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Lymphatic Filariasis
SECTION II: PATHOGENS
PART I: Nematode Infections
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CHAPTER 104 Lymphatic Filariasis Thomas B. Nutman • James W. Kazura
INTRODUCTION Lymphatic filariasis is caused by infection with any of three closely related parasitic nematodes – Wuchereria bancrofti, Brugia malayi, or Brugia timori. Unlike most other helminthiases endemic in tropical areas of the world, the burden of infection and disease in lymphatic filariasis occurs primarily during adulthood and not childhood or infancy. The greater impact of lymphatic filariasis on older age groups is due to the fact that infection burdens are determined by the chronicity and intensity of exposure to infective stages of the organisms, which cannot multiply in the mammalian host. Because disease due to lymphatic filariasis is characterized by disfigurement of the limbs (elephantiasis) and genitalia (hydroceles and other anatomical changes in the male genitalia), it is often perceived as having adverse economic and psychosexual effects as well as medical consequences. This is particularly evident in many tropical countries where physical labor is still the major means of earning money. Indeed, lymphatic filariasis is among the leading health-related impediments to economic and social development in economically disadvantaged areas of the tropics.1,2 Lymphatic filariasis can be transmitted in any region of the world where the appropriate mosquito vector breeds. It currently is a significant health problem in tropical Africa, Asia, and the Indian subcontinent, many islands of the western and southern Pacific, and focal areas of Latin America. In the tropics, the geographic distribution of W. bancrofti and B. malayi infections is expanding due to increased numbers of breeding sites that appear when large numbers of people migrate from rural to urban areas. These pessimistic epidemiologic trends contrast with the recent gains and successes by the Global Program to Eliminate Lym phatic Filariasis using yearly single dose administration of antifilarial chemotherapy.3
THE AGENT The existence of lymphatic filariasis has been recorded in ancient Chinese, Indian, Persian, and Arabic writings, but causative agents and their life cycles were not described until the late nineteenth century.4,5 Microfilariae of W. bancrofti, first discovered by Demarquay in hydrocele fluid from a patient in Cuba in 1863,6 were later identified in the urine by Wucherer in 18687 and in the blood by Lewis in 1872.8 Manson described the periodicity of microfilariae in the peripheral blood9 and demonstrated that mosquitoes transmit the parasite.10 Bancroft first described the adult female worm11 and Bourne later described the adult male worm.12 Bancroft in 189913 and Low in 190014 established the mode of transmission of the parasite. Lichtenstein, Brug and Buckley were primarily responsible for identification of brugian parasites.15 W. bancrofti, B. malayi, and B. timori are threadlike nematodes having five morphologically and biochemically distinct stages in their life cycle
(Fig. 104.1). Infective or third-stage larvae, transmitted to humans during blood feeding by mosquitoes, are deposited from the mouthparts of the mosquito in the vicinity of the skin puncture wound, and within several minutes make their way through the dermis to enter the local lymphatics. Several hours later, infective larvae shed their cuticle and develop a new surface (a process referred to as molting) that presents novel antigens and other molecules to the mammalian host. These fourthstage larvae migrate centrally in lymphatic vessels and over a period of approximately 6–9 months develop into sexually mature adult male or female worms. Adult worms are considerably larger than larval stages (male worms are 20–40 mm in length, and female worms 40–100 mm) and have highly differentiated and complex reproductive and digestive systems. This stage of the parasite dwells primarily in the afferent lymphatics. Although all the anatomical areas in which adult lymphatic filariae live in humans are not known with certainty, large numbers are present in the lymphatics of the lower extremities (inguinal and obturator groups), upper extremities (axillary lymph nodes), and, for W. bancrofti, male genitalia (epididymis, spermatic cord, testicle). Based on observations of inflammatory reactions elicited by administration of drugs that kill adult worms, it is likely that adult filariae are distributed in subcutaneous tissues more than several centimeters distant from major lymph node groups. The mean life span of adult worms is approximately 5 years. Following copulation with male worms, fecund female parasites release large numbers (often more than 10 000 per day) of first-stage larvae, microfilariae. Microfilariae are distinguished by their small size (260 mm in length and approximately 10 mm in width). Microfilariae of the lymphatic filariae have an acellular sheath, which is a chitin-containing remnant of the embryonic eggshell or vitelline membrane. Microfilariae of W. bancrofti and B. malayi differ morphologically from each other in the pattern of nuclei in the cephalic and caudal regions. W. bancrofti and Brugia microfilariae frequently have a nocturnal periodicity whereby the number present in the peripheral circulation peak at midnight (with large numbers between 10 p.m. and 4 a.m. with few or none present during the day). When absent from the peripheral circulation, microfilariae are sequestered in deep vascular beds of the lung and other organs. This peculiar behavior appears to be an example of adaptation to local ecological conditions in that the time at which peak parasitemia occurs coincides with the time when the local mosquito vectors take their blood meal.16 The mechanisms that regulate microfilarial periodicity in humans are poorly understood. After ingestion in a blood meal taken by a female mosquito, microfilariae exsheath within 24 hours, penetrate the chitinous gut wall of the mosquito, and migrate into the thoracic musculature. Over a period of 10–14 days, microfilariae mature to become third-stage larvae capable of infecting another human. The nature of the relationship between filarial larvae and the local mosquito populations has a profound impact on local transmission efficiency. For example, if mosquitoes ingest unusually large numbers of microfilariae, the overall efficiency of transmission may be
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PATHOGENS
Section II
Lymphatic filariasis Wuchereria bancrofti and Brugia malayi/timori
Microfilariae released into peripheral blood after 6 –12 months (diagnostic)* causing:
Larvae migrate to lymphatics where adults mature and mate (releasing microfilariae over 5–10 years) and cause:
Tropical pulmonary eosinophilia (in some sensitized hosts)
Recurring lymphadenitis, fever, lymphangitis, elephantiasis, hydrocele
Night (or day) biting mosquitoes (Anopheles, Culex, Aedes or Mansonia) bite, introducing infective 3rd stage larvae*
1st–3rd stage larvae develop over 10–14 days in thorax muscles of mosquito
Night (or day) biting mosquitoes bite taking up microfilariae*
Figure 104.1 Life cycle of lymphatic filariasis. *For many filarial strains (e.g., W. bancrofti in Africa), microfilariae become abundant in blood only at night (nocturnal periodicity), when they may be detected by night-biting mosquitoes. For other strains, microfilariae are present by day and are spread by day-biting mosquitoes.
reduced by virtue of the fact that heavily infected mosquitoes have a shortened life span, precluding development of infective larvae. Conversely, in some mosquito–filarial interactions, there may be more efficient transmission at lower microfilarial densities, a phenomenon referred to as facilitation. An important biologic feature of W. bancrofti and Brugia species relates to the fact that these nematodes carry an obligate bacterial endosymbiont Wolbachia. Ultrastructural studies performed in the 1970s recognized the presence of intracellular bacteria in adult worms and microfilariae;17,18 but it was not until the late 1990s when molecular probes and genome sequence data became available that Wolbachia were definitively identified in human filarial parasites.19,20 These endosymbiotic bacteria appear to affect filariae in several ways that are pertinent to human filariasis. Incubation of Brugia worms with tetracycline and other antibiotics known to kill Wolbachia diminishes the release of microfilariae and suppresses larval molting, suggesting that the bacteria are involved in embryogenesis and regulation of the parasite life cycle.21,22 In the context of human lymphatic filariasis, administration of doxycycline to persons with W. bancrofti or B. malayi infection augments the suppression of microfilaremia induced by both ivermectin23 or combination diethylcarbamazine/ albendazole.24 Moreover, 6 weeks of doxycycline has been shown to have macrofilaricidal (killing adult parasites) activity for both Wuchereria and Brugia infections.24–26 There is a need, however, to identify anti-Wolbachia agents that can be given for short periods of time (and with broader applicability) than the tetracycline antibiotics, which cannot be given to pregnant women or young children.
