The Burden of Filarial Lymphedema and the GPELF Approach
Lymphatic filariasis (LF), a mosquito-borne parasitic disease, is known to cause permanent disability and deformity through impairment in the lymphatic system and subsequent abnormal enlargement of body parts such as limbs, scrotum, breast, and vulva.1 As one of the neglected tropical diseases, LF is targeted for elimination by the WHO through the Global Program for Elimination of Lymphatic Filariasis (GPELF) by 2030.2
The Essential Package of Care developed toward the elimination process consists of two pillars: 1) eliminating transmission of LF through mass drug administration (MDA) and 2) alleviating the suffering of individuals with chronic conditions such as lymphedema (LE; enlargement of other body parts) and hydrocele (enlargement of the scrotum) through morbidity management and disability prevention (MMDP) methods.3
While MDA has led to a significant decline in LF prevalence from 199 million cases in 2000 to 51 million by 2018, there has only been a marginal reduction in chronic cases from about 40 million people in 2000 to 36 million in 2014.1,3–5 This suggests that countries that have achieved elimination will still have many individuals with debilitating LE for years to come.
The Ghanaian Experience with LF Morbidity Management
In Ghana, MDA through the Ghana Filariasis Elimination Program started in 2000, leading to interrupted transmission. However, the scaling up of MMDP programs has been slow and has not received maximum attention.7,8 To address this gap, a previous study in the southern part of Ghana, where transmission was ongoing and hygiene was not strictly adhered to, investigated the use of 200 mg/day of doxycycline (DOX) for 6 weeks in addition to standard MDA and hygiene management.10 This study showed significant improvement in LE stage and reduced acute adenolymphangitis (ADL) attacks.
Doxycycline has been found to be effective in depleting the Wolbachia endobacteria required by filariae, killing both microfilaria and adult worms.12,13 A lower dose of 100 mg/day DOX for 6 weeks has also been shown to be effective for Wolbachia depletion in onchocerciasis.14 Therefore, the current study aimed to assess the impact of two different dosages of DOX (100 and 200 mg/day) along with strict adherence to hygiene measures in the management of LF-related LE in Ghana.
Study Design and Methodology
This 24-month, randomized, double-blind, placebo-controlled trial was conducted in 125 rural communities across 13 subdistricts in the Kassena Nankana East Municipal (KNEM) and Kassena Nankana West (KNW) Districts of Ghana’s Upper East Region.16,17 These districts were previously mapped as LF-endemic and are currently considered LF hotspots.9,15,16
A total of 356 participants with LE stages 1-3 were enrolled and randomized to receive either 200 mg/day DOX (n=117), 100 mg/day DOX (n=120), or placebo (n=119) for 6 weeks. All participants received regular training on the Essential Package of Care for LE management, including limb hygiene, elevation, exercise, and use of appropriate footwear.
Participant screening, enrollment, and follow-up were conducted within the communities. LE staging was done using the 7-stage Dreyer scale, and participants were evaluated at baseline and 6, 12, 18, and 24 months post-treatment.11,16,19 Blood samples were collected for filarial antigen testing and microfilaria quantification.26,27 Safety assessments, including clinical chemistry and hematology tests, were also performed.16
Adherence to Hygiene Protocols
One of the key findings of this study was the strong benefit from adherence to the strict hygiene protocol provided to all participants, regardless of treatment group. Over 80% of participants had clean, washed legs at baseline, and this proportion increased further after the initial hygiene training, reaching a peak at 4 months before slightly declining and then continually increasing again until 24 months (Figure 4A).
Factors associated with higher hygiene scores included longer residence in the endemic area, lower body weight, and assessments done during the dry season (Figure 4B). Conversely, male sex, increasing age, and assessments during the rainy season were associated with lower hygiene scores.
Importantly, participants who did not experience an ADL attack in the 6 months prior to a follow-up visit were twice as likely to show improvement in their LE stage compared to those who had an attack (Figure 3C). This highlights the effectiveness of the standardized hygiene-based MMDP practices in preventing acute episodes and ameliorating LE morbidity.
Impact of Doxycycline Therapy
Contrary to previous studies,10,12 the addition of DOX therapy did not show a significant effect on LE stage progression or improvement compared to the placebo group. In all treatment groups, including the placebo group, a considerable proportion of participants experienced LE stage improvement (ranging from 19.5% to 27.4% across the groups at 24 months), while only a small percentage had worsening of their condition (1.7% to 2.5%) (Figures 2 and 3).
However, there was a trend towards a delay in the time to first ADL attack in the DOX groups compared to the placebo group (Figure 5A). The multivariable analysis also revealed that having limbs that appeared unclean during the hygiene assessment and being assessed during the rainy season were associated with a higher number of ADL attacks over the 2-year study period (Figure 5B).
Improvements in Quality of Life
Importantly, the participants in this trial demonstrated a clear improvement in their quality of life, as measured by the WHO Disability Assessment Schedule (WHODAS 2.0), regardless of treatment group. The mean disability score decreased from 27.5 at baseline to 12.8 at 12 months and further to 7.2 at 24 months (Figure 6A).
The key factors associated with this improvement in quality of life were having LE stage 2 compared to stage 3, and not experiencing an ADL attack in the 6 months prior to the assessment (Figure 6B). This highlights the significant benefits that can be derived from adherence to the standardized hygiene-based MMDP practices provided to all participants.
Lessons Learned and Implications
The findings of this study underscore the importance of strictly adhering to hygiene-based MMDP practices in managing filarial LE, even in areas where transmission has been interrupted. The regular training, follow-up, and provision of hygiene supplies contributed to the high adherence and significant improvements observed across all treatment groups.
While doxycycline did not show a direct effect on LE stage progression, the trend towards delayed ADL attacks in the DOX groups suggests a potential role for the drug in preventing acute inflammatory episodes. This could be particularly relevant in areas where active LF transmission is still ongoing.
To ensure sustainable impact, it is crucial to establish MMDP centers in endemic communities and integrate LE management into national health insurance schemes. Empowering LE patients through social protection programs can also help improve their quality of life and socioeconomic status.
In conclusion, this study demonstrates the power of a comprehensive, community-based approach to LE management, focusing on the strict adherence to hygiene-based MMDP practices. By providing regular training, support, and resources, significant improvements in LE morbidity and quality of life can be achieved, even in areas where LF transmission has been interrupted.
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