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LYMPHEDEMA LYMPHATIC FILARIASIS

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Lymphatic Filariasis

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Lymphedema Filariasis

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Discussion:

Lymphatic Filariasis is the leading type of lymphedema worldwide, affecting an estimated 120 million people. It is an endemic conditions located in the tropical regions of the world.  These areas include SE Asia, the Indian sub-continent, Africa, and areas of South America.

Cause:  Infestation or infection by a microscopic threat like parasitic worm.  The three main worms include Wuchereria bancrofti , Brugia malayi , and B. timori.  The infections is spread through mosquito bites.  However, there are five other species that may be involved, these include The other five species are Loa loa, Mansonella perstans, M. streptocerca, M. ozzardi, and Brugia timori. 

The worm larvae (microfilaria)  may be injected by an infected mosquito directly into the blood. The microfilaria then reproduce and spread throughout the bloodstream, eventually traveling to the lymph system where they grow into adults.  What makes this condition frustrating difficult to diagnosis and treat early is that the symptoms of infection may not show up for years.

Symptoms:  The symptom of infection swelling of an arm, leg or genital areas.

Complications:  It is not the actual infection that can be life threatening, but the complications that occur as a result of the lymphedema.  The most serious  complication is massive infection (cellulitis, lymphangitis). Other complications include fibrosis (hardening) of the affected tissue, severe pain, gross disfigurement, sexual dysfunction.  Long term fibrosis or tissue hardening can also cause venous thrombosis (blood clot). 

Diagnosis:  Suspicion of lymphatic filiarisis of course, may be made upon the appearance of the lymphedema.  However, to prevent this it is imperative to diagnosis filariare infection before it gets to this stage.   This is usually done through microscopic examination of blood samples.  However, there are other diagnostic tools available.  These include antigen detection, molecular diagnosis (polymerase chain reaction), identification of adult worms through tissue samples, and antibody detection.

Treatment:  Treatment generally has a dual focus.  First, you must eliminate the infection that caused the lymphedema and then you must subsequently treat the lymphedema itself.

Treatment for the parasitic infection include the administration of drugs such as diethylcarbamazine (DEC), albendazole and ivermectin.

Treatment for the lymphedema includes decongestive therapy on the affected limbs, surgical procedures on genital lymphedema and treatment of the numerous complications.

Prevention:  The real goal goal however, is in the prevention of this condition.  A massive global alliance including the World Health Organization, medical professional and pharmacy companies (SmithKline Beecham and Merck and Co.) is se

Seeking to eliminate this disease through preventative therapy. 

Through studies being conducted in the affected regions, it has been found that preventative doses of the above medicines can actually prevent the initial infection.  Other modalities include extensive community education, and intensive improvement in local hygiene.

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Key facts

More than 1.3 billion people in 81 countries worldwide are threatened by lymphatic filariasis, commonly known as elephantiasis.

Over 120 million people are currently infected, with about 40 million disfigured and incapacitated by the disease.

Lymphatic filariasis can result in an altered lymphatic system and the abnormal enlargement of body parts, causing pain and severe disability.

Acute episodes of local inflammation involving the skin, lymph nodes and lymphatic vessels often accompany chronic lymphoedema.

To interrupt transmission WHO recommends an annual mass drug administration of single doses of two medicines to all eligible people in endemic areas.

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For Further Information

Excerpt from Hydrocele, Filarial - Filariasis

Synonyms, Key Words, and Related Terms: scrotal lymphedema, filarial worms, filaria, filariae, Filaria bancrofti, F bancrofti, Wuchereria bancrofti, W bancrofti, Brugia malayi, B malayi, Filaria malaya, F malaya, Culex pipiens, C pipiens, parasitic disease, parasitemia, parasite infection, filariasis, mosquito bite, lymphatic filariasis, nematode, roundworm, round worm, lymphangiectasia, filarial infestation, scrotal filarial infestation, skin sclerosis, elephantiasis, tropical eosinophilia, eosinophilic interstitial pneumonitis, chyluria

http://www.emedicine.com/med/byname/hydrocele-filarial.htm

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Lymphatic filariasis - World Health Organization

This page provides links to descriptions of activities, reports, news and events, as well as contacts and cooperating partners in the various WHO programmes and offices working on this topic. Also shown are links to related web sites and topics.

MeSH scope note: Infections with nematodes of the superfamily FILARIOIDEA. The presence of living worms in the body is mainly asymptomatic but the death of adult worms leads to granulomatous inflammation and permanent fibrosis. Organisms of the genus Elaeophora infect wild elk and domestic sheep causing ischaemic necrosis of the brain, blindness, and dermatosis of the face.

RELATED SITES

FACT SHEETS

- Lymphatic filariasis

RELATED LINKS

- Eliminating lymphatic filiariasis
http://apps.who.int/tdr/svc/diseases

http://www.who.int/mediacentre/factsheets/fs102/en/

Lymphatic filariasis

Lymphatic Filariasis, known as Elephantiasis, puts at risk more than a billion people in more than 80 countries. Over 120 million have already been affected by it, over 40 million of them are seriously incapacitated and disfigured by the disease. One-third of the people infected with the disease live in India, one third are in Africa and most of the remainder are in South Asia, the Pacific and the Americas. In tropical and subtropical areas where lymphatic filariasis is well-established, the prevalence of infection is continuing to increase. A primary cause of this increase is the rapid and unplanned growth of cities, which creates numerous breeding sites for the mosquitoes that transmit the disease.

In its most obvious manifestations, lymphatic filariasis causes enlargement of the entire leg or arm, the genitals, vulva and breasts. In endemic communities, 10-50% of men and up to 10% of women can be affected. The psychological and social stigma associated with these aspects of the disease are immense. In addition, even more common than the overt abnormalities is hidden, internal damage to the kidneys and lymphatic system caused by the filariae.