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It is estimated that 120 million people (in 81 countries) are infected with one of the three genera of lymphatic filariae (Fig. 104.2).27 More than
90% of infections are due to W. bancrofti, and, of these, the greatest number are in sub-Saharan Africa, Southeast Asia, and the western Pacific. The infection is prevalent in India, Indonesia, the Philippines, Papua New Guinea, and several Pacific countries such as parts of Fiji and Tahiti. Bancroftian filariasis is also a significant public health problem in many countries of tropical Africa (see Fig. 104.2). Within Africa, W. bancrofti infection is not limited to these tropical zones since endemic foci are found as far north as the Nile delta in Egypt and Sudan. In the Americas, endemic foci persist in several islands in the Caribbean (Haiti and the Dominican Republic) and coastal areas of South America (Brazil and Guyana). There are no animal reservoirs of W. bancrofti. Infection with B. malayi is limited to Asia (China, India, and Malaysia) and several Pacific island groups (e.g., Indonesia and the Philippines). There are fewer than 10 to 20 million persons in these areas infected with B. malayi, which may coexist with W. bancrofti. B. malayi infection is a zoonosis in that there are feline and primate reservoirs. B. timori infection is limited in its distribution to the islands of southeastern Indonesia. Within a given geographic area, the distribution of lymphatic filariasis is highly focal such that the frequency of infection in some communities is high compared with physically approximate localities. This heterogeneity of infection patterns, both locally and globally, is due in large part to the peculiarities of the ecological relationships between the mosquito vector and the human host, and the impact of filarial parasites on both of these. Unlike other common vector-borne infectious diseases of the tropics (e.g., malaria), several genera of mosquitoes are capable of transmitting lymphatic filariae. W. bancrofti is transmitted in many rural areas of Africa and the Pacific by Anopheles species.28 The proximity of human dwellings to breeding sites increases the risk of repeated contact with mosquitoes bearing infective larvae. In many urban areas of the world, including India, Culex species is the major vector of W. bancrofti and B. malayi.29 Unlike anopheline mosquitoes, larvae of these mosquitoes breed
Lymphatic Filariasis Chapter 104 Lymphatic filariasis Wuchereria bancrofti Wuchereria bancrofti and Brugia malayi Note: Brugia timori is limited to the Timor Island of Indonesia
Figure 104.2 World map of lymphatic filariasis infection.
readily in small pools of water that form in discarded tires and cans. Other vectors include Aedes aegypti in some Pacific islands (e.g., Tahiti) and Mansonia, which transmits only B. malayi. These various genera of mosquitoes also differ in their efficiency of transmission. In general, anopheline mosquitoes are more efficient vectors of W. bancrofti than are culicine mosquitoes. The age-related pattern of infection, as judged by the proportion of persons harboring microfilariae in the blood (the “microfilarial carrier rate,” see below), increases gradually with age up until the third or fourth decade of life, after which it remains constant or slightly decreases. This epidemiologic pattern is related to the gradual slow accumulation of adult-stage worms over time. The proportion of the entire population or a specific age group with patent infection is remarkably variable in different endemic areas. In addition to these differences in infection patterns, there is remarkable variation in the frequency of various disease manifestations based on age and geographic area. Lymphatic disease, manifest by persistent lymphedema of the lower extremity or genital disease in males (see below), is rare in persons less than 10 years of age, and tends to increase gradually throughout life. Of the total 120 million persons estimated to be infected in all endemic areas, about onethird have clinically overt disease. The likelihood of developing such manifestations appears to be particularly high in some areas of the world, such as India, Pacific islands such as Papua New Guinea, and in equatorial Africa, whereas it is considerably lower in the Caribbean and South America. Local transmission conditions may account for the striking heterogeneity of disease manifestations that may be observed within a given geographic area. Indeed the cumulative exposure to infective larvae may be an important risk factor for lymphatic pathology at the population level.30
THE DISEASE Infection with W. bancrofti, B. malayi or B. timori can cause a wide variety of clinical manifestations, ranging from those without apparent clinical disease to those with lymphedema and/or severe disfigurement of the limbs and genitalia. From the clinical perspective, it should be stressed that there is a great deal of overlap in these symptom complexes, several of which may occur contemporaneously.
Subclinical Patent Infection The overwhelming majority of filarial-infected inhabitants in endemic areas have few overt clinical manifestations of their filarial infection despite large numbers of circulating microfilariae in the peripheral blood.31 Although they may be clinically asymptomatic, virtually all persons with patent W. bancrofti or B. malayi infection (microfilariaand/or circulating filarial antigen-positive) have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria,32 dilated (and tortuous) lymphatics (visualized by lymphoscintigraphy33–35), and, in men with W. bancrofti infection, scrotal lymphangiectasia (detectable by ultrasound).36–38
Acute Adenolymphangitis Acute adenolymphangitis (ADL) is often the first manifestation of lymphatic filariasis. It is characterized by the sudden onset of high fever, painful, lymph node and lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside – the retrograde nature of the lymphadenitis distinguishes filarial-induced disease from bacterial-induced lymphangitis. Regional lymph nodes (e.g., inguinal, obdurator, axillary, epitrochlear) are often enlarged, and the entire lymphatic channel can become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis can involve both the upper and lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection.39 This genital involvement can be manifested by funiculitis, epididymitis, scrotal pain, tenderness as well as a condition termed lymph scrotum.40 In endemic areas, another type of acute disease – dermatolymph angioadenitis (DLA)41,42 – is recognized as a syndrome that includes high fever, chills, myalgias, and headache. Edematous inflammatory plaques clearly demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation may also be noted. There is often a history of trauma, burns,
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Figure 104.4 Hydrocele and inguinal lymph node enlargement in bancroftian filariasis. The patient is a 40-year-old man who first experienced epididymitis at the age of 20. The hydrocele has been present for 2 years.
Disease Involving the Genitourinary System
Figure 104.3 Lymphedema of the upper and lower extremities in a 50-year-old man. Swelling had been present for approximately 10 years, and the level of microfilaremia was 1000 parasites per milliliter of blood.
radiation, insect bites, punctiform lesions, or chemical injury. Entry lesions, especially in interdigital areas, are common. DLA is often diagnosed as cellulitis.
