The literature on lymphoedema in filariasis-endemic areas suffers from a lack of standardization, terminology, and agreed-upon criteria for diagnosis and case definition. Indeed, many authors use the term 'elephantiasis' for all forms of lymphoedema. Further, even in non-endemic areas, there is no one system for classifying or staging lymphoedema that is universally accepted . The lack of standardization limits our understanding of the epidemiology, prevalence, and severity of lymphoedema. Further, the prevalence of co-morbidity, especially venous disease, associated with lymphoedema in filariasis-endemic areas is unknown. An urgent need exists for standardization of terms and common case definitions, and for improved knowledge about co-morbidity and its effect on recommended treatment practices.
The pathogenesis of lymphoedema in filariasis-endemic areas has been a matter of intense debate. For many years, it was believed that a shift in antifilarial immunity triggered the onset of lymphoedema, before which time the asymptomatically infected host was 'in harmony' with the parasite [96, 97]. However, clinical observations and ultrasonographic and lymphoscintigraphic examinations demonstrated that lymphatic vessel dilatation and dysfunction commonly occur in the absence of lymphoedema. The molecules or processes that stimulate lymphatic vessel dilatation, and the mechanisms by which this process is maintained, are unknown. The clinical model proposed by Dreyer emphasizes that lymphoedema in filariasis-endemic areas is a multifactorial process .
Alternative models have been proposed. Epidemiologic associations between transmission intensity and the prevalence of lymphoedema have suggested to some investigators that third-stage larvae trigger lymphoedema [18, 98]. This hypothesis is supported by observations of decreases in lymphoedema prevalence and severity following mass treatment with antifilarial drugs . Although such reductions are not always observed, these findings suggest that mass drug administration could have therapeutic benefits on filarial morbidity.
Longitudinal studies showing that asymptomatic microfilaraemic persons are less likely than uninfected persons to develop lymphoedema suggest an immunologic mechanism . Recent studies also have suggested a possible role for Wolbachia in the pathogenesis of lymphoedema [19, 20].
Globally, an estimated 16 million persons suffer from lymphoedema in filariasis-endemic areas of the world . Clinically, so-called filarial lymphoedema is often indistinguishable from lymphoedema of other causes, and there is no laboratory marker that proves, at the individual level, that the initial (or only) cause of lymphatic vessel dysfunction was damage associated with adult filarial worms.
The earliest onset of lymphoedema in filariasis-endemic areas is usually observed around the time of puberty, and the prevalence increases with age [101–103]. In many areas where bancroftian filariasis is endemic, lymphoedema of the leg is more common in women than in men [104–106], although this finding is not universal , especially in areas with brugian filariasis . Gyapong and colleagues have reported an association between the community prevalence of lymphoedema and that of microfilaraemia .
Little is known about what triggers the onset of clinical lymphoedema in filariasis-endemic areas, or about what factors cause lymphoedema, once triggered, to persist. After lymphoedema is established, recurrent episodes of ADLA are thought to be the major factor associated with disease progression, although the role of other factors remains largely unexplored. Scarification of the skin, a traditional practice in many filariasis-endemic areas, is considered a risk factor for rapid progression of filarial elephantiasis because of the increased risk of ADLA .
Economic and psychosocial impact
Costs to patients for lymphoedema treatment, reported as both per-visit and per-year costs, vary greatly by study. A study in India reported an average of US$ 0.56 per visit, more than half a day's wages . A Ghanaian study reported costs for treatment of chronic disease (both lymphoedema and hydrocele) of US$ 0.87 per visit, equivalent to almost one day's wages , and greater than costs incurred by controls with other chronic diseases. In India, the annual cost for lymphoedema treatment ranges from US$ 2.17 to US$ 8.70 per person [108, 109]. Average treatment costs are often low, in part because many patients who find potential treatment costs prohibitive either self-treat or do not seek treatment [109–111].
Productivity losses from lymphoedema have been captured as lost working hours and as changes in individual output. Lymphoedema patients in India lose 0.55 to 1.61 hours per day in time at work; 11%–31% of workdays are lost annually [66, 109]. These findings are similar to those of another study of both lymphoedema and hydrocele patients, which estimated 1.13 hours lost per day, for a total of 19% of workdays lost per year . In Ghana, female labour input loss due to lymphoedema was estimated at 1.5% per year, using the average percentage of lymphoedema patients unable to complete certain activities and the local prevalence of lymphoedema . In general, many patients report changing to less strenuous occupations or giving up working altogether due to lymphoedema and ADLA [69, 72, 75, 112]. A study of male weavers in India with chronic disease, 26% of whom had lymphoedema, found a 27% decrease in output compared to controls .
