Chapter 84

Section 11
Helminthic Infections
Chapter 84
Filariases
P. E. Simonsen
The lariases result from infection with vector-borne tissuedwelling nematodes called lariae. Depending on the species, adult lariae may live in the lymphatics, blood vessels, skin, connective tissues or serous membranes. The females produce larvae (microlariae) which live in the bloodstream or skin. All true lariae that infect humans (superfamily Filarioidea; family Onchocercidae) are transmitted by dipteran vectors. The guinea worm (superfamily Dracunculoidea) is not a true laria, but is included in this section as a related nematode transmitted by arthropod vectors. A summary of the common larial worms infecting humans and the common disease symptoms is shown in Table 84.1. A few species of animal lariae may accidentally infect humans. The transmission of human lariae is conned to warm climates, a high temperature being necessary for the parasites to develop in the vectors. The pattern of the life cycle of all species of lariae is shown in Figure 84.1. Detailed life cycles of the species infecting humans are given in Appendix III. The infective form is the third-stage larva which is transmitted by the vector. The rate of growth and differentiation of worms and longevity of both microlariae and adult worms differ markedly between different species. Some adult worms may live as long as 20 years. A high specicity of the laria-vector and the laria-host relationships has evolved over a long period of time. From the public health point of view, onchocerciasis and lymphatic lariasis are the most important larial infections. Dracunculiasis (guinea worm infection) results in severe ulceration, and Calabar swellings and other clinical manifestations of loiasis may have severe consequences for the patient.
Historical background
Our present knowledge of lariasis owes much to investigations carried out towards the end of the nineteenth and the beginning of the twentieth centuries. Microlariae, recovered in hydrocele uid from a Cuban patient, were rst described by Jean-Nicolas Demarquay in Paris in 1863.2 Three years later, microlariae were found in chylous urine in a patient in Brazil by Otto Wucherer, who was unaware of the earlier French report.3 Timothy Lewis, working in India, rst reported the nding of microlariae in human blood in 1872.4 Adult worms were recovered by Joseph Bancroft in Australia in 1876 and named Filaria bancrofti.5 In 1921 this species was included in the genus Wuchereria. The distinguished pioneer of tropical medicine, Sir Patrick Manson, while working in Amoy in China, made several contributions to the understanding of the biology of W. bancrofti.6 Thus, in 1877 he observed the development of the parasite in mosquitoes fed on the blood of his microlaraemic gardener, and he speculated that it was transmitted by mosquitoes. He also noticed that microlariae could not always be found in the blood of infected patients. By serial blood examinations every few hours, he then revealed the nocturnal periodicity of the microlariae. Examination of specimens of adult worms revealed two new species, subsequently called Brugia malayi (1960) and B. timori (1977). A detailed history of lymphatic lariasis has been written.7
Geographical distribution
The distribution of the three causal parasites of lymphatic lariasis, W. bancrofti, B. malayi and B. timori, is shown in Figure 84.2. W. bancrofti is distributed throughout the tropical regions of Asia, Africa, the Americas and the Pacic, and is particularly prevalent in areas with hot and humid climates. B. malayi is found in Southeast Asia and in areas of south-west India, whereas B. timori occurs only on some islands in Indonesia. In 1997, it was estimated that at least 128 million individuals were infected, 115 million with W. bancrofti and 13 million with the Brugia spp.8 India (48 million cases) and sub-Saharan Africa (51 million cases) accounted for most of this burden. Results from many recent surveys indicate that the true gures could be much higher. Lymphatic lariasis has disappeared from North America,
LYMPHATIC FILARIASIS
Three species of lymphatic dwelling larial worms, Wuchereria bancrofti, Brugia malayi and B. timori, cause lymphatic lariasis in humans. The vectors are species of mosquitoes (Anopheles, Culex, Aedes and Mansonia spp). Infection with W. bancrofti is sometimes called bancroftian lariasis, while brugian lariasis refers to infection by the other two species. W. bancrofti is geographically much more widespread than the Brugia spp. Lymphatic lariasis is a major cause of debilitating and disguring chronic disease manifestations (especially lymphoedema, elephantiasis and hydrocele) in endemic areas.1
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Table 84.1 Characteristics of larial parasites and guinea worm and common clinical manifestations in humans Species
Wuchereria bancrofti
Distribution
Tropics
Vectors
Mosquito spp.
Main location of adults

Lymphatics
Main location of microlariae

Blood
Common disease symptoms

Lymphangitis Elephantiasis Hydrocele Lymphangitis Elephantiasis Lymphangitis Elephantiasis Calabar swellings Usually symptomless Usually symptomless Usually symptomless Dermatitis Nodules Eye lesions Ulceration
Brugia malayi Brugia timori Loa loa Mansonella perstans Mansonella streptocerca Mansonella ozzardi Onchocerca volvulus
South, East and South-east Asia Indonesia Central and West Africa Africa, Central and South America Central and west Africa Central and South America Africa, Yemen, Central and South America Africa
Mosquito spp. Mosquito spp. Chrysops spp. Culicoides spp. Culicoides spp. Culicoides spp. Simulium spp. Simulium spp.
Lymphatics Lymphatics Connective tissue Body cavities Serous membranes Skin Peritoneal cavity Serous membranes Skin
Blood Blood Blood Blood Skin Blood and skin Skin
Dracunculus medinensis
Copepods
Connective tissue, including skin
Male
Female
Adult worms in tissues
Japan and Australia, and in some countries, especially China, control programmes have greatly decreased the prevalence. It continues to be a major public health problem in most of southern and South-east Asia, in Africa, and in a number of Caribbean and Pacic islands. In recent years the amount of urban lariasis has increased due to an increase in both human and vector populations in these areas.
Larvae migrate to final location and develop to adults
Life cycle and transmission

Females produce microfilariae
Human infected when vector bites Human Vector Infected larvae in vector
Microfilariae to blood or skin
Microfilariae ingested by vector
Development in vector Figure 84.1 General life cycle of lariae.
The adult worms reside in the lymphatics of the human host. Female W. bancrofti measure 80100 0.25 mm and the male 40 0.1 mm. The adult Brugia spp. have only half of this dimension. Microlariae are produced from ova in the uterus of the female worm. They are sheathed and measure on average 260 8 m (Figures 84.3, 84.4). Microlariae are ingested by the vector female mosquito during a blood meal. They exsheath in the mosquito stomach, becoming rst-stage larvae which penetrate the stomach wall of the mosquito and migrate to the thorax muscles. There they develop through two moults to the infective third-stage larvae (1500 20 m). The development in the mosquito takes a minimum of 1012 days. Mature infective larvae then migrate to the mouthparts of the mosquito from where they enter the skin of the human host, probably through the puncture site made by the proboscis of the vector when it takes its blood meal. The larvae migrate to the lymphatics and develop to adult worms. Microlariae appear in the blood after a minimum of 8 months in W. bancrofti and 3 months in B. malayi. The adult worms may live and produce microlariae for more than 20 years, but on average the lifespan is shorter. Microlariae have a lifespan of approximately 1 year. Microlarial densities may reach 10 000 per mL of blood or more, but are usually lower.
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Lymphatic Filariasis
A.
B.
Figure 84.2 Geographical distribution of human lymphatic lariasis. (A) In Africa and the Americas. (B) In Asia. (Adapted from WHO.1)
For details of the life cycles of the three causal parasites of lymphatic lariasis and of the mosquito vectors transmitting this infection in different geographical zones, see Appendices III and IV.
Microlarial periodicity
Like many larial species, W. bancrofti, B. malayi and B. timori exhibit a daily periodicity in the concentration of microlariae in the peripheral blood of the host. The different periodicities of microlariae correspond with the biting habits of their principal vector. This adaptation enhances their chances of onward trans-
mission. The details of microlarial periodicity are discussed in Appendix III. Depending on whether the highest microlarial density over a 24-h period occurs during the night or the day, periodicity is termed nocturnal or diurnal (Figure 84.5). In most areas the periodicity of both W. bancrofti and B. malayi is nocturnal, with peak concentrations in the blood around midnight, and none or very few at midday.9 In these areas, the parasites are transmitted by night-biting mosquitoes. There are also diurnally subperiodic and nocturnally subperiodic forms of W. bancrofti, where microlariae are present continuously in the peripheral blood but where the concentrations are higher than average during day and night,
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A D B
E C
Figure 84.3 Microlaria of W. bancrofti in thick blood lm.
Figure 84.5 Observed () and theoretical (- - -) periodicity of microlariae in peripheral blood. (A) Diurnally subperiodic W. bancrofti in the South Pacic. (B) Nocturnally subperiodic W. bancrofti from west Thailand. (C) Nocturnally subperiodic B. malayi in the Philippines. (D) Nocturnally periodic B. malayi in Malaysia. (E) Nocturnally periodic W. bancrofti in Malaysia. (Reproduced from Control of Lymphatic Filariasis. A Manual for Health Personnel. Geneva: WHO; 1987.)
Figure 84.4 Microlaria of B. malayi in thick blood lm.
laraemia, and individuals who have cleared the infection. Another group of individuals in the endemic community shows microlariae in their blood but no obvious clinical manifestations. Some of these may remain microlaraemic and asymptomatic for years or even for the rest of their lives. Recent surveys employing diagnostic tests that detect circulating antigens from adult W. bancrofti worms have demonstrated that many of the amicrolaraemic individuals in endemic areas actually harbour adult worms.10 Through the use of ultrasonography and lymphoscintigraphy it has been recognized that most infected but apparently asymptomatic individuals (with or without microlaraemia) suffer from subclinical lymphatic abnormalities, especially dilatation of the vessels (lymphangiectasis).11,12 Obvious symptomatic larial disease manifests itself in both acute and chronic forms, and may be with or without infection.
Bancroftian lariasis
respectively. A strain of B. malayi also exhibits nocturnal subperiodicity (Figure 84.5). The periodicity is due to a biological rhythm inherent in the microlariae but inuenced by the circadian rhythm of the host. Microlaraemia of nocturnally periodic W. bancrofti ceases to be periodic in persons who start work at night and sleep during the day, and in patients who have been hospitalized for long periods. Common clinical manifestations of bancroftian lariasis are acute adenolymphangitis, hydrocele, lymphoedema and elephantiasis. Chyluria and tropical pulmonary eosinophilia are more rarely seen manifestations. Although frequent in males, genital manifestations do not appear to be a substantial problem in females.13
Acute manifestations
Manifestations of acute larial disease (larial fever), often described as adenolymphangitis (ADL), are characterized by episodic attacks of malaise, fever and chills, and by the appearance of enlarged painful lymph nodes draining the affected part, usually the lower limb, followed by an acute, warm and tender swelling. The episodes usually resolve spontaneously after about a week, and may recur several times within a year. Regression of the swelling after an ADL attack of the leg is commonly followed by excessive skin exfoliation.14 In males the genitals are frequently affected
Clinical features
Lymphatic lariasis is characterized by a wide range of clinical presentations. One group of individuals in the endemic community shows no clinical manifestations or microlariae. This includes individuals who have not been sufciently exposed to be infected, individuals with prepatent infection or adult worm infection without micro-
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and attacks may present as acute funiculitis or epididymo-orchitis. Acute attacks may be unilateral or bilateral, and commonly occur also in individuals with chronic manifestatons.15 Two distinct syndromes of acute larial attacks in the extremities have recently been recognized.16 One, called acute larial lymphangitis (AFL), is caused by the death of adult worms, either spontaneously or after treatment. It presents as a circumscribed inammatory nodule or cord centred around degenerating adult worms, with lymphangitis spreading in a descending (centrifugal) fashion. It usually has a mild clinical course and rarely causes residual lymphoedema. The other syndrome, acute dermatolymphangioadenitis (ADLA) is not caused by larial worms per se, but probably results from secondary bacterial infections in the legs with compromised lymphatics. It is characterized by diffuse subcutaneous inammation with or without ascending lymphangitis, and is often accompanied by oedema in the affected leg. It is believed to be the common cause of chronic lymphoedema and elephantiasis.
Hydrocele
Hydrocele is the most common chronic manifestation in bancroftian lariasis. It results from the accumulation of clear strawcoloured uid in the sac surrounding the testicles. The onset may be silent, i.e., without accompanying acute episodes, or it may be preceded by one or more attacks of funiculitis or epididymoorchitis. Following early acute episodes, the swelling around the testis usually disappears completely, but over the years the tunica vaginalis becomes thickened and there is progressive enlargement of the hydrocele (Figure 84.6). Most cases are unilateral, but bilateral hydrocele, often with different sizes on the two sides, is not uncommon. Rarely, the uid may have a milky appearance if lymph from a ruptured lymphatic vessel pours into the hydrocele to form a chylocele. In clinical surveys, hydrocoele is graded according to developmental stage and size. A commonly used scale records swelling of the spermatic cord as hydrocele grade I, and true hydroceles are classied from their length as grade II (6.08.0 cm), III (8.111.0 cm), IV (11.115.0 cm) and V (>5 cm).17,18
Lymphoedema and elephantiasis

Chronic lymphoedema progressing to elephantiasis most commonly affects the legs (Figure 84.7). The arms (Figure 84.8), scrotum, penis, vulva and breasts may also more rarely be affected. Following recurrent episodes of acute attacks, rst pitting oedema and then chronic non-pitting oedema with loss of skin elasticity and brosis develops. The development of elephantiasis may be arrested at any stage. It commences on one side but often becomes bilateral. In the leg, loss of contour is rst observed around the ankles. Following initial attacks the limb returns to normal. Over several years the oedema becomes non-pitting with thickening and loss of skin elasticity. Further progression leads to evident elephantiasis with skin folds, dermatosclerosis and papillomatous lesions. Secondary bacterial and fungal infections are common in the lymphoedematous skin, and probably exacerbate the progression of elephantiasis. In severe cases pus may ooze from chronic ulcerations in the affected part, which may also emanate a foul smell.
B Figure 84.6 Lymphatic lariasis: hydrocele. (A) Early; (B) advanced.
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Filariases
Figure 84.7 Lymphatic lariasis: elephantiasis of the leg. (A, B) Early stage lymphoedema of left leg; (C, D) advanced stage elephantiasis of left leg.
Scarication, a common traditional treatment for body swellings in many lariasis endemic areas (see Figure 84.8), has been recognized as a risk factor for rapid progression of larial elephantiasis.19 In clinical surveys, leg lymphoedemas are commonly classied as grade I: pitting lymphoedema spontaneously reversible on elevation; grade II: non-pitting lymphoedema, loss of skin elasticity; and grade III: evident elephantiasis with skin folds and papules.17,18 A more detailed classication with seven stages has recently been devised.20
Chyluria
Chyluria, the presence of chyle in the urine, follows the rupture of dilated lymphatics into the urinary excretory system. Chylous urine is milky in appearance (Figure 84.9). Blood may sometimes be present. Chyluria is frequently a recurrent phenomenon, with episodes lasting for days or weeks. The onset may be insidious or sudden. Retention of urine from the presence of chylous or blood clots may occur. Chyluria is more pronounced in the morning and after a heavy meal containing fat. Prolonged chyluria may result
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in loss of weight and subcutaneous fat, hypoproteinaemia, lymphopenia and anaemia. In most areas endemic for lariasis, the prevalence of chyluria is low.
Tropical pulmonary eosinophilia

Tropical pulmonary eosinophilia (TPE) is a syndrome of immunological hyperresponsiveness to microlariae in the lungs.21,22 It occurs with low frequency in most areas endemic for lymphatic lariasis. It is more common in males than in females. Microlariae are absent from the blood but have been recognized in lung biopsies, and adult worms have been seen on ultrasonography. Patients present with paroxysmal coughing and wheezing that is worse at night, and extreme blood eosinophilia with eosinophil counts above 3000 cells/mm3 of blood. This hypereosinophilia, and a therapeutic response to diethylcarbamazine (DEC) treatment, is the most constant feature of the syndrome. The level of eosinophilia is not related to the severity of symptoms. Patients have extremely high titres of larial antibodies. There is radiological evidence of diffuse miliary lesions. Extrapulmonary manifestations occur in some patients and include splenomegaly, lymphadenopathy and hepatomegaly. In most cases of TPE lung function is impaired, with a reduction in the vital capacity, total lung capacity and residual volume. If left untreated, TPE may progress to a chronic stage with interstitial brosis and permanent loss of lung function.
Figure 84.8 Lymphatic lariasis: elephantiasis of the arm, with visible scarication marks.
Other conditions
Monoarthritis is common in larial endemic areas, and a possible association has long been recognized.22 The knee joint is most frequently affected, followed by the ankle. The joint becomes painful, warm and tender, and the condition is indistinguishable from other forms of arthritis. A rapid cure follows treatment with DEC. Haematuria (usually microscopic) and proteinuria occur in many microlaraemic persons.22 The pathogenesis probably relates to immune complexes deposited on the basement membrane of the renal glomeruli. Scattered reports associate endomyocardial brosis, tenosynovitis, thrombophlebitis, nerve palsies and dermatoses with lariasis. These conditions sometimes coexist with lariasis and may be atypical manifestations of other diseases conditioned by preexisting larial infection.
Brugian lariasis
The main difference in the clinical manifestations between brugian and bancroftian lariasis is the rarity of hydroceles and other genital lesions in areas endemic for B. malayi. Chyluria is another sign not associated with B. malayi. Elephantiasis of the legs in B. malayi infections is often conned to below the knee, whereas in infections with W. bancrofti the lower leg as well as the thigh is frequently involved. B. timori infections produce similar clinical manifestations to those seen in infections due to B. malayi, i.e. scrotal lesions are almost absent and elephantiasis tends to be below the knee.23
Figure 84.9 Lymphatic lariasis: chyluria milky urine with blood. Before (left) and after (right) sedimentation.
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Filariases
Geographical variation in clinical picture