Lymphedema of the Arms, Legs, and Breasts
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Swelling of the upper or lower extremities is the most common chronic manifestation of lymphatic filarial infection. Disease of the lower extremities is more prevalent. Leg involvement in bancroftian filariasis may include the entire limb, whereas only the area below the knee is usually involved in brugian filariasis. The World Health Organization has adopted a grading system to quantify the severity of involvement.43 Grade I indicates pitting edema that is reversible upon elevation of the leg; grade II, non-pitting edema that does not resolve with elevation of the extremity; grade III, nonpitting edema of the limb that is not reversible with elevation and with thickened skin or skin folds; and grade IV, non-pitting edema with fibrotic and verrucous skin changes (elephantiasis), and the presence of skin folds (Fig. 104.3). Although both lower extremities may be involved, asymmetrical involvement is the rule. In some persons with filarial-associated edema, the overlying skin may exude serous fluid suggestive of lymph. Although it is possible that this sign occurs as a result of increased hydrostatic pressure in the lymphatics draining the skin, skin turgor alone cannot reliably be used to distinguish between edema due to lymphatic disease and that from other causes, such as cardiac failure and liver disease. Unilateral or bilateral involvement of the female breast occurs in adult residents of filarial endemic areas. This should be distinguished from chronic mastitis and other causes of chronic breast inflammation.
Along with lymphatic disease of the lower extremities, disease of the male genitalia is the most common manifestation of bancroftian filariasis. Indeed, in many endemic areas, its prevalence is greater than that of lymphedema. Genital involvement is uncommon in Brugia infection. The prevalence of disease of the female genitalia is not known since systematic surveys have not included examination of this anatomical area. Anecdotal evidence suggests that the frequency of vulvar disfigurement is low. Genital disease is usually not experienced until the teenage years. Acute painful episodes of epididymitis or funiculitis last several days and are accompanied by fever and malaise. Involvement is most commonly unilateral.
Hydroceles Chronic disease of the male genitals mostly produces hydroceles, which vary in diameter from less than 5 cm to over 30 cm (Fig. 104.4). As is the case with other causes of hydrocele, the scrotal contents appear translucent when transilluminated. Hydroceles are usually not painful unless they are complicated by acute epididymitis or funiculitis. Thickening of the spermatic cord commonly accompanies hydroceles. The skin of the scrotum may also be thickened and have a “brawny” character on palpation. If hydrocele fluid is drained, it is clear and straw-colored. Parasites are usually not found in this fluid. Inguinal lymph nodes and other nearby lymph nodes may also be enlarged (see Fig. 104.4).
Lymphedema of the genitalia Swelling of the scrotum when accompanied by thickened scrotal or penile skin may have a characteristic “peau d’orange” appearance.39 In longstanding cases verrucous lesions and lymphorrhea are common,40 the latter being a condition in which lymph oozes out to the exterior directly from dilated ruptured lymphatic vessels in the scrotal wall. The genitals may be grossly deformed and terms such as “ram horn penis” have been used to describe the gross distortion of the penis seen in this condition.
Chyluria Chyluria, resulting from obstruction or physiologic impairment of the renal lymphatics with passage of lymph from the lacteals draining the genitourinary tract, is a rare but serious manifestation of lymphatic filariasis. Chyluria may have serious nutritional consequences in that large amounts of fat and protein are lost in the urine. Its precise frequency in filarial endemic areas has not been established, but is exceedingly low compared to lymphedema of the extremities and hydroceles.44
Tropical pulmonary eosinophilia (TPE) is a distinct syndrome that develops in some individuals infected with either W. bancrofti or B. malayi.45,46 The majority of cases have been reported from India, Pakistan, Sri Lanka, Brazil, Guyana, and Southeast Asia. The main clinical features include paroxysmal cough and wheezing that are usually nocturnal (and probably related to the nocturnal periodicity of microfilariae), weight loss, lowgrade fever, adenopathy, and pronounced blood eosinophilia (>3000 eosinophils/µL). Chest radiographs may be normal but generally show increased bronchovascular markings; diffuse miliary lesions or mottled opacities in the middle and lower lung fields. Tests of pulmonary function show restrictive abnormalities in most cases and obstructive defects in half. Total serum IgE levels (10 000–100 000 ng/mL) and antifilarial antibody titers are characteristically elevated. Typically those with TPE do not have microfilaremia. Administration of the antifilarial drug diethylcarbamazine (see below) leads to significant symptomatic improvement with commensurate decreases in eosinophilia and serum IgE. If patients with TPE are not treated appropriately, the disease may progress to chronic restrictive lung disease with interstitial fibrosis.47
Lymphatic Filariasis in Expatriates and Travelers American servicemen returning from prolonged exposure to infectious mosquitoes in the South Pacific during World War II and French soldiers exposed in Indochina (now Vietnam) suffered from acute episodes of acute adenolymphangitis of the legs accompanied by eosinophilia. These acute disease manifestations were apparently caused by immune-mediated inflammatory responses to developing larvae, and resolved on departure from the endemic area.48 Progression to chronic lymphedema or elephantiasis was rare. Studies of Indonesian transmigrants from nonendemic to endemic regions49 as well as studies in which volunteers were experimentally infected with infective larvae of B. malayi50 provide corroboration of these early clinical manifestations. The risk of developing acute or chronic manifestations of lymphatic filariasis for the traveler to endemic areas is extraordinarily small, given the inefficiency of transmission by infected mosquitoes, although it has been seen rarely.51
PATHOGENESIS AND IMMUNITY The precise and likely multiple mechanisms leading to the diverse clinical manifestations of lymphatic filariasis have not been established. However, several factors have been suggested to underlie the development of lymphedema, including parasite-derived factors52,53 that may be responsible for the lymphatic dilatation seen early in infection, host genetic susceptibility,54–59 secondary bacterial infections,60–63 specific host adaptive immune responses to parasite antigens,64,65 and inflammatory responses to dying or dead parasite material.39,60,66–69 Establishing the relative importance of these diverse factors and a central unifying hypothesis to explain the pathogenesis of human lymphatic filariasis has been difficult because the onset of disease occurs over a period of years or decades and because of the marked heterogeneity in transmission and disease in geographically distinct filarial-endemic areas. The immunologic basis for the relative lack of pathology seen in the majority of individuals with patent infection, however, has been reasonably well studied in both cross-sectional and longitudinal populationbased studies. Studies in animal models and in vitro human systems have suggested that the initial immune response to infective stage larvae (L3) and to the next developmental stages (L4 and early adult stages) are dominated by proinflammatory and a mixed Th1-like and Th2-like T-cell responses.70,71 With the onset of patency (when microfilariae appear in the blood), there is a marked diminution of the parasite antigen-specific T-cell responses (both proliferation and Th1 cytokine responses)72–78 that is primarily mediated by interleukin (IL)-1079–82 and other regulatory cell
