Blood and Tissue Nematodes: Filarial Worms

Epidemiology

Lymphatic filariasis is caused by three species of filarial worms, Wuchereria bancrofti, Brugia malayi, and Brugia timori, but most (>90%) infections are caused by W. bancrofti. Once globally distributed in tropical and subtropical climates, since the initiation of the WHO Global Program to Eliminate Lymphatic Filariasis , infections have declined markedly through community mass drug administration campaigns. In 2000, an estimated 199 million people in 72 countries were infected. However, by 2020, the numbers had declined to about 51 million infections in 50 endemic countries in Africa, South and Southeast Asia, some Western Pacific islands, and Guyana and Hispaniola in the Americas ( Table 278.1 ). ^,

Parasites causing lymphatic filariasis are transmitted to humans through various mosquito vectors, with genera or species depending on the geographic locale. Initial infection occurs when an infective mosquito deposits the third-stage larvae into the bloodstream of its host, often a child aged 2–4 years. Children are typically asymptomatic or with only occasional disease manifestations before puberty. In areas of intense transmission, microfilaremia prevalence increases rapidly between the ages of 5 and 10 years. After entering a human host, larvae migrate to lymph nodes, where they grow into adult worms that can live in the lymphatic vessels for 5–10 years. The proliferation of the threadlike worms within lymphatic vessels can disrupt lymphatic drainage and increase susceptibility to secondary bacterial or fungal infections. In about a third of infected people, chronic inflammation over time promotes remodeling of the lymphatic vessels, leading to swelling of the extremities (“elephantiasis”), hydroceles, or testicular masses. The three species cause similar lymphatic disruption, although genital involvement occurs primarily with W. bancrofti infection. Chronic manifestations of lymphatic filariasis are often disfiguring and associated with marked morbidity and occur with increasing frequency over time but infrequently in people aged <20 years.

Clinical Manifestations

A notable feature of filarial infection is the lack of overt clinical symptoms or signs despite many thousands of actively motile worms. Most infected people are asymptomatic. However, filarial lymphadenopathy can be common in infected children, and before the children reach puberty, adult worms can be detected by ultrasonography of the inguinal, crural, or axillary lymph nodes and vessels. In boys after puberty, the adult worms tend to live in the intrascrotal lymphatic vessels.

Ultrasonography of lymphatic vessels can reveal motile adult worms (i.e., the filarial dance sign). Even in asymptomatic people, the presence of adult worms living in tangled nests within lymphatic vessels leads to lymphatic dilation and abnormal lymph flow, which can be demonstrated by lymphoscintigraphy. In about a third of infected people, these changes predispose to lymphedema. Lymphatic vessel dilation, lymph node enlargement, and fibrosis can be visualized when lymph nodes ( Fig. 278.1 ) are examined histopathologically. Microscopic hematuria and proteinuria also can be found. Factors that predispose some infected people but not others to develop clinical disease are not well understood, but frequency and intensity of infection and host inflammatory response are likely related. ^{, ,}

Acute filarial lymphangitis has been well documented in travelers to endemic areas. At 2–6 months after exposure, acute inflammation can develop in a lymphatic vessel and its associated lymph nodes, most frequently in the leg, scrotal area, or arm. Inflammation characteristically progresses distally along the lymphatic vessel, which becomes indurated, tender, and erythematous, and then resolves spontaneously within 3–7 days. Because biopsies reveal intense inflammation and nonliving adult worms, acute filarial lymphangitis is thought to be caused by the death of an adult worm.

Acute dermatolymphangioadenitis (ADLA) is a clinically distinct syndrome that is often confused with filarial lymphangitis. ADLA is caused by bacterial infection of the small collecting lymphatic vessels in areas of lymphatic dysfunction. Unlike true filarial lymphangitis, this syndrome develops in a reticular rather than in a linear pattern and is more commonly associated with severe pain, fever, and chills. Lymphedema occurs in the legs, arms, scrotum, penis, and extremities is usually unilateral. The most important factor involved in the progression of filarial lymphedema to elephantiasis is repeated episodes of ADLA, originating from breaks in the epidermis, which contribute to further lymph stasis, secondary bacterial and fungal infections, and fibrosis. ^, ADLA and acute filarial lymphangitis predominantly occur in adults but have been reported in children.

The pathogenesis of filarial hydrocele is unclear but is thought to be a consequence of lymphatic damage caused by living adult W. bancrofti . In filariasis-endemic areas, clinically apparent hydrocele instead may be a chylocele, resulting from rupture of dilated intrascrotal lymphatic vessels and leakage of lymph into the cavity of the testicular tunica vaginalis. Chyluria results from rupture of dilated retroperitoneal lymphatic structures into the renal pelvis.

Tropical pulmonary eosinophilia—caused by immune hyper-response to microfilariae trapped in the lungs—can occur in children but most commonly occurs among men aged 20–40 years. Most cases have been reported in long-term residents from Asia. Tropical pulmonary eosinophilia is characterized by marked peripheral blood eosinophilia (>3000 cells/μL), elevated serum IgE (>10,000 ng/mL), low-grade fever, lymphadenopathy, and a nonproductive cough that is more severe at night; peripheral microfilaremia typically is absent.