Clinical manifestations of lymphatic lariasis have been reported in the past to differ considerably between geographical zones. However, as examination and grading procedures become more standardized, differences appear to be less marked. Most cases of TPE and chyluria have been reported from south and South-east Asian countries. In Africa, the prevalence of both chyluria and TPE is low. A recent search for TPE cases in a highly endemic lymphatic lariasis area of Tanzania conrmed the rarity of this syndrome in the population.24 In W. bancrofti endemic areas of Papua New Guinea, microlarial prevalences can be exceedingly high, reaching 6080% for the overall population, whereas clinical sign rates for hydrocele and elephantiasis tend to be similar or even lower than those seen in highly endemic areas (overall 1530% microlarial prevalence) elsewhere in the world.25
ened skin that results from the intense itching and scratching in scabies infections. TPE should be differentiated from bronchial asthma and other allergic conditions, tuberculosis and eosinophilic leukaemia. TPE must also be distinguished from helminth infections that have a stage of the life cycle that involves lung tissue: Ascaris, Strongyloides, Schistosoma spp. and trichinosis. Confusion may also arise with visceral larva migrans caused by Toxocara. A rapid benecial response to DEC therapy distinguishes TPE from the abovementioned conditions.
Parasitological diagnosis
Adult worms are recovered only rarely from the tissues, and parasitological diagnosis is usually based on recovery of microlariae from the patients blood. Amicrolaraemia does not exclude larial disease, nor does microlaraemia denote it. Blood samples taken from patients with clinical manifestations, whether acute or chronic, are often negative for microlariae. In individuals there is no relationship between microlarial density and severity of disease. Microlariae frequently occur in hydrocele uid and may occasionally be seen in urine or other body uids. For parasitological diagnosis of lymphatic lariasis, a blood specimen should be obtained at the time of the day when the peak concentration of microlariae is expected (e.g. between 21:00 and 03:00 hours for nocturnally periodic forms).9 Many techniques have been described for demonstrating microlariae in blood samples (see also Appendix V). The counting chamber technique is fast, quantitative and cheap.27 An aliquot of 100 mL of nger-prick blood is added to a tube containing 0.9 mL of 3% acetic acid. Microlariae are counted in a counting chamber under the low power of a compound microscope. If only one species of laria is present in the area, this technique is the most suitable for routine hospital diagnosis as well as for eld surveys. Species identication of the microlariae may be difcult with the counting chamber technique. In areas where more than one species of blood microlaria exists, staining techniques are recommended. These are simple to perform but sensitivity is rather low owing to the small amount of blood examined and loss of microlariae during the staining procedure. Microlariae of W. bancrofti, B. malayi and B. timori have sheaths (see Figures 84.3 and 84.4). Microlariae of W. bancrofti measure on average 260 8 m, whereas those of B. malayi are slightly shorter and can be distinguished from microlariae of W. bancrofti by the two isolated nuclei at the tip of the tail and the absence of nuclei in the cephalic space (see Appendix III). Microlariae of B. timori are longer than those of B. malayi. Apart from microlariae of W. bancrofti, two other species of microlariae found in the blood in parts of Africa are those of Loa loa and Mansonella perstans. Staining with Giemsa or haematoxylin enables microlariae of these species to be differentiated morphologically. M. perstans and M. ozzardi microlariae also occur in the blood in South America and the West Indies. The membrane (Nuclepore) ltration techniques are sensitive and excellent if the high cost of lters can be afforded. Staining of lters enables identication of the microlariae. The techniques are impractical for eld surveys because venous blood is needed. If lters are not available for examination of large quantities of
Diagnosis Clinical diagnosis

Acute or chronic manifestations resembling those described above in individuals who live in or who have visited areas endemic for transmission of W. bancrofti, B. malayi or B. timori are indicative of lymphatic lariasis. A sudden onset of fever, accompanied by acute groin pain with swollen tender lymph glands and/or oedematous swelling of the leg distinguishes an acute attack of larial ADL from the many other causes of fever and adenitis that occur in tropical countries. Filarial funiculitis needs to be differentiated from funiculitis due to bacterial infection. Inguinal hernia is the most common scrotal swelling that needs to be distinguished from hydrocele. If the hernia is irreducible then the translucency test and the inability of the examiner to get above the swelling distinguish it from hydrocele. Both irreducible hernias and hydroceles often exist in the same patient. Obstructed hernias, tumours of the testis, tuberculosis and other bacterial infections of the epididymis, Schistosoma haematobium of the cord and acute lymphadenitis of the groin glands need to be distinguished from genital lesions of larial origin. Common conditions that need to be distinguished from larial lymphoedema are swollen limbs due to congestive cardiac failure, subacute nephritis or blockage of venous (thrombosis) or lymphatic (tuberculosis, leprosy) systems, and Kaposis sarcoma. In all these conditions the patients history greatly assists in differentiating them from larial elephantiasis. The oedema of cardiac failure and subacute nephritis has a painless onset and is bilateral. Secondary carcinoma of lymph glands and surgical ablation may also result in elephantiasis of the limbs. An endemic form of leg elephantiasis occurs in many parts of Africa at altitudes that preclude a larial aetiology.26 Mineral particles from volcanic soils, absorbed through the plantar skin of bare-footed peoples, are believed to be the causative agents (see Chapter 34). Such non-larial tropical elephantiasis has also been reported from South and Central America. Early stages of scrotal elephantiasis need to be distinguished from other conditions that affect the scrotal skin, such as fungal infections, scrotal oedema due to onchocerciasis and the thick-
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blood, the Knott concentration technique may be used as an alternative, highly sensitive test (see Appendix V).
Diethylcarbamazine provocative day test

Nocturnally periodic microlariae of W. bancrofti and B. malayi may be provoked, by the administration of DEC, to enter the peripheral blood in the daytime. Between 30 and 60 min is the optimum time for blood examination after the administration of a dose of 2 mg/kg of DEC (usually 100 mg of DEC is given to adults and 50 mg to children below 12 years of age).28 The DEC provocative day test results in a signicant long-term reduction of microlaraemia, and therefore should not be used for diagnosis in follow-up studies on microlaraemia.29 In contrast to its daytime action on nocturnally periodic W. bancrofti, the administration of DEC at night reduces the microlaraemia. A similar reduction occurs following the daytime administration of the drug to diurnally subperiodic W. bancrofti. In hospitalized patients and others whose sleep rhythms have been altered, the test is of little use. Because of the risk of a severe Mazzotti reaction, the test is contraindicated in onchocerciasis endemic regions. A similar provocative effect is not exerted by daytime administration of ivermectin or albendazole.30
lia) is a semiquantitative sandwich ELISA for detection of CFA in serum or plasma specimens. A sub-version of this test is adapted for analysis of nger-prick blood collected on lter paper discs. The NOW Filariasis Test (Binax Inc., USA) is an immunochromatographic card test that in a few minutes can provide a yes/no answer for serum or fresh nger-prick blood specimens. In contrast to the parasitological tests, the CFA-based tests diagnose adult worm infection and not just microlaraemia. Their sensitivity and specicity appear to be close to 100%. As the tests are not dependent on the microlarial periodicity, blood specimens can be collected and examined at any time of the day. No such test is currently available for brugian lariasis. Polymerase chain reaction (PCR) assays for the detection of microlarial infections in humans have been developed for both W. bancrofti and B. malayi.36,37 The techniques need at least one microlaria in the volume of blood used for DNA extraction, and therefore are not more sensitive than microscopic blood examination for microlariae. In contrast, these tests appear to be powerful tools for detection of infection in vectors.
Ultrasonography
Adult W. bancrofti can be detected by ultrasonography in lymphatic vessels of the scrotal area of infected males.38,39 They are more dispersed and more difcult to detect within the lymphatic system of infected females.40 The live worms wriggle continuously inside the dilated vessel (laria dance sign). There are often several worms clumped together, and they show a remarkable long-term stability in location. Attempts to detect adult B. malayi by ultrasonography in the scrotal lymphatics of infected males have failed, but they were recently detected in the breast, the thigh, the calf and in an inguinal lymph node of infected individuals.41
Immunological and polymerase chain reaction (PCR)-based diagnosis

Filarial worms induce a wide range of immune responses in the host, and several immunodiagnostic techniques for lymphatic lariasis, based on the detection of specic antibodies in the patients serum, have been devised in the past. These have generally been of limited value in endemic areas, because most individuals are positive for antibodies to crude larial antigens as a result of constant exposure. They have furthermore suffered from cross-reactions to other nematode infections and from being unable to distinguish past and present infection. The tests can be of some value in diagnosing visitors to endemic areas who develop symptoms of lymphatic lariasis but have no microlaraemia. The development of new, specic and sensitive immunodiagnostic tests has been a priority in lymphatic lariasis research. Cross-reactions have been reduced through detection for specic IgG4 antibodies, and specic IgG4 has been reported to be a good marker of active infection. Such tests may be of particular value in brugian lariasis, for which progress in development of circulating antigen detection-based diagnosis has been limited. A rapid format dipstick test (Brugia Rapid) detecting IgG4 to a B. malayi recombinant antigen in whole blood is currently undergoing eld evaluation.31 Other recombinant antigen based antibody assays are being developed and tested for their usefulness in monitoring human exposure and infection in control programs.32 Specic IgG4 can also be detected in the urine of patients infected with W. bancrofti.33 Highly sensitive and specic tests for detection of specic circulating larial antigens (CFAs) have been produced for bancroftian lariasis. These tests rely on the capture of larial antigens in serum, plasma or blood specimens by use of specic monoclonal antibodies. Two different test principles have been utilized by two companies in the manufacture of test kits, which are now commercially available.34,35 The TropBio-test (TropBio Pty Ltd, Austra-
Pathology and immunology

Most of the pathology in lymphatic lariasis is associated with the adult worms and their location in the lymphatics. A wide range of manifestations is seen in endemic regions. On one hand are people with no obvious signs of infection or disease and asymptomatic microlaria carriers, and on the other are those who develop signs of lymphatic responsiveness to adult worms, with fever, and who later develop chronic lymphatic pathology. In the case of TPE there is a vigorous immune response directed against the microlariae, with consequent pathology. The pathogenesis of lymphatic lariasis has long been a matter of debate. The majority of individuals in endemic areas mount an immunological response to larial antigens as a result of the constant exposure. Polarization of the antibody and T-cell responses towards a T helper cell (Th) type 2 response in microlaraemic individuals, as opposed to a Th1-type response in patients with chronic disease, has been recognized.42 A relative Th1-type hyporesponsiveness in infected individuals appears to be limited to larial antigens, and its existence is presumably important for the successful persistence of the parasites within the host. When examining patients with lariasis in studies on pathogenesis, a common approach has been to compare and contrast two poles in the clinical spectrum, namely individuals with detectable microlaraemia but with no evident clinical manifestations, and individuals with chronic lymphatic disease who have
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generally been assumed to be amicrolaraemic.42 A hypothesis claiming a developmental sequence from the rst to the second of these categories has been supported by the observation of more vivid immunological sensitization to larial antigen in patients with chronic disease than in those with asymptomatic microlaraemia. According to this hypothesis, microlaraemic individuals are in a state of immunological tolerance. Breakdown of tolerance (for whatever reason) and activation of host protective responses would lead to clearing of the parasites but would at the same time have detrimental immunopathological effects. This hypothesis of a basically immune-mediated pathogenesis of lymphatic disease has recently been challenged by observations from several lines of research. Analysis of epidemiological data has shown that in most endemic communities microlaraemia is equally likely to occur in individuals with or without chronic pathology.10,18,43 Use of strict classication criteria based on circulating antigenaemia, microlaraemia and clinical status has furthermore indicated that host immune responses are more related to infection status than to disease status in the endemic population.4446 Further evidence for a different pathway of disease development in lymphatic lariasis comes from studies applying the imaging techniques of ultrasonography and lymphoscintigraphy in the assessment of lymphatic damage, and from detailed clinical, microbiological and histological observations.44,47 According to these, two different pathological syndromes may lead to lymphatic larial disease (Figure 84.10). Dilatation of the lymphatics (lymphangiectasia) appears to be the basic lesion in the more common and more severe of these syndromes. Lymphangiectasia is present in virtually all individuals with adult worms whether or not they are microlaraemic or have obvious signs of clinical disease. Apparently, the adult worms
ADLA pathway Live adult worm in lymphatic vessel
AFL pathway Dead adult worm in lymphatic vessel
Secrete toxins
Induce granuloma formation
Lymphangiectasia (dilated lymphatics) Microbes enter via lesions ADLA (oedema)
Obstruction of lymph flow
AFL
Common cause of filarial lymphoedema/ elephantiasis
Rarely causes residual lymphoedema; may be common cause of filarial hydrocele
Figure 84.10 Sequence of development of the two types of acute larial syndromes, acute dermatolymphangioadenitis (ADLA) and acute larial lymphangitis (AFL), and their possible relationship to chronic larial disease.
themselves are capable of inducing endothelial cell proliferation and lymphatic dilatation via mechanisms that do not involve lymphatic obstruction or involvement of the hosts immune responses. Toxins released from endosymbiotic Wolbachia bacteria, which are found in abundance within the W. bancrofti and B. malayi worms, have been suspected to play a role.48 The lymphangiectasia impairs lymphatic function and predisposes to microbial infection that may result in acute dermatolymphangioadenitis (ADLA). This is frequently accompanied by oedema in the affected part, and repeated attacks of ADLA might lead the way to chronic lymphoedema.16 Recurrent secondary bacterial and fungal infections gaining access via entry lesions in the skin thus become important co-factors in the development of larial lymphoedema and elephantiasis.49,50 The second syndrome is caused by the death of adult worms, either naturally or drug induced. The subsequent activation of host inammatory reactions may result in formation of granulomatous nodules and episodes of acute larial lymphangitis (AFL). These usually have a mild clinical course, and rarely cause residual lymphoedema in the extremities. Acute hydrocele appears to result from an AFL attack in the intrascrotal lymphatics, with granuloma formation and temporary obstruction of the lymphatic ow from the tunica vaginalis.51 Most acute hydroceles disappear within a short time. The risk factors for progression to chronic hydrocele are still unclear, but probably include worm burden and granuloma location. In the case of TPE there is a vigorous immune response directed against the microlariae, with consequent pathology. Patients with TPE are immunologically hyperresponsive to larial antigens.21 Laboratory studies demonstrate high serum levels of laria-specic IgG and IgE, and marked peripheral blood eosinophilia. The manifestations of TPE are most marked in the lungs. Lung biopsies have shown inammatory foci around degenerating microlariae. These ndings, together with the absence of circulating microlariae, suggest that an antibody-mediated mechanism of microlaria destruction occurs in the lungs of these patients. Protective immunity has not been proved in lymphatic lariasis. Epidemiological analyses of observed age-infection patterns in endemic communities do not generally suggest that infection prevalence is systematically reduced in older age groups, which would be expected as a consequence of acquired immunity.52,53 Visitors to endemic from non-endemic areas only rarely develop microlaraemia, but they may acquire adult worms. Expatriates, exposed to intense transmission, may develop symptoms faster than is the case with resident natives of the endemic area. During World War II, 40 000 American service personnel were exposed to infection with W. bancrofti. More than 10 000 cases of disease were diagnosed, but microlaraemia developed in fewer than ten of these. In a study of expatriate mineworkers with a length of exposure ranging from 1 to 8 years, some were positive for specic IgG1 and IgG4 antibody responses to the parasite but none was positive for specic circulating antigens.54 The effects of human immunodeciency virus (HIV) infection on concurrent lymphatic lariasis, and vice versa, are largely unknown, but a positive cross-sectional relation between HIV and lymphatic lariasis has been observed among adults in an endemic area of Tanzania.55
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Table 84.2 Effect of diethylcarbamazine and ivermectin on microlariae and adults of human larial parasites Drug
Diethylcarbamazine Ivermectin
Stage
Microlaria Adult Microlaria Adult
Wuchereria bancrofti and Brugia spp.

++ + ++
Loa loa
++a + ++a ?
a
Mansonella perstans
+ ?
Mansonella streptocerca
++ ++ ++ ?
Mansonella ozzardi
++ ?
Onchocerca volvulus
++a ++ ?
, No effect; +, few/some are eliminated; ++, most are eliminated; ?, unknown.
Severe side-effects may occur.
Management
Individual treatment of lariasis aims to prevent or reverse progression of disease. Detailed accounts of current knowledge and experience on the treatment and management of lymphatic lariasis in its different clinical forms have been given.19,56
Antilarial drugs
For almost half a century, the drug most commonly used has been diethylcarbamazine citrate (DEC). DEC is a microlaricidal agent also capable of killing a proportion of the adult W. bancrofti, B. malayi and B. timori (Table 84.2). Ivermectin (Mectizan) is a potent microlaricide, but has no macrolaricidal effect. A promising area of research is the use of antibiotics to deplete the larial worms of endosymbiontic Wolbachia bacteria. Trials with a 68 week course of doxycycline have shown signicant activity against adult worms and microlariae as well as improvement of pathology.57,58
temic reactions tend to be related to the intensity of infection. Localized reactions include lymphadenitis, abscess formation and transient lymphoedema. In bancroftian lariasis funiculitis, epididymitis and hydrocele formation also occur. These local reactions tend to occur later and last longer than the systemic effects. Interruption of treatment is not usually necessary. Side-effects of DEC therapy are reduced, and efcacy increased, when treatment is spaced, for example when single doses (6 mg/kg) are given weekly or monthly. The passing of Ascaris worms is often a benecial side-effect of DEC therapy. Treatment may be repeated every 6 months for as long as the person remains microlaraemic or has symptoms. There may be severe reactions to DEC in persons infected with Onchocerca volvulus or Loa loa. Therefore, special care must be taken in areas where these two parasites occur. The recommended treatment for TPE is a 3-week course of DEC. Following DEC therapy most patients show rapid improvement. Repeat treatment may be necessary.
Diethylcarbamazine
DEC exerts no direct lethal action on the microlariae but apparently modies them so that they are removed by the hosts immune system. The lethal effect of DEC on adult worms in vivo can be directly monitored by ultrasonography.59 DEC treatment of microlaraemic patients (and amicrolaraemic circulating antigen-positive patients) may prevent development of lymphatic damage by eliminating adult worms. It apparently has little or no effect on already induced lymphatic damage, or on chronic obstructive disease.60 Dying adult worms following DEC treatment may trigger transient attacks of acute larial lymphangitis.16 DEC treatment is not recommended during acute episodes because it may provoke additional adult worm death and exacerbate the inammatory response. DEC is administered orally. The recommended therapeutic dose is 6 mg/kg body weight daily, in three divided doses after food, for 12 days. The number of microlariae in the blood usually decreases rapidly after the start of treatment and then increases, usually at reduced intensity, after some months. Clearance of circulating larial antigen is highly variable, probably because some living adult worms persist after treatment.59,61 Drug reactions, due to dying parasites, may commence a few hours after the start of treatment. They are less severe in bancroftian lariasis than in brugian lariasis. There are two groups of reactions: systemic and local.62 Systemic reactions include headache, joint and body pain, dizziness, anorexia, malaise and vomiting. Fever and sys-
Ivermectin
Owing to its efcacy in killing microlariae of O. volvulus, studies were initiated to test the efciency of ivermectin against W. bancrofti and B. malayi (Table 84.2). Results indicated that a single oral dose of ivermectin (150 mg/kg body weight) effectively removes microlariae of W. bancrofti,63 but microlariae reappear in the blood faster than after treatment with a dose of DEC and there is no evidence of a macrolaricidal effect. In brugian lariasis the fall in microlaraemia is more gradual than is the case in bancroftian lariasis. Side-effects of ivermectin therapy are generally similar to those mentioned above for DEC. Ivermectin should not be used in pregnant women or in children below 5 years of age. The major role of ivermectin in lymphatic lariasis is for treatment and control of infection in areas that are co-endemic for onchocerciasis and/or loiasis (i.e. many parts of Africa). Since it has no macrolaricidal effect, repeated half-yearly or yearly treatments are needed to keep the microlaraemia at a low level. Ivermectin also has an effect against Ascaris, hookworm and scabies infection.
Symptomatic treatment
It has increasingly been recognized that microbial co-infections play an important role in the aetiology of most ADL attacks, and that foot care combined with antibiotic and antifungal therapy can play an important role in their prevention and cure.20,64,65
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Chronic lymphoedema and elephantiasis can also benet greatly from prevention and treatment of supercial bacterial and fungal infections. Patient education should emphasize the importance of hygiene and skin care to reduce the number of acute attacks and thereby to prevent progression of the disease.20 Wearing of shoes, made to t the often deformed feet, is an important way to limit the risk of skin lesions. Physiotherapy and bandaging are more professional approaches which can be very helpful to alleviate and reduce the lymphoedema. Elevation of the affected limb during rest and sleep may also be benecial.
100
Microfilariae
A.
80 Prevalence (%) 60 40 20 0
1-4
Circulating antigens (adult worms)
Surgical management
Before any surgical procedure, a course of DEC is recommended. Chronic hydroceles require excision and eversion of the sac. In scrotal elephantiasis the surgical removal of the grossly elephantoid skin and scrotal tissues with preservation of the penis and testicles has proved worthwhile. Surgical treatment of limb elephantiasis has generally proved unsuccessful. Earlier techniques involving the excision of redundant tissue from severely affected limbs generally led to long-term results that were unsatisfactory. More benecial responses have been obtained recently with lymphovenous procedures, followed by removal of excess subcutaneous and fatty tissue from the affected extremities and adequate postural drainage and physiotherapy. In chyluria, if conservative approaches using DEC therapy and restriction of dietary fats are not helpful, then surgery is indicated.
5-9
10-14 15-19 20-29 30-39 40-49 50-59
60+
80 Prevalence (%)
Hydrocele
B.
60 40 20 0
1-4
Lymphoedema/elephantiasis
5-9
10-14 15-19 20-29 30-39 40-49 50-59
60+
Age group (years)
Epidemiology
Humans are infected by mosquitoes carrying infective larvae. There is no evidence for animals being infected with W. bancrofti under natural conditions. The nocturnally periodic form of B. malayi has been reported only in humans, but the subperiodic form is found also in a wide variety of domestic and wild animals (monkeys, cats). There appears to be no animal reservoir of B. timori. Microlariae of all species can be transmitted in blood transfusions and will circulate in the recipients blood for weeks. Congenital transmission of microlariae has been reported but seems to be of little signicance, and these microlariae do not undergo further development.
Figure 84.11 The pattern of W. bancrofti infection and chronic disease as seen in an endemic village on the coast of north-east Tanzania. Prevalence of (A) microlaraemia and circulating larial antigenaemia among all, and (B) prevalence of hydrocele grade 2 and above among males and lymphoedema/elephantiasis among all. (Based on Simonsen et al.10)
Infection and disease in the endemic community

