Background: As new lymphatic filariasis infections are eliminated through mass chemotherapy, previously affected individuals are left with the sequellae, especially chronic progressive lymphoedema. Currently this is managed by careful attention to limb hygiene to prevent infection. Studies over the past 15 years have suggested that the incorporation of doxycycline treatment may arrest or even reverse progression of lymphoedema. Most of this work has been observational or based on small studies, and if this intervention is effective, studies need to be conducted on a larger scale and under diverse geographical and social conditions before it can be incorporated into treatment policy. Methods/Design: The double-blind, placebo-controlled study was designed to investigate the impact of six weeks treatment with doxycycline added to standard limb hygiene on early stage filarial lymphoedema in five sites in Africa and the Indian subcontinent. One site in Cameroon is selected for studying lymphoedema in podoconiosis. Each site was individually powered with the potential to undertake a meta-analysis on completion. Evaluation methods followed those used in Ghana in 2012 with additions resulting from advances in technology. The details of the core protocol and how it was varied to take account of differing situations at each of the sites are provided. The study will enrol up to 1800 patients and will complete in mid-2021. Conclusions: This paper provides details of what challenges were faced during its development and discusses the issues and how they were resolved. In particular, the reasons for inclusion of new technology and the problems encountered with the supply of drugs for the studies are described in detail. By making these details available, it is hoped that the study protocol will help others interested in improving treatment for filarial lymphoedema in the design of future studies. Trial registration India: Clintrials.gov. NCT02929121 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929121 Mali: Clintrials.gov. NCT02927496 registered 7 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT0292749 Sri Lanka: Clintrials.gov. NCT02929134 registered 10 Oct 2016: https://clinicaltrials.gov/ct2/show/NCT02929134 Ghana: ISRCTN. 14042737 registered 10 July 2017: 10.1186/ISRCTN14042737 Tanzania: ISRCTN. 65756724 registered 21 July 2017: 10.1186/ISRCTN65756724 Cameroon: ISRCTN. 1181662 registered 25 July 2017: 10.1186/ISRCTN11881662

: Lymphedema (LE) is one the most disfiguring chronic manifestations of lymphatic filariasis. Its management relies primarily on limb hygiene and local care. A previous study in Ghana demonstrating a beneficial effect of doxycycline on LE led to the current multicenter trial on the efficacy of doxycycline in filarial LE. A randomized placebo-controlled trial was initiated in two rural health districts in Mali. Patients with LE stages 1–3 were randomized to receive either doxycycline (200 mg/day) or placebo over a 6-week monitored treatment period and were then followed every 6 months for 2 years. Both groups received materials for limb hygiene that was carried out daily for the entire 2-year study. The primary endpoint was lack of progression in LE stage at 24 months. One hundred patients were enrolled in each study arm. The baseline sociodemographic characteristics of each group were largely similar. There was no significant difference at month 24 after treatment initiation in the number of subjects showing progression in LE stage between the two treatment arms (P = 0.5921). Importantly, however, the number of attacks of acute adenolymphangitis (ADLA) was reduced in both arms, but there was no significant difference between the two groups at any follow-up time point (all P >0.23). Doxycycline was well tolerated in those receiving the drug. When added to daily self-administered limb hygiene, a 6-week course of doxycycline (200 mg) was not superior to placebo in increasing the improvement associated with hygiene alone in LE volume, stage, or frequency of ADLA attacks over a 24-month period.

: Lymphedema, hydrocele, and acute adenolymphangitis (ADL) are chronically disabling consequences in patients with lymphatic filariasis (LF). Provision of morbidity management and disability prevention and concurrent mass drug administration of anthelmintics are two pillars for elimination of LF. This study assessed the impact of strict hygiene protocols with or without doxycycline on the progression of filarial lymphedema. A randomized, placebo-controlled, double-blind trial was conducted in two regions in Tanzania. We enrolled 362 participants with lymphedema stages 1–3 assigned into three treatment groups of doxycycline 200 mg once daily, doxycycline 100 mg once daily, or matching placebo for 42 days in addition to hygiene measures. The participants were followed every 2 months for 2 years. Twenty-four months after treatment onset, 17.7% of participants displayed improved limb conditions, including 15/104 (14.4%) in the doxycycline 200 mg group, 16/105 (15.2%) in the doxycycline 100 mg group, and 25/107 (23.4%) in the placebo group. During the first 6 months after treatment, the number of participants experiencing an ADL attack was significantly lower in the doxycycline groups than in the placebo group. The study also found that hygiene was one of the factors associated with preventing the occurrence of acute attacks over the whole study period. Doxycycline 100 mg was a significant factor for the halt of progression (odds ratio: 0.53, P = 0.0239) when both legs if affected at baseline were considered. These findings emphasize the importance of practicing hygiene in reducing the occurrence of ADL attacks and the benefits of doxycycline with regards to acute attacks and halt of progression.

