Filariasis

NEMATODES

Filariasis

nied by high eosinophilia and microfilaraemia. Epididymo-orchitis with scrotal oedema is also common. Manifestations of chronic infection occur in a minority of individuals, usually after 10–15 years of infection in endemic areas, but within 1–2 years in patients from non-endemic areas. They are probably caused by a combination of obstruction and dilatation of lymphatic vessels by adult worms, and host immune responses. Microfilariae are not detectable in blood at this stage. • Swelling and growth of thickened skin often leads to secondary bacterial or fungal infection in the affected area. • Hydrocele occurs in up to 50% of males. • Blockage of lymph vessels around the bladder occasionally leads to chyluria (lymph causing milky urine, Figure 2). • Elephantiasis (lymphoedema causing gross enlargement and fibrosis of the limbs, breasts or genitalia) is an irreversible late stage (Figure 3). The course of brugian filariasis is similar, but elephantiasis usually involves only the limbs. Hyper-reactive syndromes occur occasionally. The most common is tropical pulmonary eosinophilia, which is seen predominantly in South India and South East Asia, and in individuals from non-endemic regions exposed to short-term, intense transmission. Asthma-like symptoms, including a paroxysmal, severe dry cough and wheezing, predominate. Fever and splenomegaly may occur. These features resolve after about 1 year, with no elephantiasis and only rarely microfilaraemia.

James A G Whitworth Kirsten Hewitt

Filarial infections are caused by parasitic, tissue-dwelling filarial nematode worms that are transmitted by biting insects. The three main filarial diseases in humans are: • lymphatic filariasis • onchocerciasis • loiasis.

Lymphatic filariasis The infecting parasite is usually Wuchereria bancrofti, though Brugia malayi or B. timori may be responsible in South East Asia and Indonesia. A wide range of mosquitoes transmit the parasites; Culex quinquefasciatus is the major vector. Adult female worms inhabit lymph nodes and produce sheathed microfilarial larvae that circulate in the peripheral blood (Figure 1). Microfilariae are generally nocturnally periodic (circulating in the blood only at night, with no detectable circulating microfilariae at other times). However, the periodicity of microfilarial circulation varies geographically and may be subperiodic (constantly circulating in blood with peaks at certain times of day or night) or non-periodic (constantly circulating with no peaks).

Diagnosis Acute and chronic manifestations can usually be diagnosed clinically, particularly in endemic areas. Microfilariae can be detected microscopically in peripheral blood films after passing 20 ml of citrated blood taken between 11 p.m. and 1 a.m. through a polycarbonate filter (20 mm pore size). This method is difficult, because of the periodicity of microfilarial circulation. Provocation can be used in regions where onchocerciasis (see below) does not occur; diethylcarbamazine (DEC), 6 mg/kg, is administered to induce a peak of microfilaraemia 15 minutes later (60 minutes in B. malayi infection). Filarial antigen card testing has recently been developed. This is highly sensitive and specific for W. bancrofti circulatory antigen, avoiding the need for collection of blood at night. Eosinophilia – high eosinophilia occurs in all filarial infections; however, this is of diagnostic use only in patients with tropical pulmonary eosinophilia, who also have very high serum IgE levels (usually more than 10,000 ng/ml) and specific IgG and IgE antifilarial antibodies.

Epidemiology More than 1 billion individuals in more than 80 countries are at risk of infection and 120 million are infected, one-third in Africa, one-third in India and others throughout Asia, the Pacific and the Americas. Associated disability occurs in 40 million individuals. Clinical features Larvae migrate to lymph nodes and mature into adult worms over about 6 months. During this period, no microfilariae are found in blood, though subclinical disease and lymphatic damage may occur. Adult worms are relatively harmless; major symptoms result from the host’s immune response to infection, which varies between individuals. Most patients present with acute attacks of ‘filarial fever’ up to 15 months after infection; headache and malaise are accompanied by swelling, erythema and aches around lymph vessels and glands, caused by lymphangitis and lymphadenitis. These attacks typically last 3–15 days and are accompa-

James A G Whitworth is Professor of International Public Health at the London School of Hygiene and Tropical Medicine, London, UK. Conflicts of interest: none declared. Kirsten Hewitt is Associate Scientist in the Emerging Infections and Zoonoses Section at the Health Protection Agency Centre for Infections, London, UK. Conflicts of interest: none.

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1 Wuchereria bancrofti microfilaria in a blood slide.