Characteristic patterns of microlaraemia, circulating antigenaemia and disease are seen in affected populations in endemic areas.10,17,18 An example of this pattern in a highly W. bancrofti endemic East African village is seen in Figure 84.11. Usually, microlaraemia starts to appear in children of about 5 years of age. The prevalence then rises with increasing age and commences to level out above the age of 30 years. The prevalence rarely goes above 4050% in any age group. It may decrease slightly in older persons. The prevalence of specic circulating antigenaemia is higher than that of microlaraemia in all age groups. Signs of disease begin to develop around the onset of puberty or in early adult life, with recurrent ADL attacks. Hydroceles also begin to appear around this age. The prevalence of signs rises steadily, and in highly endemic areas the majority of elderly males may have
hydroceles. In stable endemic communities elephantiasis is seen mainly in older people, but younger persons may also be affected. The overall burden of infection and disease in the endemic community is proportional to the intensity of transmission. Cross-sectional surveys, although providing important information on the distribution of infection and disease in the affected population, give only a static view of the situation. In reality there is a dynamic sequel in development of infection and disease. Some of the people who are uninfected during the survey may have been positive for microlariae or adult worms previously, or will become so later. Also, clinical manifestations often develop late in the course of infection, when some people have reached an uninfected stage. However, a recent 26-year follow-up survey indicated that once infection has been acquired, the chance of ever becoming naturally free of infection is small.66 In many surveys the prevalence and intensity of microlaraemia has been slightly higher in males than in females, and this appears to be especially signicant for those aged 1540 years. It has been suggested that hormonal factors in females of reproductive age make them more resistant to infection than males of the same age group.67 Exposure to intense transmission over long periods is necessary before a patent infection with microlariae is acquired, and visitors to endemic areas rarely acquire microlaraemia. Prenatal
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exposure to parasite antigens may explain why children born to microlaraemic mothers appear to have a higher chance of developing microlaraemia later, than do those born to amicrolaraemic mothers,18,68 but increased household exposure may also be a contributing factor.69
Geographical variation in transmission

The epidemiology of W. bancrofti and B. malayi infections varies in different geographical areas, especially with respect to the prevalence and intensity of infection, the transmission pattern and the clinical manifestations. Differences in vectorial capacity and density are important factors inuencing these epidemiological parameters in different endemic areas.70 Even within the endemic community there can be considerable variation in vector abundance and transmission between different sections and from one household to the next.71 There are also inherent differences in the parasite; for example, three strains of W. bancrofti and two strains of B. malayi have been recognized on the basis of differences in periodicity of the microlariae. In most areas the microlariae of W. bancrofti are nocturnally periodic, being adapted to transmission by night-biting Culex and Anopheles mosquitoes. A diurnal subperiodic form is found in the South Pacic and in the Andaman and Nicobar Islands (India), whereas a nocturnally subperiodic form is found in Thailand. B. malayi occurs both in a nocturnal periodic and a nocturnal subperiodic form, whereas B. timori is nocturnally periodic. The subperiodic forms are transmitted by vectors that bite mainly during the daytime. It is possible that variation in worm habitat preferences within the hosts lymphatic system may contribute to differences in clinical manifestations. For details of the vector species and their bionomics, see Appendix IV. Different geographical vector zones have been recognized on the basis of the predominant vector species responsible for transmission in the areas.72 Culex quinquefasciatus is the principal vector of W. bancrofti in urban and semiurban areas of southern and South-east Asia, East Africa and America. Increased pollution of freshwater bodies and the introduction of pit latrines, which favour breeding of this mosquito, has led to increased transmission in many areas. C. quinquefasciatus is an endophilic night-biter. There is no evidence that it is transmitting lariasis in West Africa. In rural areas of Asia and Africa, Anopheles spp. are the main vectors, with the A. gambiae complex and A. funestus being the most important vectors in Africa. The main vectors of the Anopheles spp. bite indoors at night and breed in open, rather clean, water. In the South Pacic islands the predominant vectors of W. bancrofti belong to day-biting Aedes spp., especially A. polynesiensis. The majority of these mosquitoes bite outdoors and breed in small temporary water collections: tree holes, empty cans and bottles, coconut shells, plant axils and crab holes. In Papua New Guinea night-biting Anopheles spp. are the principal vectors. The nocturnally subperiodic form of B. malayi is transmitted by Mansonia mosquitoes in dense swamp forest areas. This form is commonly found also in wild monkeys. Nocturnally periodic B. malayi has been reported only from humans. It is transmitted in open plains and agricultural areas, mainly by Mansonia spp. mosquitoes, although in some areas species of Anopheles and Aedes also play a role. The larvae and pupae of Mansonia mosquitoes
obtain their oxygen directly from the cells of certain species of aquatic plants present in clean water-bodies. Survival of the Mansonia spp. is dependent on the association with the plants. Increased pollution has in some places led to a decrease in breeding of Mansonia, with a subsequent drop in transmission of B. malayi. Mansonia spp. prefer to feed outside and biting usually commences shortly after dusk. A. barbirostris is the only mosquito to date to have been identied as a vector of B. timori.
Control
In communities endemic for lymphatic lariasis, the disguring and debilitating clinical manifestations result in much suffering and have severe socioeconomic and psychological consequences for those affected.73,74 The objective of control is to reduce transmission and morbidity, thereby eliminating lymphatic lariasis as a public health problem. Successful programmes for the control of lymphatic lariasis must be based on a thorough understanding of the distribution and dynamics of the disease in the targeted population. The diverse characteristics of communities in endemic foci, as well as differences in vector, parasite and disease parameters, emphasize the importance of having multiple measures and approaches for control. The main method used in the control of lymphatic lariasis is mass chemotherapy.75 It may be supplemented by mosquito control.72 Morbidity control through patient management (hygiene, antimicrobial treatment, physiotherapy) and establishment of self-help groups is recommended.20 To achieve success in a control programme it is necessary for the community to be actively involved. Community leaders and motivated persons should be identied and approached for the purpose of obtaining their cooperation. Adequate health education should be given regarding the nature of the disease and on the methods used for its control.76,77 Before starting a control programme, knowledge of the geographical delimitation of the disease is essential. Rapid assessment procedures are based on examination of specic age-sex groups in selected populations to determine the prevalence of easily recognizable signs such as hydrocele or circulating antigenaemia. Geographical information system (GIS) has been utilized for largescale mapping of the disease.78,79 All areas with indigenously acquired infections are considered to be endemic. Criteria for distinguishing different levels of endemicity have so far not been established. Mathematical models of lymphatic lariasis transmission, infection and disease within the endemic community have been developed. It is envisaged that such models can be used to predict the outcome of control based on different measures, and thus can provide guidance towards the most cost-effective control strategies in specic settings.80,81
Chemotherapeutic control
Chemotherapeutic control of lymphatic lariasis is generally based on mass treatment, i.e. the drug is administered to the total population in the community (except individuals in whom it is contraindicated). In mass treatment campaigns there is no need to conduct parasitological or other diagnoses before treatment. Thus cost is reduced. The amicrolaraemic infections and persons
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who may have been falsely negative in a diagnostic test are included for treatment. A continued high population treatment coverage is essential for a mass treatment programme to produce sustained reduction in transmission.80,81 Chemotherapeutic regimens of DEC have been used for several decades for the control of bancroftian and brugian lariasis. DEC is relatively cheap, it rapidly reduces the prevalence and intensity of microlaraemia, and it also kills a proportion of the adult worms. The 12-day standard regimen of DEC is not feasible for use on a mass scale because of the many daily dosages. Rather, the drug may be administered in widely spaced doses, in regularly repeated low doses, or it may be added to salt.82 These regimens effectively reduce microlaraemias and have fewer and less severe side-effects than the more intensive regimens. Control programmes with DEC-medicated salt have successfully controlled lymphatic lariasis in parts of China and Taiwan. Owing to the risk of inducing severe adverse reactions in individuals with onchocerciasis, DEC should not be used on a mass scale for control of lymphatic lariasis in areas co-endemic for O. volvulus infection. For these areas, ivermectin is the drug of choice. When distributed in a dose of 150 mg/kg body weight it effectively reduces microlaraemias. Side-effects are few and comparable to those of DEC. Adult worms are not affected by the ivermectin treatment, and regularly repeated treatments (half-yearly or yearly) are therefore even more important in control programmes based on ivermectin than for those based on DEC, to gain a long-term effect on transmission. Since 1998, ivermectin has been available free of charge for control of lymphatic lariasis in countries of Africa with endemic onchocerciasis, through the Mectizan Donation Program. Combinations of DEC and ivermectin have proved even more effective in lymphatic lariasis than any of the drugs alone but, because ivermectin is currently available only in countries where the use of DEC is contraindicated, this increased effect is of mainly theoretical interest. The combination of albendazole with either ivermectin or DEC appeared in recent studies to give a considerably more effective and sustained reduction in lymphatic lariasis microlaraemia than ivermectin or DEC alone.75 Macrolaricidal properties of albendazole apparently prolonged and reinforced the microlaricidal suppression produced by the other two drugs. Following these promising ndings it was recommended that DEC and ivermectin should be given in combination with albendazole in programmes for lymphatic lariasis control. The effect of albendazole on intestinal helminth infections would be an additional benet of the combination treatments. Other recent studies have failed to provide clear evidence for the superiority of these combinations in the clearing of microlaraemias.83,84
The main antivector measures that have been used in the control of lariasis are environmental control of breeding sites, larviciding, and the use of insecticides against adult mosquitoes. Environmental management varies from the lling in of temporary pools and clearing of refuse that collects water, to the construction of drainage systems in urban areas. C. quinquefasciatus breeds in highly polluted water and plays a major role in the transmission of W. bancrofti in urban and semi-urban areas. A new method, aimed at controlling C. quinquefasciatus in stagnant water, especially cesspits and latrines, utilizes a layer of expanded polystyrene beads that oat on the water surface and prevent the mosquito larvae from breathing. This method has proved to be long lasting and has been successful in lariasis control in Zanzibar. The usefulness of Bacillus sphaericus, a toxin-producing bacteria, as a biological agent for control of C. quinquefasciatus is also being assessed. Anopheles vectors are responsible for transmission of much rural lariasis. In areas where malaria and lariasis transmission depends on the same Anopheles species or vectors with similar bionomics, lariasis control may benet from malaria vector control programmes. In the Solomon Islands, bancroftian lariasis was eliminated as a result of a malaria control programme utilizing residual insecticides against Anopheles mosquitoes. Because of variability in feeding behaviour and resting places of Mansonia mosquitoes, control using insecticides is not very effective. Mansonia larvae are best controlled by destruction of the host plants. Aedes vectors have scattered and inaccessible breeding sites, and vector control is not easily accomplished. Disadvantages of using chemical insecticides in control schemes may include their high cost, development of resistance by the target organisms and environmental damage. Despite these problems, insecticides remain the major weapon in the control of vectors. The use of pyrethroid-impregnated bed-nets (Figure 84.12) can signicantly reduce morbidity due to malaria and has recently been shown to have a strong suppressive effect on the transmission of lymphatic lariasis.85
Mosquito control
Vector control can provide a useful supplement to chemotherapy in control of lymphatic lariasis. Effective vector control rapidly reduces transmission but, because it is slow to reduce the prevalence of lariasis in a population, it should be combined with chemotherapy. The feasibility and value of vector control as one of the components of lariasis control depends upon the local epidemiological conditions, including the species of vectors, their biting, resting and breeding habits, and the type of environment (e.g. rural or urban).72
Figure 84.12 A bed covered with an insecticide-impregnated bed-net, to protect against mosquito transmission of malaria and lymphatic lariasis. (Courtesy of E. M. Pedersen.)
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Onchocerciasis
Programme for global elimination

Increased awareness of the public health burden of lymphatic lariasis combined with development of better tools for diagnosis, development of effective mass drug treatment strategies, and improved knowledge on disease development processes has greatly stimulated political interest and commitment towards its control. Compared with many other vector-borne diseases, a number of biological features furthermore favours the control of lymphatic lariasis, namely its almost exclusive human reservoir, its inability to multiply in the vectors and its inefciency of transmission. In 1997, the World Health Assembly called for a strengthening of activities to eliminate lymphatic lariasis as a public health problem. Subsequently, the Global Programme to Eliminate Lymphatic Filariasis was founded as a partnership of interested parties, including ministries of health from endemic countries, international and national development agencies and academic institutions, and with the World Health Organization (WHO) serving as the secretariat.86 In essence, the programme assists in the preparation of national plans of actions for individual endemic countries, and coordinates and advises on nancial, technical and managerial matters. The programme is supported by a large-scale donation of albendazole for worldwide elimination of lymphatic lariasis (from Glaxo SmithKline), and by an expansion of the Mectizan Donation Program for onchocerciasis to include free ivermectin for elimination of lymphatic lariasis in African countries where the two infections co-exist. Programme strategies focus on both transmission and morbidity control. For interruption of transmission, it is recommended that the entire population at risk be treated once yearly with single-dose two-drug regimens (albendazole 400 mg plus ivermectin 150 mg/kg in countries of Africa co-endemic for onchocerciasis; albendazole 400 mg plus DEC 6 mg/kg in other parts of the world). Treatment should continue until the level of microlariae in the blood is below the level required for transmission (estimated at 46 years for most endemic areas). Alternatively, daily treatment for a 612-month period with DEC-medicated salt is recommended. Morbidity control focuses on improved hygiene, treatment of secondary infections, proper limb care and increased access to hydrocelectomy, to alleviate suffering and decrease disability among those already affected. To ensure sustainability of programme activities, the design of lariasis control programmes emphasizes their integration into existing national health structures and facilities.
craw-craw.87 Later (1893) Rudolf Leuckart described the adult worms and named the parasite Filaria volvulus. Rodolfo Robles,88 working in Guatemala, rst associated subcutaneous nodules with eye lesions. The pioneer studies of Donald Blacklock89 in Sierra Leone culminated in the discovery of the life cycle of O. volvulus. A detailed history of onchocerciasis has been written.7
Geographical distribution
WHO in 1995 estimated that about 17.7 million individuals worldwide were infected with O. volvulus, of whom some 270 000 were blind and 500 000 severely visually disabled (Figure 84.13).90
ONCHOCERCIASIS
Onchocerciasis (river blindness) results from infection with Onchocerca volvulus. Humans are the natural hosts and the vectors are species of blackies (Simulium spp.). In endemic regions, it is a major cause of severe disguring skin changes and damaging eye lesions.
Historical background
In 1875, in the Gold Coast (now Ghana), John ONeill described microlariae recovered from the skin of Africans suffering from
B Figure 84.13 Geographical distribution of human onchocerciasis. (A) In Africa and the Arabian peninsula. (B) In Central and South America.
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Filariases
More than 99% of all cases are in Africa in a zone that spreads from west to east. This band extends between 15N and 15S in the west, and widens slightly towards the east. As a result of recent mapping surveys, the estimate for numbers infected in Africa is likely to be revised upwards.91 Foci in Guatemala and Mexico of about 90 000 infected individuals exist mainly on the Pacic slope of the Sierra Madra between altitudes of 500 and 1500 m. Northern Venezuela has a focus with about 40 000 infected individuals. Smaller foci have been found in southern Venezuela, Columbia, Brazil, Ecuador and Yemen.90