Cause

The thread-like, parasitic filarial worms Wuchereria bancrofti and Brugia malayi that cause lymphatic filariasis live almost exclusively in humans. These worms lodge in the lymphatic system, the network of nodes and vessels that maintain the delicate fluid balance between the tissues and blood and are an essential component for the body's immune defence system. They live for 4-6 years, producing millions of immature microfilariae (minute larvae) that circulate in the blood.

Transmission

The disease is transmitted by mosquitoes that bite infected humans and pick up the microfilariae that develop, inside the mosquito, into the infective stage in a process that usually takes 7-21 days. The larvae then migrate to the mosquitoes' biting mouth-parts, ready to enter the punctured skin following the mosquito bite, thus completing the cycle.

Signs and symptoms

The development of the disease itself in humans is still something of an enigma to scientists. Though the infection is generally acquired early in childhood, the disease may take years to manifest itself.

Indeed, many people never acquire outward clinical manifestations of their infections. Even though there may be no clinical symptoms, studies have now disclosed that such victims, outwardly healthy, actually have hidden lymphatic pathology and kidney damage as well. The asymptomatic form of infection is most often characterized by the presence in the blood of thousands or millions of larval parasites (microfilariae) and adult worms located in the lymphatic system.

The worst symptoms of the chronic disease generally appear in adults, and in men more often than in women. In endemic communities, some 10-50% of men suffer from genital damage, especially hydrocoele (fluid-filled balloon-like enlargement of the sacs around the testes) and elephantiasis of the penis and scrotum. Elephantiasis of the entire leg, the entire arm, the vulva, or the breast - swelling up to several times normal size - can affect up to 10% of men and women in these communities.

Acute episodes of local inflammation involving skin, lymph nodes and lymphatic vessels often accompany the chronic lymphoedema or elephantiasis. Some of these are caused by the body's immune response to the parasite, but most are the result of bacterial infection of skin where normal defences have been partially lost due to underlying lymphatic damage. Careful cleansing can be extremely helpful in healing the infected surface areas and in both slowing and, even more remarkably, reversing much of the overt damage that has occurred already.

In endemic areas, chronic and acute manifestations of filariasis tend to develop more often and sooner in refugees or newcomers than in local populations continually exposed to infection. Lymphoedema may develop within six months and elephantiasis as quickly as a year after arrival.

Diagnosis

Until very recently, diagnosing lymphatic filariasis had been extremely difficult, since parasites had to be detected microscopically in the blood, and in most parts of the world, the parasites have a "nocturnal periodicity" that restricts their appearance in the blood to only the hours around midnight. The new development of a very sensitive, very specific simple "card test" to detect circulating parasite antigens without the need for laboratory facilities and using only finger-prick blood droplets taken anytime of the day has completely transformed the approach to diagnosis. With this and other new diagnostic tools, it will now be possible both to improve our understanding of where the infection actually occurs and to monitor more easily the effectiveness of treatment and control programmes.

Treatment

Communities where filariasis is endemic. The primary goal of treating the affected community is to eliminate microfilariae from the blood of infected individuals so that transmission of the infection by the mosquito can be interrupted. Recent studies have shown that single doses of diethylcarbamazine (DEC) have the same long-term (1-year) effect in decreasing microfilaraemia as the formerly-recommended 12-day regimens of DEC and, even more importantly, that the use of single doses of 2 drugs administered concurrently (optimally albendazole with DEC or ivermectin) is 99% effective in removing microfilariae from the blood for a full year after treatment. It is this level of treatment effectiveness that has made feasible the new efforts to eliminate lymphatic filariasis.

Treating the individual. Both albendazole and DEC have been shown to be effective in killing the adult-stage filarial parasites (necessary for complete cure of infection), but ideal treatment regimens still need to be defined. It is clear that this anti-parasite treatment can result in improvement of patients' elephantiasis and hydrocoele (especially in the early stages of disease), but the most significant treatment advance to alleviate the suffering of those with elephantiasis has come from recognizing that much of the progression in pathology results from bacterial and fungal "superinfection" of tissues with compromised lymphatic function caused by earlier filarial infection. Thus, rigorous hygiene to the affected limbs, with accompanying adjunctive measures to minimize infection and promote lymph flow, results both in a dramatic reduction in frequency of acute episodes of inflammation ("filarial fevers") and in an astonishing degree of improvement of the elephantiasis itself.

WHO's strategy to eliminate lymphatic filariasis

The strategy of the Global Programme to Eliminate Lymphatic Filariasis has two components: firstly, to stop the spread of infection (i.e. interrupt transmission), and secondly, to alleviate the suffering of affected individuals (i.e. morbidity control).

To interrupt transmission, districts in which lymphatic filariasis is endemic must be identified, and then community-wide ("mass treatment") programmes implemented to treat the entire at-risk population. In most countries, the programme will be based on once-yearly administration of single doses of two drugs given together: albendazole plus either diethylcarbamazine (DEC) or ivermectin, the latter in areas where either onchocerciasis or loiasis may also be endemic; this yearly, single-dose treatment must be carried out for 4-6 years. An alternative community-wide regimen with equal effectiveness is the use of common table/ cooking salt fortified with DEC in the endemic region for a period of one year.

To alleviate the suffering caused by the disease, it will be necessary to implement community education programmes to raise awareness in affected patients. This would promote the benefits of intensive local hygiene and the possible improvement, both in the damage that has already occurred, and in preventing the debilitating and painful, acute episodes of inflammation.

The generous pledge in 1998 by the global healthcare company SmithKline Beecham to collaborate with the World Health Organization in its elimination efforts included the donation of numerous resources (but especially albendazole, one of the mainstay drugs in the elimination strategy), free of charge, for as long as necessary to ensure success of the elimination programme. This donation, coupled with the recent decision by Merck and Co., Inc., to expand its ongoing Mectizan® (ivermectin) Donation Programme to include treatment of lymphatic filariasis where appropriate, and the creation of additional partnerships with other private, public and international organizations, including the World Bank, have all further strengthened the prospects for success of these elimination efforts.