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for 4–6 years (the lifespan of adult worms); in 2003, more than 70 million individuals in 36 countries were treated. DEC-fortified cooking salt has been used in a highly successful control campaign in China. Single-dose combination therapy aims to kill microfilariae and interrupt transmission. Single doses of albendazole, 400 mg, and DEC, 6 mg/kg, can completely clear microfilariae for up to 1 year. A single dose of ivermectin, 150–200 µg/kg, is useful in West Africa where DEC cannot be used, particularly in combination with albendazole. Education to reduce the stigma associated with elephantiasis is important to improve the quality of life of affected individuals.

2 Chyluria on the left caused by lymphatic filariasis.

Ultrasonography has been used to detect the movement of living adult W. bancrofti in lymph nodes (‘filaria dance sign’). This is useful for evaluating the efficacy of macrofilaricidal drugs, but is relatively insensitive as a general diagnostic indicator.

Onchocerciasis ‘River blindness’ is caused by Onchocerca volvulus and transmitted by day-biting Simulium blackflies. The greatest disease burden occurs near fast-flowing rivers, where adult blackflies lay their eggs. Blackflies bite exposed skin only, because their broad mouthparts cannot penetrate clothing. Larvae take about 1 year to mature into adults and start producing microfilarial larvae. Adult female worms live for 10–15 years and release up to 10,000 microfilariae per day. Heavily infected individuals may carry 50–200 million larvae, 90% of which are in the skin.

Management In early-stage disease, treatment is ideally undertaken through referral to a specialist tropical medicine unit for diagnosis and management, and is important to prevent lymphatic damage and progression to chronic disease. Treatment with DEC, 6 mg/kg daily for 21 days in W. bancrofti infection and 15 days in Brugia infection, kills microfilariae and adult worms. To minimize adverse reactions, lower doses can be used initially and increased each day. Hyperreactive syndromes resolve rapidly after treatment with high-dose DEC, 10 mg/kg daily. DEC can cause a severe reaction in patients co-infected with onchocerciasis (see below) and therefore cannot be used on a large scale in most of West Africa. In the later stages of infection, with largely irreversible lymphatic damage and elephantiasis, management focuses on hygiene and prevention of secondary bacterial and fungal infection. Elevation of affected limbs, washing with soap and water, treatment and prevention of secondary infections with topical antifungal drugs and antibiotics, and physiotherapy when possible are important and may partially reduce elephantiasis. Surgery can be considered in some cases.

Epidemiology Onchocerciasis occurs mainly in Sub-Saharan Africa, with foci in Central and South America and Yemen; 90 million individuals live in endemic zones, of whom 17 million are infected and 0.5 million blind. There are forest and savannah strains in West Africa; typically, eye disease is more common in those infected with savannah strains. Clinical features Infection with adult worms produces non-painful, subcutaneous nodules that are usually less than 2 cm in diameter and situated over bony prominences. The site of nodules varies geographically; in Africa, they are commonly found on the pelvic girdle. Head nodules are more common in children (Figure 4). Infection is often asymptomatic. The most common symptoms are pruritus and skin disease from immune responses to microfilariae. The main dermatological presentations are itchy, papular dermatitis, dermal atrophy and depigmentation (Figure 5). Hyperreactive skin disease (Sowda) is most common in the Yemen and usually affects a single limb, with no microfilariae or nodules. Eye disease is the most devastating clinical feature, occurring mainly in individuals with high microfilarial loads. Microfilariae can enter all eye tissues, leading to punctate and sclerosing keratitis, iritis, chorioretinitis, optic atrophy, and eventually blindness. In hyperendemic regions, 5% of the population may be blind, with severe socioeconomic consequences for affected communities.

Control The long course of DEC treatment required for radical cure is not feasible for control programmes in endemic areas. A Global Alliance to Eliminate Lymphatic Filariasis has been established, aided by public–private partnerships and the provision of free or subsidized drugs by manufacturers. Current strategies focus on annual mass treatment with single-dose combination therapy

Diagnosis Microfilariae – definitive diagnosis is by detection of microfilariae in two to six skin snips (Figure 6). Microfilariae emerge from the skin fragment after 30 minutes’ to 24 hours’ incubation in saline solution. If skin snips are negative, a Mazzotti provocation test can be performed. After administration of DEC, 50 mg,

3 Elephantiasis of the left leg caused by chronic lymphatic filariasis.

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Control The Onchocerciasis Control Programme was a great public health success. Reduced transmission, vector elimination and annual mass ivermectin chemotherapy in eleven West African countries prevented infection in about 30 million individuals. Community-directed treatment programmes continue in Africa and the Americas, reaching 40 million individuals. Development of a macrofilaricidal drug would greatly aid control efforts.

