEC, albendazole, ivermectin) resulted in better outcomes and fewer adverse events than therapy with DEC and albendazole alone.^[59]

In 2016, Abu-Hamed, Sudan, became the first focus of onchocerciasis to eliminate the disease under a mass treatment program with ivermectin.^[33] Today, continued efforts to reduce disease prevalence are conducted via guidance by the WHO and Nongovernmental Development Organizations Coordination Group for Onchocerciasis Control.

Loiasis remains of particular interest when initiating MDA programs for lymphatic filariasis, because the drugs commonly used in these regimens (DEC) may have adverse effects in patients with significant loiasis.

Although there have been efforts to develop an effective vaccine, none is currently available.^[60]

Surgery

Lymphatic filariasis

Large hydroceles and scrotal elephantiasis can be managed with surgical excision. Correcting gross limb elephantiasis with surgery is less successful and may necessitate multiple procedures and skin grafting.

Onchocerciasis

Nodulectomy with local anesthetic is a common treatment to reduce skin and eye complications.

Diet and activity

Fatty foods are restricted in individuals with proven chyluria that is associated with lymphatic filariasis. Because of associated nutritional deficiencies, diets should be high in protein.

Individuals with chronic lymphatic filariasis are encouraged to mobilize (with compression bandage support and regular exercise) the affected limb and to elevate it at night.

Prevention

Avoidance of bites from insect vectors is usually not feasible for residents of endemic areas, but visitors to these regions should use insect repellent and mosquito nets. As noted above, mass drug administration programs are the backbone of the goal to reduce prevalence rates to a point at which transmission is no longer sustainable.

Consultations

To prevent inappropriate treatment, consult an infectious disease specialist in all cases of suspected filariasis outside of endemic nations. Other possible consultations include:

• Urologist
• Ophthalmologist
• General surgeon
• Plastic surgeon

• References

Pharmacologic Therapy

Lymphatic filariasis

Diethylcarbamazine (DEC) is the treatment of choice for lymphatic filariasis. However, when co-infection with other filarial organisms exists or in the context of mass drug administration, the treatment course must be adjusted accordingly.

Treatment for lymphatic filariasis monoinfection consists of DEC 6 mg/kg for 12 days. Alternatively, doxycycline (200 mg/d) may be added to the regimen for a 6-week course. Studies indicate reduced severity of lymphedema in certain cases.^[61] Other regimens, including doxycycline for 23 days followed by doxycycline plus albendazole for 7 days, have also been shown to be safe and effective.^[62] As stated above, in the context of MDA to reduce microfilaremia in endemic areas, annual (or semi-annual) multidrug regimens of albendazole plus ivermectin or DEC are used.

Patients with asymptomatic microfilaremia can be treated on an outpatient basis. Supervision of oral DEC therapy and post-administration observation are recommended for patient compliance with therapy and for the management of febrile reactions in heavily infected patients.

Inpatient care may initially be required for adenolymphangitis (ADL) and chronic filariasis. Such care includes the use of antihistamines, steroids, pain relief, and intravenous antibiotics for secondary infections.

Lymphedema

Steroids can be used to soften and reduce the swelling of lymphedematous tissues. As noted above, mild to moderate filarial lymphedema has been shown to improve with a 6-week course of doxycycline, independent of ongoing infection.^[61]

Bed rest, limb elevation, and compression bandages traditionally have been used for the management of chronic lymphedema.

Chronic filariasis

Treatment of chronic filariasis does not change the prognosis, as irreversible fibrosis usually destroys lymphatic tissue. However, asymptomatic patients, hoping to diminish progression of the disease, still typically undergo treatment, although the benefit of this is unclear.^[63]

Chyluria

In the treatment of chyluria, a special low-fat, high-protein diet supplemented with medium-chain triglycerides may prove beneficial.

Secondary infection

Supportive care should include the prevention of secondary infection, especially in patients with advanced disease. Individuals with chronic infections should wash the affected area frequently, apply antiseptic creams to abrasions, wear comfortable footwear, and exercise the affected limb to aid lymphatic flow.

Concomitant infections

The treatment regimen must be adjusted in patients who are co-infected with onchocerciasis and/or loiasis to avoid a severe adverse reaction to DEC.