Economic and social impact

Because of its prevalence often in remote rural areas, on the one hand, and in disfavoured periurban and urban areas, on the other, lymphatic filariasis is primarily a disease of the poor. In recent years, lymphatic filariasis has steadily increased because of the expansion of slum areas and poverty, especially in Africa and the Indian sub-continent. As many filariasis patients are physically incapacitated, it is also a disease that prevents patients from having a normal working life. The fight to eliminate lymphatic filariasis is also a fight against poverty.

Lymphatic filariasis exerts a heavy social burden that is especially severe because of the specific attributes of the disease, particularly since chronic complications are often hidden and are considered shameful. For men, genital damage is a severe handicap leading to physical limitations and social stigmatization. For women, shame and taboos are also associated with the disease. When affected by lymphoedema, they are considered undesirable and when their lower limbs and genital parts are enlarged they are severely stigmatized; marriage, in many situations an essential source of security, is often impossible.

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Lymphatic abnormalities in human filariasis as depicted by lymphangioscintigraphy

Witte MH, Jamal S, Williams WH, Witte CL, Kumaraswami V, McNeill GC, Case TC, Panicker TM.

Source

Department of Surgery, University of Arizona, Tucson.

Abstract


BACKGROUND:

Investigation into filarial lymphedema has been hampered by the lack of a simple, safe, and easily repeated test to image the peripheral lymphatic system. Recent refinements in radionuclide lymphangioscintigraphy have established this noninvasive technique as the initial procedure of choice for visualizing lymphatics. Accordingly, we applied lymphangioscintigraphy to patients with filariasis and, for purposes of interpretation, compared the findings with those in patients with non-filarial lymphedema.

METHODS:

Thirty-three patients with classic symptoms or signs consistent with acute or chronic filariasis underwentlymphangioscintigraphy, and the findings were compared with those in five patients without lymphatic dysfunction and in 50 other patients with primary or secondary lymphedema without exposure to filariasis.

RESULTS:

As in patients with nonfilarial lymphedema, scintigraphic abnormalities in the 33 patients with filariasisincluded delayed or absent tracer transport of the radiotracer (25 patients), tortuous and bizarre deep lymphatics (seven patients), dermal diffusion (15 patients), retrograde tracer flow (six patients), and faint or absent regional nodal visualization (14 patients). Even in patients with long-standing filarial lymphedema, peripheral trunks were often visualized (at least in part), and regional nodes and more central lymphatics sometimes filled after light exercise. In some of the latter patients, however, discrete lymphatic trunks were not detected.

CONCLUSION:

Lymphangioscintigraphy is a simple, safe, reliable, noninvasive method with which to examine the peripheral lymphatic system, including truncal and nodal abnormalities, in endemic populations with occult and overtlymphatic filariasis.

http://archinte.ama-assn.org/cgi/content/abstract/153/6/737

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Lymphatic Filariasis (Elephantiasis)

Lymphatic Filariasis (Elephantiasis)

Elephantiasis of the legs due to filariasis (CDC). Lymphatic filariasis, also known as elephantiasis, is best known from dramatic photos of people with grossly enlarged or swollen arms and legs. The disease is caused by parasitic worms, including Wuchereria bancrofti, Brugia malayi, and B. timori, all transmitted by mosquitoes. Lymphatic filariasis currently affects 120 million people worldwide, and 40 million of these people have serious disease.

When an infected female mosquito bites a person, she may inject the worm larvae, called microfilariae, into the blood. The microfilariae reproduce and spread throughout the bloodstream, where they can live for many years. Often disease symptoms do not appear until years after infection. As the parasites accumulate in the blood vessels, they can restrict circulation and cause fluid to build up in surrounding tissues. The most common, visible signs of infection are excessively enlarged arms, legs, genitalia, and breasts.

Medicines to treat lymphatic filariasis are most effective when used soon after infection, but they do have some toxic side effects. In addition, the disease is difficult to detect early. Therefore, improved treatments and laboratory tests are needed. A vaccine is not yet available.

NIAID Research

Mosquito Studies

Several researchers study the interactions between filarial parasites and their mosquito hosts. Bruce Christensen, Ph.D., from the University of Wisconsin at Madison, studies how mosquitoes defend themselves from infections by encapsulating the microfilaria and producing toxic proteins that defend the insect against the invading parasite. Dennis Knudson, D.Phil., of Colorado State University, leads a study to decipher the genetic blueprint of mosquitoes in order to understand the molecular basis for how mosquitoes carry filarial parasites. He and his collaborator, David Severson, Ph.D. , of Notre Dame University, are using genetic and physical mapping tools with their model vector-parasite system, the Aedes aegypti mosquito and the human filarial parasite Brugia malayi, to identify the genes that allow certain mosquitoes to transmit filarial parasites

Because the geographic distributions of filariasis and dengue overlap, Jeff Vaughan, Ph.D., from the University of North Dakota, investigates how filariasis can enhance the transmission of dengue virus by mosquitoes.

Understanding the Parasite

Tufts University's Juliet Fuhrman, Ph.D., seeks to understand how filarial parasites survive within mosquitoes, with the goal of developing novel ways to manipulate the parasite's life cycle and block disease transmission.

James Kazura, M.D. , of Case Western Reserve University studies the genetics of W. bancrofti and analyzes the immune response to this parasite in infected individuals. He supervises a research laboratory in Papua New Guinea that looks at how exposure to the parasite affects susceptibility to disease.

Vaccine Research

Thomas Nutman, M.D., of NIAID's Laboratory of Parasitic Diseases searches for proteins from W. bancrofti that stimulate an immune response in people. This research focuses on finding potential molecules that can be used in a vaccine and in improved diagnostic tests.