Laboratory Findings and Diagnosis

The standard for diagnosis is microscopic detection of microfilariae on a thick blood film ( Fig. 278.2 ), but filtration of 1–5 mL blood through a 0.3- to 0.5-μm nucleopore filter is a more sensitive method. Microfilariae have nocturnal periodicity in most areas endemic for W. bancrofti, and thus blood specimens should be collected between 10 pm and 2 am. Microfilariae of the three species can be distinguished morphologically.

Infected children are frequently microfilaria negative. Serology may be useful as patients with active filarial infection typically have elevated antifilarial IgG4 levels. Ultrasonography can be used to visualize adult worms in children. In postpubertal boys and men, the living adult worms can be detected readily on ultrasonography of the scrotal area. Rapid lateral flow assays that detect circulating W. bancrofti antigen or Brugia spp. antibody are used in endemic countries but not approved for use by FDA. Laboratory tests often are negative in patients with lymphedema as this is a chronic complication resulting from lymphatic damage that can worsen after worms have died ( Table 278.2 ).

In tropical pulmonary eosinophilia, microfilaremia typically are absent. In children with a history of exposure and a clinically compatible syndrome, eosinophilia and positive IgG4 on serologic testing are important diagnostic clues. Clinical response to treatment and decline in eosinophilia can help confirm the diagnosis.

Treatment

Diethylcarbamazine (DEC) is the drug of choice for lymphatic filarial infection as it is both microfilaricidal and active against the adult worm. For adults and children aged >18 months (i.e., able to safely swallow the tablets), a single 6 mg/kg dose is as effective as the alternatively recommended dose of 6 mg/kg/day for 12 days both for killing the adult worm and long-term suppression of microfilariae. Most authorities recommend DEC treatment for infected people regardless of whether they have signs and symptoms of lymphatic filariasis to clear the infection.

Adverse reactions to DEC include fever, myalgia, headache, and malaise—with severity related directly to microfilarial density before treatment. Symptoms develop within the first 2 days after treatment and usually are self-limited. Local adverse reactions (e.g., tender nodules) can occur at the site of the adult worm, especially in the scrotal area. In the US, DEC is not FDA-approved and is available only through the CDC Drug Service (during business hours: 404-718-4745; for emergencies on evenings, weekends, and holidays: 770-488-7100 or 1-800-CDC-INFO). Although DEC is considered a low-risk drug, US authorities recommend that it not be used during pregnancy. It is not known whether DEC is excreted in breast milk. Importantly, DEC is contraindicated in patients who may have onchocerciasis co-infection due to the possibility of severe exacerbations with eye involvement (Mazzotti reaction). The drug also should be avoided in patients with circulating Loa loa microfilarial levels of 8,000/μL or higher due to the potential for severe side effects (e.g., encephalopathy, renal failure) with massive worm die-off.

Ivermectin is a potent microfilaricidal drug that may also reduce the fertility of worms but does not kill the adult worm, and thus is not recommended to treat the individual affected child. Albendazole appears to enhance the microfilarial suppression of DEC and ivermectin and may have some macrofilaricidal effect. ^, In endemic communities, recent trials using one-time dosages of ivermectin, DEC, and albendazole combined in mass drug administration campaigns found 100% clearance of microfilariae, suggesting adult worms are killed or permanently sterilized using this triple-drug regimen; the regimen appears to be well tolerated and without observed serious side effects. ^, Additionally, increasing evidence suggests that a 4- to 8-week treatment regimen with doxycycline can effectively target Wolbachia, the intracellular bacterial symbiont of filarial parasites, and thus kill most adult worms without causing severe side-effects.

There is little evidence to suggest that DEC alters the course of ADLA or results in clinical improvement of longstanding lymphedema, elephantiasis, or hydrocele. However, one published report suggested that the combination of DEC and albendazole may reverse lymphatic pathology in children infected with B. malayi . On the other hand, substantial clinical data indicate that that lymphedema of the leg can be arrested and even reversed by measures such as proper hygiene, skincare, and treatment of skin lesions (e.g., using topical antifungal and antibacterial agents); elevation of the leg and exercise; and in advanced cases, prophylactic antibiotics to prevent secondary infection. Addition of a 6-week course of doxycycline to the standard limb hygiene regimen may have further benefits. Surgical repair is effective for hydrocele, but it often is unsatisfactory for elephantiasis.

Children with tropical pulmonary eosinophilia should be treated with DEC to prevent progression to chronic interstitial lung disease. Multiple courses (6–8 mg/kg/day for 21 days) may be required. If no clinical response or decline in eosinophilia is observed with treatment, alternative diagnoses should be considered.

Special Considerations

Reproductive-aged women living in endemic areas are commonly infected with filarial worms, and microfilariae have been observed infrequently in the umbilical cord blood of infants born to infected mothers. Some data suggest that children born to infected mothers (but not fathers) are more likely to have microfilaremia during childhood than children born to uninfected mothers. It is unknown whether this apparent tolerance to infection is associated with a higher or lower risk of chronic disease.