For concomitant infection with onchocerciasis, DEC cannot be used as primary treatment owing to the risk of complications resulting from dying microfilariae in the eye or skin. To avoid this, co-infected patients can be treated first with ivermectin followed by DEC treatment one month later. However, when there is ocular involvement, this timing mechanism remains unclear.^[64] Alternatively, doxycycline 200 mg/d for 6 weeks may be given first, followed by a single dose of ivermectin 150 mcg/kg; however, these studies were solely evaluated in onchocerciasis and did not focus on individuals co-infected with lymphatic filariasis.^[65]

For concomitant infection with loiasis, treatment variation depends on the level of Loa loa microfilariae in the blood. In general, if microfilarial levels of Loa loa are low (< 2500/mL), DEC can be safely administered with low risk for serious adverse reactions. One study indicated that ivermectin could safely be used until Loa loa levels reached 8000 microfilariae/mL, at which point the threshold for a severe reaction to ivermectin significantly increased.^[66] If levels exceed 8000 microfilariae/mL, pretreatment with albendazole 200 mg bid for 3 weeks has shown potential benefit in its ability to decrease microfilarial levels in loiasis.^[67]

Onchocerciasis

The primary treatment of onchocerciasis depends on the prevalence and transmission of the disease in the area. In areas with high transmission rates, ivermectin is administered at a dose of 150 mcg/kg once every 3 months until symptoms resolve.^[68] . In nonendemic areas, the same treatment regimen as above with ivermectin may be used; however, some regimens that include doxycycline 200 mg/d for 4-6 weeks followed by ivermectin have been investigated.^[69]

Moxidectin is an antiparasitic drug that was approved by the FDA in June 2018 to treat onchocerciasis in patients aged 12 years or older. The WHO initiated clinical trials for use in onchocerciasis in 2009.^[70] Moxidectin is closely related to ivermectin but yields a more sustained reduction in microfilarial levels. FDA approval was based on a double-blind, parallel group, superiority trial (n=1472) that compared moxidectin (8 mg PO once) with ivermectin (150 mcg/kg PO once). The trial took place in Ghana, Liberia, and the Democratic Republic of the Congo. Results showed skin microfilarial loads (ie, parasite transmission reservoir) were lower from month 1 to month 18 after moxidectin treatment than after ivermectin treatment, with an 86% difference at month 12. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress toward elimination.^[71]

Loiasis

In general, DEC is used as the primary treatment for loiasis; however, owing to the risk of severe encephalopathy in patients with significant microfilaremia, the regimen is adjusted accordingly. Thus, before starting therapy, an accurate microfilarial count must be obtained.

If a patient has a low level of microfilariae in the blood (< 2500/mL), he or she can be safely treated with DEC 8-10 mg/kg/d for 21 days. If microfilarial levels are higher, patients should be treated only if they are symptomatic. In these cases of high microfilarial levels and symptoms, patients can be pretreated with albendazole 200 mg bid for 3 weeks prior to definitive treatment with DEC.^[67] When available, apheresis lowers microfilarial counts prior to treatment with DEC.^[72]

Mansonella infection

Treatment strategies for M perstans infection vary based on regional strain differences. Several treatment courses may be needed to achieve cure. Wolbachia, an endosymbiont found in many filarial species, will predict whether doxycycline is necessary to clear microfilaremia.^[73] For strains that do not contain Wolbachia, treatment with DEC and mebendazole or mebendazole alone may be effective, although rates of microfilarial clearance are low.

Doxycycline treatment typically kills or sterilizes the filarial nematode. In an open-label, randomized trial, Coulibaly et al recruited patients with M perstans infection from four African villages in Mali. Patients were randomly assigned to receive 200 mg of doxycycline orally every day for 6 weeks or no treatment. At 12 months, 97% of patients who received doxycycline had no detectable blood levels of M perstans, compared with 16% of patients in the group who did not receive treatment. At 36 months, M perstans remained suppressed in 75% of patients who had received doxycycline.^[74]

M ozzardi may be treated with ivermectin while DEC is commonly used for M streptocerca. Ivermectin has been used to treat these infections and those strains of M ozzardi that contain Wolbachia may respond to doxycycline. M ozzardi strains do not respond to DEC treatment.

Long-Term Monitoring

Patient monitoring includes posttreatment follow-up for 12 months, with examination of peripheral blood and skin snips for microfilariae.

Observe and monitor oral therapeutic plans with DEC because compliance with therapy is poor and usually incomplete.

Patients with filariasis are, by default, at risk for other parasitic infections, because areas endemic for bancroftian filariasis are also endemic for other parasites. After treatment, patients should be monitored for symptoms that are characteristic of parasitic infections.

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Medication Summary

Patients with asymptomatic microfilaremia in lymphatic filariasis can be treated on an outpatient basis. Supervision of oral DEC therapy is recommended for patient compliance with therapy and for the management of febrile reactions in heavily infected patients. Inpatient care may initially be required for adenolymphangitis (ADL) and chronic filariasis.