The general larial life cycle is shown in Figure 84.1. For details of the life cycle of O. volvulus, see also Appendix III. Adult worms live mainly in subcutaneous nodules or are free in the skin. The ratio of adult females : males in nodules is about 3 : 1. The adults are slender white worms, the male being 25 cm 0.2 mm and the females 3570 cm 0.4 mm. The female produces sheathless microlariae measuring 300 8 m with an expanded head free of nuclei and a sharply pointed tail (Figure 84.14). Microlariae are found mainly in the upper dermis and in nodules but may also appear in blood, urine or any body uid, particularly in heavy infections. They are common in the eye, with direct spread from adjacent skin appearing to be their main mode of entry. Microlarial loads can be as high as 2000/mg of skin, and heavily infected individuals may harbour >100 000 000 microlariae. The microlariae have a lifespan of 12 years. Microlariae present in the skin are ingested by the Simulium vector when feeding. Some of the ingested microlariae migrate from the gut of the blacky into the thoracic muscles and develop via two moults into infective larvae over a period of 612 days (for a description of the development in the y see Appendix III, and for the life history of Simulium see Appendix IV). Transmission of infective larvae to humans occurs when the y takes its next blood meal. The larvae migrate to the subcutaneous tissues, moult twice, and then develop over several months to adult worms. The gravid female releases microlariae, which may appear in the skin after a prepatent period of 1015 months after the introduction of infective larvae. Some 5001500 microlariae are released per female per day, and the mean duration of female reproductive life has been estimated at 911 years. Simulium ies can breed only in well oxygenated water. The gravid female oviposits into free-owing rivers and streams, particularly in rapids, and transmission takes place mainly near these locations, hence the name river blindness. Transmission in utero of microlariae of O. volvulus has been reported. These microlariae do not undergo further development.
Figure 84.14 Skin microlaria of O. volvulus.
microlariae in the skin, especially those with light infections, have no symptoms or signs.
Skin lesions
Dermal changes occur when the microlariae undergo destruction in the skin and vary from a few papules to the extensive pigmentary and chronic atrophic changes.92 A clinical classication and grading system of the cutaneous changes in onchocerciasis has been developed, with the main recognized categories being acute papular onchodermatitis, chronic papular onchodermatitis, lichenied onchodermatitis, skin atrophy, and skin depigmentation.93 Frequently a combination of these categories exists in the same person. In Africa, the skin lesions are most common over the legs but may cover the whole body. A range of skin lesions is shown in Figure 84.15. Itching and rash are the most important early manifestations of onchocercal dermatitis. The rash consists of many raised papules, which are due to microabscess formation, and may disappear within a few days or may spread. Often the rash is conned to one anatomical quarter of the body. The resulting pruritus can be very intense (larial itch), and the skin often becomes secondarily infected following scratching. In the later stages there may be heavy lichenication and thickening of the skin (lizard skin). The more chronic changes are probably related to the repeated occurrence of local pathology around dying parasites. There is skin atrophy with loss of elasticity, giving a prematurely aged appearance (presbyderma). Loss of elastic bres in the skin of the groin may lead to hernia, and to the classical hanging groin with inguinal and/or femoral glands contained in pendulous folds. A condition called leopard skin (Figure 84.15B) may occur. This results from loss of pigment, degeneration of the dermal collagen and thinning of the epidermis. Leopard skin particularly affects the pretibial regions, where trauma or scratching following the bites of Simulium ies may exacerbate, or even cause, the depigmentation of this condition.
1 2
Clinical features
The main clinical manifestations of onchocerciasis are skin lesions, eye lesions and nodule formation. In general, clinical manifestations develop after long exposure to infection, and their severity depends on the intensity of infection. Many individuals who have
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Onchocerciasis
B A
C Figure 84.15 Onchocerciasis: skin lesions. (A) Papules on skin (courtesy of C. D. Mackenzie); (B) depigmentation and leopard skin (courtesy of C. D. Mackenzie); (C) lichenied eczematoid dermatitis of the body and arms (courtesy of E. M. Pedersen).
Sowda
Sowda (Figure 84.16), from the Arabic for black or dark, is a localized form of onchodermatitis. It is common in the Yemen, but is also found elsewhere.
Sowda is the result of a strong immune response on the part of the host. The condition is usually localized to one limb but both legs and/or arms or the trunk may be involved. It is characterized by intense itching. The involved skin becomes swollen and darkened, and covered with scaly papules. Local
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Filariases
Figure 84.17 Onchocerciasis: nodule on the body. (Courtesy of C. D. Mackenzie)
Figure 84.16
Onchocerciasis: Sowda. (Courtesy of C. D. Mackenzie)
lymph glands are enlarged. Microlariae are extremely difcult to nd in skin snips.
Nodules
Nodules (onchocercomata) are granulomas resulting from a tissue reaction around adult worms. They are most often located in the subcutaneous tissues. They are painless, round to oval, rm, smooth, vary in size from a few millimetres to several centimetres and are often matted together in clumps (Figure 84.17). Some, perhaps one-quarter of nodules are found in deeper tissues and are not palpable. In Africa 80% of palpable nodules occur on the body prominences of the pelvic girdle. Others occur on the abdomen, chest wall, head or limbs. In Central America, palpable nodules are commonly found on the head. It is believed that the location of the nodules reects the biting habits of the vector ies. Nodules do not cause medical problems unless they press on vital areas. Large clumps are often aesthetically displeasing to the patient.
Figure 84.18 Onchocerciasis: punctate keratitis.
Eye lesions
Many changes in both anterior and posterior segments can occur in the eyes of infected individuals.94 The more serious lesions may progress to blindness (see also Chapter 18).
groups. These lesions are reversible. In sclerosing keratitis, vascular inltrates begin at the limbus and pass inwards, resulting in a cellular organization and excessive scarring of the cornea, which causes blindness. Microlariae dying in the ciliary body give rise to iridocyclitis and the formation of synechiae. Inammation of the uveal tract also contributes to iridial pathology.
Posterior segment lesions

Both optic nerve atrophy and choroidoretinitis of the posterior segment may result in blindness. Lesions of choroidoretinitis range from unequivocal inammatory processes to exclusively atrophic lesions with atrophy of the retinal pigment epithelium and of the choriocapillaris and hyperpigmentation of the pigment epithelial layer. Optic nerve atrophy rather than choroidoretinal degeneration is considered to be an important cause of both decreased visual
Anterior segment lesions

Punctate keratitis (snowake opacities) occurs as an acute inammatory reaction around microlariae (Figure 84.18). It appears to be the corneal equivalent of the discrete papule reactions seen in the skin. Punctate keratitis is more common in the younger age
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acuity and visual eld constriction. Acceleration of optic nerve damage may follow treatment with DEC. In fact, with any of the eye lesions, exacerbation associated with the death of microlariae may be a complication of drug therapy.
Diagnosis Clinical diagnosis

Skin lesions, eye lesions and/or subcutaneous nodules resembling those described in the clinical section and presented by individuals who live in or have visited areas with transmission of O. volvulus may be indicative of onchocerciasis. The pruritic onchodermatitis (larial itch) must be distinguished from: infection with Mansonella streptocerca, in which the legs are rarely affected; scabies, where the typical burrows and mites can be found between the ngers; reactions to insect bites that come on early after residence in the tropics; prickly heat; and contact dermatitis. In heavy infections of long standing, the skin changes must be differentiated from tertiary yaws, supercial mycoses, leprosy and chronic eczema. Painlessness, rmness and extreme mobility are characteristic of onchocercomas. However, some nodules, particularly those on the head, become xed due to adherence to underlying tissues. Nodules must be distinguished from enlarged lymph glands, lipomas, dermal cysts, ganglia and neurobromas. For the diagnosis and differential diagnosis of onchocercal eye lesions, see Chapter 18.
Other conditions
Onchocerciasis has been associated with weight loss and musculoskeletal pain. Several reports have indicated a higher than normal frequency of epilepsy in onchocerciasis hyperendemic areas.95 Onchocerciasis has also been associated with a syndrome of growth arrest and delayed sexual development (the Nakalanga syndrome) seen in Uganda and Burundi.96
Geographical variation in the clinical picture

Clinical manifestations (skin and eye lesions) are known to differ widely in varied endemic geographical areas.97 Surveys in Cameroon showed the prevalence of sclerosing keratitis and blindness to be much higher in savannah than in forest areas.98 This picture appears to be valid for most of West Africa, with a gradation from very severe ocular lesions in the dry (Sudan type) savannah, to moderately severe in wet savannah areas, to a much lower prevalence of eye lesions in forest zones. The pattern in Sierre Leone is different from this more general observation, in that the prevalence of blindness and sclerosing keratitis is higher in the forest than in the savannah areas (Figure 84.19).99 In East and Central Africa the clinical picture of onchocerciasis is generally less severe, and eye manifestations are rare in most parts. In the Yemen, and in some parts of the Sudan, a severe form of Sowda occurs. The proportion of head nodules in Mexico and Guatemala is much higher than in Africa, and these may be associated with a high prevalence of severe ocular onchocerciasis.
Ultrasonography
Ultrasonography has proved capable of detecting onchocercal nodules in the tissues of patients.100 This technique may be especially useful for detecting deep non-palpable nodules, and for assessing drug effects on adult worms.
The Mazzotti test

This test involves the administration of a small dose (usually 50 mg for an adult) of DEC by mouth and observing for intense pruritus and skin rash 124 h later. The test may precipitate serious complications and is not recommended as a routine diagnostic procedure. It can assist diagnosis when onchocerciasis is suspected in persons with a negative skin snip. A Mazzotti patch test using a topical application of DEC in lotion form on the skin is being evaluated as a diagnostic tool for epidemiological monitoring and evaluation of control programmes.91,101
100 90 80
Prevalence (%)
70 60
Parasitological diagnosis
D
50 40 30 20
C
10 0 5-9 10-14 15-19 20-29 39-39 40-49 50-59 60+
Age group (years)
Figure 84.19 Onchocerciasis: microlarial prevalence in (A) iliac crest and (B) canthus skin snips and (C) in the cornea, and (D) the prevalence of blindness and/or severe eye lesions as seen in rainforest villages of Sierra Leone. (After McMahon et al.99)
The diagnosis is made by demonstrating microlariae that have emerged from bloodless skin snips. Although most persons with clinical signs have positive skin snips, this is not always the case. The optimal site for the biopsy depends on the geographical area. In Africa, the preferred body site is from the iliac crest or below, whereas in Mexico the skin over the scapula or deltoid region is favoured. Two to four skin snips are taken. When epidemiological and clinical studies of onchocercal eye lesions are being conducted, it is important to take a skin snip from the outer canthus. After cleaning the skin with spirit and allowing it to dry, a razor blade can be used to shave off the tip of a dome of skin that has been elevated with a needle. Alternatively, a Walser corneoscleral punch is used to produce skin snips with an average weight of 1.0 mg. Punches must be very carefully sterilized before re-use.
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Snips are immersed in isotonic saline, for instance in wells of a microtitration plate. Microlariae that have emerged after 0.5 24 h are counted under the low power of a compound microscope. Teasing of the skin is unnecessary. The sensitivity of skin snips to diagnose infection depends upon the number of skin snips taken and on the intensity of infection. Microlariae of O. volvulus are 270320 m long, unsheathed, and have a characteristic head and a pointed tail (see Figure 84.14). They must be differentiated from the smaller skin-dwelling microlariae of M. streptocerca in Africa and M. ozzardi in South America. Blood microlariae W. bancrofti, Loa loa and M. perstans occasionally appear in skin snips contaminated by blood.
Figure 84.20 Onchocerciasis: microlariae of O. volvulus in subcutaneous tissue.
Immunological and PCR-based diagnosis

Several immunodiagnostic tests have been devised for onchocerciasis.102 Adult O. volvulus isolated from nodules, or adult worms or microlariae of O. gibsoni or O. gutturosa from cattle, have frequently been used as the source of antigen. Generally, immunodiagnosis based on detection of antibodies to crude antigens is of limited practical use owing to the low specicity and sensitivity of the tests. Cross-reactions to other nematode infections are common and the tests cannot distinguish between past and present infections. In endemic areas, where the population is continuously exposed to infection, most people are positive to the tests. Such tests may be of value in the diagnosis of onchocerciasis in persons from non-endemic areas who have visited an endemic area. The development of specic and sensitive immunodiagnostic tests has been a priority in onchocerciasis research. The specicity of tests has been improved by the detection of specic IgG4 antibodies and by the identication and use of specic antigens. Tests utilizing specic recombinant antigens have been developed, and an ELISA with a cocktail made from three of these antigens has shown a high sensitivity and specicity.103 A eld applicable rapidformat card test that detects IgG4 to a recombinant antigen in serum or blood specimens has also proved to be sensitive and specic,104 but is not yet commercially available. Tests for detection of specic circulating antigens in onchocerciasis have given mixed results, and in general have not been as successful as in lymphatic lariasis. However, a highly sensitive and specic dipstick assay for the detection of O. volvulus antigens in urine was recently described.105 A PCR technique with high specicity for O. volvulus DNA has been developed. In addition to identifying worm DNA in skin snips from infected humans, this technique is capable of distinguishing between various strains of the parasite and of detecting O. volvulus larvae in extracts of blacky vectors.101 The initial lesions comprise foci of inammatory reactions around degenerating microlariae, composed mainly of eosinophils, neutrophils and macrophages.107,108 Antibodies, immune complex formation and complement activation on the surface of the microlariae may be involved in attracting the immunocompetent cells.109 The dermal tissue between the early focal lesions shows no changes. Later, dermal broblasts increase in numbers, leading to brosis, and the normal collagen and elastic bres of the dermis are gradually replaced by hyalinized scar tissue. There may also be loss of pigment in the skin. The histological appearance of the skin in advanced cases closely resembles the skin of very old subjects (i.e. presbyderma). Some of the skin damage observed in onchocerciasis patients may also be caused by the mechanical effects of scratching, by toxins inoculated when blackies take a blood meal or by secondary infections. In the skin condition Sowda, there is immunological hyperactivity, and the most striking histopathological feature is the presence of an extensive inammatory cell inltrate of the upper dermis. Identication of O. volvulus collagen as a principal antigen recognized by antibodies in patients with Sowda raises the possibility that this condition might arise through cross-reactivity between these antibodies and human collagen.110 Using a slit lamp, live microlariae can be seen in the cornea of the eye. There is no visible tissue response to their presence. Dead microlariae give rise to foci of inammation which cause the characteristic punctate (snowake) keratitis, with opacities around each microlaria. The major pathology of the anterior segment is due to sclerosing keratitis. Chronic inammation and vascularization leading to scarring eventually result in complete opacication of the cornea. This process normally starts from each side and from below, and resembles an inammatory immune response. The aetiology of the posterior segment lesions is less clear.111 Some adult worms are found free in the subcutaneous tissues but most are contained in nodules. Nodules are essentially granulomatous reactions around adult worms. They often have separate chambers containing several worms. Nodules have thick brous walls and a variable degree of cellular inltration (Figure 84.21) with macrophages being the predominant cell type.108 Calcication may occur in older nodules and in dead worms. Specic humoral immune responses of individuals living in areas endemic for onchocerciasis are usually marked. Most infected individuals have a diminished cellular responsiveness to O. volvulus antigens in comparison to apparently uninfected persons from
Pathology and immunology

Large numbers of live microlariae may be present in the skin without inducing any tissue reaction (Figure 84.20). Pathology in the skin and in the anterior segment of the eye is caused mainly by dying and dead microlariae. Like many other larial parasites, O. volvulus contains endosymbiontic bacteria of the genus Wolbachia. Recent studies have implicated products from these endosymbionts in the pathogenesis of onchocerciasis, especially the ocular manifestations.48,106
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Ivermectin
Ivermectin in a single oral dose of 150 mg/kg body weight causes a rapid elimination of microlariae from the skin.118 More than 80% of skin microlariae are eliminated in the rst 48 h and this then slowly increases to 97%. The low level of microlaraemia is maintained over a period of several months, after which there is a gradual increase. Retreatment may be necessary and follow-up skin snips should be examined 612 months after the initial treatment. Treatment is contraindicated in pregnant women, breastfeeding women with infants below 1 week old, children below 5 years of age, or individuals with serious acute or chronic illnesses. Adverse reactions resemble, but appear to be much less severe than, those associated with DEC therapy. In a study in Sierra Leone119 the most common side-effect of ivermectin was the passing of Ascaris worms! Other effects in descending order of frequency were itching and/or rash, muscle and/or joint pains, fever, headache, swelling of the limbs, joint or face, dizziness, tender lymphadenopathy, conjunctivitis and tender nodules. Other investigators have noted severe postural hypotension and bronchoconstriction to be side-effects of ivermectin therapy. These conditions are reported to be transient and to respond to symptomatic management. The single-dose ivermectin regimens have no known long-lasting effect on mature worms, but the drug causes intrauterine degeneration and temporary sequestration of unborn microlariae. Recent studies suggest that the drug may have a macrolaricidal effect if more frequent (3-monthly) treatments are given.120 The disappearance of microlariae from the eye is much more gradual than microlarial reduction in the skin. Available data on the impact of repeated doses of ivermectin on ocular onchocercal disease indicate regression of early lesions of the anterior segment, including iridocyclitis and sclerosing keratitis. It also appears to have a benecial effect on optic nerve disease and visual eld loss, but not on chorioretinitis.121
Figure 84.21 Onchocerciasis: adult O. volvulus in nodule. (Courtesy of H. Zaiman.)
the same endemic areas and to patients with the more localized Sowda.108 A major role of immune responses appears to be to contain or limit inammation around dying or dead microlariae. Antibodies mediating cellular killing of microlariae and infective larvae in vitro have been observed in sera from some persons living in endemic areas.109 The presence of such antibodies may indicate that immune elimination of larval stages occurs in some infected individuals, although protective immunity has not been proved in onchocerciasis. In utero exposure to O. volvulus antigens may affect the childs immune responses and perhaps his or her susceptibility to O. volvulus infection later in life.112 In individuals from non-endemic areas who become infected during visits to endemic areas, infections are usually mild and the most common clinical presentation is dermatitis.113 Microlaraemia may be of low density or absent. Nodules or eye lesions are rare. The patients usually have specic antibody responses to O. volvulus and raised eosinophil levels. Immune responses to mycobacterial infections114 and to tetanus vaccination115 are downregulated in O. volvulus-infected individuals. HIV-infected onchocerciasis patients exhibit signicantly impaired antibody responses to O. volvulus antigens and tend to loose their reactivity to these antigens over time.116
Nodulectomy
Nodulectomy has only limited use because many worms are present outside the nodules and some nodules are not palpable. Head nodules should be excised because their presence increases the risk of eye disease and blindness.
Management Drug treatment

DEC is no longer recommended for the treatment of onchocerciasis. It can induce severe adverse reactions, especially in heavily infected individuals, and may precipitate or aggravate ocular lesions. It has now been replaced by ivermectin (Mectizan) as the drug of choice.90 Both of these drugs have a strong microlaricidal effect, whereas adult worms remain essentially unaffected (see Table 84.2). Suramin, although largely used as a macrolaricide, also has some microlaricidal effects. Fatalities due to drug toxicity may occur and its use is not recommended. The macrolaricidal effects of benzimidazoles are being investigated. Endosymbiontic bacteria (Wolbachia spp.), recently discovered in O. volvulus, are potential new targets for chemotherapy with antibiotics.117
Epidemiology
O. volvulus is transmitted between humans and the vectors. The infection is not a zoonosis. Many species and subspecies of Simulium ies can act as vectors. Despite geographical variation in pathogenicity, O. volvulus parasites are morphologically indistinguishable throughout their range of distribution.
Infection and disease in the endemic community

