Chapter 328. Lymphatic Filariasis and Onchocerciasis

Filarial worms are parasitic nematodes that dwell within the lymphatics and the subcutaneous tissues. Eight filarial species are associated with human disease, though only 4 cause significant morbidity in children (Table 328-1). These species include the causative agents of lymphatic filariasis—Wuchereria bancrofti, Brugia malayi, and Brugia timori—and the subcutaneous filariid Onchocerca volvulus, the causative agent of onchocerciasis. The other filarial parasites of humans (Loa loa, Mansonella perstans, Mansonella streptocerca, and Mansonella ozzardi) cause minimal childhood morbidity. Of the 8 filarial parasites of humans, W bancrofti is, by far, the most important in terms of both morbidity and numbers of people infected.

Each filarial parasite is transmitted by biting arthropods, either mosquitoes or flies, and all go through complex life cycles that include a slow maturation (often 3–24 months) from the infective larval stages carried by the insects to adult worms that live within the lymphatics and lymph nodes (W bancrofti and Brugia spp) or in the subcutaneous tissues (Onchocerciasis volvulus, L loa, M streptocerca). Patent infection occurs when male and female adult worms produce microfilariae offspring, 200 to 400 mm in length, that either circulate in the blood or migrate to the skin while awaiting ingestion by insect vectors. Productive infection is usually not established unless exposure to infective larvae is intense or prolonged. Therefore, while acquisition of and infection with these parasites occurs throughout childhood in endemic regions, most of the pathology associated with these infections is found primarily in older children and adults.

Lymphatic filariasis affects approximately 120 million people in Africa, Asia, India, Indonesia, the Philippines, Papua New Guinea, and focal areas of Latin America and the Caribbean. More than 90% of these infections are caused by W bancrofti and occur in Sub-Saharan Africa, Southeast Asia, and the Western Pacific. Infection with B malayi is limited to 10 to 20 million persons in South and Southeast Asia, Indonesia, and the Philippines. B timori infection exists only among the islands of southeastern Indonesia and Timor-Leste. Coinfection with W bancrofti and Brugia species can occur in some regions endemic for both species.

The distribution of lymphatic filariasis is highly focal within any geographic area, reflecting variations in ecological relationships among the human host and the various mosquito vectors. In contrast to other vector-borne parasitic diseases such as malaria, several different genera of mosquitoes may transmit lymphatic filariae. These include Anopheles species in rural Africa and the Pacific, Culex species in urban areas of the world, Aedes aegypti in some Pacific islands, and Mansonia, which is capable of transmitting only B malayi, in South Asia.

The prevalence of patent infection in endemic areas increases with age, apparently correlating to the cumulative exposure.1-4 Infection with adult worms in the absence of microfilaremia can occur in 25% or more of children between the ages of 1 and 5 years, depending on the level of filarial endemicity in the community. Productive infection is rare in travelers to or temporary residents of filarial-endemic regions, but can certainly occur most commonly with those who stay longer than a month.5 Overall microfilarial carrier rates vary significantly among endemic regions, from approximately 10% in the Nile Delta, to 20% to 40% in parts of East Africa, and often greater than 60% in Papua New Guinea. Males appear to be more susceptible to filarial infection than females, particularly after puberty.6-8

Clinical Manifestations

Clinical manifestations of disease often become apparent only after years of infection, often after the adult worms have died, and damage to lymphatic vessels probably arises from the host inflammatory response rather than as a direct result of parasite activity. Complex interactions among immune response mediators are thought to explain why certain individuals remain asymptomatic (or subclinical) despite microfilaremia whereas others develop debilitating lymphedema in the absence of detectable microfilariae. Immune desensitization with recurrent exposure to filarial antigens probably plays a significant role in this phenomenon and may also potentially account for low rates of morbidity in infected children who have likely been exposed to filarial antigens in utero.9 Current research efforts also seek to address the potential influence of filaria-driven immune modulation on coinfections with other pathogens such as malaria, tuberculosis, and intestinal helminths.

Bancroftian and brugian filariases present relatively similarly. The 3 most common manifestations of the lymphatic filariases are asymptomatic (or subclinical) microfilaremia, acute filarial adenolymphangitis, and lymphatic obstruction. Patients with asymptomatic microfilaremia may have thousands of circulating parasites per milliliter of blood but rarely come to medical attention except through the incidental finding of microfilariae in peripheral blood. Many individuals with microfilaremia, however, have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria10 or dilated and tortuous lymphatics.11 Such early lymph vessel disease appears to be irreversible, even with antifilarial therapy. With the recent availability of more sensitive imaging techniques in endemic areas, isolated lymph node enlargement without pain or inflammation has become an increasingly recognized manifestation of bancroftian filariasis in children.8,12

The most common symptomatic presentation of lymphatic filariasis in children is acute filarial adenolymphangitis, characterized by high fever, lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. Most episodes last between 3 and 7 days and may recur. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside, a finding that helps to distinguish filarial from bacterial lymphangitis. The upper and the lower extremities are most commonly involved with both bancroftian and brugian filariasis. Regional lymph nodes are often enlarged, and the entire lymphatic channel can become indurated and inflamed. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface.