Quality of life
Several studies have quantified the impact of lymphoedema on quality of life using standardized measures [44, 69, 70, 73, 78, 114, 115]. McPherson, using a 30-point Dermatology Quality of Life Index in Guyana, found a mean baseline score for lymphoedema patients of 10.9 (comparable to patients with psoriasis and atopic eczema in the United Kingdom), with controls scoring 0.5 . Six months after starting regular hygiene treatment, the scores improved significantly by an average of 6.8 points . In Haiti, Kanda compared different ways of measuring quality of life among rural people with lymphoedema . Using the EuroQol scale, he found that no respondents had extreme problems in mobility or self-care, but more than half reported pain or discomfort. On a depression scale, the CES-D, these same patients had a mean score of 13.2 (16 and above indicates depression). On the CDC Healthy Days questionnaire, Kanda found that 88% of patients ranked their health as fair or better; however, they also reported an average of 9.9 physically or mentally unhealthy days during the past month. Advanced age, advanced stage of illness, and low educational level were strongly associated with lower quality-of-life measures . In India, patients with lymphoedema scored from 9.2 to 12.4 on a 28-point scale of 'health state severity' using an extended EuroQol measuring system . Severity was associated with stage of lymphoedema; in higher stages, 'severe or very severe problems' were reported for the domains of usual activities, pain, anxiety/depression, cognition and social participation. Among men, the severity score for lymphoedema was significantly higher than that for hydrocele .
Many studies mention the stigma surrounding lymphoedema, but they differ in the severity of stigma reported. Diminished marriage prospects and/or threat of divorce due to diminished economic productivity and attractiveness are often cited as problems for persons with lymphoedema, both by the patients themselves and by other community members [65, 69–75], [116–119]. This effect appears to be dependent on age of lymphoedema onset and disease stage . In Haiti, patients reported that their children had the most difficulty coping, as they were often teased or embarrassed about the mothers' lymphoedema . Following a series of 'soap opera' radio broadcasts in Haiti, which were intended to decrease social stigma associated with lymphoedema, patients reported improved self-efficacy and social support .
Impact on activities
A study in Ghana, which did not distinguish between lymphoedema and hydrocele, found that those with chronic filariasis were significantly less likely to be able to perform market and building activities than matched controls . Among patients in India who were visited at home during the course of a year, those with chronic filarial disease were found to be totally incapacitated at 22% of visits, compared to 13.4% for controls, a significant difference . Another study in India found that lymphoedema patients reported a negative impact on domestic activities (15%–33% of patients), economic activities (65%–83%), and movement (67%–78%) . Lymphoedema patients in Haiti reported decreased ability to walk, difficulty in finding appropriate footwear, and sometimes inability to sell at the market or do household chores . Among those practicing lymphoedema self-care, 25% stated that lymphoedema limited their ability to work .
Among filariasis clinic patients in Sri Lanka, 18% felt they were being shunned by society, although these data were collected after the patients had been enrolled in treatment . In other studies, almost all patients report negative feelings of frustration, isolation, or embarrassment resulting from their condition or their inability to find effective treatment [53, 71–74, 116, 120, 122, 123]. As lymphoedema progresses, the negative emotional and psychological impact often worsens. Patients in an Indian study expressed suicidal thoughts  and depression was common among patients in Haiti and Togo [44, 49]. Anecdotal reports from other filariasis-endemic countries suggest that suicidal ideation and depression are not uncommon among persons with lymphoedema.
A study in Haiti of patients enrolled in a lymphoedema treatment clinic found that the odds of regularly practicing hygiene and skin care were 3.7 times greater among patients who believed that family members supported them than among those who didn't mention family member support . Participation in patient support groups was shown to decrease the number of ADLA episodes and improve quality of life among lymphoedema patients in Haiti . In Brazil, patient 'Hope Clubs' have been developed to provide ongoing opportunities for social and emotional support, problem-solving, and continued learning .
