Wuchereria bancrofti, Brugia malayii and Brugia timori cause lymphatic disorders. Wuchereria bancrofti is the most widespread of the human filariae in the world. The majority of infections occur in Asia, but this parasite also causes considerable problems in Africa and the north-west of South America. There is a periodic and a subperiodic form. Brugia malayi occurs in Southeast Asia and Brugia timori is limited to a few islands around Timor. Brugia malayi has two forms: a periodically transmitted form (without animal reservoir) and a subperiodic form (animal reservoir in monkeys). Consequently, subperiodic Brugia malayi infection is a zoonosis.

In 1866, the German doctor Otto Wucherer discovered numerous microfilariae in patients with haematuria and chyluria in Bahia, Brazil. In 1870 the Briton, Lewis, in Calcutta discovered that patients with elephantiasis were infected with filariae. Because microfilariae were periodically detectable in the blood, the Scottish doctor Patrick Manson suspected that night-biting mosquitoes might be responsible for transmission. He is regarded by many as the father of tropical medicine. He initially worked as a doctor in Kaohsiung, in the south of Formosa, the present-day Taiwan. In subsequent years he carried out various experiments in Amoy (Xiamen), China. He allowed mosquitoes to bite his filaria-infected gardener, afterwards dissecting the insects and detecting microfilariae. He was able to follow the metamorphosis of the parasites in the insects. Manson, however, thought that mosquitoes only sucked blood once in their lifetime. So, there was a problem in explaining transmission. He assumed that drinking water was contaminated by dead mosquitoes and that transmission occurred in this way. It later became clear that the parasites are transmitted via the bite of infected mosquitoes, primarily by the night-biting Culex and Anopheles mosquitoes. This biting behaviour is important as the numbers of microfilariae in the peripheral blood systematically fluctuate over a 24-hour period reaching their highest levels at night. There is a remarkable periodicity of the microfilariae. The density of parasites is greatest at the time when the chance of transmission is greatest (at night). In the Pacific Islands, transmission occurs via the daytime-biting Aedes mosquitoes so there is no or less diurnal variation (= subperiodic form).

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The most important species of vector is Culex quinquefasciatus. This mosquito, together with Anopheles gambiae and Anopheles funestus, is the most important vector in sub-Saharan Africa. In Egypt, Culex pipiens is the principal vector. Culex mosquitoes lay their eggs in small groups on the water surface. Mansonia mosquitoes (subgenus Mansonioides) are also vectors and are found in association with certain water plants. Transmission via mosquitoes means that there is very marked geographical heterogeneity. There can be limited transmission at one particular place, whereas 2 kilometres further on transmission might be 100 times more intense. Wuchereria bancrofti is fairly poorly transmitted by mosquitoes. On average a dozen bites are necessary before an infection becomes patent.

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After being sucked up by the mosquito, microfilaria reach the abdominal stomach via the proboscis, pharynx and thoracic oesophagus. Chitinous teeth in the foregut can mechanically damage aspirated microfilariae. These teeth are particularly pronounced in Anopheles females. In the stomach, the parasites shed their sheath, penetrate the gastric wall and migrate via the haemocoel to the insect’s thoracic muscles. After maturation, the immature worms migrate through the insect’s head to the labium ("lower lip") of the proboscis. This stage is reached approximately 10 days after the blood meal. When the mosquito again sucks blood, the 1.2-1.6 mm long infective larvae break through the labella of the labium and then creep onto the skin (the labium is not inserted into the skin, in contrast to other mouthparts). If the parasite, now known as an infective larva, finds a portal of entry (e.g. the bite wound), it enters and is transported via the lymphatics. The insect’s salivary glands play no direct role in transmission, in contrast to malaria.

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Wuchereria bancrofti becomes adult in human lymphatics and lymph nodes. The worms are 0.2 mm wide and can be up to 10 cm long. They survive for up to 10 years. Approximately 6 to 12 months after infection, microfilariae appear in the circulation. Every day, the female produces numerous microfilariae (250 to 300 µm long and 8 µm wide). They are surrounded by an egg membrane (sheath). The membrane is sometimes very difficult to see in a microscopic preparation.