: Filarial lymphedema (LE) remains a significant global problem despite the progress made toward elimination of lymphatic filariasis (LF). In Ghana, the main approach to LF is preventive chemotherapy, but this has minimal impact on individuals who have already developed LE. In 2018–2020, a 24-month randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of stringent hygiene measures using the Essential Package of Care with or without additional administration of doxycycline (DOX) to improve filarial leg LE. This study enrolled 356 participants with LE stages 1–3 from two districts in the Upper East Region of Ghana. In addition to regular training on appropriate care for their affected legs, participants were randomized to receive 6 weeks of either 200 mg/day DOX (n = 117), 100 mg/day DOX (n = 120), or matching placebo (n = 119). Participants were seen every 2 months, with clinical measurements done at 6, 12, 18, and 24 months to assess the status of affected legs. There was a trend toward later appearance of acute attacks after DOX, but surprisingly, DOX showed no effect on LE stage progression. In all groups, leg LE improvement was more common (DOX 200 mg: n = 23 [20%]; DOX 100 mg: n = 23 [19.5%]; placebo: n = 32 [27.4%]) than LE worsening (DOX 200 mg: n = 2 [1.7%]; DOX 100 mg: n = 3 [2.5%]; placebo: n = 2 [1.7%]). Overall, these data show a strong benefit from adherence to a strict hygiene protocol, with some added potential benefit for DOX in preventing acute attacks.

Background/Objectives: The COVID-19 pandemic has significantly impacted global health. However, Africa has reported relatively low numbers of cases and fatalities. Although the pandemic has largely receded, the reasons for its milder course on the African continent have not yet been fully clarified. This study explored the hypothesis that helminth co-infections may have contributed to these observations. Methods: A retrospective cohort study was conducted using 104 plasma samples collected during the third wave of the pandemic in the Ashanti Region of Ghana. Luminex assays were used to measure SARS-CoV-2-specific IgA and IgG, neutralizing antibodies, systemic cytokines and helminth-specific IgG. Results: The results indicated that the highest cumulative seroprevalence of helminths (61.5%) was observed in asymptomatic COVID-19 patients. In comparison, mild and moderate patients had helminth seropositivity rates of 43.8% and 34.5%, respectively, which were 1.4 and 1.8 times lower than those of the asymptomatic group, respectively. Notably, the two severe COVID-19 cases investigated were seronegative for all three of the helminths tested. Strikingly, co-exposure resulted in lower SARS-CoV-2-specific IgA/IgG expression and reduced neutralization potential. However, co-seropositive individuals for helminths and SARS-CoV-2 exhibited a higher expression of Th2 cytokines and IL-10 over Th1 cytokines compared to SARS-CoV-2-positive individuals alone. Conclusion: These data suggest that co-exposure to helminths could mitigate the severity of COVID-19 outcomes by reducing the Th1 and Th17 responses; this highlights the potential protective role of helminthiasis against severe COVID-19. These findings provide valuable insights for the development of public health policies in helminth-endemic regions and underscore the importance of considering helminth co-infections in managing viral infections. It also offers a plausible explanation for the milder disease severity observed in helminth-endemic regions while raising critical considerations regarding vaccine efficacy, as helminth-induced immune modulation may influence the magnitude and quality of vaccine-induced immune responses.

Background/Objectives: Although the COVID-19 pandemic has largely concluded, the varied trajectories it has followed in different regions of the world remain incompletely understood. Intensive research is needed to fully grasp its course and the implications for future global health challenges. Notably, the milder trajectory of the COVID-19 pandemic in Sub-Saharan Africa has defied initial predictions. An emerging body of evidence suggests that, in addition to the continent’s younger average age and the lower prevalence of relevant comorbidities, co-infections with helminths may have also impressively shaped the pandemic’s milder trajectory in the region. Indeed, helminths are renowned for their ability to modulate human immune responses, which, while potentially beneficial in limiting excessive inflammation, could also diminish vaccine efficacy and impede viral clearance. This study investigated different aspects of the intricate interactions between COVID-19 and Lymphatic Filariasis (LF), a helminth infection caused by parasitic worms such as Wuchereria bancrofti, Brugia malayi, and Brugia timori and endemic to various regions in Sub-Saharan Africa and the tropics. Methods: For this purpose, samples of a larger and ongoing clinical trial (ethical approval codes: CHRPE/AP/525/17 and 325/21; trial registration number ISRCTN14042737) were collected from 222 individuals from endemic areas of Ghana, along with comprehensive clinical and demographic data. The samples include LF patients (n = 222) grouped according to their Lymphoedema (LE) stages, as well as COVID-19 vaccinated (n = 81) and non-vaccinated individuals (n = 141). All vaccinated participants received the COVID-19 vaccine ChAdOx1-S (also known as Vaxzevria) developed by the University of Oxford and AstraZenca. The expressions of SARS-CoV-2 and filarial-specific antibodies (IgG, IgA) were accessed using ELISA, while Luminex-based immunoassays were employed to measure the expression of SARS-CoV-2 variant-specific neutralizing antibodies. The interplay between vaccine responses and demographic factors was analyzed using group comparisons with the Kruskal-Wallis or Mann-Whitney U tests. Results: The results indicate that a remarkable portion of unvaccinated individuals (56% IgA seropositive, 39% IgG seropositive) developed antibodies against SARS-CoV-2 despite no confirmed infection. Notably, the study identified a robust antibody response to COVID-19 vaccination, which was independent of the degree of LF pathology or parasitic status. An important observation was the reduced SARS-CoV-2 antibody response in individuals seropositive for Ascaris lumbricoides (p = 0.0264), highlighting an interaction between roundworm infection and COVID-19. Conclusions: The study concludes that the ChAdOx1-S COVID-19 vaccine (AstraZeneca) triggers a strong immune response in LF patients; however, filarial and/or soil-transmitted helminth seropositivity might influence the COVID-19 infection-induced response. These findings emphasize the complexity of infectious disease dynamics in co-infected populations and the need to decipher parasite-induced immunomodulatory mechanisms on COVID-19 vaccination.