Additional Links:

http://www.niaid.nih.gov/newsroom/focuson/bugborne01/filar.htm

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Lymphatic Filariasis

http://www.who.int/health-topics/lymphfil.htm

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Lymphatic Filariasis

http://www.who.int/tdr/diseases/lymphfil/default.htm

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Lymphatic Filariasis

http://www.cdc.gov/ncidod/dpd/parasites/lymphaticfilariasis/default.htm

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Lymphatic Filariasis

Filariasis, Lymphatic

Description

Lymphatic filariasis is caused primarily by adult worms (filariae) that live in the lymphatic vessels. The female worms release microfilariae that circulate in the peripheral blood and are ingested by mosquitoes; thus, infected mosquitoes transmit the infection from person to person. The two major species of filariae that cause lymphatic disease in humans are Wuchereria bancrofti and Brugia malayi.

Occurrence

Lymphatic filariasis affects an estimated 120 million persons in tropical areas of the world, including sub-Saharan Africa, Egypt, southern Asia, the western Pacific islands, the northeastern coasts of South and Central America, and the Caribbean Islands.

Risk for Travelers

Short-term travelers to endemic areas are at low risk for this infection. Travelers who visit endemic areas for extended periods of time and who are intensively exposed to infected mosquitoes can become infected. Most infections seen in the United States are in immigrants from endemic countries.

Clinical Presentation

Most infections are asymptomatic, but the living adult worm causes progressive lymphatic vessel dilation and dysfunction. Lymphatic dysfunction leads to lymphedema of the leg, scrotum, penis, arm, or breast, which can increase in severity as a result of recurrent secondary bacterial infections. Tropical pulmonary eosinophilia is a potentially serious progressive lung disease with nocturnal cough, wheezing, and fever, resulting from immune hyperresponsiveness to microfilaria in the pulmonary capillaries.

Prevention

No vaccine is available, nor has the effectiveness of chemoprophylaxis been well documented. Protective measures include avoidance of mosquito bites through the use of personal protection measures (see Protection against Mosquitoes and Other Arthropods).

Treatment

The drug of choice for treatment of travelers with W. bancrofti or B. malayi infections is diethylcarbamazine (DEC). DEC, which is available to U.S.-licensed physicians for this purpose, can be obtained from the CDC Parasitic Diseases Drug Service at 404-639-3670. (See Immunobiologics Distributed by The Centers for Disease Control and Prevention from the CDC Drug Service.) DEC kills circulating microfilaria and is partially effective against the adult worms and tropical pulmonary eosinophilia. Many patients with lymphedema are no longer infected with the filarial parasite and do not benefit from antifilarial drug treatment. For chronic manifestations of lymphatic filariasis, such as lymphedema and hydrocele, specific lymphedema treatment (including hygiene, skin care, physical therapy, and in some cases, antibiotics) and surgical repair, respectively, are recommended. Travelers should be advised to consult an infectious disease or tropical medicine specialist.

http://www.cdc.gov/travel/diseases/filariasis.htm

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Filariasis

http://filariasis.net/

Recently published in Filaria Journal (Vol. 3, 2004)

Latest article, 30 January 2004

Willingness to pay for prevention and treatment of Lymphatic Filariasis in Leogane, Haiti see http://www.filariajournal.com/content/3/1/2
Rheingans RD, Haddix AC, Messonnier ML, Meltzer M, Mayard G, Addiss DG. Filaria J. 2004, 3:2

Antibody responses to Brugia malayi antigens induced by DNA vaccination  see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC343290/

Li BW, Rush A, Zhang SR, Curtis KC, Weil GJ. Filaria J. 2004, 3:1 (22 January 2004)

Brugia malayi

DNA vaccination is a convenient means of immunizing animals with recombinant parasite antigens. DNA delivery methods are believed to affect the qualitative nature of immune responses to DNA vaccines in ways that may affect their protective activity. However, relatively few studies have directly compared immune responses to plasmids encoding the same antigens after injection by different routes. Therefore, the purpose of this study was to explore the influence of the route of administration on antibody responses to plasmids encoding antigens from the filarial nematode parasite Brugia malayi. Methods: Four B. malayi genes and partial genes encoding paramyosin (BM5), heat shock protein (BMHSP-70), intermediate filament (BMIF) and a serodiagnostic antigen (BM14) were inserted in eukaryotic expression vectors (pJW4303 and pCRTM3.1). BALB/c mice were immunized with individual recombinant plasmids or with a cocktail of all four plasmids by intramuscular injection (IM) or by gene gun-intradermal inoculation (GG). Antibody responses to recombinant antigens were measured by ELISA. Mean IgG1 to IgG2a antibody ratios were used as an indicator of Th1 or Th2 bias in immune responses induced with particular antigens by IM or GG immunization. The statistical significance of group differences in antibody responses was assessed by the nonparametric Kruskal-Wallis test. Results: Mice produced antibody responses to all four filarial antigens after DNA vaccination by either the IM or GG route. Antibody responses to BM5 paramyosin were strongly biased toward IgG1 with lower levels of IgG2a after GG vaccination, while IM vaccination produced dominant IgG2a antibody responses. Antibody responses were biased toward IgG1 after both IM and GG immunization with BMIF, but antibodies were biased toward IgG2a after IM and GG vaccination with BMHSP-70 and BM14. Animals injected with a mixture of four recombinant plasmid DNAs produced antibodies to all four antigens. Conclusions: Our results show that monovalent and polyvalent DNA vaccination successfully induced antibody responses to a variety of filarial antigens. However, antibody responses to different antigens varied in magnitude and with respect to isotype bias. The isotype bias of antibody responses following DNA vaccination can be affected by route of administration and by intrinsic characteristics of individual antigens.