Prevention

Recommendations for personal protection for travelers or visitors to endemic areas include sleeping in an air-conditioned room or under a mosquito net, avoiding outdoor exposure between dusk and dawn, wearing long sleeves and trousers, wearing permethrin-treated clothing, and using mosquito repellent. When used as directed, EPA registered insect repellents are safe for children and pregnant or breastfeeding women ( https://www.epa.gov/insect-repellents ). At least one report suggests prophylactic use of DEC may be beneficial.

In 1997, WHO launched a global effort to eliminate lymphatic filariasis as a public health problem ( https://www.who.int/news-room/fact-sheets/detail/lymphatic-filariasis ). ^, Recommended interventions include periodic mass drug administration campaigns for community members aged >2 years in endemic settings using either DEC or ivermectin in combination with albendazole, along with vector control. As of 2020, 17 of 72 countries endemic for lymphatic filariasis have achieved global disease elimination as a public health problem target and no longer require community drug treatment campaigns aimed at lymphatic filariasis. ^,

Epidemiology

The blackflies that transmit O. volvulus are day-biting, and usually, many bites are required before infection occurs. In endemic settings, the prevalence of infection markedly increases during childhood. In hyperendemic areas of West Africa, for example, microfilariae can be detected in the skin of 1%–2% of children aged ≤5 years, and in approximately 90% of children aged 15. ^, Transplacental infection of microfilariae has been documented in a very low percentage of birth in untreated hyper- and meso-endemic areas. Blindness is rare in young children, but impaired vision due to onchocerciasis occurs by the second decade of life.

Onchocerciasis is a rare diagnosis in travelers, as prolonged residence in endemic areas (typically minimum of 3 months, median 2 years) is required for infection; however, travelers to highly endemic areas might acquire an infection with briefer, intense exposures. Travelers most likely to develop onchocerciasis are those who spend extended time in endemic areas, such as missionaries, Peace Corps volunteers, field researchers, or other long-term visitors.

Clinical Manifestations

Symptoms, if they occur, typically develop from 18 to 24 months after the initial infection, although many infected individuals have no symptoms. The likelihood of symptoms is directly related to microfilarial density. In addition to subcutaneous nodules ( onchocercomas ), the main clinical manifestations of onchocerciasis are dermatitis, lymphadenitis, and ocular disease. Travelers with symptoms are most likely to develop acute papular onchodermatitis , characterized by a solid, pruritic, papular rash. Inflammation surrounding dead microfilariae in the skin gives rise to pruritus, a common early symptom in children. Acute inflammation can progress to chronic inflammation, which may lead to lichenification. Prolonged inflammation also may lead to epidermal atrophy and loss of pigment (“leopard skin”), which sometimes develops in older children with high microfilarial density.

Ocular disease is the most serious complication of O. volvulus infection, but it is uncommon in people with brief exposures or light infections and is rarely seen in travelers. Disease in the anterior chamber is most common. Ocular manifestations include punctate keratitis, microfilariae in the anterior chamber, iridocyclitis, and sclerosing keratitis. Posterior chamber disease may include chorioretinitis, white intraretinal deposits, optic atrophy, and open-angle glaucoma. Inflammation associated with the death of microfilariae in the cornea causes punctate keratitis, an early ocular lesion found in heavily infected children. In the absence of treatment, punctate dermatitis may progress to sclerotic keratitis. Vision loss and blindness can result from sclerotic keratitis, anterior uveitis, chorioretinopathy, or optic nerve atrophy, usually after years of exposure.

Laboratory Findings and Diagnosis

Demonstration of microfilariae in the skin is the standard for diagnosis, and microfilariae are detectable in up to half of symptomatic infected North American travelers returning from endemic areas. Skin snips are obtained with a sclerocorneal biopsy punch or by elevating a small cone (3 mm in diameter) of skin with a needle or straight pin and shaving it off bloodlessly with a scalpel or razor blade. The skin snip is then incubated in saline at room temperature for 24 hours to allow the emergence of the microfilariae, which can be visualized microscopically.

The diagnosis of onchocerciasis can also be made by excision of subcutaneous nodules and identifying the adult worms. Ultrasonography may help detect impalpable nodules. Microfilariae in the anterior chamber of the eye are detected readily on slit-lamp examination. The chances of detection are increased if patients are asked to sit with the head between their legs for up to 10 minutes before the examination. Microfilariae also can be observed in the cornea, vitreous, and retrolental space. All people diagnosed with onchocerciasis should undergo a slit-lamp examination to assess the extent of ocular involvement. Expert ophthalmologic advice should be sought before treating eye lesions.

As in lymphatic filariasis, measuring total antifilarial IgG and IgG4 can be useful diagnostically, particularly when microfilariae are not identifiable. Serum antifilarial IgG4 testing is available in many commercial laboratories and at the Parasitic Diseases Laboratory at NIH (phone: 301-496-5398) or CDC (phone: 404-718-4745); however, the test is not specific for onchocerciasis. Assays to detect specific antibodies to Onchocerca are available in specialized laboratories but are not commercially available.