Diseases

Filariasis

Filariasis describes a group of parasitic diseases caused by roundworms. These cause a lot of hardship to around 120 million people in the tropics and subtropics. The pharmaceutical industry's response has been the development of effective medicines and involvement in eradication programmes.

What is filariasis? Top

Filariasis is the comprehensive term for a group of diseases affecting mammals and humans. It is caused by microscopic roundworms or nematode (“nema” is the Greek word for “thread”) parasites, commonly called filariae (the Latin word “filum” means “thread”). Of the hundreds of filariae, only a few species cause natural infections in humans. These parasites are classified according to the habitat of the adult worms in a patient. They are divided into a lymphatic group infects the lymphatic system of the host and into a cutaneous group that primarily invading the skin. The lymphatic group includes the parasites Wuchereria bancrofti, Brugia malayi, and Brugia timori. The cutaneous group includes the filariae Loa loa, Onchocerca volvulus, and Mansonella streptocerca.

The filarial life cycle consists of several developmental or larval stages in a mammal host and an intermediate stage in a mosquito which serves as host and vector. In the mammal host, adult female worms produce thousands of first-stage larvae or microfilariae that are taken up by a feeding insect. The microfilariae then undergo two developmental changes in the insect. Finally, third-stage larvae are inoculated back into the host by another insect bite. Then the final two stages of development take place in the human or mammal. 

Acute manifestations of lymphatic filariasis usually are characterised by episodic attacks of fever associated with inflammation of the inguinal lymph nodes, testis, oedema of the lymphatic vessels, or a combination of these. Repeated episodes of inflammation and lymph oedema lead to lymphatic damage, chronic swelling, and elephantiasis of the extremities. In endemic areas, massive swelling of the scrotum or hydrocele is the most common manifestation of chronic infection with Wuchereria bancrofti in males.

The clinical picture of onchocerciasis (or river blindness) consists of skin infection, skin nodules, and ocular lesions. The skin lesions include oedema, papules, scab-like eruptions and altered pigmentation. The ocular lesions usually are related to the duration of the disease and are caused by an abnormal immune response to microfilariae in the patient’s eye. The common eye findings are infection of the cornea, corneal fibrosis, inflammation of the iris, glaucoma, and atrophy of the optical nerve.

Filarial diseases are rarely fatal, but the consequences of infection can cause signi ficant personal and socioeconomic hardship. The World Health Organisation (WHO) has identified lymphatic filariasis as the world’s second leading cause of permanent and long-term disability after leprosy.

Who does filariasis affect? Top

In the tropics and the subtropics, around 120 million people are infected with lymphatic filariasis with 1.2 billion at risk of infection. Approximately one-third of people who carry the disease live in India, one-third in Africa and the rest in Southeast Asia, the Pacific and the Americas. At least 21 million people suffer from river blindness in equatorial Africa and Central and South America. Approximately three million people in Central Africa are infected with Loa loa.

Characteristics of the Filariae

Organism Periodicity Distribution

Vector

Wuchereria bancrofti

Nocturnal

Cosmopolitan areas worldwide,including South America and Africa

Culex (mosquitoes)

   

Mainly India

Anopheles (mosquitoes)

   

China, Indonesia

Aedes (mosquitoes)

  Subperiodic

Eastern Pasific

Aedes (mosquitoes)

Brugia malayi Nocturnal Southeast Asia, Indonesia, India Mansonia, Anopheles (mosquitoes)
  Subperiodic Indonesia, Southeast Asia

Coquilletidia, Mansonia
(mosquitoes)

Brugia timori Nocturnal Indonesia Anopheles (mosquitoes)
Loa loa Diurnal West and Central Africa Chrysops (deerflies) 

Individuals of all ages are susceptible. The manifestation of the disease usually occurs only after years of exposure to infected insects in endemic areas. The load of micro-filariae in the blood (microfilaraemia) increases with age, although clinical infection may not be apparent. There is no racial pattern and both sexes are equally susceptible to infection.