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Beyond Swollen Limbs, a Diseases's Hidden Agony
Ny Times

http://www.nytimes.com/2006/04/09/world/americas/09lymph.html?pagewanted=all

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Building a future free from lymphatic filariasis

http://www.filariasis.org.uk/

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Lymphatic Filariasis (Elephantiasis)

http://www.niaid.nih.gov/newsroom/focuson/bugborne01/filar.htm

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Elephantiasis

Gale Encyclopedia of Medicine

http://www.findarticles.com/cf_0/g2601/0004/2601000473/p1/article.jhtml

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Some observations on the effect of Daflon (micronized purified flavonoid fraction of Rutaceae aurantiae) in bancroftian filarial lymphoedema

LK Das1 , G Subramanyam Reddy2 and SP Pani1
1Vector Control Research Centre, (Indian Council of Medical Research), Pondicherry-605006, India
2Government General Hospital, Pondicherry-605001, India

Filaria Journal 2003, 2:5     doi:10.1186/1475-2883-2-5

The electronic version of this article is the complete one and can be found online at:

 http://www.filariajournal.com/content/2/1/5

Received   25 June 2002
Accepted   12 March 2003
Published   12 March 2003

© 2003 Das et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Abstract

Background

Morbidity management is a core component of the global programme for the elimination of lymphatic filariasis. In a double-blind clinical trial, the tolerability and efficacy of Daflon (500 mg) + DEC (25 mg) or DEC (25 mg) alone, twice daily for 90 days, was studied in 26 patients with bancroftian filarial lymphoedema.

Results

None of the patients in either drug group reported any adverse reaction throughout the treatment period (90 days). Haematological and biochemical parameters were within normal limits and there was no significant difference between the pre-treatment (day 0) and post-treatment (day 90) values. The group receiving Daflon showed significant reduction in oedema volume from day 90 (140.6 ± 18.8 ml) to day 360 (71.8 ± 20.7 ml) compared to the pre-treatment (day 0, 198.4 ± 16.5 ml) value. This accounted for a 63.8% reduction in oedema volume by day 360 (considering the pre-treatment (day 0) as 100%). In the DEC group, the changes in oedema volume (between day 1 and day 360) were not significant when compared to the pre-treatment (day 0) value. The percentage reduction at day 360 was only 9%, which was not significant (P > 0.05).

Conclusion

This study has shown that Daflon (500 mg, twice a day for 90 days) is both safe and efficacious in reducing oedema volume in bancroftian filarial lymphoedema. Further clinical trials are essential for strengthening the evidence base on the role of this drug in the morbidity management of lymphatic filariasis.

Background

Lymphatic filariasis (LF) is endemic in as many as 80 countries [1,2]. An estimated 1.1 billion people are at risk of infection, and there are approximately 120 million people with patent infection or disease round the globe [3-5]. In India alone, 553 million people are estimated to live in areas endemic for lymphatic filariasis and there are approximately 21 million people with symptomatic filariasis [6]. Progressive lymphoedema (from the early reversible stages to irreversible and complicated stages) associated with the increase in episodic attacks of acute adenolymphangitis (ADL) [7] is the most important cause of physical suffering, permanent disability and economic loss [8-10]. It has been estimated that there are some 16.02 million cases of lymphoedema caused by LF globally, and of these, 7.44 million (46.4%) live in India [3].

LF is recognized as one of six potentially eradicable diseases [11] and in 1997, the World Health Assembly (WHA) passed a resolution calling for it's global elimination as a public health problem [4,12].

The current strategy for the global elimination of LF recommended by the Global Alliance for the Elimination of Lymphatic Filariasis (GAELF) [1] has two major components: transmission control and morbidity management [13].

Transmission control

The most important transmission control strategy being implemented is the annual mass administration of single-dose anti-parasitic drugs (albendazole with diethylcarbamazine citrate (DEC) in countries where onchocerciasis or loiasis is not co-endemic with LF, or albendazole with ivermectin in countries where onchocerciasis or loaiasis is co-endemic with LF) to the entire at risk community, aimed at a significantly reducing community parasite load [14,15].

Morbidity management

For morbidity management, the current emphasis is on use of an appropriate hygiene and skin care regimen, (pioneered by Gerusa Dryer in Brasil), that lymphoedema patients can use everyday [16] for the prevention of episodic attacks of adenolymphangitis (ADL) and progression of disease [2,17].

Availability of other measures for morbidity management (such as drugs or physiotherapy or surgery) which can reduce oedema volume (along with appropriate hygiene and skin care) will be important in the alleviation of suffering and consequent improvement in psycho-social condition of these patients.

Daflon, (micronized purified flavonoid fraction of Rutaceae aurantiae) [18] has been used in clinical practice to treat a variety of lymphoedemas, such as post radical mastectomy oedema [19], chronic venous insufficiency [20], haemorrhoids [21,22], varicose ulcers [23,24], post-phlebitic syndrome, dysfunctional uterine bleeding [25] and idiopathic cyclic oedema syndrome [26].

To date, no clinical trials have been conducted to assess the suitability of this drug in the treatment of filarial lymphoedema. In this paper, we are presenting our observations on the tolerability and efficacy of Daflon (500 mg, twice a day for 90 days) in reducing oedema volume in patients with bancroftian filarial lymphoedema.

Materials and Methods

Selection of patients

Initially, patients with unilateral lower limb lymphoedema were detected by conducting a morbidity survey in a village known to be endemic for lymphatic filariasis near Pondicherry in south India (recording Wuchereria bancrofti microfilaria rate of 17.2%, an overall disease rate of 14.1%, lymphoedema rate of 6.3% and antigenaemia rate of 28.6% using ICT card test; Vector Control Research Centre – unpublished data). These patients were referred to the Government General Hospital at Pondicherry, where they were examined by a senior physician and recruited to the study as per inclusion/exclusion criteria (Table 1).