The epidemiology of onchocerciasis varies throughout its distribution. Different patterns of infection and disease are associated with differences in the abundance, vector competence and feeding characteristics of the local blacky populations, differences in parasite strains and differences in the human host response to the
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Table 84.3 Prevalence of microlaraemia (iliac crest), pruritus and nodules by age seen in a rainforest village of Sierre Leone endemic for onchocerciasis Age group (years)
14 59 1014 1519 2029 3039 4049 5059 60+ Total
After McMahon et al. 1986.
122
No. examined
70 82 67 29 68 73 79 59 71 598
Microlariae (%)
5.9 26.8 50.8 71.4 76.1 73.6 93.6 91.5 87.3 63.1
Pruritus (%)
1.4 2.4 6.0 20.7 30.9 30.1 46.8 50.8 50.7 26.6
Nodules (%)
0.0 8.5 20.9 31.0 44.1 54.8 79.7 89.9 85.9 46.3
parasites. Other human host factors that may affect the epidemiology are occupation, seasonal migration, economic or social standing, concurrent infections and racial group. The prevalence and intensity of infection and the amount of clinical disease within the endemic community are generally low in the young children and increase gradually with age (Figure 84.19; Table 84.3122). The overall burden of infection and disease in the population is proportional to the intensity of transmission.97 In hyperendemic communities almost all adult individuals are infected and have clinical disease. Males and females generally appear to be affected by infection and disease to a similar extent. Available quantitative data on the transmission, infection and disease in endemic populations have been used to develop mathematical models describing the population biology of human onchocerciasis.123,124 Analysis of these models is useful for understanding the transmission dynamics and disease processes and for assessing the potential effect of control measures.
levels based on microlarial detection. Other methods with less sensitivity and specicity have utilized the prevalence of leopard skin or blindness.
African onchocerciasis
Members of the Simulium damnosum complex are the predominant vectors in most of the endemic areas of Africa (see Appendix IV). In parts of East and Central Africa species of S. neavei group also transmit the infection. Flies of the S. damnosum complex breed in large rivers or small streams where there is an adequate velocity of water, adequate food supplies and suitable attachment sites (rocks, sticks, trailing vegetation). Primary larval habitats are rivers in which exposed rocks create white water rapids. Female blackies generally restrict their ight to within a few kilometres of breeding sites and bite most intensely in the immediate vicinity. However, with the assistance of prevailing winds, they may migrate several hundred kilometres from one river basin to another. The female ies feed mainly on humans but in some areas blood meals are also taken from animals, particularly bovines, horses and small ruminants. S. damnosum s.l. is a complex of numerous sibling species that differ in bionomics and vectorial capacity. They are very similar morphologically but can be distinguished by the banding patterns of their larval salivary gland chromosomes.
Endemicity
Different criteria have been used to dene the level of endemicity of onchocerciasis in a population. Most commonly used today is a classication of levels as hypoendemic, mesoendemic or hyperendemic on the basis of the population microlarial prevalence being less than 40, 4059 and 60% or more, respectively.90 In hyperendemic areas, blindness rates can exceed 10%, the disease is socially intolerable and fertile lands are often abandoned. In hypoendemic areas, the blindness rate is generally below 1% and the disease has few or no social effects. In the course of the development of a programme for onchocerciasis control, the endemicity should be mapped, to help to focus efforts where most needed. Methods for rapid epidemiological mapping have been developed which depend on determining the prevalence of nodules in a specic agesex group of selected communities. The current standard practice is to examine a sample of 50 males per community for nodules. Nodule prevalences of <20%, 2039% and 40% or more correspond approximately to the hypoendemic, mesoendemic and hyperendemic
West Africa
The main West African onchocerciasis vectors of the S. damnosum complex can be grouped in three pairs: the S. damnosum s.s.S. sirbanum pair, the S. sanctipauliS. leonense pair and the S. squamosumS. yahense pair. The geographical distribution of these species is considerably inuenced by local climatic and ecological characteristics. The rst two are termed savannah species, and the other four forest species. The S. damnosum s.s.S. sirbanum pair occupies the savannah zone as far as 14N, which is also the northern limit of the endemic area for onchocerciasis. These species may nd their way into forest areas along the major water
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courses. The S. sanctipauliS. leonense pair is forest dwelling but spreads into the savannah up to 10N. S. squamosum has a focal distribution in forest and savannah with a preference for small or medium-sized rivers in hilly and mountainous areas, and S. yahense is limited to small forest water courses. Experimental infection studies have indicated that the different sibling species of Simulium allow development of the savannah and forest strains of O. volvulus with widely different efciency, and have suggested that separate vector-parasite complexes exist in West Africa. However, use of new PCR techniques to identify the strain of parasite in the vectors has not supported this hypothesis.125 Blinding lesions are much more severe in the dry savannah than in forest areas, and there is evidence that two different strains of O. volvulus are transmitted in these areas.126,127 However, when considering the pathogenicity of eye lesions, as well as possible strain difference of the parasite, it is also important to consider environmental factors a dry atmosphere, photophobic effects, dust or exposure to higher levels of ultraviolet radiation that may in combination or separately result in damage to the cornea. All of these factors are likely to be higher in dry savannah than in rainforest zones. In the dry savannah, transmission of onchocerciasis is seasonal. This contrasts to a much longer transmission period in wet savannah and in forest areas.
lar it affects both Chachi Indians and the Black population of the Santiago River Basin, with severe skin and eye lesions. Owing to the presence of an efcient vector (S. exiguum s.l.) and the migration of infected individuals, onchocerciasis is increasing in prevalence and becoming more widespread.133 In Brazil, onchocerciasis occurs in the north: in the Amazonia, in a focus bordering Venezuela. The prevalence of onchocerciasis in the focus is not known.
Control
Onchocercal skin and eye lesions can have serious social and socioeconomic consequences in the affected communities, especially in areas of high endemicity.134,135 Considerable efforts have been made in the last decades to establish control programmes aiming at eliminating onchocerciasis as a public health problem.91 Antivector control, particularly larviciding of breeding sites, was previously the main control measure used in onchocerciasis. In the late 1980s, mass chemotherapy with ivermectin proved to be a practical and feasible alternative to vector control.
Vector control
The Onchocerciasis Control Programme (OCP) was established in 1974 in an attempt to control the savannah species of the vectors of onchocerciasis in seven West African countries (Burkina Faso, Benin, Ivory Coast, Ghana, Mali, Niger and Togo) in the Volta River Basin area. In 1986 the programme expanded its operations and included four additional countries (Guinea, GuineaBissau, Senegal and Sierre Leone). During the following decade successful vector control by aerial larviciding of Simulium breeding sites reduced the parasite to such a level that it was close to being eliminated from the hyperendemic foci of the core area of the programme.136,137 The campaign also markedly reduced the incidence of skin and eye lesions. The emergence of resistance to larvicides being applied and the reinvasion of treated areas from non-controlled areas were major problems encountered. Attempts to counter the resistance problem involved alternating the larvicides being used, while extension of the programme into countries to the west and south reduced the reinvasion problem. The cost of this large control scheme was high. During wet seasons, a eet of up to 11 helicopters and two xed-wing aircraft operated over 23 000 km of rivers. In later years, the programme included mass treatment with ivermectin as an important additional intervention measure, and vector control activities were considerably reduced. Vector control programmes of a much smaller scale than the OCP have been conducted in several African countries. S. neavei has been eradicated from Kenya by larvicidal treatments. Transmission was completely interrupted and no new cases of onchocerciasis have been reported in any of the districts since the elimination of the vector.
East and central Africa

The most important vectors in East and Central Africa belong to the S. damnosum complex, but vectors of the S. neavei group also transmit onchocerciasis in Ethiopia, Tanzania, Malawi, Uganda and parts of Zaire. This group includes all Simulium species with larvae and pupae that become attached to riverine crabs of the genus Potamonautes. In Tanzania, S. woodi is the most important vector within the S. neavei group. In the Tukuyu valley and Mahenge mountains transmission is by S. damnosum s.l.128 In East Africa onchocerciasis rarely causes blindness, but itching and dermatitis may be severe.129
Central and South American onchocerciasis

Onchocerciasis is believed to have been introduced recently to the New World, possibly as a result of the slave trade.130 In America, the parasites have adapted to transmission by local species of Simulium ies. In Mexico and Guatemala, the principal vector is S. ochraceum s.l, which breeds in small streams at altitudes between 500 and 1500 m. Transmission is mainly conned to the dry season. In some foci there are many head nodules, and eye involvement is common. In Venezuela, clinical manifestations in northern and eastern foci are mild and S. metallicum s.l. is the principal vector. In the south, onchocerciasis occurs in both highland and lowland areas, being hyperendemic in some groups of Yanomana Indians.131 S. guianense s.l. is the main vector in the highlands and S. oyapockense s.l. in the lowlands. In the western Andes in Columbia, where S. exiguum s.l. is the vector, lesions are mild.132 In Ecuador, onchocerciasis occurs in the north-western coastal province of Esmeraldas, and in particu-
Chemotherapeutic control
After community trials in several endemic areas had shown that ivermectin was acceptable for mass treatment,138 annual mass
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Filariases
treatment with ivermectin became the principal control strategy for onchocerciasis control. It reduces the microlarial burden and thus transmission in the community.139 Since ivermectin is only microlaricidal, treatments should continue for a period equivalent to the reproductive lifespan of the adult female worms, in order to halt transmission. Currently a dose of 150 mg/kg body weight once yearly is being encouraged for most endemic areas. Children under the age of 5 years should not be treated. The manufacturer of Mectizan (Merck) has made this product available free of charge through the Mectizan Donation Program to governmental and non-governmental healthcare organizations involved in onchocerciasis control programmes.140 Repeated treatments with ivermectin result in signicant improvement of itching and severe onchocercal skin disease141 and in regression of both early and advanced lesions of the anterior segment of the eye.94,121 As an additional benet ivermectin reduces the prevalence and intensity of Ascaris infections. Following the initial eld testing of ivermectin, the OCP started large-scale distribution for transmission and morbidity control in the programme area.91,135 Numerous smaller control programmes utilizing mass treatment were also started in other endemic areas. Partnerships of non-governmental organizations involved in blindness prevention, international organizations (including the WHO and the World Bank) and governments of endemic countries subsequently established the African Programme for Onchocerciasis Control (APOC) and the Onchocerciasis Elimination Program in the Americas (OEPA) for the promotion and coordination of control activities on the African and American continents, respectively. APOC took over as the leading coordinating body of onchocerciasis control in Africa when the OCP ended its activities in 2002. Serious reactions, including death after mass ivermectin treatment for onchocerciasis have recently been reported in individuals with high-intensity Loa loa microlaraemia,142 and call for caution when using ivermectin in loiasis endemic areas. Most of these reactions have been observed in Cameroon. To date, resistance of O. volvulus to ivermectin has not been observed.143 However, there is an urgent need for development of new backup drugs should this occur. In particular it would be benecial with a safe and easily administered macrolaricidal drug, which could reduce the time needed to eliminate the adult worms from endemic areas.91,144
streptocerca and M. ozzardi (see Table 84.1). A few species of animal lariae cause rare zoonotic infections in humans.
Loa loa
Loa loa is a larial parasite of humans in parts of West and Central Africa.145 It is commonly known as the eye-worm, because adult worms are occasionally seen to move across the eye of the patient.

Adult L. loa live and move around in the connective tissues of humans. They frequently wander through the subcutaneous tissues and may sometimes pass beneath the conjunctiva of the eye. The females measure 5070 0.5 mm and the males 3035 0.4 mm. More detailed morphology is given in Appendix III. The sheathed microlariae circulate in the blood and measure 230300 68 m (Figure 84.22). Human L. loa is transmitted by tabanid ies of the genus Chrysops. The microlarial periodicity is adapted to the day-biting habits of the vectors. It is diurnal, with peak concentration in the peripheral blood around noon (Figure 84.23). Microlariae ingested by the vectors during feeding penetrate the stomach wall of the ies and migrate to the fat body where they develop in 812 days. Infective larvae (2 mm 25 m) then move via the thorax to the proboscis. The larvae burrow into the skin of the human host when the vector feeds. The minimum prepatent period (until appearance of microlariae) is 56 months, but it can be much longer, and adult worms may live for 17 years or more.
Clinical features
The most common clinical manifestations of loiasis are recurrent angio-oedema (Calabar swellings) and pruritus. Adult worms may be noticed when they pass under the conjunctiva of the eye (Figure 84.24) or under the skin (Figure 84.25).146148 They usually appear and then disappear within 1015 min, leaving no trace behind.
Nodulectomy
Nodulectomy campaigns have been encouraged in some countries, especially in those where head nodules are common. The impact of such campaigns on ocular disease can be difcult to assess. In Guatemala, for example, where systematic campaigns have been associated with decreased blindness, other factors, particularly changes in socioeconomic conditions, may have decreased humanvector contact.
OTHER FILARIAL INFECTIONS

In addition to the larial worms resulting in human lymphatic lariasis and onchocerciasis, four other species of lariae commonly infect humans. These are Loa loa, Mansonella perstans, M.
Figure 84.22 Microlaria of L. loa.
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Other Filarial Infections
100
80
Percent of maximum
60
40
20
0 12 16 20 24 4 8 12 16 20
Hours
Figure 84.23 Periodicity of L. loa microlariae in the peripheral blood.
Figure 84.25 L. loa migrating under the skin. (Courtesy of P. G. P. Manson-Bahr.)
Figure 84.24 Transocular migration of adult L. loa. (Courtesy of J. Anderson.)
Hypereosinophilia, especially in expatriates, is common. Calabar swellings (Figure 84.26) are most commonly observed on the hands, wrists and forearms, but they may appear anywhere on the body. The swellings are painless, and do not pit on pressure. They may last from a few hours to several days. Usually one swelling occurs at a time, and may recur at irregular intervals for years after the patient has left the endemic area. Calabar swellings probably reect the hosts response to parasite antigens at the site of the swellings. Other common symptoms include generalized pruritus, fatigue and arthralgia. The death of an adult worm may occasionally cause a localized abscess. Dead worms sometimes calcify and are then easily seen on radiography. More serious complications can occur when L. loa invade the central nervous system and other vital organs. An epidemiological correlation has been observed between loiasis and the occurrence of endomyocardial brosis, and it is possible that hypereosinophilia induced by the infection may lead to the cardiac damage.149
Figure 84.26 Calabar swelling.
Nephropathy and encephalopathy are less common pathological changes. Nodules in the conjunctiva, swelling of the eyelids and proptosis were previously reported from Uganda as complications of loiasis. However, histological evidence has shown that these lesions are due to M. perstans.150 (For Ocular loiasis, see Chapter 18.) As in other larial infections, expatriates entering an endemic area are more troubled by clinical manifestations than are the indigenous inhabitants. However, the prevalence of microlaraemia is apparently lower in expatriates than in the local inhabitants.148,151
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Diagnosis
The appearance of characteristic Calabar swellings in persons who live in an endemic area or who have visited such an area, or a history by the patient of a worm having crossed the eye, is strongly suggestive of L. loa infection. Other helminths may migrate under the skin and cause cutaneous reactions. Swellings produced by M. perstans are similar to Calabar swellings. Cutaneous larva migrans (caused by Strongyloides or hookworm larvae) moves slowly, causes intense irritation and leaves multiple tracks which may last for hours or even weeks. Subcutaneous L. loa causes little or no reaction, is usually single and appears only transiently for a few minutes. Guinea worm is a very large worm which can be palpated under the skin. In the eye, L. loa is subconjunctival and much larger than Toxocara, which may appear in the anterior chamber. L. loa infections can be parasitologically diagnosed by removal of adult worms from the skin or conjunctiva, but it is usually done by identication of the characteristic microlariae in the blood (see Figure 84.22). Microlariae are, however, absent in many persons with clinical loiasis (occult loiasis).152 The optimal time for taking a blood sample is around noon, when the concentration of microlariae in the peripheral blood is highest (see Figure 84.23). The various techniques for concentration and examination of the blood for microlariae mentioned under lymphatic lariasis can also be used for L. loa. The sheath of L. loa microlariae stains with haematoxylin but not with Giemsa stain. Other characteristic features used in the identication of the microlariae are indicated in Appendix III. Immunodiagnosis on its own is of limited value because of low sensitivity and cross-reactions with other larial species. Detection of specic IgG4 can be useful for conrming the diagnosis of L. loa in amicrolaraemic individuals with clinical signs suggesting loiasis.153 A PCR assay with high specicity and sensitivity for microlaraemia and occult loiasis has been developed.154
infections it is recommended to start with very small doses of DEC combined with administration of steroids. Because of the danger of inducing Mazzotti reactions, care must be taken when patients with loiasis are also infected with O. volvulus. DEC is also recommended for treatment of loiasis acquired by expatriate visitors to endemic areas.157 Ivermectin (200 mg/kg body weight) is an efcient microlaricide.158 However, recent reports of serious reactions after mass treatment of onchocerciasis in areas co-endemic for loiasis call for caution.144 Reactions are perhaps due to extremely high L. loa microlarial counts. Mebendazole in low doses has been shown to reduce microlaraemia signicantly in persons with heavy L. loa infections.159 Side-effects were low. A three-day albendazole regimen did not give a sustained reduction in microlaraemia.160 However, a 3-week albendazole regimen may be useful for the treatment of symptomatic loiasis in cases when DEC is ineffective.161
Epidemiology
Human loiasis occurs only in Africa, where transmission is conned to the rainforest and swamp forest areas of West and Central Africa (Figure 84.27). The vectors breed in these areas. It is estimated that 2030 million people reside in endemic areas. The parasite was previously also observed in the more western rainforests of Sierre Leone, Liberia, Ivory Coast and Ghana, but it has not been reported from these countries for many years and may have disappeared spontaneously.145 Human L. loa is transmitted by day-biting female tabanid ies of the genus Chrysops, mainly C. silacea and C. dimidiata. Other species of Chrysops are of local importance, especially in the periphery of the transmission zone. Chrysops ies rest in the forest
Immunology
Most infected individuals show high antibody titres to larial antigen.148,153 Antibodies recognizing a surface antigen on L. loa microlariae have been demonstrated in persons with amicrolaraemic adult infections, whereas these antibodies were not present in microlaraemic persons from the same endemic area.155 Microlaraemic individuals furthermore have diminished cellular responsiveness to specic antigens compared with amicrolaraemic individuals.156 Occult loiasis may thus result from the development of an immune response specic ally eliminating the microlarial stage of the parasite. Some cases may also be due to single sex infections.
Management
DEC rapidly eliminates microlariae of L. loa from the blood (see Table 84.2) in dosages varying from 5 to 10 mg/kg body weight divided daily into three doses for 24 weeks. DEC has some effect on adult worms, but complete cure may require repeated treatment with this drug regimen. Side-effects may include fever, malaise, angio-oedema and pruritus. In patients with high microlaraemia, the side-effects may be severe, and there is a risk of severe central nervous system complications. When treating heavy
Figure 84.27 Geographical distribution of L. loa.
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canopy and are attracted mainly by movement, dark colours and wood smoke. They lay their eggs in swamps and river edges below the forest trees, and the larvae move about in the mud. Larval development is slow, taking up to a year or more to reach the adult stage. Transmission takes place mainly during the wet season. More information on the vectors and their bionomics is given in Appendix IV. The possible existence of an animal reservoir for L. loa has been studied extensively. Species of forest-dwelling primates, including the mandril and several species of Cercopithecus, harbour lariae that closely resemble L. loa. The periodicity of these parasites is nocturnal. Monkeys can be infected with the human parasite, which retains its diurnal periodicity in the new host. The nonhuman primate L. loa are transmitted by species of Chrysops which are feeding only at night on monkeys living in the canopy, whereas blood meal analyses have shown that C. silacea and C. dimidiata do not feed on non-human primates. Thus it appears that, in nature, human and monkey L. loa comprise two distinct transmission complexes, and that the parasite is not a zoonosis. The microlaria rate in children tends to be low. It gradually rises with age, but even in old age rarely exceeds 40%. Despite the lack of microlaraemia, many children harbour the adult parasites, which occasionally cross the eye. Within an endemic community, the microlarial prevalence is commonly higher in males than in females.162
Figure 84.28 Geographical distribution of M. perstans.
Control
Methods to control loiasis include environmental modications, personal protection and vector control. No large-scale control programmes have been conducted. The siting of houses and plantations should be established some distance from the forest edge and swamps where the vectors breed. The larvae of Chrysops live in the mud and can be destroyed there with insecticides. However, this method is impractical. The wearing of light-coloured clothing and frequent application of insect repellent reduces the risk of bites by the ies. Personal prophylaxis with a 300-mg dose of DEC once a week has proven efcient in expatriates working in endemic areas.163
Mansonella perstans
M. perstans is a human larial parasite, widely distributed in Africa as well as in parts of Central and South America and in the Caribbean (Figure 84.28). It is transmitted by tiny biting midges of the genus Culicoides. Rarely have adult worms been recovered from humans. They live in the serous cavities, mainly the peritoneal cavity, and usually cause no symptoms. Occasionally they have been found subcutaneously. The adult female measures 7080 0.1 mm and the male 3545 0.06 mm. Microlariae (200 4.5 m) are unsheathed, non-periodic and circulate in the blood (Figure 84.29). In the vector, following a blood meal, the ingested microlariae develop to the infective stage. Infective larvae penetrate the skin of humans when the vector feeds again. The time from infection until appearance of microlariae in the blood of humans is unknown. M. perstans infections are largely non-pathogenic, but a variety of clinical manifestations can occur in some infected individuals.
Figure 84.29 Microlaria of M. perstans.
Symptoms are more common in expatriates coming to endemic areas from non-endemic ones. Transient swellings resembling the Calabar swellings of loiasis occur. Other manifestations are pruritus, fever, and pain or ache in bursae and/or joint synovia. Severe abdominal pain, especially in the liver region, may occur. Nodules in the conjunctiva, swelling of the eyelids and proptosis have also been attributed to M. perstans infections.150 Eosinophilia is common, and cases of symptomatic hypereosinophilia have recently been reported from expatriates returning from an endemic area.164 It is likely that some of the pathological changes observed are induced by immune responses to the infection.
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Diagnosis is by recovering the microlariae (Figure 84.29) from the blood. Blood samples may be obtained at any time of the day, and techniques similar to those used for concentration and examination of blood samples for the diagnosis of lymphatic lariasis are utilized. For morphological features of the microlariae, see Appendix III. Ivermectin has no effect on M. perstans (see Table 84.2). DEC (200 mg twice daily for 21 days with a gradual dosage increase the rst 3 days) reduce the microlaraemias, but mebendazole (100 mg twice daily for 28 days) appears to be more effective in eliminating the infection. A combination of mebendazole and DEC resulted in a signicantly higher activity than each of these drugs alone.165 Albendazole (400 mg twice daily) given for 10 days resulted in a slow but signicant decrease in M. perstans microlaraemia after 13 months.166 Few studies have been carried out on the epidemiology of M. perstans infections. The microlarial prevalence is generally higher in adults than in children, and males are usually more frequently infected than females.167 In some localities very high prevalences microlaraemia are found.168 The main vectors in Africa are C. grahami and C. inornatipennis, but other species of Culicoides also play a role. The species of Culicoides transmitting M. perstans in the Americas have not been identied. M. perstans is found commonly in chimpanzees and gorillas, but it is also widespread in areas where there are no large apes.
Mansonella streptocerca
M. streptocerca is a larial parasite of humans, having a limited distribution in Central and West Africa (Figure 84.30). A new focus in Uganda was described recently.169 The adult worms inhabit the dermis of the upper thorax and shoulders, but they
have rarely been recovered and very few have been examined in detail. The adult female measures 27 0.08 mm and the male 17 0.05 mm. The microlariae (Figure 84.31) also inhabit the dermis. They are unsheathed, measure 180240 35 m and exhibit no periodicity. M. streptocerca is transmitted by tiny biting midges of the genus Culicoides, the most common vector probably being C. grahami. Complete development in the vector has been observed experimentally to take 9 days. Information on the development of M. streptocerca in the human host is lacking, and the prepatent period is unknown. The infection generally causes few clinical manifestations. Dermatitis is the most common sign and is most marked over the thorax and shoulders.169 It is characterized by pruritus, hypopigmented macules and papules. Microscopically, infected skin shows dilated dermal lymphatics, and it has been suggested that M. streptocerca might be a cause of lymphoedema and elephantiasis. Clinically the infection must be distinguished from onchocerciasis and leprosy. Diagnosis is made by nding the unsheathed microlariae of M. streptocerca in skin snips (for the technique, see Onchocerciasis). The microlariae have a characteristic shepherds crook tail. Other distinguishing features of the microlariae are shown in Figure 84.31 and mentioned in Appendix III. A sensitive and specic PCR assay for specic detection of M. streptocerca DNA in skin biopsies has been developed.170 DEC eliminates both microlariae and adults (see Table 84.2) of M. streptocerca when given in a dosage of 26 mg/kg body weight for 21 days. In most patients, the DEC treatment causes intense pruritus and development of cutaneous papules in which degenerating adult worms may be found. Other side reactions similar to the Mazzotti reaction during DEC treatment of onchocerciasis may occur but are not common. Ivermectin in a single dose of 150 mg/kg body weight leads to sustained suppression of microlaraemia in the skin.171 Common short-term adverse reactions are increased pruritus and dermatitis. Adults and microlariae of M. streptocerca are found in the skin of chimpanzees, but whether the infection is a zoonosis is not known.
Mansonella ozzardi
M. ozzardi is a human larial parasite found only in the New World. Foci exist in Central America, in northern South America and in some Caribbean islands (Figure 84.32). A new focus in Bolivia was described recently.172 Adult worms have been recov-
Figure 84.30
Geographical distribution of M. streptocerca.
Figure 84.31 Microlaria of M. streptocerca. (Courtesy of P. Fischer.)
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months. Natural M. ozzardi infections have not been reported from animals. In endemic foci, human infections tend to be highly prevalent, with the microlarial infection rates increasing with age.172,173 Most people infected with M. ozzardi are symptomless. Symptoms of severe articular pain, headache, fever and pruritus have been reported, but these have generally not been closely associated to infection.172,173 Eosinophilia is common. Individuals in endemic areas have high titres of antibodies against larial antigens. The infection is diagnosed by nding the microlariae in blood or in skin biopsies.174 The techniques described under Lymphatic lariasis and Onchocerciasis can be used. For characteristics of the microlariae, see Figure 84.33 and Appendix III. DEC has little or no effect on M. ozzardi infections (see Table 84.2), but a single dose of 6 mg ivermectin has been reported to provide signicant long-term reduction in microlaraemia.175
Rare larial infections