Because of the absence of suitable mosquito vectors no form of human filariasis currently is endemic to Europe. But immigrants or people who have lived or travelled long-term in the tropics may be at risk. Both lymphatic filariasis and onchocerciasis are characterised by a long period required between exposure to infective insect stings and the development of adult worms in the human body, so that signs and symptoms of manifest disease may be misinterpreted.

 

Loa loa worms infiltrating the sclera of the eye

Source: UNDP/Worldbank/WHO

Present treatments Top

The goals of pharmacotherapy are to eradicate the infestation, reduce morbidity, and prevent complications. Prognosis is good if infection is recognised and treated early with medicines.

Patients suffering from lymphatic filariasis and with asymptomatic microfilaraemia are treated on an outpatient basis, with anthelmintics (the Greek noun “helmins” means “worms”) of the azole group. These medicines kill worms by blocking uptake of glucose and other nutrients or decrease adenosine triphosphate production in the parasites, causing energy depletion and finally, death. Inpatient care initially may be required for individuals with chronic filariasis. Apart from antiparasitic medication, treatment includes antihistamines to decrease pruritus and itching, corticosteroids to reduce the swelling of lymph oedematous tissue, compounds to relieve pain, and intravenous antibiotics to combat secondary infections.

Since the year 2000, under the Global Alliance to Eliminate Lymphatic Filariasis (GAELF) around 80 million people, including 30 million children, have been treated to prevent the disease in 37 countries where filariasis is endemic. GAELF’s members include 80 health ministries, two global pharmaceutical manufacturers, WHO, UNICEF and the World Bank. The alliance aims to reach 350 million people by the end of 2005 and to eliminate the disease entirely by 2020. Companies will be continuing to donate the antiparasitic medicines for the duration of the programme.

The elimination strategy involves once-yearly community-wide treatment for five years with an azole compound plus either a GABA receptor agonist or diethylcarbamazine (DEC).

In river blindness, recent studies have validated the use of single-dose regimens of anthelmintics for large-scale control and elimination programs. One compound exerts its action against Onchocerca volvulus by acting as a potent agonist at GABA receptors, which paralyses the parasite. Molecules of the azole group may be used together in cases where patients suffer from both lymphatic and cutaneous filariasis.

In December 2002, the Onchocerciasis Control Programme (OCP) was officially wound up after 28 years of work to eliminate this public health threat in 11 West African countries. More than 250 million doses of medicine had been distributed. The WHO estimated that nine million children born since 1974 have been spared the risk of blindness and more than one million people have recovered from infection. Meanwhile, the programme has been replaced by a national surveillance capacity which will be able to detect any new outbreaks of onchocerciasis.

What’s in the development pipeline? Top

In May 2004, a Phase 2 clinical trial has started to investigate the safety and efficacy of an oral form of another anthelmintic for river blindness. The compound has been used as an antiparasitic in livestock for many years and if proven also to be effective in man may be another alternative to existing medication.

Recent research on the bacterial species Wolbachia which live as essential endosymbionts in filarial worms may lead to novel schemes for therapy and possibly also control of both lymphatic filariasis and onchocerciasis. Administration of a tetracycline compound for six weeks results in sterilisation of the roundworm parasites. New research on Wolbachia has also been demonstrating their role in the immunopathology of filariasis.

The longer-term future Top

The OCP has been successful in halting transmission of river blindness in the 11 West African countries involved. However, total eradication has not been possible. Epidemiological simulation models suggest that 65 per cent coverage would suffice for annual treatment of communities with low to medium-high microfilarial burden but that at least 80 per cent is required in populations with higher loads. Elimination is only feasible where high treatment coverage can be maintained for the entire period – which is several years, and in areas which remain free from re-invasion by infective black-flies. It also requires absence of prolonged civil unrest and a stable supply of medicines.

The impact of more frequent administration of medicines on the development of resistance suggests that priority should be given to research into further safe and effective medicines and affordable alternative elimination strategies.