In the natural history of LF, many patients with lymphoedema do not have demonstrable microfilaraemia [27-29] nor antigenaemia [30]. Therefore, in areas which are considered to be highly endemic for LF, (such as in the current study), cases of unilateral lymphoedema are considered to be of filarial origin by exclusion of all other conditions, (such as venous insufficiency and varicose ulcers, which could also present with lymphoedema), by careful history taking and clinical examination, using the clinical criteria for diagnosis and grading recommended by the World Health Organization (WHO) [31].

Study design and treatment regimen

Twenty-six patients (18 female and 8 male patients) between the ages of 20 and 55 years, (mean 39 years), who met the inclusion / exclusion criteria [Table 1], and who had given written informedconsent, were admitted to the Government General Hospital at Pondicherry for a period of four days and randomly allocated into one of two drug groups:

Group A: Daflon (500 mg) + DEC (25 mg) twice a day for 90 days

Group B: DEC (25 mg) twice a day for 90 days.

The drugs were repackaged in look-alike capsules containing either Daflon (500 mg) + DEC (25 mg) or DEC (25 mg).

The appropriate drug regimen was administered to the patients twice daily (morning and evening) from day 1 to day 3 (three days excluding day 0, i.e. day of admission) of hospitalization, under the direct supervision of the medical team. Patients were discharged on the morning of day 4 with a pack of the appropriate drug capsules (for the next 12 days: to complete the treatment up to day 15). The patients were educated and instructed by the physician and a social worker to comply with the dosage schedule and were asked initially to report every fortnight for measurement of oedema volume and to receive a further supply of drug capsules for the proceeding 15 days, up to day 90. Thereafter, patients were requested to attend 3 subsequent times, day(s) 180, 270 and 360 to allow measurement of oedema volume.

Ethical considerations

The study conformed to the principles of Helsinki Declaration II [32], the Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products [33] and the guidelines of the Indian Council of Medical Research for bio-medical research involving human subjects [34]. Furthermore, the study was approved by the Institutional Scientific Advisory Committee and the Institutional Ethical Committee. The study was "blind" to the extent that patients, clinicians evaluating the adverse effects, and laboratory staff carrying out the laboratory tests were unaware of the individual treatment schedules. Blinding and coding of the drugs was done by an independent monitor (a senior scientist who was not an investigator) after repacking in look-alike capsules by a pharmaceutical company in Pondicherry. The codes were broken only after completion of the study.

Assessment of results

Tolerability

All patients were clinically monitored for any adverse reactions (such as abdominal pain, nausea, vomiting, chest pain, arthralgia, diarrhoea, fever, headache, myalgia and chills) at 8 hourly intervals for first 24 hours and thereafter every 24 hours for further two days (until the end of day 3). All systemic reactions, if any, were recorded in a pre-designed form. Laboratory investigations on haematology and biochemistry parameters (haemoglobin concentration, total white blood count, differential count, absolute eosinophil count, erythrocyte sedimentation rate, packed cell volume, blood urea, sugar, bilirubin, creatinine, cholesterol, serum sodium, potassium, chloride, protein, albumin, globulin, glutamic pyruvic transaminase, alkaline phosphatase) were assessed on day 0, (pre-treatment), and on completion of treatment (day 90).

Efficacy

Oedema volume was recorded using a water displacement method [35] on day 0 (pre-treatment) and every fortnight from day 15 to day 90, and thereafter every 3 months on day(s) 180, 270 and 360.

On day 0, during the clinical history taking, the senior physician enquired about patient experiences of ADL attacks, and their frequency in the past 6 months prior to admission. At each follow-up point the patients were asked about the occurrence of ADL attacks in the period between the visits, and were also clinically examined for signs and symptoms of acute disease, as per WHO criteria [31].

Statistical analysis

The mean age of the patients and the mean frequency of ADL attacks (6 months prior to treatment) in the two drug groups were compared using independent t test. The statistical significance in the difference between the mean oedema volume was calculated using paired t-test.

Results

A total of 26 ambulatory patients with unilateral lymphoedema, (selected as per inclusion and exclusion criteria [Table 1]), were recruited to the study; 13 in each drug group (Group A: Daflon (500 mg) + DEC (25 mg) twice a day, for 90 days; Group B: DEC (25 mg) twice a day, for 90 days). The mean age (± SD) of the patients in the Daflon + DEC group was 40 (± 11.5) years (range 20–55) and in the DEC group it was 38 (± 6.8) years (range 24–50) (P > 0.05 between the two groups). There were 12 patients with grade II oedema and one patient with grade I oedema in each drug group. There was no significant difference in the pre-treatment (day 0) mean oedema volume (± SEM) between the Daflon + DEC (198.4 ± 16.5 ml) and the DEC alone (272.9 ± 48.0 ml) groups (P > 0.05). All the 26 patients completed the full 90 day treatment schedule.

Tolerability

None of the patients in either study group complained of any adverse reaction during the 90 days of treatment. The haematological and biochemical parameters were within normal limits for all patients, and did not vary significantly between pre-treatment (day 0) and on completion of treatment (day 90) (data not shown).

Efficacy

The mean oedema volume (± SEM) in the Daflon + DEC group was 140.6 (± 18.8) ml at the end of treatment period (day 90) and it was 71.8 (± 20.7) ml at the end of the follow-up period (day 360) (Figure 1). There was a significant difference in the mean oedema volume on day 90 and on day 360 in comparison to the pre-treatment value (198.4 ± 16.5 ml on day 0, P < 0.05) (Table 2). The mean oedema (± SEM) volume in the DEC group was 272.9 ± 48.0 ml the end of the follow-up period (day 360) (Figure 1). There was no significant difference in the mean oedema volumes on day 90 and on day 360 in comparison to the pre-treatment value (272.9 ± 48.0 ml on day 0, P > 0.05).