populations (e.g., adaptive and natural Treg cells, alternatively activated macrophages/monocytes83–85). Examination of protective immunity in lymphatic filariasis in human populations has been extraordinarily difficult. However, populationbased studies86–88 have identified groups of individuals who appear to be infection-free despite long-term exposure to the filarial parasites. When looked at immunologically, on balance cells from these individuals are more likely to respond to parasite antigen than were those with patent infection. The best evidence, however, for the induction of protective immunity has come from studies in animals (jirds, cats, ferrets) permissive for Brugia spp. given radiation attenuated L3; in these studies irradiated L3s induced protection to varying degrees (60–95% protection from challenge).89–92 Attempts with subunit vaccines using recombinant antigens or DNA vaccination have been less successful but levels of protection that range between 30% and 69% have been achieved.93–97
Lymphatic Filariasis Chapter 104
Tropical Pulmonary Eosinophilia
DIAGNOSIS Lymphatic filariasis is diagnosed by a combination of the appropriate epidemiologic history, physical findings, and laboratory tests. In residents of endemic areas, the appearance of lymphedema of the extremities or disease of the male genitalia is most likely due to filarial infection if there is no other obvious other secondary cause, such as trauma to the lymphatics or congestive heart failure. A definitive diagnosis can be made only by detection of the parasites, parasite antigen, or parasite DNA. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Examination, however, of the scrotum or the female breast using high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics.98–101 Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of infected men.98 Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the filaria dance sign).36,98 Microfilariae can be found in blood, in hydrocele fluid, or (occasionally) in other body fluids. Such fluids can be examined microscopically, either directly using a Giemsa-stained thin blood smear or – for greater sensitivity – after concentration of the parasites by the passage of blood through a polycarbonate cylindrical 3–5 mm pore filter (Nuclepore) or by the centrifugation of fluid fixed in 2% formalin (Knott’s concentration technique).102 The timing of blood collection is critical and should be based on the periodicity of the microfilariae in the endemic region involved. Many infected individuals do not have microfilaremia, and definitive diagnosis in such cases can be difficult. Assays for circulating antigens of W. bancrofti permit the diagnosis of both microfilaremic and amicrofilaremic infection. Two tests are commercially available: one is an enzyme-linked immunosorbent assay (ELISA)103 and the other a rapidformat immunochromatographic card test.104 Both assays have sensitivities that range from 96% to 100% and specificities that approach 100%. There are currently no tests for circulating antigens in brugian filariasis. Polymerase chain reaction (PCR)-based assays for DNA of W. bancrofti and B. malayi in blood have been developed.105–110 A number of studies indicate that this diagnostic method is of equivalent or greater sensitivity compared with parasitologic methods, detecting patent infection in almost all infected subjects. Antibody-based assays for diagnosing filarial infection have typically used crude parasite extract and have suffered from poor specificity. Improvements have been made by the use of detection of antifilarial IgG4 antibodies111 in that they have relatively less cross-reactivity to non-filarial helminth antigens. Specificity has also been improved by the use of species-specific recombinant antigens for both brugian and bancroftian infection;112 indeed a diagnostic dipstick test has been developed for use in areas endemic for brugian filariasis.113 In cases of suspected lymphatic filariasis, radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaremic persons and those with
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clinical manifestations of lymphatic pathology. While of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection. It is important to note, however, that it is not possible to exclude a diagnosis of filarial-induced disease in the absence of circulating antigens or parasites since disease may persist in persons with so-called burned-out infections. This situation may occur in persons who have received multiple courses of treatment or who have left endemic areas.
TREATMENT AND PROGNOSIS Chemotherapeutic Agents Diethylcarbamazine (DEC, 6 mg/kg daily for 12 days), which has both macro- and microfilaricidal properties, remains the treatment of choice for the individual with active lymphatic filariasis (microfilaremia, antigen positivity, or adult worms on ultrasound), although albendazole (400 mg twice daily for 21 days) has also demonstrated macrofilaricidal efficacy. The use of a 4- to 6-week course of doxycycline (targeting the intracellular Wolbachia) has also been demonstrated to have significant macrofilaricidal activity,24,26 as has daily DEC/albendazole used for 7 days.114 Adding diethylcarbamazine to a 3-week course of doxycycline has also recently been shown to be efficacious.25 Regimens that utilize combinations of single doses of albendazole (400 mg) and either DEC (6 mg/kg) or ivermectin (200 µg/kg) have all been demonstrated to have a sustained microfilaricidal effect,115–118 and are the mainstay of control programs in Africa (albendazole/ivermectin) or elsewhere (albendazole/DEC) for the eradication of lymphatic filariasis (see below). Side effects of DEC treatment include fever, chills, arthralgias, headaches, nausea, and vomiting. In heavily infected patients, painful nodules in the skin, lymph node enlargement, and epididymitis may appear. Both the development and the severity of these reactions are directly related to the number of microfilariae circulating in the bloodstream and likely represent an acute inflammatory reaction to either the antigens being released by dead and dying parasites or Wolbachia endosymbionts freed from their intracellular niche. Ivermectin has a side effect profile similar to that of DEC when used in lymphatic filariasis. Albendazole (when used in single dose regimens) has relatively few side effects associated with its use in lymphatic filariasis, but when used in multiday regimens has been associated with painful scrotal nodules.
Pathology Based Therapy As has already been mentioned, a growing body of evidence indicates that, although they may be clinically asymptomatic, most patients with W.
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bancrofti or B. malayi microfilaremia have some degree of subclinical disease (hematuria, proteinuria, abnormalities on lymphoscintigraphy). Thus, early treatment of asymptomatic individuals is recommended to prevent further lymphatic damage. For ADL, supportive treatment (including the administration of antipyretics and analgesics) is recommended, as is antibiotic therapy if secondary bacterial infection is likely. Similarly, because lymphatic disease is associated with the presence of adult worms, treatment is recommended for microfilaria-negative adult worm carriers. In persons with chronic manifestations of lymphatic filariasis, treatment regimens that emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy have gained wide acceptance for morbidity control. These regimens are similar to those recommended for lymph edema of most non-filarial causes, and are known by a variety of names, including complex decongestive physiotherapy and complex lymphedema therapy. Drainage of hydroceles provides immediate relief, though they recur in the absence of drug therapy or surgical removal of the tunica albuginea. With chronic manifestations of lymphatic filariasis, drug treatment should be reserved for individuals with evidence of active infection; therapy has been associated with clinical improvement and, in some cases, reversal of lymphedema. In severe cases of deforming elephantiasis, surgical approaches involving lymphatic-venous and nodal-venous anastomoses have been somewhat successful in diminishing the degree of leg swelling,119 as has reconstructive surgery for genital involvement. The long-term effects of these expert surgical techniques have not been determined.