The adult worm induces an immunological reaction in humans. The basic lesion is a sterile inflammation around the worm, in and around the lymph nodes and lymph vessels. In the case of lymphangitis, there is often retrograde inflammation (centrifugal spread). This inflammation leads to obstruction of lymph vessels, resulting in temporary lymphostasis and lymphoedema. Following repeated attacks, irreversible damage to the lymphatics occurs with permanent "non-pitting" lymphoedema. Sometimes abscesses occur at the site of dead adult worms. There are also findings that indicate that adult worms can themselves directly attack the lymphatics (irrespective of the immunological response). Children born to microfilaraemic mothers have reduced immunological reactions to microfilaria antigens in comparison to children of non-infected mothers. This immunological tolerance lasts for many years after birth. Occasionally microfilariae penetrate the placenta, but this has no major consequences (microfilariae are not pathogenic). True congenital transmission does not occur. Microfilariae that are accidentally transmitted via a blood transfusion remain present in the recipient’s blood for approximately one month. In humans with severe symptoms, low or no microfilaraemia is found in most cases, whereas humans with high microfilaraemia often have no symptoms. The reasons for this apparent paradox is that the pathology is caused by the patient’s immunological response to the adult worms. If the reaction is violent, few adult worms and microfilariae survive, but considerable inflammation will occur with sequelae. During infection with the filariae, the immunological response evolves. Down-regulation can occur and some patients do not produce any interferon-gamma after exposure to parasitic antigen. This is currently the subject of intense study.

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Filariae have a triple genome: a nuclear, a mitochondrial and that of an endosymbiotic bacterium, Wolbachia. The nuclear genome of B. malayi is approximately 100 million base pairs, about the same size as that of the free-living nematode Caenorhabditis elegans, a standard test organism. The genome is rich in AT (71%) and is distributed over five chromosomes, four autosomes and a pair of sex chromosomes. The Filarial Genome Project was started in 1994 and is intended to map and annotate the genome.

The intracellular Wolbachia endosymbiont is apparently an obligate parasite of these worms. The bacteria are related to Rickettsiae. In view of the fact that this might be a target for therapeutic intervention (Wolbachia is susceptible to tetracyclines), a Wolbachia Genome Consortium has been formed to map the endosymbiont of Brugia malayi. At the same time it is intended to map the Wolbachia endosymbionts of Culex pipiens and Drosophila melanogaster to make comparative studies possible.

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In certain insects, Isopoda and mites, infection with Wolbachia causes various effects, such as parthenogenesis (e.g. in wasps), cytoplasmic incompatibility, feminisation of genetic males, death of male insects and embryolethality. The Wolbachia present in filariae appear not to cause these reproductive modifications. However, their presence appears to be favourable for the growth and fertility of the nematode. Tetracycline given to dogs infected with Dirofilaria immitis inhibits embryogenesis of the nematode. When rats infected with endosymbiont-containing Litosomoides sigmodontis filaria are given tetracycline, the parasites are severely damaged and produce a much smaller number of microfilariae. Obviously more study is necessary on this subject.

The majority of infected people exhibit few if any obvious clinical signs, even though they can have microfilariae in their peripheral blood. Although these people are asymptomatic, almost all have subclinical disease with microscopic haematuria or proteinuria, dilated tortuous lymphatics and, in males, scrotal lymphangiectasia. Among the more obvious symptoms, the acute, temporary signs and symptoms caused by inflammation should be distinguished from those resulting from chronic lymph tract obstruction.

Tropical pulmonary eosinophilia is particularly common in India, but also in Southeast Asia. Pulmonary symptoms are predominant: cough, dyspnoea, "asthmatic syndrome". Chest X-rays very consistently show patchy infiltrates, in contrast to Loeffler’s syndrome in which they are more fleeting. Sometimes the lymph nodes swell and splenomegaly occurs. The erythrocyte sedimentation rate increases and there is marked eosinophilia. There are no microfilariae in the peripheral blood. Serological tests for filariae are strongly positive. This condition responds very well to therapy with DEC (in contrast to Loeffler’s syndrome). Steroids can be given if other diagnoses (e.g. strongyloidosis) can be excluded.