Loiasis

4 Onchocercal nodule containing adult worms on the head of an African child.

Adult female Loa loa worms are 5–7 cm in length; males are smaller (3 cm). Microfilariae are sheathed and circulate in the blood during the day (diurnally periodic). These are taken up and transmitted by tabanid mango flies (Chrysops spp.). Epidemiology L. loa is found in the rainforest belt of West Africa, where 3–13 million individuals are infected, particularly in Cameroon, Congo, Gabon, southern Nigeria and Sudan. Populations living near streams, where tabanid flies breed, are most at risk. Clinical features Infection is often asymptomatic. The most common clinical features are puffy swellings on the face or limbs lasting for several days (calabar swellings). These are caused by adult worms (Figure 7). Adult worms sometimes migrate across the eye under the conjunctiva and can be seen for a few minutes or hours, causing painful periorbital swelling (Figure 8). Nonspecific features include eosinophilia, hydrocele and pruritus. Rare severe manifestations include cardiomyopathy, nephropathy and fatal encephalitis, mainly in patients from non-endemic areas.

5 Depigmentation (‘leopard skin’) caused by chronic Onchocerca volvulus infection.

infected individuals develop pruritus and swelling, and sometimes fever, cough and oedema, over 24–48 hours. Diagnosis is occasionally possible using a slit lamp to view living or dead microfilariae in the anterior chamber of the eye. Eosinophilia can suggest onchocerciasis, but is not specific. Other tests – DNA-based detection is possible, but is of more use in research. General filarial enzyme-linked immunosorbent assays based on B. pahangi antigen are available, but are not speciesspecific and are therefore useful only in non-endemic regions or where there is only one filarial species.

Diagnosis Ocular passage of the worm, calabar swelling or extraction of an adult worm is diagnostic. Microfilariae can be found in daytime blood samples, which can be filtered to increase the sensitivity. Management Drug therapy – albendazole and ivermectin are active against microfilariae, but only DEC, 8–10 mg/kg daily for 10–21 days, is active against pathogenic adult worms. In regions where DEC is not advised because of onchocerciasis, a single dose of ivermectin, 200 µg/kg, can reduce microfilaraemia by 87% for up to 1 year.

Management Drug therapy – treatment with a single dose of ivermectin, 150 µg/kg, kills microfilariae. This drug does not kill adult worms, however, and may have to be re-administered every 6–12 months to prevent accumulation of microfilariae in the skin during the lifespan of the adult worm. In non-endemic countries, single doses of ivermectin (available on a named-patient basis in the UK) are usually given 0, 2 and 4 months after diagnosis, then repeated at 6-monthly intervals depending on the presence of symptoms or eosinophilia. Recent research has shown the importance of Wolbachia, an endosymbiotic bacterium of many filarial parasites, in worm reproduction. Daily treatment with doxycycline for several weeks disrupts worm embryogenesis and may kill adult worms. Nodulectomy can be useful, particularly in children, because nodules on the head have been associated with ocular disease.

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6 Using a corneoscleral punch to take skin snips for the diagnosis of onchocerciasis.

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7 Calabar swelling of the left hand caused by an adult Loa loa.

8 Adult Loa loa passing across the eye.

In patients with high microfilarial counts, DEC or ivermectin can lead to severe encephalopathic reactions; administration of prednisolone, 20 mg/day 3 days either side of treatment, can reduce the risk. Plasmapheresis has also been used before treatment in very heavily microfilaraemic individuals. Control Adverse reactions to ivermectin and DEC in individuals with very high L. loa microfilarial loads hamper control programmes in areas where loiasis coexists with onchocerciasis or lymphatic filariasis. Geographical and epidemiological mapping can be used to identify communities with a low prevalence of loiasis, where normal control measures can proceed.

Minor filariases Mansonella streptocerca, transmitted by Culicoides midges, is found widely in forested parts of Africa. Skin microfilariae may cause mild, itchy dermatitis and depigmentation. M. perstans and M. ozzardi microfilariae are commonly found in blood. They are probably non-pathogenic.  FURTHER READING Gillespie S, Pearson R, eds. Principles and practice of clinical parasitology. New York: Wiley, 2001. Parry E, Godfrey R, Mabey D et al., eds. Principles of medicine in Africa. 3rd ed. Cambridge: Cambridge University Press, 2004.

Acknowledgements Figures 1–3, 7 and 8 were provided by Dr T Doherty, and Figures 4–6 by Dr D Morgan.

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