Persistent infection and recurrent inflammation lead to dilatation and obstruction of lymphatics, resulting in lymphedema (and in the worst cases) or elephantiasis (eFig. 328.1). Bacterial and/or fungal superinfection of these poorly vascularized tissues eventually becomes a significant problem and can be associated with what has been termed dermatolympangioadenitis.13-15 Hydroceles and chyluria result from obstruction of genital lymphatics exclusively with bancroftian filariasis. Chyluria, when it occurs, is characteristically intermittent. Adenolymphangitis with eosinophilia can occur in travelers to endemic regions early in infection. This presumed inflammatory response to developing filarial larvae can resolve with departure from the endemic area; long-term sequelae are rare.

Tropical pulmonary eosinophilia occurs in an extremely small percentage of individuals infected with filarial parasites. The syndrome consists of cough and wheezing, diffuse lung infiltrates on chest x-ray, and restrictive (with or without obstructive) defects on pulmonary function testing. Extremely high levels of blood eosinophils (> 3000/mm3), serum IgE, and antifilarial IgG are thought to reflect an immunologic hyperresponsiveness to the parasite.16 Circulating microfilariae are almost never detected in these individuals.17 Repeated episodes of tropical pulmonary eosinophilia or inadequate treatment can result in chronic interstitial (and irreversible) lung disease.18,19

Diagnosis

Definitive diagnosis depends on identification of parasites directly. Adult worms can be identified on biopsy or by high-frequency Doppler ultrasound, where the “filarial dance sign”20 provides sonographic evidence of live adult worms in the inguinal lymph nodes, scrotum or breast (bancroftian filariasis), or in superficial lymphatic vessels of axilla and proximal extremities (brugian filariasis).21,22 Microfilariae are found in the blood almost exclusively between 10 pm and 4 am, times that coincide with the nocturnal biting habits of the arthropod vector, except in some areas of the South Pacific where subperiodic forms are common (Fig. 328-1). Filaria-specific antibody testing is highly sensitive but has suffered from cross-reactivity among the filarial species. More recently, 96% to 100% sensitivity and specificity has been demonstrated with a B malayi recombinant antigen that detects species-specific IgG4 in an ELISA-based assay.23 For bancroftian filariasis, detection of circulating parasite antigen (enzyme-linked immunosorbent assay [ELISA] or rapid immunochromatographic testing) is highly sensitive (> 98%) and specific (> 99%), and antigen detection has largely supplanted microscopy because the antigen can be detected in whole blood or serum drawn at any time of the day.24,25 Recently, 96% to 100% sensitivity and specificity has been demonstrated with a B malayi recombinant antigen that detects species-specific IgG4 in an ELISA-based assay.23 PCR detection of filarial DNA in whole blood remains largely a research technique.26 In children with suspected or proven filariasis, 99Tc lymphoscintigraphy is useful in defining the nature and extent of lymphatic damage or dysfunction and in distinguishing lymphedema from other causes of swelling.

Elevated total serum IgE, absolute eosinophil counts, and antifilarial antibodies provide strong supportive evidence for the diagnosis of lymphatic filariasis, but they are commonly elevated in many parasitic infections and therefore must be considered in conjunction with more specific tests. With the extreme IgE elevations seen in tropical pulmonary eosinophilia, not only should a chest x-ray and pulmonary function testing results be obtained for help in diagnosis but other causes of elevated IgE and eosinophils in children (eg, visceral larva migrans, allergic bronchopulmonary aspergillosis) must be excluded.

Treatment and Prevention

Diethylcarbamazine (DEC) has both macrofilaricidal and microfilaricidal properties and remains the treatment of choice for the individual with active lymphatic filariasis (microfilaremia, antigen positivity, or adult worms on ultrasound). Typically, treatment is 6 mg/kg/day by mouth in 3 doses for 12 days. Reactions that occur after treatment consist of fever, chills, myalgias, arthralgias, headaches, nausea, and vomiting. The intensity of these reactions that usually last only 24 to 48 hours and remit spontaneously are directly related to the number of microfilariae circulating in the bloodstream and may be more pronounced in brugian filariasis. Both the development and the severity of these reactions are directly related to the number of microfilariae circulating in the bloodstream and may represent an acute reaction to the antigens being released by dead and dying parasites. These reactions may be more pronounced in brugian filariasis, usually lasting only 24 to 48 hours and remitting spontaneously.