Chronic hypereosinophilia can cause cardiac lesions such as or fibroplastic endocarditis. The contents of the eosinophilic granules (including major basic protein) are toxic to the endocardium and the adjacent myocardium. A restrictive cardiomyopathy can follow.

Lymphoedema can be primary (agenesis or hypoplasia of the lymphatics, Milroy's syndrome) or secondary to mechanical or inflammatory obstruction. In addition to lymphatic filariasis, there are other causes of elephantiasis such as onchocerciasis, lepromatous leprosy, surgical resection or trauma, lymph node destruction by tuberculosis, chromomycosis, metastasis, genital infection with certain strains of Chlamydia trachomatis (Nicholas-Favre disease = lymphogranuloma venereum), severe urinary schistosomiasis, phlebitis, repeated erysipelas ("elephantiasis nostras") and podoconiosis. In a limb with long-standing elephantiasis, a haemangiolymphosarcoma can develop after 5-20 years. This is known as Stewart-Treves syndrome.

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Self-help groups in a community can play an important role. In an acute situation, pain relief, antipyretics and antiphlogistics are indicated. In chronic lesions of the scrotum, surgery can be performed. Elephantiasis of the limbs is relatively treatment-resistant. Physical methods (lymph drainage by massage) should be continued for a long time and will not in any way alter the fibrotic component of the swelling. Permanent compressive bandages are not practical in a warm, moist environment. A firm, compressive dressing (elastic bandages) may be applied centripetally. These are then changed daily and relatively good results can be achieved in this way, particularly if elastic compressive stockings can be worn afterwards. Microsurgery with the creation of several lymphovenous anastomoses is difficult, but can yield good results.

Good, enforced hygiene can dramatically reduce the number of complications. General cleanliness, washing with soap and disinfection of wounds are crucial. If bacterial superinfection is present, this should be treated appropriately. There is often a fungal infection between the toes (athlete’s foot), which acts as a portal of entry for various bacteria. Simple hygiene is important and should be stressed:

• Washing the affected part of the body twice daily with soap and water
• Elevation of the affected limb at night
• Daily physical exercise to improve lymph drainage
• Keeping nails clean
• Wearing shoes
• Disinfecting skin wounds rapidly and properly
• Systemic antibiotics for superinfection
• Treating athlete’s foot

Diethylcarbamazine (= DEC) was introduced in 1947. DEC (Notezine®, Hetrazan®, Banocide®) has a rapid, but indirect microfilaricidal effect on Wuchereria and Brugia. If it is taken for prolonged periods, there is also an incomplete macrofilaricidal effect. The dose conventionally given as monotherapy is 72 mg/kg over 12 days (e.g. 50 tablets of 100 mg). There is evidence to show that lower doses for shorter periods are as effective (e.g. single dose of 6 mg/kg). DEC in monotherapy has an efficacy of ± 90%. Pregnancy is a contra-indication for the administration of DEC. This medication is fairly well tolerated, but systemic reactions can occur, caused by the massive and sudden death of microfilariae. Malaise, pruritus, urticaria, fever, headache, vomiting, asthmatic crisis (cf. the Mazzotti reaction in onchocerciasis and the Jarish-Herxheimer reaction in spirochaetosis). This usually happens in the first 48 hours. Local tissue reactions can also occur around dead macrofilariae (lymphangitis, abscess, funiculitis). They can also occur up to several weeks after therapy. Most microfilaraemic patients have a transient increase of haematuria and/or proteinuria after starting DEC. Because of these potential side effects, treatment is started with a low dose and increased progressively. It sometimes needs to be repeated. The microfilariae are not killed immediately by DEC, but their phagocytosis is facilitated. The indirect effect of DEC means that microfilariae remain alive in cavities (e.g. hydrocoele). This can give rise to confusion, but otherwise is not important as microfilariae are not pathogenic. If the adult worms are not killed, microfilariae reappear in the blood 3-6 months later.