PREVENTION AND CONTROL Individual protection against filarial infection may be achieved by avoiding contact with infected mosquitoes. This can be done by use of personal protective measures including bednets, particularly those impregnated with insecticides such as permethrin. Created in 1997, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was based on mass drug administration with single annual doses of diethylcarbamazine plus albendazole (non-African regions) or albendazole plus ivermectin in Africa.116,120–124 Information at the end of 2008 indicates that >695 million persons in 51 countries have thus far participated.125 Not only has there been success in eliminating lymphatic filariasis in some defined areas, but also collateral benefit in averting disability (estimated 32 million disability-adjusted life-years averted)122 and treating intestinal helminths and other conditions (e.g., scabies, lice). The strategy of the global program is being refined and guided by ongoing research aimed at understanding the ecology and transmission efficiency of the various mosquito vector species and integration with other mass treatment strategies (e.g., deworming programs, malaria control, trachoma control).126–132
PART I: Nematode Infections
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CHAPTER 104 Lymphatic Filariasis Thomas B. Nutman • James W. Kazura
INTRODUCTION Lymphatic filariasis is caused by infection with any of three closely related parasitic nematodes – Wuchereria bancrofti, Brugia malayi, or Brugia timori. Unlike most other helminthiases endemic in tropical areas of the world, the burden of infection and disease in lymphatic filariasis occurs primarily during adulthood and not childhood or infancy. The greater impact of lymphatic filariasis on older age groups is due to the fact that infection burdens are determined by the chronicity and intensity of exposure to infective stages of the organisms, which cannot multiply in the mammalian host. Because disease due to lymphatic filariasis is characterized by disfigurement of the limbs (elephantiasis) and genitalia (hydroceles and other anatomical changes in the male genitalia), it is often perceived as having adverse economic and psychosexual effects as well as medical consequences. This is particularly evident in many tropical countries where physical labor is still the major means of earning money. Indeed, lymphatic filariasis is among the leading health-related impediments to economic and social development in economically disadvantaged areas of the tropics.1,2 Lymphatic filariasis can be transmitted in any region of the world where the appropriate mosquito vector breeds. It currently is a significant health problem in tropical Africa, Asia, and the Indian subcontinent, many islands of the western and southern Pacific, and focal areas of Latin America. In the tropics, the geographic distribution of W. bancrofti and B. malayi infections is expanding due to increased numbers of breeding sites that appear when large numbers of people migrate from rural to urban areas. These pessimistic epidemiologic trends contrast with the recent gains and successes by the Global Program to Eliminate Lym phatic Filariasis using yearly single dose administration of antifilarial chemotherapy.3
THE AGENT The existence of lymphatic filariasis has been recorded in ancient Chinese, Indian, Persian, and Arabic writings, but causative agents and their life cycles were not described until the late nineteenth century.4,5 Microfilariae of W. bancrofti, first discovered by Demarquay in hydrocele fluid from a patient in Cuba in 1863,6 were later identified in the urine by Wucherer in 18687 and in the blood by Lewis in 1872.8 Manson described the periodicity of microfilariae in the peripheral blood9 and demonstrated that mosquitoes transmit the parasite.10 Bancroft first described the adult female worm11 and Bourne later described the adult male worm.12 Bancroft in 189913 and Low in 190014 established the mode of transmission of the parasite. Lichtenstein, Brug and Buckley were primarily responsible for identification of brugian parasites.15 W. bancrofti, B. malayi, and B. timori are threadlike nematodes having five morphologically and biochemically distinct stages in their life cycle
(Fig. 104.1). Infective or third-stage larvae, transmitted to humans during blood feeding by mosquitoes, are deposited from the mouthparts of the mosquito in the vicinity of the skin puncture wound, and within several minutes make their way through the dermis to enter the local lymphatics. Several hours later, infective larvae shed their cuticle and develop a new surface (a process referred to as molting) that presents novel antigens and other molecules to the mammalian host. These fourthstage larvae migrate centrally in lymphatic vessels and over a period of approximately 6–9 months develop into sexually mature adult male or female worms. Adult worms are considerably larger than larval stages (male worms are 20–40 mm in length, and female worms 40–100 mm) and have highly differentiated and complex reproductive and digestive systems. This stage of the parasite dwells primarily in the afferent lymphatics. Although all the anatomical areas in which adult lymphatic filariae live in humans are not known with certainty, large numbers are present in the lymphatics of the lower extremities (inguinal and obturator groups), upper extremities (axillary lymph nodes), and, for W. bancrofti, male genitalia (epididymis, spermatic cord, testicle). Based on observations of inflammatory reactions elicited by administration of drugs that kill adult worms, it is likely that adult filariae are distributed in subcutaneous tissues more than several centimeters distant from major lymph node groups. The mean life span of adult worms is approximately 5 years. Following copulation with male worms, fecund female parasites release large numbers (often more than 10 000 per day) of first-stage larvae, microfilariae. Microfilariae are distinguished by their small size (260 mm in length and approximately 10 mm in width). Microfilariae of the lymphatic filariae have an acellular sheath, which is a chitin-containing remnant of the embryonic eggshell or vitelline membrane. Microfilariae of W. bancrofti and B. malayi differ morphologically from each other in the pattern of nuclei in the cephalic and caudal regions. W. bancrofti and Brugia microfilariae frequently have a nocturnal periodicity whereby the number present in the peripheral circulation peak at midnight (with large numbers between 10 p.m. and 4 a.m. with few or none present during the day). When absent from the peripheral circulation, microfilariae are sequestered in deep vascular beds of the lung and other organs. This peculiar behavior appears to be an example of adaptation to local ecological conditions in that the time at which peak parasitemia occurs coincides with the time when the local mosquito vectors take their blood meal.16 The mechanisms that regulate microfilarial periodicity in humans are poorly understood. After ingestion in a blood meal taken by a female mosquito, microfilariae exsheath within 24 hours, penetrate the chitinous gut wall of the mosquito, and migrate into the thoracic musculature. Over a period of 10–14 days, microfilariae mature to become third-stage larvae capable of infecting another human. The nature of the relationship between filarial larvae and the local mosquito populations has a profound impact on local transmission efficiency. For example, if mosquitoes ingest unusually large numbers of microfilariae, the overall efficiency of transmission may be
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Lymphatic filariasis Wuchereria bancrofti and Brugia malayi/timori
Microfilariae released into peripheral blood after 6 –12 months (diagnostic)* causing:
Larvae migrate to lymphatics where adults mature and mate (releasing microfilariae over 5–10 years) and cause:
Tropical pulmonary eosinophilia (in some sensitized hosts)
Recurring lymphadenitis, fever, lymphangitis, elephantiasis, hydrocele
Night (or day) biting mosquitoes (Anopheles, Culex, Aedes or Mansonia) bite, introducing infective 3rd stage larvae*
1st–3rd stage larvae develop over 10–14 days in thorax muscles of mosquito
Night (or day) biting mosquitoes bite taking up microfilariae*
Figure 104.1 Life cycle of lymphatic filariasis. *For many filarial strains (e.g., W. bancrofti in Africa), microfilariae become abundant in blood only at night (nocturnal periodicity), when they may be detected by night-biting mosquitoes. For other strains, microfilariae are present by day and are spread by day-biting mosquitoes.
reduced by virtue of the fact that heavily infected mosquitoes have a shortened life span, precluding development of infective larvae. Conversely, in some mosquito–filarial interactions, there may be more efficient transmission at lower microfilarial densities, a phenomenon referred to as facilitation. An important biologic feature of W. bancrofti and Brugia species relates to the fact that these nematodes carry an obligate bacterial endosymbiont Wolbachia. Ultrastructural studies performed in the 1970s recognized the presence of intracellular bacteria in adult worms and microfilariae;17,18 but it was not until the late 1990s when molecular probes and genome sequence data became available that Wolbachia were definitively identified in human filarial parasites.19,20 These endosymbiotic bacteria appear to affect filariae in several ways that are pertinent to human filariasis. Incubation of Brugia worms with tetracycline and other antibiotics known to kill Wolbachia diminishes the release of microfilariae and suppresses larval molting, suggesting that the bacteria are involved in embryogenesis and regulation of the parasite life cycle.21,22 In the context of human lymphatic filariasis, administration of doxycycline to persons with W. bancrofti or B. malayi infection augments the suppression of microfilaremia induced by both ivermectin23 or combination diethylcarbamazine/ albendazole.24 Moreover, 6 weeks of doxycycline has been shown to have macrofilaricidal (killing adult parasites) activity for both Wuchereria and Brugia infections.24–26 There is a need, however, to identify anti-Wolbachia agents that can be given for short periods of time (and with broader applicability) than the tetracycline antibiotics, which cannot be given to pregnant women or young children.