Humans occasionally become infected with species of lariae normally found in animals.150 Among these zoonotic infections, those due to Dirolaria spp. are the most frequently reported and the most widespread.
Figure 84.32 Geographical distribution of M. ozzardi.
Dirolariasis
Dirolaria spp. are natural parasites of various species of carnivores. In these hosts, the microlariae circulate in the blood. Transmission is by mosquitoes. In human infections, parasite development is impaired and no microlariae are produced.176,177
Pulmonary dirolariasis
D. immitis is a larial parasite of dogs. It is transmitted worldwide, except in cold climates. In the dog, adult D. immitis inhabit the pulmonary arteries and right ventricle of the heart, where they may occur in large coiled masses. Pulmonary dirolariasis in humans results from infection with D. immitis. In humans, the parasite may develop partially in the pulmonary arterial tree, where it ultimately dies perhaps as a result of an inammatory response. Typically a spherical nodule 13 cm in diameter is discovered in the lungs on routine radiography (a coin lesion) or at autopsy. A single worm, usually necrotic and sometimes calcied, is present in the lumen of the artery. Most patients are asymptomatic. When present, symptoms include cough, chest pain, eosinophilia, haemoptysis and fever. Diagnosis is usually based on biopsy. Serological diagnosis has not been very successful. The only treatment is surgical excision.
Figure 84.33 Microlaria of M. ozzardi. (Courtesy of M. Eberhard.)
ered from the peritoneal cavity of humans. Females measure 50 0.15 mm and males 26 0.07 mm. The microlariae (220 34 m, see Figure 84.33) are unsheathed, non-periodic and are found in both blood and skin. Two groups of vectors have been shown to transmit M. ozzardi infections. In the Caribbean islands the vectors are biting midges of the genera Culicoides, whereas in the Amazon basin Simulium blackies have been incriminated. The development of the parasite has been studied in the vectors and in experimental infections in patas monkeys. In the monkeys the prepatent period was 56
Subcutaneous dirolariasis
D. repens is a natural parasite of dogs and cats in warmer climates of the Old World. It has not been reported from America. In the normal hosts, adult worms are located in the subcutaneous tissues. In humans, occasional infections may result in the formation of subcutaneous nodules consisting of a degenerating immature worm surrounded by granulomatous tissue.178 Nodules occur in
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Filariases
many parts of the body, especially the breasts, arms, legs, scrotum, eyelid and conjunctiva. The nodules may occasionally be slowly migrating. Immunodiagnosis has not proved useful, and diagnosis is by biopsy. Treatment is by surgical removal of the nodule. In North America, other species of Dirolaria, especially D. tenuis and D. ursi (natural parasites of racoons and bears, respectively), have been reported to cause subcutaneous dirolariasis in humans.
Other rare larial infections

Human infections with Brugia parasites have occasionally been reported from countries where transmission of human Brugia spp. does not occur. This includes infections acquired in Africa and America. These Brugia parasites are believed to be of animal origin.1 Microlariae with no resemblance to those of human larial species have been reported from humans.150 Cases of encephalopathy with microlariae found in the cerebrospinal uid were described from Zimbabwe. The microlariae were shown to be Meningonema peruzzi, a larial parasite of Cercopithecus monkeys. Microlariae similar to Microlaria rodhaini from chimpanzees were recovered in skin biopsy specimens from humans during a survey in Gabon. Microlariae of unknown species found in the blood of native South Americans in a remote jungle area in Venezuela were named Microlaria bolivarensis. In a survey in northwestern Zaire, many villagers had microlariae of unknown species in the blood. These were named Microlaria semiclarum.
DRACUNCULIASIS (GUINEA WORM)

Dracunculiasis or guinea worm disease in humans results from infection with Dracunculus medinensis.
Figure 84.34 Blister on the skin prior to the appearance of guinea worm. (Courtesy of P. Bloch.)