This drug became available in 1984 for the treatment of onchocerciasis. It is also active as a microfilaricide against W. bancrofti. It has the enormous advantage that it can be given in one oral dose and that it has few side effects. It is, however, not macrofilaricidal, even if repeated at high doses. It is useful in the control of bancroftiasis (suppressing microfilaraemia stops transmission), but probably not in helping individual patients. The combination of single dose DEC with single dose ivermectin is much more effective (99%) than each medication alone.

Albendazole has a partial macrofilaricidal effect. It has been shown that the combination of single doses of ivermectin with albendazole suppresses microfilaraemia by 99% for at least 15 months. This combination is more effective than each medication used separately. This combination also has the great advantage of eliminating diverse intestinal worms and of treating scabies (ivermectin).

This is an experimental macrofilaricidal agent. Initially it was thought that a dosage of 3 mg/kg bid for 3 days would suffice, but research on the drug has at the moment been discontinued. UMF-078, an experimental benzimidazole and extracts of Cardiospermum halicacabum ("balloon vine", "heart pea", fam. Sapindaceae) are being studied for their activity and possible place in treatment. UMF-078, however, is possibly teratogenic and carcinogenic.

Benzopyrones are experimental products related to coumarins, but without an anticoagulant effect. They stimulate proteolysis by macrophages. They can be used to remove an excess of proteins in lymphoedema, which is a form of high-protein oedema. If there are fewer proteins present, the quantity of fluid is decreased by the reduction in oncotic pressure. Probably, the fibrotic component of lymphoedema also declines. Benzopyrones can be administered orally (400 mg/day) and have few side effects. The treatment is long-term (a year or possibly longer). The medication, however, is still experimental and not routinely available. More research is necessary to determine its potential place in therapy.

Tetracyclines are active against the endosymbiotic Wolbachia present in Onchocerca volvulus. This might be a new therapeutic point of attack. Initial clinical studies show a favourable effect of the combination of ivermectin with 6 weeks of doxycycline. It is however possible that the release of the intracellular bacteria and their lipopolysaccharide is responsible for the observed side effects involving inflammatory reactions soon after treatment. Clearly, more research is necessary on this subject.

Combination therapy (albendazole 400 mg + ivermectin 200 µg/kg) or (albendazole 400 mg + DEC 6 mg/kg) is preferred at present. The second regimen is not used in countries where onchocerciasis occurs.

In May 1997, the WHO adopted a resolution to eliminate lymphatic filariasis as a public health problem. The programme "Global Programme to Eliminate Lymphatic Filariasis" or "Global Lymphatic Filariasis Initiative" was launched in the year 2000. It is based on two approaches: (1) annual single dose, two-drug treatment allowing suppression of microfilaraemia for a year and which can be given as mass treatment for 5-6 successive years [albendazole + ivermectin in onchocerciasis areas; albendazole + DEC in other areas], (2) simple diagnostic tests that can be performed by a finger prick at any time of the day. It is hoped to eradicate lymphatic filariasis by about 2020. Good financial backing has been provided but this still needs to be extended. Technical training, logistics and management support should be organised. Continuous monitoring and evaluation should constitute an integral part of the programme. Nigeria, Egypt and Samoa were the first three countries in which the programme was started. By the end of 2001, the programme was already active in 36 countries. It began with a pilot programme and the updating of the maps of endemic regions. This involved the use of Geographic Information Systems, risk profiling according to climate, rapid assessment questionnaires on the occurrence of hydrocoeles and lymphoedema, incidence of hydrocoelectomy, standard surveys for the detection of microfilariae, blood collection for PCR and circulating antigen assays and clinical trials. Other components are the development of mathematical models for the better understanding and prediction of transmission dynamics, socio-economic projections for quantifying the impact and cost/benefit calculations. The programme requires that mass treatment and patient-oriented therapy with DEC, in combination with ivermectin or albendazole, should be associated with vector control and improved personal protection against mosquito bites (impregnated mosquito nets, household insecticides). Albendazole has been donated by GlaxoSmithKline. Ivermectin is supplied by Merck & Company. By means of mass campaigns involving annual administration of DEC with ivermectin or albendazole + ivermectin, bancroftiasis problems can be considerably reduced. The use of DEC is problematical in an area where there is still much onchocerciasis. Ivermectin can cause occasional problems in areas with severe Loa loa infections. In some places, such as China, DEC is added to salt with beneficial consequences (cf. the addition of iodine to prevent iodine deficiency). A small dose of DEC can also be taken weekly, for example 100 mg/week. As a favourable "side-effect", reductions may also be expected in the levels of hookworms, various other intestinal helminths and also ectoparasites (lice and scabies), hopefully with the associated improvement in nutrition and cognitive function.