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It is estimated that 120 million people (in 81 countries) are infected with one of the three genera of lymphatic filariae (Fig. 104.2).27 More than
90% of infections are due to W. bancrofti, and, of these, the greatest number are in sub-Saharan Africa, Southeast Asia, and the western Pacific. The infection is prevalent in India, Indonesia, the Philippines, Papua New Guinea, and several Pacific countries such as parts of Fiji and Tahiti. Bancroftian filariasis is also a significant public health problem in many countries of tropical Africa (see Fig. 104.2). Within Africa, W. bancrofti infection is not limited to these tropical zones since endemic foci are found as far north as the Nile delta in Egypt and Sudan. In the Americas, endemic foci persist in several islands in the Caribbean (Haiti and the Dominican Republic) and coastal areas of South America (Brazil and Guyana). There are no animal reservoirs of W. bancrofti. Infection with B. malayi is limited to Asia (China, India, and Malaysia) and several Pacific island groups (e.g., Indonesia and the Philippines). There are fewer than 10 to 20 million persons in these areas infected with B. malayi, which may coexist with W. bancrofti. B. malayi infection is a zoonosis in that there are feline and primate reservoirs. B. timori infection is limited in its distribution to the islands of southeastern Indonesia. Within a given geographic area, the distribution of lymphatic filariasis is highly focal such that the frequency of infection in some communities is high compared with physically approximate localities. This heterogeneity of infection patterns, both locally and globally, is due in large part to the peculiarities of the ecological relationships between the mosquito vector and the human host, and the impact of filarial parasites on both of these. Unlike other common vector-borne infectious diseases of the tropics (e.g., malaria), several genera of mosquitoes are capable of transmitting lymphatic filariae. W. bancrofti is transmitted in many rural areas of Africa and the Pacific by Anopheles species.28 The proximity of human dwellings to breeding sites increases the risk of repeated contact with mosquitoes bearing infective larvae. In many urban areas of the world, including India, Culex species is the major vector of W. bancrofti and B. malayi.29 Unlike anopheline mosquitoes, larvae of these mosquitoes breed
Lymphatic Filariasis Chapter 104 Lymphatic filariasis Wuchereria bancrofti Wuchereria bancrofti and Brugia malayi Note: Brugia timori is limited to the Timor Island of Indonesia
Figure 104.2 World map of lymphatic filariasis infection.
readily in small pools of water that form in discarded tires and cans. Other vectors include Aedes aegypti in some Pacific islands (e.g., Tahiti) and Mansonia, which transmits only B. malayi. These various genera of mosquitoes also differ in their efficiency of transmission. In general, anopheline mosquitoes are more efficient vectors of W. bancrofti than are culicine mosquitoes. The age-related pattern of infection, as judged by the proportion of persons harboring microfilariae in the blood (the “microfilarial carrier rate,” see below), increases gradually with age up until the third or fourth decade of life, after which it remains constant or slightly decreases. This epidemiologic pattern is related to the gradual slow accumulation of adult-stage worms over time. The proportion of the entire population or a specific age group with patent infection is remarkably variable in different endemic areas. In addition to these differences in infection patterns, there is remarkable variation in the frequency of various disease manifestations based on age and geographic area. Lymphatic disease, manifest by persistent lymphedema of the lower extremity or genital disease in males (see below), is rare in persons less than 10 years of age, and tends to increase gradually throughout life. Of the total 120 million persons estimated to be infected in all endemic areas, about onethird have clinically overt disease. The likelihood of developing such manifestations appears to be particularly high in some areas of the world, such as India, Pacific islands such as Papua New Guinea, and in equatorial Africa, whereas it is considerably lower in the Caribbean and South America. Local transmission conditions may account for the striking heterogeneity of disease manifestations that may be observed within a given geographic area. Indeed the cumulative exposure to infective larvae may be an important risk factor for lymphatic pathology at the population level.30
THE DISEASE Infection with W. bancrofti, B. malayi or B. timori can cause a wide variety of clinical manifestations, ranging from those without apparent clinical disease to those with lymphedema and/or severe disfigurement of the limbs and genitalia. From the clinical perspective, it should be stressed that there is a great deal of overlap in these symptom complexes, several of which may occur contemporaneously.
Subclinical Patent Infection The overwhelming majority of filarial-infected inhabitants in endemic areas have few overt clinical manifestations of their filarial infection despite large numbers of circulating microfilariae in the peripheral blood.31 Although they may be clinically asymptomatic, virtually all persons with patent W. bancrofti or B. malayi infection (microfilariaand/or circulating filarial antigen-positive) have some degree of subclinical disease that includes microscopic hematuria and/or proteinuria,32 dilated (and tortuous) lymphatics (visualized by lymphoscintigraphy33–35), and, in men with W. bancrofti infection, scrotal lymphangiectasia (detectable by ultrasound).36–38
Acute Adenolymphangitis Acute adenolymphangitis (ADL) is often the first manifestation of lymphatic filariasis. It is characterized by the sudden onset of high fever, painful, lymph node and lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside – the retrograde nature of the lymphadenitis distinguishes filarial-induced disease from bacterial-induced lymphangitis. Regional lymph nodes (e.g., inguinal, obdurator, axillary, epitrochlear) are often enlarged, and the entire lymphatic channel can become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis can involve both the upper and lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection.39 This genital involvement can be manifested by funiculitis, epididymitis, scrotal pain, tenderness as well as a condition termed lymph scrotum.40 In endemic areas, another type of acute disease – dermatolymph angioadenitis (DLA)41,42 – is recognized as a syndrome that includes high fever, chills, myalgias, and headache. Edematous inflammatory plaques clearly demarcated from normal skin are seen. Vesicles, ulcers, and hyperpigmentation may also be noted. There is often a history of trauma, burns,
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Figure 104.4 Hydrocele and inguinal lymph node enlargement in bancroftian filariasis. The patient is a 40-year-old man who first experienced epididymitis at the age of 20. The hydrocele has been present for 2 years.
Disease Involving the Genitourinary System
Figure 104.3 Lymphedema of the upper and lower extremities in a 50-year-old man. Swelling had been present for approximately 10 years, and the level of microfilaremia was 1000 parasites per milliliter of blood.
radiation, insect bites, punctiform lesions, or chemical injury. Entry lesions, especially in interdigital areas, are common. DLA is often diagnosed as cellulitis.