The percentage change of oedema volume in comparison to pre-treatment (day 0) (considering day 0 volume as 100%) in the two treatment groups is shown in Figure 2. It was observed that in the Daflon + DEC group the oedema volume reduced by 29.1% at the end of treatment period (day 90) and by 63.8% at the end of the follow-up period (day 360). On the other hand, in the DEC group the percentage reduction was nil at the end of the treatment period (day 90) and it was 9% at the end of the follow-up period (day 360).

Comparison of the patterns of change in the day-specific mean oedema volume (Figure 1) and its percentage change (considering day 0 as 100%) (Figure 2) between the two treatment groups (Table 2) showed that in the Daflon + DEC group, maximum reduction was observed between day 75 to day 180 (significant reduction in oedema volume; t = 3.31, P < 0.01) and stabilized thereafter (no significant difference in oedema volume between day 180 versus day 270 or between day 180 versus day 360, P > 0.05). In the DEC group, the mean oedema volume was more or less stable through out the observation period (Table 2).

In the 6 month period prior to starting the treatment, the mean frequency of episodic ADL attacks (± SD) was 0.9 ± 1.1 in the Daflon + DEC group and it was 0.6 ± 0.9 in the DEC group (P > 0.05 between the two groups). None of the patients in either of the drug groups suffered from an ADL attack through out the treatment and follow-up period (i.e. between day 1 and day 360).

Discussion

The World Health Organisation has targeted lymphatic filariasis for elimination as a public health problem by the year 2020 [1,2]. India, which has the highest burden of LF, has set a target for national elimination of LF by the year 2015 [36]. Although annual mass administration of single-dose anti-filarial drugs to entire endemic communities for the control of transmission of lymphatic filariasis is being implemented in many counties, including India, (under which approximately 50 million citizens are currently being covered annually) [2,15], morbidity management [13] aimed at the alleviation of suffering of the individual patients has, in many countires, only recently begun to be addressed.

There is no doubt that the introduction of an appropriate hygiene and skin care regimen that patients can practice in their own environment will be most important in providing long term gains in the management of their morbidity. However, realisation of this strategy in many communities (living in rural and urban settings) in different endemic countries with wide socio-economic diversity remains a major challenge [17].

While the above strategy is being implemented, it is important to develop other measures, which could reduce oedema volume in patients with filarial lymphoedema, and, which can be integrated alongside a hygiene and skin care regimen.

Although, surgical procedures have been developed for filarial lymphoedema cases [37,38], these can only be performed in a few specialized centers, where expertise is available. Furthermore, it is costly and it has been observed that sustaining the gains achieved by surgery depends on the ability to prevent subsequent ADL episodes (by following a hygiene and skin care regimen) [38].

Physiotherapeutic measures such as manual massage, pneumatic compression and interferential current therapy have been found to be useful in odemea volume reduction in other secondary lymphoedema cases [39,40,43], however, these have yet to be properly evaluated in the management of filarial lymphoedema. Interferential current therapy showed significant oedema reduction in brugian filarial lymphoedema cases [41]. Although, pneumatic compression also results in oedema volume reduction, the results are not sustained [42]. Manual massage could be most useful as a self-help measure [43], but objective data are yet to be generated in LF cases. Of the chemotherapeutic agents investigated previously, 5,6 benzo-alpha-pyrone was most promising. In a double-blind placebo controlled study on bancroftian filarial lymphoedma cases in south India, it was observed that 5,6 benzo-alpha-pyrone (given at the dosage of 200 mg twice daily) resulted in significant reduction in oedema volume (63% in grade II cases) at the end of a two year treatment period [44]. The efficacy of this drug has also been demonstrated in a study in China [45]. However, 5,6 benzo-aplha-pyrone cannot be currently recommended for use as the drug has been shown to be hepato-toxic [46].

Earlier studies have shown that DEC has limited role in the management of filarial lymphoedema. In areas endemic for burgian filariasis in Indonesia considerable improvement in lymphoedema, including reversal of elephantiasis, has been reported [47]. However, these observations were based on community studies and objective measurement of oedema volume was not carried out. A significant reduction in oedema volume was reported with repeated courses of DEC along with supportive measures (such as pneumatic compression, use of crepe bandage etc.) in a study, again on brugian filarial lymphoedema cases, from south India [48]. However, this was an open trial and it is not possible to differentiate the effect of DEC alone from that of the supportive measures. In bancroftian filarial lymphoedema cases, long term DEC therapy (6 mg /kg /day in two divided doses for 2 years) resulted in reduction in oedema volume ranging only between 3 to 7 % in different grades of oedema [44]. A double blind clinical trial with single dose DEC (6 mg / kg body weight) or ivermectin (400 mg / kg body weight) did not show any significant change in oedema volume in bancroftian filarial lymphoedema cases over a one-year follow-up period (Vector Control Research Centre – unpublished data). In the current study, DEC treatment alone at the dosage of 25 mg twice a day for 90 days did not result in significant change oedema volume in filarial lymphoedema cases. Freedman et al., using lymphoscintigraphy did not observe any improvement in lymphatic pathology after two courses of DEC (for 12 days each) in bancroftian filarial lymphoedema cases [49]. Furthermore, DEC did not reduce the incidence of episodic ADL attacks in individual lymphoedema cases [50,51] as well as in the community after mass drug administration [52]. These results suggest the limitations of DEC in the morbidity management in LF.