Culex mosquitoes can breed easily in polluted water (drainage canals, septic pits, etc.). The vectors thrive under urban conditions of poverty, poor water drainage and pollution. The introduction of very light (and therefore floating) polystyrene granules into septic tanks can produce a marked reduction in the Culex mosquito population by mechanical protection. The polymer beads expand upon heating which facilitates transport of the unheated material (more compact). Bacillus sphaericus is a toxin-producing bacterium used against various vectors.

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There is evidence to show that Culex quinquefasciatus has developed resistance to insecticides belonging to the organophosphates, such as fenthion. This is due to the presence of an esterase that splits the poisonous molecule. These resistant mosquitoes, however, are much less often infected with W. bancrofti than might be expected. The esterase also possibly has an effect on the microfilariae, as a result of which their development in the insect is inhibited.

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In the mosquito genus Mansonia there are two subgenera: Mansonia and Mansonoides. Mansonoides mosquitoes are vectors for Brugia. They bite preferably at dusk and at daybreak, but nocturnal biting also occurs. If it is dark (heavily overcast, wooded environment) they can also bite during the day. The bites are typically painful. The females of these mosquitoes (like Coquillettidia sp.) lay their eggs under floating vegetation. Their larvae breathe air through a siphon via the roots and stems of water plants. Pistia sp., Zuzania sp, water hyacinth (Eichhornia) and marsh grass (Isachne) are the principal host plants. The larvae do not come to the surface and are difficult to reach with insecticides. This is of importance in the control of the insects. The clearance of water plants, overgrown canals, etc., will substantially reduce a mosquito population.

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In the context of a prevention programme, it is important to know how many mosquitoes are infected in a specific region. The presence of the parasite in a mosquito population can be investigated by catching the insects, dissecting them one by one and establishing the percentage and degree of infection. If transmission is less intense, however, large numbers of mosquitoes have to be studied. This is cumbersome work (maximum 100-200 mosquitoes a day per person). A more modern technique is to catch the mosquitoes and to test them for the parasite in groups of 50, for example, by PCR. In this way up to 2000-3600 mosquitoes per day can be analysed. For PCR, however, special equipment, training and quality control is required.

The plant genus Eichhornia contains 6 species with a natural distribution in tropical and subtropical America. The genus name derives from the Prussian minister J. Eichhorn. Eichhornia crassipes or water hyacinth is a water and marsh plant with short swollen leaf stalks, a characteristic to which the plant owes its species name. Air chambers are found in the tissues of these distended stalks, which contribute to their ability to float. The plant has beautiful flowers and an extensive root system. It was introduced into India in the 19th century and rapidly became a pest as there were no natural enemies. The plant proliferates rapidly. Within a few months one plant can produce sufficient offspring to cover a surface are of 100 m². As a result canals can clog up and fish ponds become unusable. In the late twentieth century the species became a pest in Lake Victoria (Africa). Along with the introduction of the large Nile perch into this lake, it caused an ecological disaster. Herbicides have little success against this water plant. Attempts are now being made to combat the plant by mechanical methods and by the introduction of two small weevils (beetles of the Neochetina family) that specifically attacks it.