Lymphedema of the Arms, Legs, and Breasts
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Swelling of the upper or lower extremities is the most common chronic manifestation of lymphatic filarial infection. Disease of the lower extremities is more prevalent. Leg involvement in bancroftian filariasis may include the entire limb, whereas only the area below the knee is usually involved in brugian filariasis. The World Health Organization has adopted a grading system to quantify the severity of involvement.43 Grade I indicates pitting edema that is reversible upon elevation of the leg; grade II, non-pitting edema that does not resolve with elevation of the extremity; grade III, nonpitting edema of the limb that is not reversible with elevation and with thickened skin or skin folds; and grade IV, non-pitting edema with fibrotic and verrucous skin changes (elephantiasis), and the presence of skin folds (Fig. 104.3). Although both lower extremities may be involved, asymmetrical involvement is the rule. In some persons with filarial-associated edema, the overlying skin may exude serous fluid suggestive of lymph. Although it is possible that this sign occurs as a result of increased hydrostatic pressure in the lymphatics draining the skin, skin turgor alone cannot reliably be used to distinguish between edema due to lymphatic disease and that from other causes, such as cardiac failure and liver disease. Unilateral or bilateral involvement of the female breast occurs in adult residents of filarial endemic areas. This should be distinguished from chronic mastitis and other causes of chronic breast inflammation.
Along with lymphatic disease of the lower extremities, disease of the male genitalia is the most common manifestation of bancroftian filariasis. Indeed, in many endemic areas, its prevalence is greater than that of lymphedema. Genital involvement is uncommon in Brugia infection. The prevalence of disease of the female genitalia is not known since systematic surveys have not included examination of this anatomical area. Anecdotal evidence suggests that the frequency of vulvar disfigurement is low. Genital disease is usually not experienced until the teenage years. Acute painful episodes of epididymitis or funiculitis last several days and are accompanied by fever and malaise. Involvement is most commonly unilateral.
Hydroceles Chronic disease of the male genitals mostly produces hydroceles, which vary in diameter from less than 5 cm to over 30 cm (Fig. 104.4). As is the case with other causes of hydrocele, the scrotal contents appear translucent when transilluminated. Hydroceles are usually not painful unless they are complicated by acute epididymitis or funiculitis. Thickening of the spermatic cord commonly accompanies hydroceles. The skin of the scrotum may also be thickened and have a “brawny” character on palpation. If hydrocele fluid is drained, it is clear and straw-colored. Parasites are usually not found in this fluid. Inguinal lymph nodes and other nearby lymph nodes may also be enlarged (see Fig. 104.4).
Lymphedema of the genitalia Swelling of the scrotum when accompanied by thickened scrotal or penile skin may have a characteristic “peau d’orange” appearance.39 In longstanding cases verrucous lesions and lymphorrhea are common,40 the latter being a condition in which lymph oozes out to the exterior directly from dilated ruptured lymphatic vessels in the scrotal wall. The genitals may be grossly deformed and terms such as “ram horn penis” have been used to describe the gross distortion of the penis seen in this condition.
Chyluria Chyluria, resulting from obstruction or physiologic impairment of the renal lymphatics with passage of lymph from the lacteals draining the genitourinary tract, is a rare but serious manifestation of lymphatic filariasis. Chyluria may have serious nutritional consequences in that large amounts of fat and protein are lost in the urine. Its precise frequency in filarial endemic areas has not been established, but is exceedingly low compared to lymphedema of the extremities and hydroceles.44
Tropical pulmonary eosinophilia (TPE) is a distinct syndrome that develops in some individuals infected with either W. bancrofti or B. malayi.45,46 The majority of cases have been reported from India, Pakistan, Sri Lanka, Brazil, Guyana, and Southeast Asia. The main clinical features include paroxysmal cough and wheezing that are usually nocturnal (and probably related to the nocturnal periodicity of microfilariae), weight loss, lowgrade fever, adenopathy, and pronounced blood eosinophilia (>3000 eosinophils/µL). Chest radiographs may be normal but generally show increased bronchovascular markings; diffuse miliary lesions or mottled opacities in the middle and lower lung fields. Tests of pulmonary function show restrictive abnormalities in most cases and obstructive defects in half. Total serum IgE levels (10 000–100 000 ng/mL) and antifilarial antibody titers are characteristically elevated. Typically those with TPE do not have microfilaremia. Administration of the antifilarial drug diethylcarbamazine (see below) leads to significant symptomatic improvement with commensurate decreases in eosinophilia and serum IgE. If patients with TPE are not treated appropriately, the disease may progress to chronic restrictive lung disease with interstitial fibrosis.47
Lymphatic Filariasis in Expatriates and Travelers American servicemen returning from prolonged exposure to infectious mosquitoes in the South Pacific during World War II and French soldiers exposed in Indochina (now Vietnam) suffered from acute episodes of acute adenolymphangitis of the legs accompanied by eosinophilia. These acute disease manifestations were apparently caused by immune-mediated inflammatory responses to developing larvae, and resolved on departure from the endemic area.48 Progression to chronic lymphedema or elephantiasis was rare. Studies of Indonesian transmigrants from nonendemic to endemic regions49 as well as studies in which volunteers were experimentally infected with infective larvae of B. malayi50 provide corroboration of these early clinical manifestations. The risk of developing acute or chronic manifestations of lymphatic filariasis for the traveler to endemic areas is extraordinarily small, given the inefficiency of transmission by infected mosquitoes, although it has been seen rarely.51
PATHOGENESIS AND IMMUNITY The precise and likely multiple mechanisms leading to the diverse clinical manifestations of lymphatic filariasis have not been established. However, several factors have been suggested to underlie the development of lymphedema, including parasite-derived factors52,53 that may be responsible for the lymphatic dilatation seen early in infection, host genetic susceptibility,54–59 secondary bacterial infections,60–63 specific host adaptive immune responses to parasite antigens,64,65 and inflammatory responses to dying or dead parasite material.39,60,66–69 Establishing the relative importance of these diverse factors and a central unifying hypothesis to explain the pathogenesis of human lymphatic filariasis has been difficult because the onset of disease occurs over a period of years or decades and because of the marked heterogeneity in transmission and disease in geographically distinct filarial-endemic areas. The immunologic basis for the relative lack of pathology seen in the majority of individuals with patent infection, however, has been reasonably well studied in both cross-sectional and longitudinal populationbased studies. Studies in animal models and in vitro human systems have suggested that the initial immune response to infective stage larvae (L3) and to the next developmental stages (L4 and early adult stages) are dominated by proinflammatory and a mixed Th1-like and Th2-like T-cell responses.70,71 With the onset of patency (when microfilariae appear in the blood), there is a marked diminution of the parasite antigen-specific T-cell responses (both proliferation and Th1 cytokine responses)72–78 that is primarily mediated by interleukin (IL)-1079–82 and other regulatory cell
populations (e.g., adaptive and natural Treg cells, alternatively activated macrophages/monocytes83–85). Examination of protective immunity in lymphatic filariasis in human populations has been extraordinarily difficult. However, populationbased studies86–88 have identified groups of individuals who appear to be infection-free despite long-term exposure to the filarial parasites. When looked at immunologically, on balance cells from these individuals are more likely to respond to parasite antigen than were those with patent infection. The best evidence, however, for the induction of protective immunity has come from studies in animals (jirds, cats, ferrets) permissive for Brugia spp. given radiation attenuated L3; in these studies irradiated L3s induced protection to varying degrees (60–95% protection from challenge).89–92 Attempts with subunit vaccines using recombinant antigens or DNA vaccination have been less successful but levels of protection that range between 30% and 69% have been achieved.93–97