D. medinensis is a nematode parasite related to larial worms. The vectors are cyclopoid copepods (water eas), which are tiny freeswimming crustaceans usually found in abundance in natural freshwater bodies. Humans acquire the infection by drinking water containing the vectors infected with guinea worm larvae. The presence of guinea worm in an area is therefore essentially due to the poor quality of drinking water. Adult female D. medinensis (up to 6080 cm long and 1.5 2.0 mm in thickness) inhabit the subcutaneous connective tissues of humans. They may be located anywhere on the body but in the late stage of infection they are usually attracted to the legs and feet. At this stage most of the interior of the worm is occupied by the uterus, which contains thousands of rst-stage larvae. A blister (Figure 84.34) is formed on the skin of the host around the anterior end of the worm, and, when exposed to water, the blister ruptures. The female guinea worm protrudes its anterior end from the ulcer and discharges rst-stage larvae (650 20 m) into the water. It remains protruding for the following 26 weeks, releasing larvae each time it is immersed in water. After this period, it dies. The larvae are infective in freshwater for 56 days, and for further development must, within this period, be swallowed by a copepod of the right species. The larva penetrates the gut wall, and in the haemocoel it moults twice. It can reach the infective third stage (450 14 m) in about 2 weeks. Vectors that contain thirdstage larvae become sluggish and sink to the bottom of a pond. Many species of cyclopoid copepods have been found naturally infected in various parts of the world, mainly being of the genera Mesocyclops and Thermocyclops.179 In humans, vectors ingested in drinking water are dissolved by the gastric juice. The guinea worm infective larvae are released and penetrate the stomach or intestine of the new host. After a period in the abdominal cavity, the larvae enter the connective tissues, where they develop to mature worms. Mating occurs about 3 months after the initial infection, and the males, which are much smaller than the females (14 cm 0.4 mm), die shortly thereafter. The females move about in the connective tissues and usually reach the lower extremities between 8 and 10 months after infection.
Clinical features
There are usually no symptoms in the prepatent period. The rst sign appears a few days before the worm pierces the skin. The dermis becomes elevated and a blister develops (Figure 84.34).
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Dracunculiasis (Guinea Worm)
Figure 84.35 Mature adult female guinea worm protruding from a foot. (Courtesy of P. Bloch.)
The patient feels a burning sensation and itching, which he or she tries to relieve by placing the affected part in water. On exposure to water the blister ruptures, the anterior part of the worm protrudes and Dracunculus larvae are discharged into the water. The worm is most frequently located in the foot or lower leg (Figure 84.35), but may appear on arms, breasts, head, back, scrotum or anywhere on the body surface. When it is close to joints it may cause arthritis. Further inammation, or the calcication of worms, may cause joints of legs and feet to become stiff, thereby crippling the patient. In many cases (sometimes 50% or more), the ulcer caused by the parasite becomes secondarily infected with bacteria, and a spreading cellulitis may develop. Tetanus infection is a serious complication of guinea worm infection. Inammation around it makes the whole worm difcult to extricate before the uterus is empty of larvae. Provided there is no secondary infection, the ulcer heals spontaneously after extrication of the empty worm. If broken, the remainder of the worm withdraws into the host tissue, causing a severe inammatory reaction followed by an ulcer and later scar tissue. Usually only a single worm appears in the patient annually, but up to 20 or more can appear at the same time in one individual. Some female worms fail to emerge and die in the body. Usually they become encysted and calcify, and are then only apparent on radiography. Dead or ruptured worms may lead to formation of a sterile subcutaneous abscess. Migration of worms to vital organs can cause serious consequences. Such migrations are rare.
Figure 84.36 Traditional method of removal of guinea worm. (Courtesy of P. Bloch.)
the sufferer. Active larvae can be obtained by immersing the protruding adult female in a small tube or container with water. The rst-stage larvae, with their characteristic pointed tails (see Appendix III), can then be observed under the microscope. Serology is of no practical use in diagnosis. High eosinophilia is commonly observed in guinea worm infections. Dead calcied worms are easily seen on radiological examination.
Immunology
Owing to constant exposure, all persons in endemic areas usually have high antibody titres. These responses vary with infection status and transmission season.180,181 There is no evidence of acquired immunity: people in endemic areas suffer from infections year after year. Whether the vigorous antibody response has any effect on the course of the infection is unknown.
Management Diagnosis
Guinea worm infections cannot be diagnosed in the prepatent period, i.e. for the rst 810 months of infection. Shortly before appearance the adult female worm can sometimes be seen or palpated under the skin. A clinical diagnosis is made by examining the guinea worm ulcer and observing the female protruding from the blister (see Figure 84.35). The appearance of the blister, with local itching and burning pain, makes diagnosis simple, even for The traditional method of slow extraction of the emergent guinea worm is usually the most effective. The protruding part of the female worm is attached to a small stick, which is twisted a small amount each day until the worm has been removed (Figure 84.36). Care should be taken not to break the worm. Administration of antibiotics and cleaning and dressing of the ulcers are important in reducing secondary infections, and tetanus vaccination is recommended.
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84.
Filariases
200
GW cases Rainfall
600 500 400
150 Rainfall (mm) No. of cases
100
300 200
50 100 0
M J S N J M M J S N J M M J S N
0
1989 1990 1991
Figure 84.38 Seasonal variation in rainfall and number of guinea worm ulcers in a village in the northern region of Ghana. (Courtesy of P. Magnussen.)
Figure 84.37
Geographical distribution of guinea worm.
A technique for surgical extraction of the guinea worm prior to eruption through the skin has been described.182 In the eld, surgical removal of unerupted worms resulted in a signicant decrease in guinea worm associated disability. No anthelmintic treatment is available. Some drugs, especially niridazole (given orally at 12.5 mg/kg body weight daily) have been reported to reduce inammation around the worm, thereby allowing easier extraction. Treatment of prepatent guinea worm infections with ivermectin had no effect.183
is closely related to the rainfall. In the arid areas the transmission usually coincides with the rainy season, when surface water is available, whereas in wet areas transmission is most intense in the dry season, when drinking water sources are few. Previously, 50% or more of the population in highly endemic areas could be affected by the infection every year. However, as a consequence of control efforts the incidence of infection in most areas is now low. There is considerable variation in sex prevalence between different endemic areas. Persons aged between 1540 years are mostly affected. The transmission season often coincides with the peak period of agricultural work. Because a large proportion of the farmers may be incapacitated, guinea worm infection can severely reduce agricultural output. Parasites resembling D. medinensis are seen in animals, especially in dogs, but there is no evidence that they are a reservoir of infection for humans.184
Control
Owing to its simple life cycle, and the apparent lack of an animal reservoir, the elimination of guinea worm appears feasible. The United Nations-supported International Drinking Water and Sanitation decade (19811990) raised global attention to the possibility of eradicating the infection by improving the quality of human drinking water, and in 1986 the Worlds Health Assembly adopted a resolution calling for worldwide elimination of dracunculiasis. Many organizations are currently involved in programmes to reach this goal.185 Asia was declared free of transmission in 1997, and in 2004 the global incidence had been reduced by more than 99%, from an estimated 3.5 million cases in 1986 to less than 20 000 cases. Dracunculiasis is now conned to 12 countries in Africa, with most of the remaining cases in the Sudan and Ghana. Provision of safe drinking water in the form of boreholes is the most expensive, but also the most effective, measure and has been shown to result in a dramatic reduction in the incidence of guinea worm infection.186 Other measures to control guinea worm transmission are health education and chemical vector control. Health education focuses on drinking water as the source of infection and
Epidemiology
Human guinea worm infections were previously much more widespread, but as a result of extensive control efforts (see below) the distribution is now limited to Sahelian and sub-Sahelian areas of Africa (Figure 84.37). The occurrence of guinea worm infection is associated with the use of small sources of water in semi-arid countries. Humans contract the infection by drinking the water containing infected cyclopoid copepods, and again contribute to transmission by immersing the guinea worm ulcer in water, thereby allowing the release of rst-stage larvae. In the Sahelian region of Africa, transmission occurs mainly in small surface water pools used for collecting drinking water and for washing. The transmission of guinea worm is frequently seasonal, with the majority of patent infections and infected copepods occurring within a few months of the year (Figure 84.38). The seasonality
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References
on the importance of boiling or ltering the water before use. Special monolament nylon material has been produced for ltering water, but effective and less expensive lters can be made from polyester cloth187 or even from a layer of tightly woven cotton cloth. To prevent infestation of the water with guinea worm larvae, health education also emphasizes the reasons why people with guinea worm ulcers should avoid entering water sources. Vector control can be achieved in ponds and wells by applying the insecticide temephos (Abate). In the later stages of control, active surveillance on the increasingly smaller number of infected villages is being adopted, with the aim of implementing all possible control measures around each case immediately (case containment).
REFERENCES
1. World Health Organization. Lymphatic lariasis: the disease and its control. Fifth report of the WHO expert committee on lariasis. WHO Tech Rep Ser 1992; 821. 2. Demarquay JN. Note sur une tumeur des bourses contenant un liquide laiteux (galactocle de Vidal) et referment des petits tres vermiformes que lon peut considrer comme des helminthes hematoides ltat dembryon. Gaz Md Paris 1863; 18:665667. 3. Wucherer OE. Noticia preliminar sobre vermes de una especie ainda no descripta, encontrados na urina de doentes de hematuria intertropical no Brazil. Gaz Med Bahia 1868; 3:9799. 4. Lewis TR. On a haematozoon inhabiting human blood, its relation to chyluria and other diseases. Lancet 1872; i:889890. 5. Cobbold TS. Discovery of the adult representative of microscopic lariae. Lancet 1877; ii:7071. 6. McGregor IA. The Third Manson Oration. Patrick Manson 18441922: the birth of the science of tropical medicine. Trans R Soc Trop Med Hyg 1995; 89:18. 7. Grove DI. A History of Human Helminthology. London: CAB International; 1990. 8. Michael E, Bundy DA P. Global mapping of lymphatic lariasis. Parasitol Today 1997; 13:472476. 9. Simonsen PE, Niemann L, Meyrowitsch DW. Wuchereria bancrofti in Tanzania: microlarial periodicity and effect of blood sampling time on microlarial intensities. Trop Med Int Hlth 1997; 2:153158. 10. Simonsen PE, Meyroitsch DW, Jaoko WG, et al. Bancroftian lariasis infection, disease, and specic antibody response patterns in a high and a low endemicity community in East Africa. Am J Trop Med Hyg 2002; 66: 550559. 11. Dreyer G, Addiss D, Roberts J, et al. Progression of lymphatic vessel dilatation in the presence of living adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 2002; 96:157161. 12. Freedman DO, Filho PJ A, Besh S, et al. Lymphoscintigraphic analysis of lymphatic abnormalities in symptomatic and asymptomatic human lariasis. J Infect Dis 1994; 70:927933. 13. Bernhard P, Makunde RW, Magnussen P, et al. Genital manifestations and reproductive health in female residents of a Wuchereria bancrofti-endemic area in Tanzania. Trans R Soc Trop Med Hyg 2000; 94:409412. 14. Dunyo SK, Nkrumah FK, Ahorlu CK, et al. Exfoliative skin manifestations in acute lymphatic lariasis. Trans R Soc Trop Med Hyg 1998; 92: 539540. 15. Gasarasi DB, Premji ZG, Mujinja PG M, et al. Acute adenolymphangitis due to bancroftian lariasis in Ruji district, south east Tanzania. Acta Trop 2000; 75:1928. 16. Dreyer G, Medeiros Z, Netto MJ, et al. Acute attacks in the extremities of persons living in an area endemic for bancroftian lariasis: differentiation of two syndromes. Trans R Soc Trop Med Hyg 1999; 93:413417.
17. McMahon JE, Magayuka SA, Kolstrup N, et al. Studies on the transmission and prevalence of bancroftian lariasis in four coastal villages of Tanzania. Ann Trop Med Parasitol 1981; 75:415431. 18. Meyrowitsch DW, Simonsen PE, Makunde WH. Bancroftian lariasis: analysis of infection and disease in ve endemic communities of northeastern Tanzania. Ann Trop Med Parasitol 1995; 89:653663. 19. Dunyo SK, Ahorlu CK, Simonsen PE. Scarication as a risk factor for rapid progression of larial elephantiasis. Trans R Soc Trop Med Hyg 1997; 91:446. 20. Dreyer G, Addiss D, Dreyer P, et al. Basic Lymphoedema Management, Treatment and Prevention of Problems Associated with Lymphatic Filariasis. Middlesex: Hollis Publishing; 2002. 21. Ottesen EA, Nutman TB. Tropical pulmonary eosinophilia. Annu Rev Med 1992; 43:417424. 22. Dreyer G, Dreyer P, Piessens WF. Extralymphatic disease due to bancroftian lariasis. Braz J Med Biol Res 1999; 32:14671472. 23. Supali T, Wibowo H, Rckert P, et al. High prevalence of Brugia timori infection in the highland of Alor Island, Indonesia. Am J Trop Med Hyg 2002; 66:560565. 24. Magnussen P, Makunde W, Simonsen PE, et al. Chronic pulmonary disorders, including tropical pulmonary eosinophilia, in villages with endemic lymphatic lariasis in Tanga region and in Tanga town, Tanzania. Trans R Soc Trop Med Hyg 1995; 89:406409. 25. Kazura JW, Bockarie M, Alexander N, et al. Transmission intensity and its relationship to infection and disease due to Wuchereria bancrofti in Papua New Guinea. J Infect Dis 1997; 176:242246. 26. Onapa AW, Simonsen PE, Pedersen EM. Non-larial elephantiasis in the Mt. Elgon area (Kapchorwa District) of Uganda. Acta Tropica 2001; 78:171176. 27. McMahon JE, Marshall TF C, Vaughan JP, et al. Bancroftian lariasis: a comparison of microlariae counting techniques using counting chamber, standard slide and membrane (nuclepore) ltration. Ann Trop Med Parasitol 1979; 73:457464. 28. McMahon JE, Marshall TF C, Vaughan JP, et al. Tanzania lariasis project: a provocative day test with diethylcarbamazine for the detection of microlariae of nocturnally periodic Wuchereria bancrofti in the blood. Bull World Health Organ 1979; 57:759765. 29. Simonsen PE, Meyrowitsch DW, Makunde WH. Bancroftian lariasis: longterm effect of the DEC provocative day test on microlaraemia. Trans R Soc Trop Med Hyg 1997; 91:290293. 30. Dunyo SK, Nkrumah FK, Simonsen PE. A study on the provocative day test effect of ivermectin and albendazole on nocturnal periodic Wuchereria bancrofti microlaraemia. Trans R Soc Trop Med Hyg 1999; 93:608610. 31. Jamail M, Andrew K, Junaidi D, et al. Field validation of sensitivity and specicity of rapid test for detection of Brugia malayi infection. Trop Med Int Hlth 2005; 10:99104. 32. Lammie PJ, Weil G, Noordin R, et al. Recombinant antigen-based antibody assays for the diagnosis and surveillance of lymphatic lariasis a multicenter trial. Filaria J 2004; 3:9. 33. Weerasooriya MV, Itoh M, Islam MZ, et al. Prevalence and levels of lariaspecic urinary IgG4 among children less than ve years of age and the association of antibody positivity between children and their mothers. Am J Trop Med Hyg 2003; 68:465468. 34. Simonsen PE, Dunyo SK. Comparative evaluation of three new tools for diagnosis of bancroftian lariasis based on detection of specic circulating antigens. Trans R Soc Trop Med Hyg 1999; 93:278282. 35. Walther M, Muller R. Diagnosis of human lariasis (except onchocerciasis). Adv Parasitol 2003; 53:149193. 36. Williams SA, Laney SJ, Bierwert LA, et al. Development and standardization of a rapid, PCR based method for the detection of Wuchereria bancrofti in mosquitoes, for xenomonitoring the human prevalence of bancroftian lariasis. Ann Trop Med Parasitol 2002; 96:S41S46. 37. Fischer P, Boakye D, Hamburger J. Polymerase chain reaction-based detection of lymphatic lariasis. Med Microbiol Immunol 2003; 192:37. 38. Dreyer G, Santos A, Nores J, et al. Ultrasonographic detection of living adult Wuchereria bancrofti using a 3.5-MHz transducer. Am J Trop Med Hyg 1998; 59:399403.
33
Ch084-X4470.indd 33
6/10/2008 8:04:17 PM
84.
Filariases
39. Mand S, Marfo-Debrekyei Y, Dittrich M, et al. Animated documentation of the laria dance sign (FDS) in bancroftian lariasis. Filaria J 2003; 2:3. 40. Mand S, Debrah A, Batsa L, et al. Reliable and frequent detection of adult Wuchereria bancrofti in Ghanaian women by ultrasonography. Trop Med Int Hlth 2004; 9:11111114. 41. Mand S, Supali T, Djuardi J, et al. Detection of adult Brugia malayi lariae by ultrasonography in humans in India and Indonesia. Trop Med Int Hlth 2006; 11:13751381. 42. Maizels RM, Sartono E, Kurniawan A, et al. T-cell activation and the balance of antibody isotypes in human lymphatic lariasis. Parasitol Today 1995; 11:5056. 43. Michael E, Grenfell BT, Bundy DA P. The association between microlaraemia and disease in lymphatic lariasis. Proc R Soc Lond B Biol Sci 1994; 256:3340. 44. Freedman DO. Immune dynamics in the pathogenesis of human lymphatic lariasis. Parasitol Today 1998; 14:229233. 45. Nicolas L, Langy S, Plichart C, et al. Filarial antibody responses in Wuchereria bancrofti transmission area are related to parasitological but not clinical status. Parasite Immunol 1999; 21:7380. 46. Jaoko WG, Simonsen PE, Meyrowitsch DW, et al. Filarial-specic antibody response in East African bancroftian lariasis: effects of host infection, clinical disease, and larial endemicity. Am J Trop Med Hyg 2006; 75: 97107. 47. Dreyer G, Nores J, Figueredo-Silva J, et al. Pathogenesis of lymphatic disease in bancroftian lariasis: a clinical perspective. Parasitol Today 2000; 16:544 548. 48. Taylor MJ. Wolbachia in the inammatory pathogenesis of human lariasis. Ann NY Acad Sci 2003; 990:444449. 49. Olszewski WL, Jamal S, Manokaran G, et al. Bacteriological studies of blood, tissue uid, lymph and lymph nodes in patients with acute dermatolymphanioadenitis (DLA) in course of larial lymphedema. Acta Trop 1999; 73:217224. 50. Dreyer G, Addiss D, Gadelha P, et al. Interdigital skin lesions of the lower limbs among patients with lymphoedema in an area endemic for bancroftian lariasis. Trop Med Int Hlth 2006; 11:14751481. 51. Nores J, Addiss D, Cedenho A, et al. Pathogenesis of larial hydrocele: risk associated with intrascrotal nodules caused by death of adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 2003; 97:561566. 52. Michael E, Simonsen PE, Malecela M, et al. Transmission intensity and the immunoepidemiology of bancroftian lariasis in East Africa. Parasite Immunol 2001; 23:373388. 53. Stolk WA, Ramaiah KD, van Oortmarssen GJ, et al. Meta-analysis of ageprevalence patterns in lymphatic lariasis: no decline in microlaraemia prevalence in older age groups as predicted by models with acquired immunity. Parasitology 2004; 129:605612. 54. Melrose W, Usurup J, Selve B, et al. Development of anti-larial antibodies in a group of expatriate mine-site workers with varying exposure to the disease. Trans R Soc Trop Med Hyg 2000; 94:706707. 55. Nielsen NO, Simonsen PE, Magnussen P, et al. Cross-sectional relationship between HIV, lymphatic lariasis and other parasitic infections in adults in coastal northeastern Tanzania. Trans R Soc Trop Med Hyg 2006; 100: 543550. 56. Addiss DG, Dreyer G. Treatment of lymphatic lariasis. In: Nutman TB, ed. Lymphatic Filariasis. London: Imperial College Press; 2000:151199. 57. Taylor MJ, Makunde WH, McGarry HF, et al. Macrolaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomized placebo-controlled trial. Lancet 2005; 365:21162121. 58. Debrah AY, Mand S, Specht S, et al. Doxycycline reduce plasma VEGF-C/ sVEGFR-3 and improves pathology in lymphatic lariasis. PLoS Pathog 2006; 2:829843. 59. Hussein O, El Setouhy M, Ahmed E.S, Kandil AM, Ramzy RM R, Helmy H, Weil GJ. Duplex Doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult larial worms and adjacent host tissues in bancroftian lariasis. Am J Trop Med Hyg 2004; 71:471477.
60. Freedman DO, Bui T, Filho PJ A, et al. Lymphoscintigraphic assessment of the effect of diethylcarbamazine treatment on lymphatic damage in human bancroftian lariasis. Am J Trop Med Hyg 1995; 52:258261. 61. Simonsen PE, Magesa SM, Meyrowitsch DW, et al. The effect of eight halfyearly single-dose treatments with DEC on Wuchereria bancrofti circulating antigenemia. Trans R Soc Trop Med Hyg 2005; 99:541547. 62. Dreyer G, Pires ML, Andrade LD, et al. Tolerance of diethylcarbamazine by microlaraemic and amicrolaraemic individuals in an endemic area of bancroftian lariasis, Recife, Brazil. Trans R Soc Trop Med Hyg 1994; 88: 232236. 63. Cao W, Ploeg CP B, Plaisier AP, et al. Ivermectin for the chemotherapy of bancroftian lariasis: a meta-analysis of the effect of single treatment. Trop Med Int Hlth 1997; 2:393403. 64. Shenoy RK, Kumaraswami V, Suma TK, et al. A double-blind, placebocontrolled study of the efcacy of oral penicillin, diethylcarbamazine or local treatment of the affected limb in preventing acute adenolymphangitis in lymphoedema caused by brugian lariasis. Ann Trop Med Parasitol 1999; 93:367377. 65. Kerketta AS, Babu BV, Rath K, et al. A randomized clinical trial to compare the efcacy of three treatment regimens along with footcare in the morbidity management of larial lymphoedema. Trop Med Int Hlth 2005; 10:698705. 66. Meyrowitsch DW, Simonsen PE, Magesa SM. A 26-year follow-up of bancroftian lariasis in two communities in north-eastern Tanzania. Ann Trop Med Parasitol 2004; 98:155169. 67. Alexander ND E, Grenfell BT. The effect of pregnancy on Wuchereria bancrofti microlarial load in humans. Parasitology 1999; 119:151156. 68. Lammie PJ, Hitch WL, Allen EM W, et al. Maternal larial infection as risk factor for infection in children. Lancet 1991; 337:10051006. 69. Das PK, Sirvidya A, Vanamail P, et al. Wuchereria bancrofti microlaraemia in children in relation to parental infection status. Trans R Soc Trop Med Hyg 1997; 91:677679. 70. Rwegoshora RT, Pedersen EM, Mukoko DA, et al. Bancroftian lariasis: patterns of vector abundance and transmission in two East African communities with different levels of endemicity. Ann Trop Med Parasitol 2005; 99:253265. 71. Rwegoshora RT, Simonsen PE, Meyrowitsch DW, et al. Bancroftian lariasis: house-to-house variation in the vectors and transmission and the relationship to human infection in an endemic community of coastal Tanzania. Ann Trop Med Parasitol 2007; 101:5160. 72. World Health Organization. Dening the roles of vector control and xenomonitoring in the Global programme to Eliminate Lymphatic Filariasis. WHO/ CDS/CPE/PVC/2002.3. Geneva: WHO; 2002. 73. Dreyer G, Nores J, Addiss D. The silent burden of sexual disability associated with lymphatic lariasis. Acta Trop 1997; 63:5760. 74. Ahorlu CK, Dunyo SK, Asamoah G, et al. Consequences of hydrocele and the benets of hydrocelectomy: a qualitative study in lymphatic lariasis endemic communities on the coast of Ghana. Acta Trop 2001; 80:215221. 75. Ottesen EA, Duke BO L, Karam M, et al. Strategies and tools for the control/ elimination of lymphatic lariasis. Bull World Health Organ 1997; 75:491 503. 76. Factors associated with participation in a campaign of mass treatment against lymphatic lariasis, in Leogane, Haiti. Ann Trop Med Parasitol 2004; 703714. 77. Krentel A, Fischer P, Manoempil P, et al. Using knowledge, attitudes and practice (KAP) surveys on lymphatic lariasis to prepare a health promotion campaign for mass drug administration in Alor District, Indonesia. Trop Med Int Hlth 2006; 11:17311740. 78. Gyapong JO, Kyelem D, Kleinschmidt I, et al. The use of spatial analysis in mapping the distribution of bancroftian lariasis in four West African countries. Ann Trop Med Parasitol 2002; 96:695705. 79. Onapa AW, Simonsen PE, Baehr I, et al. Rapid assessment of the geographical distribution of lymphatic lariasis in Uganda, by screening of schoolchildren for circulating larial antigens. Ann Trop Med Parasitol 2005; 99:141153. 80. Michael E, Malecela-Lazari MN, Simonsen PE, et al. Mathematical modelling and the control of lymphatic lariasis. Lancet Inf Dis 2004; 4:223234.
34
Ch084-X4470.indd 34
6/10/2008 8:04:17 PM
References
81. Stolk W, de Vlas SJ, Habbema JD F. Advances and challenges in predicting the impact of lymphatic lariasis elimination programmes by mathematical modelling. Filaria J 2006; 5:5. 82. Meyrowitsch DW, Simonsen PE. Long-term effect of mass diethylcarbamazine chemotherapy on bancroftian lariasis: results at four years after start of treatment. Trans R Soc Trop Med Hyg 1998; 92:98103. 83. Critchley J, Addiss D, Ejere H, et al. Albendazole for the control and elimination of lymphatic lariasis: systematic review. Trop Med Int Hlth 2005; 10:818825. 84. Dreyer G, Addiss D, Williamson J, et al. Efcacy of co-administered diethylcarbamazine and albendazole against adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 2006; 100:11181125. 85. Pedersen EM, Mukoko DA. Impact of insecticide-treated materials on laria transmission by the various species of vector mosquito in Africa. Ann Trop Med Parasitol 2002; 96:S91S95. 86. Ottesen EA. Lymphatic lariasis: treatment, control and elimination. Adv Parasitol 2006; 61:395441. 87. ONeill J. On the presence of a laria in craw-craw. Lancet 1875; i:265266. 88. Robles R. Enfermedad nueva en Guatemala. Juventud Med 1917; 17:97115. 89. Blacklock DB. The development of Onchocerca volvulus in Simulium damnosum. Ann Trop Med Parasitol 1926; 20:148. 90. World Health Organization. Onchocerciasis and its control. Report of a WHO expert committee on onchocerciasis control. WHO Tech Rep Ser 1995; 852. 91. Boatin BA, Richards FO. Control of onchocerciasis. Adv Parasitol 2006; 61:349394. 92. Murdoch ME, Asuzu MC, Hagan M, et al. Onchocerciasis: the clinical and epidemiological burden of skin disease in Africa. Ann Trop Med Parasitol 2002; 96:283296. 93. Murdoch ME, Hay RJ, Mackenzie CD, et al. A clinical classication and grading system of the cutaneous changes in onchocerciasis. Br J Dermatol 1993; 129:260269. 94. Abiose A. Onchocercal eye disease and the impact of Mectizan treatment. Ann Trop Med Parasitol 1998; 92(suppl 1):S11S22. 95. Marin B, Boussinesq M, Druet-Cabanac M, et al. Onchocerciasis-related epilepsy? Prospects at a time of uncertainty. Trends Parasitol 2006; 22: 1720. 96. Kipp W, Burnham G, Bamuhiiga J, et al. The Nakalanga syndrome in Kabarole District, western Uganda. Am J Trop Med Hyg 1996; 54:8083. 97. Kale OO. Onchocerciasis: the burden of disease. Ann Trop Med Parasitol 1998; 92:S101S115. 98. Anderson J, Fuglsang H, Hamilton PJ S, et al. Studies on onchocerciasis in The United Cameroon Republic. II. Comparison of onchocerciasis in rainforest and Sudan-savanna. Trans R Soc Trop Med Hyg 1974; 68:209222. 99. McMahon JE, Sowa SC I, Maude GH, et al. Epidemiological studies of onchocerciasis in forest villages of Sierra Leone. Trop Med Parasitol 1988; 39:251259. 100. Mand S, Marfo-Debrekyei Y, Debrah A, et al. Frequent detection of worm movements in onchocercal nodules by ultrasonography. Filaria J 2005; 4:1. 101. Ozoh G, Boussinesq M, Bissek AZ, et al. Evaluation of the diethylcarbamazine patch to evaluate onchocerciasis endemicity in Central Africa. Trop Med Int Hlth 2007; 12:123129. 102. Bradley JE, Unnasch TR. Molecular approaches to the diagnosis of onchocerciasis. Adv Parasitol 1996; 37:57106. 103. Rodrguez-Prez MA, Domnguez-Vzquez A, Mndez-Galv J, et al. Antibody detection tests for Onchocerca volvulus: comparison of the sensitivity of a cocktail of recombinant antigens used in the indirect enzyme-linked immunosorbent assay with a rapid-format antibody card test. Trans R Soc Trop Med Hyg 2003; 97:539541. 104. Lipner EM, Dembele N, Souleymane S, et al. Field applicability of a rapidformat anti-Ov-16 antibody test for the assessment of onchocerciasis control measures in regions of endemicity. J Infect Dis 2006; 194:216221. 105. Ayong LS, Tume CB, Wembe FE, et al. Development and evaluation of an antigen detection dipstick assay for the diagnosis of human onchocerciasis. Trop Med Int Hlth 2005; 10:228233.
106. Gillette-Ferguson I, Hise AG, Sun Y, et al. Wolbachia- and Onchocerca volvulusinduced keratitis (river blindness) is dependent on myeloid differentiation factor 88. Infect Immun 2006; 74:24422445. 107. Pearlman E. Immunopathology of onchocerciasis: a role for eosinophils in onchocercal dermatitis and keratitis. Chem Immunol 1997; 66:2640. 108. Ottesen EA. Immune responsiveness and the pathogenesis of human onchocerciasis. J Infect Dis 1995; 171:659671. 109. Greene BM, Taylor HR, Aikawa M. Cellular killing of microlariae of Onchocerca volvulus: eosinophil and neutrophil-mediated immune serumdependent destruction. J Immunol 1981; 127:16111618. 110. Garate T, Conraths FJ, Harnett W, et al. Identication of Onchocerca volvulus collagen as an antigen mainly recognized by antibodies in chronic hyperactive onchodermatitis (Sowda). Am J Trop Med Hyg 1996; 54: 490497. 111. Van der Lelij A, Rothova A, Stilma JS, et al. Humoral and cell-mediated immune response against retinal antigens in relation to onchocerciasis. Acta Leiden 1990; 59:271283. 112. Soboslay PT, Geiger SM, Drabner B, et al. Prenatal immune priming in onchocerciasis-Onchocerca volvulus-specic cellular responsiveness and cytokine production in newborns from infected mothers. Clin Exp Immunol 1999; 117:130137. 113. McCarthy JS, Ottesen EA, Nutman TB. Onchocerciasis in endemic and nonendemic populations: differences in clinical presentation and immunologic ndings. J Infect Dis 1994; 170:736741. 114. Stewart GR, Boussinesq M, Coulson T, et al. Onchocerciasis modulates the immune response to mycobacterial antigens. Clin Exp Immunol 1999; 117:517523. 115. Cooper PJ, Espinel I, Wieseman M, et al. Human onchocerciasis and tetanus vaccination: impact on the postvaccination antitetanus response. Infect Immunol 1999; 67:59515957. 116. Tawill SA, Gallin M, Erttmann, et al. Impaired antibody responses and loss of reactivity to Onchocerca volvulus antigens by HIV-seropositive onchocerciasis patients. Trans R Soc Trop Med Hyg 1996; 90:8589. 117. Debrah AY, Mand S, Marfo-Debrekyei Y, et al. Assessment of microlarial loads in the skin of onchocerciasis patients with different regimens of doxycycline regimens plus ivermectin. Filaria J 2006; 5:1. 118. Awadzi K, Dadzie KY, Klager S, et al. The chemotherapy of onchocerciasis. XIII. Studies with ivermectin in onchocerciasis patients in northern Ghana, a region with long lasting vector control. Trop Med Parasitol 1989; 40: 361366. 119. Whitworth JA, Morgan D, Maude GH, et al. Community-based treatment with ivermectin. Lancet 1988; ii:9798. 120. Gardon J, Boussinesq M, Kamgno J, et al. Effects of standard and high doses of ivermectin on adult worms of Onchocerca volvulus: a randomized controlled trial. Lancet 2002; 360:203210. 121. Mabey D, Whitworth JA, Eckstein M, et al. The effects of multiple doses of ivermectin on ocular onchocerciasis. Ophthalmology 1996; 103:10011008. 122. McMahon JE, Davies JB, White MD, et al. Onchocerciasis in Sierra Leone I. Studies on the prevalence and transmission at Gbaiima village. Trans R Soc Trop Med Hyg 1986; 80:802809. 123. Habbema JD F, Alley ES, Plaisier AP, et al. Epidemiological modelling for onchocerciasis control. Parasitol Today 1992; 8:99103. 124. Basez M-G, Boussinesq M. Population biology of human onchocerciasis. Philos Trans R Soc Lond [Biol] 1999; 354:809826. 125. To L, Tang J, Back C, et al. Vector-parasite transmission complexes for onchocerciasis in West Africa. Lancet 1997; 349:163166. 126. Zimmerman PA, Dadzie KY, DeSole G, et al. Onchocerca volvulus DNA probe classication correlated with epidemiological patterns of blindness. J Infect Dis 1992; 165:964968. 127. Higazi TB, Filiano A, Katholi CR, et al. Wolbachia endosymbiont levels in severe and mild strains of Onchocerca volvulus. Mol Biochem Parasitol 2005; 141:109112. 128. Pedersen EM, Maegga BT. Quantitative studies on the transmission of Onchocerca volvulus by Simulium damnosum s.l. in the Tukuyu Valley, south west Tanzania. Tropenmed Parasitol 1985; 36:249254.
35
Ch084-X4470.indd 35
6/10/2008 8:04:17 PM
84.
Filariases
129. Makunde WH, Salum FM, Massaga JJ, et al. Clinical and parasitological aspects of itching caused by onchocerciasis in Morogoro, Tanzania. Ann Trop Med Parasitol 2000; 94:793799. 130. Zimmerman PA, Katholi CR, Wooten MC, et al. Recent evolutionary history of American Onchocerca volvulus, based on analysis of a tandemly repeated DNA sequence family. Mol Biol Evol 1994; 11:384392. 131. Botto C, Gillespie AJ, Vivas-Martinez S, et al. Onchocerciasis hyperendemic in the Unturn Mountains: the value of recombinant antigens in describing a new transmission area in southern Venezuela. Trans R Soc Trop Med Hyg 1999; 93:2530. 132. Corredor A, Nicholls RS, Duque S, et al. Current status of onchocerciasis in Columbia. Am J Trop Med Hyg 1998; 58:594598. 133. Guderian RH, Shelley AJ. Onchocerciasis in Ecuador: the situation in 1989. Mem Inst Oswaldo Cruz 1992; 87:405415. 134. Evans TG. Socioeconomic consequences of blinding onchocerciasis in West Africa. Bull World Health Organ 1995; 73:495506. 135. Vlassoff C, Weiss M, Ovuga EB L, et al. Gender and the stigma of onchocercal skin disease in Africa. Soc Sci Med 2000; 50:13531368. 136. Boatin B, Molyneux DH, Hougard JM, et al. Patterns of epidemiology and control of onchocerciasis in West Africa. J Helminthol 1997; 71:91101. 137. Hougard J-M, Yamogo L, Sktli A, et al. Twenty-two years of blacky control in the Onchocerciasis Control Programme in West Africa. Parasitol Today 1997; 13:425431. 138. De Sole G, Awadzi K, Remme J, et al. A community trial of ivermectin in the onchocerciasis focus of Asubende, Ghana. II. Adverse reactions. Trop Med Parasitol 1989; 40:375382. 139. Boatin BA, Hougard J-M, Alley ES, et al. The impact of Mectizan on the transmission of onchocerciasis. Ann Trop Med Parasitol 1998; 92:S47S60. 140. Alleman MM, Twum-Danso NA Y, Thylefors BI. The Mectizan Donation Program highlights from 2005. Filaria J 2006; 5:11. 141. Brieger WR, Awedoba AK, Eneanya CI, et al. The effects of ivermectin on onchocercal skin disease and severe itching: results of a multicentre trial. Trop Med Int Hlth 1998; 3:951961. 142. Gardon J, Gardon-Wendel N, Demanga-Ngangue, et al. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet 1997; 350:1822. 143. Awadzi K, Boakye DA, Edwards G, et al. An investigation of persistent microlaridermia despite multiple treatments with ivermectin in two onchocerciasis endemic foci in Ghana. Ann Trop Med Parasitol 2004; 98: 231249. 144. Hopkins AD. Ivermectin and onchocerciasis: is it all solved? Eye 2005; 19:10571066. 145. Boussinesq M. Loiasis. Ann Trop Med Parasitol 2006; 100:715731. 146. Noireau F, Apembet JD, Nzoulani A, et al. Clinical manifestations of loiasis in an endemic area in the Congo. Trop Med Parasitol 1990; 41:3739. 147. Klion AD, Massougbodji M, Sadeler B-C, et al. Loiasis in endemic and nonendemic populations: immunologically mediated differences in clinical presentation. J Infect Dis 1991; 163:13181325. 148. Andy JJ, Bishara FF, Soyinka OO. Relation of severe eosinophilia and microlariasis to chronic African endomyocardial brosis. Br Heart J 1981; 45:672680. 149. Lukiana T, Mandina M, Situakibanza NH, et al. A possible case of spontaneous Loa loa encephalopathy associated with a glomerulopathy. Filaria J 2006; 5:6. 150. Orihel TC, Eberhard ML. Zoonotic lariasis. Clin Microbiol Rev 1998; 11: 366381. 151. Churchill DR, Morris C, Kakoya A, et al. Clinical and laboratory features of patients with loiasis (Loa loa lariasis) in the UK. J Infect 1996; 33: 103109. 152. Dupont A, Zue-Ndong J, Pinder M. Common occurrence of amicrolaraemic Loa loa lariasis within the endemic region. Trans R Soc Trop Med Hyg 1988; 82:730. 153. Klion AD, Vijaykumar A, Oei T, et al. Serum immunoglobulin G4 antibodies to the recombinant antigen, Ll-SXP-1, are highly specic for Loa loa infection. J Infect Dis 2003; 187:128133.
154. Tour FS, Mavoungou E, Kassambara L, et al. Human occult loiasis: eld evaluation of a nested polymerase chain reaction assay for the detection of occult infection. Trop Med Int Hlth 1998; 3:505511. 155. Pinder M, Dupont A, Egwang TG. Identication of a surface antigen on Loa loa microlariae the recognition of which correlates with the amicrolaraemic state in man. J Immunol 1988; 141:24802486. 156. Baize S, Wahl G, Soboslay PT, et al. T helper responsiveness in human Loa loa infection; defective specic proliferation and cytokine production by CD4+ T cells from microlaraemic subjects compared with amicrolaraemics. Clin Exp Immunol 1997; 108:272278. 157. Klion AD, Ottesen EA, Nutman TB. Effectiveness of diethylcarbamazine in treating loiasis acquired by expatriate visitors to endemic regions: long-term follow-up. J Infect Dis 1994; 169:604610. 158. Duong TH, Kombila M, Ferrer A, et al. Reduced Loa loa microlaria count ten to twelve months after a single dose of ivermectin. Trans R Soc Trop Med Hyg 1997; 91:592593. 159. Hoegaerden MV, Ivanoff B, Flocard F, et al. The use of mebendazole in the treatment of lariases due to Loa loa and Mansonella perstans. Ann Trop Med Parasitol 1987; 81:275282. 160. Tabi T-E, Bedi-Mengue R, Nutman TB, et al. Human loiasis in a Cameroonian village: A double-blind, placebo-controlled, crossover clinical trial of a three-day albendazole regimen. Am J Trop Med Hyg 2004; 71:211 215. 161. Klion AD, Horton J, Nutman TB. Albendazole therapy for loiasis refractory to diethylcarbamazine treatment. Clin Infect Dis 1999; 29:680682. 162. Wanji S, Tendongfor N, Esum M, et al. Heterogeneity in the prevalence and intensity of loiasis in ve contrasting bioecological zones in Cameroon. Trans R Soc Trop Med Hyg 2003; 97:182187. 163. Nutman TB, Miller KD, Mulligan M, et al. Diethylcarbamazine provides effective prophylaxis for human loiasis. N Engl J Med 1988; 319:752756. 164. Fux CA, Chappuis B, Holzer B, et al. Mansonella perstans causing symptomatic hypereosinophilia in a missionary family. Travel Med Infect Dis 2006; 4:275 280. 165. Bregani ER, Rovellini A, Mbadoum M, et al. Comparison of different anthelminthic drug regimens against Mansonella perstans lariasis. Trans R Soc Trop Med Hyg 2006; 100:458463. 166. Duong TH, Kombila M, Ferrer A, et al. Decrease in Mansonella perstans microlaraemia after albendazole treatment. Trans R Soc Trop Med Hyg 1998; 92:459. 167. Fischer P, Kilian AH D, Bamuhiiga J, et al. Prevalence of Mansonella perstans in western Uganda and its detection using the QBC-uorescence method. Appl Parasitol 1996; 37:3237. 168. Onapa AW, Simonsen PE, Baehr I, et al. Rapid assessment of the geographical distribution of Mansonella perstans infections in Uganda, by screening schoolchildren for microlariae. Ann Trop Med Parasitol 2005; 99:383393. 169. Fischer P, Bamuhiiga J, Bttner DW. Occurrence and diagnosis of Mansonella streptocerca in Uganda. Acta Trop 1997; 63:4355. 170. Fischer P, Bttner DW, Bamuhiiga J, et al. Detection of the larial parasite Mansonella streptocerca in skin biopsies by a nested polymerase chain reaction-based assay. Am J Trop Med Hyg 1998; 58:816820. 171. Fischer P, Tukesiga E, Bttner DW. Long-term suppression of Mansonella streptocerca microlariae after treatment with ivermectin. J Infect Dis 1999; 180:14031405. 172. Bartoloni A, Cancrini G, Bartalesi F, et al. Mansonella ozzardi infection in Bolivia: prevalence and clinical association in the Chaco Region. Am J Trop Med Hyg 1999; 61:830833. 173. McNeeley DF, Raccurt CP, Boncy J, et al. Clinical evaluation of Mansonella ozzardi in Haiti. Trop Med Parasitol 1988; 40:107110. 174. Post RJ, Adams Z, Shelley AJ, et al. The morphological discrimination of microlariae of Onchocerca volvulus from Mansonella ozzardi. Parasitology 2003; 127:2127. 175. Gonzlez AA, Chadee DD, Rawlins SC. Single dose of ivermectin to control mansonellosis in Trinidad: a four-year follow-up study. Trans R Soc Trop Med Hyg 1998; 92:570571.
36
Ch084-X4470.indd 36
6/10/2008 8:04:18 PM
References
176. Simn F, Lpez-Belmonte J, Marcos-Atxutegi C, et al. What is happening outside North America regarding human dirolariasis. Vet Parasitol 2005; 133:181189. 177. Theis JH. Public health aspects of dirolariasis in the United States. Vet Parasitol 2005; 133:157180. 178. Pampiglione S, Trotti GC, Rivasi F. Human dirolariasis due to Dirolaria (Nochtiella) repens: a review of world literature. Parassitologia 1995, 37: 149193. 179. Yelifari L, Frempong E, Olsen A. The intermediate hosts of Dracunculus medinensis in Northern Region, Ghana. Ann Trop Med Parasitol 1997; 91: 403409. 180. Bloch P, Simonsen PE. Immunoepidemiology of Dracunculus medinensis infections. I. Antibody responses in relation to infection status. Am J Trop Med Hyg 1998; 59:978984. 181. Bloch P, Simonsen PE. Immunoepidemiology of Dracunculus medinensis infections. II. Variation in antibody responses in relation to transmission season and patency. Am J Trop Med Hyg 1998; 59:985990.
182. Rohde JE, Sharma BL, Patton H, et al. Surgical extraction of guinea worm: disability reduction and contribution to disease control. Am J Trop Med Hyg 1993; 48:7176. 183. Issaka-Tinorgah A, Magnussen P, Bloch P, et al. Lack of effect of ivermectin on prepatent guinea-worm: a single-blind, placebo-controlled trial. Trans R Soc Trop Med Hyg 1994; 88:346348. 184. Bimi L, Freeman AR, Eberhard ML, et al. Differentiating Dracunculus medinensis from D. insignis, by the sequence analysis of the rRNA gene. Ann Trop Med Parasitol 2005; 99:511517. 185. Ruiz-Tiben E, Hopkins DR. Dracunculiasis (Guinea worm disease) eradication. Adv Parasitol 2006; 61:275309. 186. Hunter JM. Bore holes and the vanishing of guinea worm disease in Ghanas Upper Region. Soc Sci Med 1997; 45:7189. 187. Olsen A, Magnussen P, Anemana S. The acceptability and effectiveness of a polyester drinking-water lter in a dracunculiasis-endemic village in Northern Region, Ghana. Bull World Health Organ 1997; 75: 449452.
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Chapter 84