Studies in India and Ghana show that 46%–100% of persons with lymphoedema sought treatment from health care centres, local healers, or pharmacies during the previous year [61, 62, 108, 109]. The studies in Ghana show that modern medical care often is avoided due to lack of interest from health care workers and a belief by patients that lymphoedema treatment requires spiritual interventions [74, 118]. Although many patients believe lymphoedema progression cannot be prevented, they continue to consult spiritualists and treat themselves with herbal preparations or analgesics . In contrast, in areas of India with networks of public healthcare facilities, most patients seek care from modern medical practitioners, although a minority consult Ayurvedic doctors or use home remedies first [72, 111]. Access to care is not necessarily universal, however; young women in India may not seek treatment because of social constraints, such as the paucity of female doctors . Other barriers to care include distance to a health facility, lack of awareness, lack of time, lack of child care, perceived severity of disease, and dissatisfaction with previous treatment [74, 116, 122, 123]. Even when patients seek treatment, health personnel often will prescribe antifilarial or other drugs that are expensive and ineffective. Inadequate knowledge of lymphoedema management by health workers results in suboptimal patient care [105, 111, 123, 125, 126].
Beliefs and traditional practices
Beliefs about the cause of lymphoedema include heredity, supernatural and spiritual causes, and natural causes such as injury, standing in cold water, stepping on insects, and ingesting unhygienic food or drinks [52, 71, 74, 75, 110, 116, 119, 122, 127–131].
In filariasis-endemic areas, people with lymphoedema seek help from traditional healers, herbalists, sorcerers, and pharmacies, or they self-treat. Traditional treatment for lymphoedema includes herbal preparations, burial of the leg, scrubbing the surface of the foot with ants, bloodletting, and scarification, among others [71, 74, 76, 110, 119, 122]. Even in areas with established clinics for lymphoedema management, where patients have learned the importance of hygiene, skin care, elevation and proper footwear, many still hope for a permanent cure [64, 71, 120, 132] (B. Person, personal communication).
Treatment and prevention
Recognition of the importance of ADLA in the progression of lymphoedema has led to basic recommendations for the treatment of lymphoedema in filariasis-endemic areas. The cornerstones of this treatment include hygiene, skin care (early detection, treatment, and prevention of entry lesions), exercise, and elevation of the affected limb [27, 36, 133]. In addition to the above measures, appropriate footwear is recommended, and prophylactic antibiotics are recommended for some patients.
All of these recommendations are consistent with proper lymphoedema care in developed countries where lymphatic filariasis is not endemic [134, 135]. However, in these areas, additional modalities are also used, including compressive bandages, compressive garments, and manual lymphatic drainage [134–137]. These and other measures would no doubt be helpful for individual patients in filariasis-endemic areas , but require more training, experience, and resources, and are therefore not included in the public health approach to managing lymphoedema adopted by the GPELF for filariasis-endemic countries .
Effectiveness of treatment on acute dermatolymphangioadenitis
Relatively few studies have documented the effectiveness or impact of the basic package of lymphoedema management, and most of these have focused on ADLA. The available data indicate that such treatment is associated with a marked reduction in incidence of ADLA [30, 32, 47, 55, 56, 58, 78]. An unpublished study from Haiti reported that risk factors for continued ADLA include more advanced disease, 'negligence', and illiteracy .
Effectiveness of treatment on leg volume
A few studies have documented changes in leg volume or circumference in response to basic lymphoedema management. Although an 'objective' measurement, leg volume can vary considerably with time of day, exercise, elevation, and other factors. In Orissa, India, Kerketta and colleagues reported significant reductions in leg circumference with all treatment regimens that included basic foot care . Pani and colleagues reported greater volume reductions in patients with oedema of recent onset than in those with lymphoedema of longer duration . An unpublished study from Haiti, which initially included compressive bandaging as one of its modalities, reported that more than 65% of 178 patients had a reduction in leg volume after two years when compared with pre-treatment measurements .
Effectiveness of treatment on entry lesions
It is commonly observed that, with basic lymphoedema management, the prevalence and severity of entry lesions decrease .
Effectiveness of treatment on odour
Reduction in offensive odour is commonly observed with regular hygiene. To our knowledge, there have been no studies focusing on reduction in odour as an outcome of lymphoedema treatment in filariasis-endemic areas, although anecdotally this improvement has an important effect on quality of life.
Effectiveness of treatment on stage of lymphoedema
Few studies have attempted to address the degree to which basic lymphoedema management results in regression of lymphoedema stage or grade. In part, this is because most staging systems have not been developed for this purpose. Thus, considerable improvement in skin condition or even leg volume is possible without regression in stage per se.