Mass drug administration in filariasis reduces the transmission of filarial infection and disease morbidity by decreasing the burden of microfilaremia, resulting in suboptimal levels for transmission by disease vectors.^{[48, 49, 50, 51, 52, 53]}

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Ivermectin (Mectizan)

• Dosing, Interactions, etc.

Clinical Context:  Ivermectin is a potent microfilaricide against W bancrofti and O volvulus; however, it has limited macrofilaricidal activity.^[74]

Ivermectin exerts its antiparasitic action by acting as a potent agonist at gamma-aminobutyric acid (GABA) receptors and potentiating the inhibitory signals sent to motor neurons, thus paralyzing the parasite. Because GABA is confined to the CNS in humans and ivermectin does not cross the blood-brain barrier, the drug has no paralytic action in humans.

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Moxidectin

• Dosing, Interactions, etc.

Clinical Context:  Moxidectin, a macrocyclic lactone, is an anthelmintic indicated for the treatment of onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older. Plasma half-life is 20-43 days and thereby reduces and maintains low skin microfilarial density effectively. Moxidectin does not kill adult O volvulus. Follow-up evaluation is advised. Safety and efficacy of repeat administration has not been studied.

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Diethylcarbamazine (Hetrazan)

• Dosing, Interactions, etc.

Clinical Context:  Diethylcarbamazine (DEC) is commonly used in lymphatic filariasis and acts as both a microfilaricidal and macrofilaricidal agent. Its precise mechanism of action is not understood, but it has been shown to induce immobilization of microfilariae by using hyperpolarization effects to decrease muscle activity. Alteration of the surface membrane also occurs, with enhanced destruction by the host's immune system. Evidence exists that DEC may enhance adhesion of granulocytes via antibody-dependent and -independent mechanisms. Hypotheses also include interference by microfilarial intracellular processing and transport of specific macromolecules by DEC.^[75]

Concurrent administration of corticosteroids should be considered with DEC treatment to minimize the allergic manifestations secondary to the disintegration of microfilariae, particularly in O volvulus and L loa infections.

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Suramin

• Dosing, Interactions, etc.

Clinical Context:  Suramin is an antitrypanosome and an anthelminthic. Its use is restricted because of its intrinsic toxicity and the frequency with which associated complications occur. The WHO has advised that it only be considered for the curative treatment of individuals in areas without transmission of onchocerciasis, in individuals leaving an endemic area, and in individuals with severe hyperreactive onchodermatitis if their symptoms are not adequately controlled with ivermectin.

The WHO has recommended that suramin not be used to treat onchocerciasis in individuals who are elderly or infirm or in patients with severe liver or renal disease. The drug is not recommended for children younger than 10 years, in totally blind persons (unless they require relief from intensely itchy lesions), in lightly to moderately infected people with no symptoms and whose eyes are not at risk, or in pregnant women (who should be treated after delivery).

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Mebendazole

• Dosing, Interactions, etc.

Clinical Context:  Mebendazole causes worm death by selective and irreversible blockade of uptake of glucose and other nutrients in a susceptible adult intestine where helminths dwell. 

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Albendazole

• Dosing, Interactions, etc.

Clinical Context:  Albendazole is a broad-spectrum anthelmintic. It decreases adenosine triphosphate (ATP) production in worms, causing energy depletion, immobilization, and, finally, death.

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Class Summary

Anthelminthic agents include the macrocyclic lactone derivatives ivermectin and moxidectin, piperazine derivatives, and benzimidazole derivatives.

The biochemical pathways of parasites differ from those of their human host. Thus, the toxicity of anthelminthic agents can be directed at the parasite or its egg or larvae. The antiparasitic actions of these drugs vary and include the following:

- Inhibition of microtubules, causing irreversible block of glucose uptake

- Tubulin polymerization inhibition

- Depolarization of neuromuscular blockade

- Cholinesterase inhibition

- Increased cell membrane permeability, resulting in intracellular calcium loss

- Vacuolization of the schistosome tegument

- Increased cell membrane permeability to chloride ions via alteration of chloride channels

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Doxycycline (Doxy 100, Vibramycin, Doryx, Monodox, Alodox)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is a broad-spectrum, synthetically derived, bacteriostatic antibiotic in the tetracycline class. In filariasis, it is primarily used to target Wolbachia, an endosymbiotic bacterium in onchocerciasis and lymphatic filariasis. Doxycycline is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.

Doxycycline inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl transfer RNA (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

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Class Summary

These agents may provide an alternative to traditional antihelminthics.

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