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Section 11

Main location of adults

Main location of microlariae

Common disease symptoms

Blood Blood Blood Blood Skin Blood and skin Skin

Connective tissue, including skin

Adult worms in tissues

Larvae migrate to final location and develop to adults

Life cycle and transmission

Microfilariae to blood or skin

Microfilariae ingested by vector

Development in vector Figure 84.1 General life cycle of lariae.

Figure 84.3 Microlaria of W. bancrofti in thick blood lm.

Figure 84.4 Microlaria of B. malayi in thick blood lm.

Lymphoedema and elephantiasis

B Figure 84.6 Lymphatic lariasis: hydrocele. (A) Early; (B) advanced.

Tropical pulmonary eosinophilia

Geographical variation in clinical picture

Diagnosis Clinical diagnosis

Diethylcarbamazine provocative day test

Immunological and polymerase chain reaction (PCR)-based diagnosis

Pathology and immunology

ADLA pathway Live adult worm in lymphatic vessel

AFL pathway Dead adult worm in lymphatic vessel

Induce granuloma formation

Lymphangiectasia (dilated lymphatics) Microbes enter via lesions ADLA (oedema)

Obstruction of lymph flow

Common cause of filarial lymphoedema/ elephantiasis

Rarely causes residual lymphoedema; may be common cause of filarial hydrocele

Wuchereria bancrofti and Brugia spp.

, No effect; +, few/some are eliminated; ++, most are eliminated; ?, unknown.

Severe side-effects may occur.

Circulating antigens (adult worms)

10-14 15-19 20-29 30-39 40-49 50-59

10-14 15-19 20-29 30-39 40-49 50-59

Age group (years)

Infection and disease in the endemic community

Geographical variation in transmission

Programme for global elimination

Life cycle and transmission

Figure 84.14 Skin microlaria of O. volvulus.

Figure 84.17 Onchocerciasis: nodule on the body. (Courtesy of C. D. Mackenzie)

Onchocerciasis: Sowda. (Courtesy of C. D. Mackenzie)

Figure 84.18 Onchocerciasis: punctate keratitis.

Posterior segment lesions

Anterior segment lesions

Diagnosis Clinical diagnosis

Geographical variation in the clinical picture

The Mazzotti test

Age group (years)

Figure 84.20 Onchocerciasis: microlariae of O. volvulus in subcutaneous tissue.

Immunological and PCR-based diagnosis

Pathology and immunology

Figure 84.21 Onchocerciasis: adult O. volvulus in nodule. (Courtesy of H. Zaiman.)

Management Drug treatment

Infection and disease in the endemic community

East and central Africa

Central and South American onchocerciasis

Life cycle and transmission

OTHER FILARIAL INFECTIONS