Effectiveness of treatment on limb flexibility and range of motion
Improved flexibility and a feeling of 'lightness' are commonly reported by patients, but few studies have documented the effectiveness of basic lymphoedema management on limb range of motion.
Effectiveness of treatment on quality of life
Several studies are currently underway that address the extent to which basic lymphoedema management in filariasis-endemic areas improves quality of life. One study, by McPherson in Guyana, documented highly significant improvement in quality of life as measured by the Dermatology Quality of Life Index . Similar work in non-endemic areas has shown substantial gains in quality of life with lymphoedema treatment. Patients who incorporate regular lymphoedema management into their daily routines have reported satisfaction with the results [53, 138].
Effectiveness of treatment on chronic inflammation
A study in Haiti collected skin punch biopsy specimens from the lymphoedematous legs of 27 patients before and about 12 months after they initiated basic lymphoedema management . Follow-up biopsies showed significant reductions in perivascular mononuclear infiltrate in the superficial dermis (41% decrease in prevalence), in perivascular fibrosis in the deep dermis (58% decrease), and in periadnexal mononuclear infiltrate (53% decrease).
Optimization of treatment protocols
Although there is general agreement as to the basic elements of lymphoedema management within the GPELF, considerable regional variation exists in the availability of supplies, including soap, water, and topical skin preparations (e.g. antiseptics, antifungal and antibacterial agents). These differences contribute to variation in approaches used in different regions. For example, in some countries, macerated interdigital lesions are treated with Whitfield ointment, an inexpensive antifungal agent, on the presumption that dermatophytes are the primary pathogen. In Guyana, McPherson and colleagues attempted to culture fungi from these lesions and concluded that bacteria probably play a more important role than fungi . McPherson's observations are consistent with studies of intertriginous lesions in non-endemic areas [140, 141].
Controlled studies of how best to optimize the effectiveness of treatment, particularly for skin care, have not been published. Some investigators have argued for more widespread adoption of breathing exercises to mobilize lymph fluid, and for emollients to protect and rebuild the skin barrier function . These are issues that are amenable to basic, inexpensive clinical trials.
Although there remains some debate about the optimal package of interventions for basic lymphoedema management in filariasis-endemic areas, the benefits of such treatment are generally recognized, and foci of activity in several countries have demonstrated success. However, relatively few persons with lymphoedema living in filariasis-endemic areas currently have access to treatment. Thus, the key programmatic issue is how best to 'scale up' basic lymphoedema management to state and national levels. The challenges can be considered in four major categories:
• Finding patients and bringing them to treatment (many are reluctant to seek care as discussed above)
• Education of patients and family members on the principles and practice of lymphoedema self-care
• Encouragement and support to sustain daily self-care (this support may include improved access to supplies such as clean water, soap, antiseptics, topical antibacterial and antifungal agents, and oral antibiotics)
• Referral networks for management of ADLA and for patients with advanced lymphoedema or lymphoedema complicated by other diseases.
There is general agreement that most patients can manage their lymphoedema routinely at home, and that this is preferable and less costly than clinic-based care. WHO has developed training packages for 'informal caregivers' to instruct patients on home-based care, and this approach has been adopted by most programmes. However, numerous key programmatic and operational research questions remain unanswered for each of the four major programme components. For example: 1) although McPherson and colleagues have shown that health workers in Guyana with limited training can reliably stage lymphoedema and identify entry lesions , the ability of such workers to recognize or diagnose lymphoedema in other settings is unknown; 2) the frequency and intensity of education required for patients to become competent in lymphoedema self-care has not been evaluated; and 3) basic requirements for referral care, provider training, and clinical competency have not been determined. The costs of treatment need to be better understood, as well as the benefits. These are areas in urgent need of investigation if the benefits of lymphoedema management are to reach those who most need it.
Considerable anecdotal evidence suggests that the onset of chronic lymphoedema is triggered by the first or second episode of ADLA. Data from a filariasis-endemic area of Haiti indicate that skin lesions between the toes, which could provide portals of entry for bacteria, are common in children, and are significantly more common in those who test positive for circulating filarial antigenaemia . Similar findings have been observed in northeast Brazil (G. Dreyer, personal communication). The degree to which initial ADLA episodes, and therefore lymphoedema, can be prevented through school-based education programmes focused on hygiene, skin care, and recognition and treatment of entry lesions has not been studied.