Lymphatic Filariasis Chapter 104
Tropical Pulmonary Eosinophilia
DIAGNOSIS Lymphatic filariasis is diagnosed by a combination of the appropriate epidemiologic history, physical findings, and laboratory tests. In residents of endemic areas, the appearance of lymphedema of the extremities or disease of the male genitalia is most likely due to filarial infection if there is no other obvious other secondary cause, such as trauma to the lymphatics or congestive heart failure. A definitive diagnosis can be made only by detection of the parasites, parasite antigen, or parasite DNA. Adult worms localized in lymphatic vessels or nodes are largely inaccessible. Examination, however, of the scrotum or the female breast using high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics.98–101 Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of infected men.98 Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the filaria dance sign).36,98 Microfilariae can be found in blood, in hydrocele fluid, or (occasionally) in other body fluids. Such fluids can be examined microscopically, either directly using a Giemsa-stained thin blood smear or – for greater sensitivity – after concentration of the parasites by the passage of blood through a polycarbonate cylindrical 3–5 mm pore filter (Nuclepore) or by the centrifugation of fluid fixed in 2% formalin (Knott’s concentration technique).102 The timing of blood collection is critical and should be based on the periodicity of the microfilariae in the endemic region involved. Many infected individuals do not have microfilaremia, and definitive diagnosis in such cases can be difficult. Assays for circulating antigens of W. bancrofti permit the diagnosis of both microfilaremic and amicrofilaremic infection. Two tests are commercially available: one is an enzyme-linked immunosorbent assay (ELISA)103 and the other a rapidformat immunochromatographic card test.104 Both assays have sensitivities that range from 96% to 100% and specificities that approach 100%. There are currently no tests for circulating antigens in brugian filariasis. Polymerase chain reaction (PCR)-based assays for DNA of W. bancrofti and B. malayi in blood have been developed.105–110 A number of studies indicate that this diagnostic method is of equivalent or greater sensitivity compared with parasitologic methods, detecting patent infection in almost all infected subjects. Antibody-based assays for diagnosing filarial infection have typically used crude parasite extract and have suffered from poor specificity. Improvements have been made by the use of detection of antifilarial IgG4 antibodies111 in that they have relatively less cross-reactivity to non-filarial helminth antigens. Specificity has also been improved by the use of species-specific recombinant antigens for both brugian and bancroftian infection;112 indeed a diagnostic dipstick test has been developed for use in areas endemic for brugian filariasis.113 In cases of suspected lymphatic filariasis, radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities in both subclinical microfilaremic persons and those with
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clinical manifestations of lymphatic pathology. While of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection. It is important to note, however, that it is not possible to exclude a diagnosis of filarial-induced disease in the absence of circulating antigens or parasites since disease may persist in persons with so-called burned-out infections. This situation may occur in persons who have received multiple courses of treatment or who have left endemic areas.
TREATMENT AND PROGNOSIS Chemotherapeutic Agents Diethylcarbamazine (DEC, 6 mg/kg daily for 12 days), which has both macro- and microfilaricidal properties, remains the treatment of choice for the individual with active lymphatic filariasis (microfilaremia, antigen positivity, or adult worms on ultrasound), although albendazole (400 mg twice daily for 21 days) has also demonstrated macrofilaricidal efficacy. The use of a 4- to 6-week course of doxycycline (targeting the intracellular Wolbachia) has also been demonstrated to have significant macrofilaricidal activity,24,26 as has daily DEC/albendazole used for 7 days.114 Adding diethylcarbamazine to a 3-week course of doxycycline has also recently been shown to be efficacious.25 Regimens that utilize combinations of single doses of albendazole (400 mg) and either DEC (6 mg/kg) or ivermectin (200 µg/kg) have all been demonstrated to have a sustained microfilaricidal effect,115–118 and are the mainstay of control programs in Africa (albendazole/ivermectin) or elsewhere (albendazole/DEC) for the eradication of lymphatic filariasis (see below). Side effects of DEC treatment include fever, chills, arthralgias, headaches, nausea, and vomiting. In heavily infected patients, painful nodules in the skin, lymph node enlargement, and epididymitis may appear. Both the development and the severity of these reactions are directly related to the number of microfilariae circulating in the bloodstream and likely represent an acute inflammatory reaction to either the antigens being released by dead and dying parasites or Wolbachia endosymbionts freed from their intracellular niche. Ivermectin has a side effect profile similar to that of DEC when used in lymphatic filariasis. Albendazole (when used in single dose regimens) has relatively few side effects associated with its use in lymphatic filariasis, but when used in multiday regimens has been associated with painful scrotal nodules.
Pathology Based Therapy As has already been mentioned, a growing body of evidence indicates that, although they may be clinically asymptomatic, most patients with W.
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bancrofti or B. malayi microfilaremia have some degree of subclinical disease (hematuria, proteinuria, abnormalities on lymphoscintigraphy). Thus, early treatment of asymptomatic individuals is recommended to prevent further lymphatic damage. For ADL, supportive treatment (including the administration of antipyretics and analgesics) is recommended, as is antibiotic therapy if secondary bacterial infection is likely. Similarly, because lymphatic disease is associated with the presence of adult worms, treatment is recommended for microfilaria-negative adult worm carriers. In persons with chronic manifestations of lymphatic filariasis, treatment regimens that emphasize hygiene, prevention of secondary bacterial infections, and physiotherapy have gained wide acceptance for morbidity control. These regimens are similar to those recommended for lymph edema of most non-filarial causes, and are known by a variety of names, including complex decongestive physiotherapy and complex lymphedema therapy. Drainage of hydroceles provides immediate relief, though they recur in the absence of drug therapy or surgical removal of the tunica albuginea. With chronic manifestations of lymphatic filariasis, drug treatment should be reserved for individuals with evidence of active infection; therapy has been associated with clinical improvement and, in some cases, reversal of lymphedema. In severe cases of deforming elephantiasis, surgical approaches involving lymphatic-venous and nodal-venous anastomoses have been somewhat successful in diminishing the degree of leg swelling,119 as has reconstructive surgery for genital involvement. The long-term effects of these expert surgical techniques have not been determined.
PREVENTION AND CONTROL Individual protection against filarial infection may be achieved by avoiding contact with infected mosquitoes. This can be done by use of personal protective measures including bednets, particularly those impregnated with insecticides such as permethrin. Created in 1997, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was based on mass drug administration with single annual doses of diethylcarbamazine plus albendazole (non-African regions) or albendazole plus ivermectin in Africa.116,120–124 Information at the end of 2008 indicates that >695 million persons in 51 countries have thus far participated.125 Not only has there been success in eliminating lymphatic filariasis in some defined areas, but also collateral benefit in averting disability (estimated 32 million disability-adjusted life-years averted)122 and treating intestinal helminths and other conditions (e.g., scabies, lice). The strategy of the global program is being refined and guided by ongoing research aimed at understanding the ecology and transmission efficiency of the various mosquito vector species and integration with other mass treatment strategies (e.g., deworming programs, malaria control, trachoma control).126–132