As an alternative to DEC, albendazole (400 mg twice a day for 21 days) has macrofilaricidal efficacy but no microfilaricidal activity and therefore does not immediately lower blood microfilarial counts. Conversely, the microfilaricidal agent ivermectin (given in single annual doses of 200–400 μg/kg) achieves sustained suppression of microfilaremia, but has no activity against adult worms and is not recommended as monotherapy. Regimens that emphasize combinations of single doses of albendazole and DEC or albendazole and ivermectin have demonstrated sustained microfilaricidal effects.27 Whether these combinations offer increased efficacy over single-agent therapies in children remains unclear.28 Interestingly, 6 weeks of daily doxycycline (200 mg/day)29—a regimen that targets an intracellular, Rickettsiae-like Wolbachia endosymbiont)—or a 7-day course of DEC/albendazole has both significant macrofilaricidal activity and sustained microfilaricidal activity.30

In individuals with chronic manifestations of lymphatic filariasis, treatment regimens emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy. Hydroceles can be drained repeatedly or managed surgically.

Vaccine development for lymphatic filariasis is still in its infancy. Single-dose combinations of albendazole with either diethylcarbamazine or ivermectin are now being used by filariasis control programs in many countries for annual communitywide treatment with the goal of interrupting transmission of infective larvae.31,32 Preventative measures also focus on avoidance of exposure to arthropod vectors through combinations of protective clothing and shelter, chemically impregnated bednets, activity modification, and vector control strategies.

Onchocerciasis affects approximately 18 million people, the overwhelming majority of whom live in Sub-Saharan Africa; the rest live in small endemic foci in Latin America and the Arabian peninsula. Approximately 600,000 of those infected are severely visually impaired as a consequence of onchocercal eye disease (river blindness), the second leading cause of infectious blindness worldwide. Disease transmission is most intense near free-flowing rivers and streams where the blackfly vector breeds.

Inflammatory responses directed toward the microfilariae likely account for much of the clinical findings in infected individuals. In contrast to the situation with lymphatic filariasis, inflammation seems to be elicited against microfilariae rather than adult worms. The precise details of these host-parasite interactions remain largely undeciphered.

Clinical Manifestations

Skin and eye disease are the most common manifestations of onchocerciasis; both may occur in childhood in areas of high transmission. Adult worms in subcutaneous fibrous capsules can be palpated as nodules (onchocercomas), particularly over bony prominences. Microfilariae in the skin induce inflammation that manifests as intense pruritus and papular dermatitis (eFig. 328.2). With long-standing cutaneous inflammation, lichenification, depigmentation (“leopard skin”), and eventual skin atrophy with loss of elastic fibers can occur (eFig. 328.3).33 Ocular pathology, the most serious consequence of infection, is related to intensity of infection.34,35 Lesions may develop in all parts of the eye. The most common early finding is conjunctivitis with photophobia. In the cornea, punctate keratitis—consisting of acute inflammatory reactions surrounding dying microfilariae manifested as “snowflake” opacities—is frequent in younger patients and resolves without apparent complications. Sclerosing keratitis is the leading cause of onchocercal blindness. Anterior uveitis and iridocyclitis occur in up to 5% of infected patients. Complications of the anterior uveal tract (pupillary deformity) may cause secondary glaucoma. Although much rarer than anterior chamber disease, posterior eye disease, including chorioretinitis, chorioretinal atrophy, and optic nerve involvement can lead to constriction of the visual field and eventual blindness.

Diagnosis

Microfilariae can be recovered from skin snips of the epidermis obtained as superficial (1 mm) skin slices using a scalpel or a corneoscleral punch as is used for biopsy. Six skin snips (typically bilaterally from the iliac crests, scapulae, and lower extremities) are recommended for maximal diagnostic yield. When incubated in saline or culture medium, microfilariae may be seen emerging from these snips under low-power microscopy. Microfilariae may also be identified in the anterior chamber of the eye on slit-lamp examination. Adult worms can be identified in excised nodules. Highly sensitive and specific assays to detect Onchocerca-specific antibodies in serum36,37 and O volvulus DNA in skin snips38,39 are in use in specialized laboratories.

Treatment and Prevention

The main goals of therapy are to prevent irreversible lesions (particularly blindness) and to alleviate symptoms. Ivermectin (150 μg/kg) is microfilaricidal40 and is first-line therapy for treatment of onchocerciasis. Ivermectin is given annually or more often (up to 4 times yearly), depending on clinical response.41 Treatment is complicated by pruritus, cutaneous edema, and/or maculopapular rash in 1% to 10% of cases.42 In areas coendemic for O volvulus and L loa, fatal encephalopathy has occurred rarely in individuals with high levels of L loa microfilaremia,43,44 though few of these reports have involved children. A 6-week course of doxycycline has been demonstrated to be macrofilaristatic (rendering the female adult worms sterile) by targeting the rickettsial-like Wolbachia endosymbiont of the filarial parasite.29 The use of this regimen in children, however, is contraindicated.

Community-based administration of ivermectin every 6 to 12 months is now being used to interrupt transmission in endemic areas. This strategy, in conjunction with vector control, has helped to reduce the prevalence of disease in endemic foci in Africa and Latin America.