This is the first report of a clinical trial on the tolerability and efficacy of Daflon in filarial lymphoedema cases. Daflon is known to be phlebotonic, it reduces capillary permeability and has an anti-lipidaemic effect [19,26]. This drug is known to be safe and without any adverse reaction in the dosage of 2 tablets of 500 mg each per day, and it has been given up to one-year period [53,54]. The results of the current study showed that there was neither any adverse reaction during the 90 days treatment period nor any significant change between the pre-treatment (day 0) and post-treatment (day 90) haematological or biochemical parameters in any of the patients (which were within normal limits). This demonstrates that Daflon (500 mg, twice a day for 90 days) is safe, well tolerated, and can be used up to 90 days in patients with filarial lymphoedema. Furthermore, the drug is also efficacious, reflected by a significant reduction in oedema volume of 63.8% (recorded between day 0 and day 360, inclusive of 90 days of treatment period) (Figure 2). A significant reduction in oedema volume was detected by the end of day 90 (Table 2). In other clinical conditions, appreciable change has been detected between 6 weeks to 6 months [55]. The pattern of change in oedema volume showed a marked reduction from day 75 until day 180 (Figure 1), after which the change was marginal (Table 2). This could suggest that repeat course(s) may be required for further decrease in oedema volume. Although Daflon was given along with DEC in the current study, since DEC alone did not show any significant reduction in oedema volume (Table 2, Figure 1), the results seen in the former group is likely to be due to Daflon.

None of the patients in either drugs group suffered from an ADL attack during the treatment and follow-up period. The reason for this, however, is not clear. Although DEC, (25 mg twice a day for 90 days), was given to all patients, it is difficult to assign this effect to DEC, as previous experience, in both hospital and community studies, did not favour this [50-52]. All the patients were also from a limited geographical area with similar environmental and socio-economic conditions having similar risk for ADL. None of the patients were advocated a specific hygiene and skin care regimen as a part of the protocol (since this is not yet a routine measure advocated by the National Filariasis Control Programme [56] and also as this could confound the results of effects of the drug (however, for ethical reasons all patients were educated in an appropriate hygiene and skin care regimen after completion of the study)).

We conclude that Daflon (500 mg, twice a day for 90 days) is both safe and efficacious in reducing oedema volume in filarial lymphoedema. DEC, at the dosage given, did not result in any significant change in oedema volume. However, as the current study was limited to a few patients in south India (and did not have an arm of Daflon alone) further clinical trials (preferably multi-centre) with larger numbers of patients need to be carried out (and should address the effect of Daflon on lymphatic pathology). This is essential for strengthening the evidence base on the use of Daflon in the management of filarial lymphoedema, before recommending its use in morbidity management to the Global Programme for the Elimination of Lymphatic Filariasis.

Competing interests

None declared

Authors' contributions

LKD; Study design, case detection, recruitment and follow-up, data analysis and manuscript preparation. GSR; Study of tolerability and efficacy in the hospital. SPP; Study concept, design, implementation and manuscript preparation.

Acknowledgements

The authors would like to thank Dr. Vijayan for his assistance in organizing the laboratory investigations and Dr. P. Vanamail, Senior Research Scientist, Vector Control Research Centre (VCRC) for his help in the statistical analysis and Dr P.K.Das, Director, VCRC for his initiative and administrative support. The authors acknowledge the gift of the Daflon by M/S Serdia Phramaceutical Ltd., Mumbai, India (coordinated by Dr. Prashant Desai).

The authors would also like to thank Mr. Palaniswamy of Caplin Laboratories Ltd., Pondicherry, India, for repacking the drugs used in the study.

The study was funded by the Indian Council of Medical Research, New Delhi, India http://icmr.nic.in/.

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http://www.filariajournal.com/content/2/1/5

Submitted by member: Tania

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Enlarging the "Audacious Goal": Elimination of the World's high prevalence neglected tropical diseases. 2011

Keywords: Neglected tropical diseases; Ascariasis; Hookworm infection; Trichuriasis; Schistosomiasis; Lymphatic filariasis (LF); Blinding trachoma; Onchocerciasis; Kinetoplastid infections; Leprosy; Disease; Elimination; Disease eradication

http://www.sciencedirect.com/science/article/pii/S0264410X11008887

Lymphatic Filariasis and its Control in Japan —The Background of Success 2011 

http://www.sciencedirect.com/science/article/pii/S0035920311002100

Neglected Tropical Diseases and the Millenium Development Goals - why the "other" diseases" matter:  reality versus rhetetoric 2011

http://www.parasitesandvectors.com/content/4/1/234/abstract

Lymphatic filariasis in western Ethiopia with special emphasis on prevalance of Wuchereria bancrofti antigenaemia in and around onchoceriasis endemic areas 2011

http://www.sciencedirect.com/science/article/pii/S0035920311002100

Managing morbidity and preventing disability in the Global Programme to Eliminate Lymphatic Filariasis: WHO position statement.  Dec 2011

http://www.who.int/wer/2011/wer8651_52.pdf

Epidemiological and entomological evaluations after six years or more of mass drug administration for lymphatic filariasis elimination in Nigeria. Oct 2011

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191131/?tool=pubmed

Bayesian geostatistical modelling of malaria and lymphatic filariasis infections in Uganda: predictors of risk and geographical patterns of co-endemicity. Oct 2011

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216645/?tool=pubmed

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Join us as we work for lymphedema patients everywehere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

http://health.groups.yahoo.com/group/AdvocatesforLymphedema/

Subscribe: AdvocatesforLymphedema-subscribe@yahoogroups.com

Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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For information about Lymphedema

http://www.lymphedemapeople.com/thesite/all_about_lymphedema.htm

For Information about Lymphedema Complications

http://www.lymphedemapeople.com/thesite/lymphedema_complications.htm

For Lymphedema Personal Stories

http://www.lymphedemapeople.com/forum/forum.asp?FORUM_ID=7

For information about Lymphedema Wounds

http://www.lymphedemapeople.com/thesite/lymphedema_wound_care_revised.htm

For information about Lymphedema Treatment Options

http://www.lymphedemapeople.com/thesite/lymphedema_treatment_options_revised.htm

For information about Children's Lymphedema

http://www.lymphedemapeople.com/thesite/lymphedema_childrens_pediatric.htm

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Lymphedema People

Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION 

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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Our Home Page: Lymphedema People

http://www.lymphedemapeople.com/

Updated Jan. 5, 2012