The aim of this study was to determine whether improvement of filarial lymphedema (LE) by doxycycline is restricted to patients with ongoing infection (positive for circulating filarial antigen [CFA]), or whether the majority of CFA-negative patients with LE would also show a reduction in LE severity. One hundred sixty-two Ghanaian participants with LE stage 1–5 (Dreyer) were randomized blockwise into 2 groups (CFA positive or negative) and allocated to 3 treatment arms of 6 weeks: (1) amoxicillin (1000 mg/d), (2) doxycycline (200 mg/d), or (3) placebo matching doxycycline. All groups received standard hygiene morbidity management. The primary outcome was reduction of LE stages. Secondary outcomes included frequency of acute attacks and ultrasonographic assessment of skin thickness at the ankles. Parameters were assessed before treatment and after 3, 12, and 24 months. Doxycycline-treated patients with LE stage 2–3 showed significant reductions in LE severity after 12 and 24 months, regardless of CFA status. Improvement was observed in 43.9% of doxycycline-treated patients, compared with only 3.2% and 5.6% in the amoxicillin and placebo arms, respectively. Skin thickness was correlated with LE stage improvement. Both doxycycline and amoxicillin were able to reduce acute dermatolymphangioadenitis attacks. Doxycycline treatment improves mild to moderate LE independent of ongoing infection. This finding expands the benefits of doxycycline to the entire population of patients suffering from LE. Patients with LE stage 1–3 should benefit from a 6-week course of doxycycline every other year or yearly, which should be considered as an improved tool to manage morbidity in filarial LE. ISRCTN 90861344.

Background. Ivermectin (IVM) has been the drug of choice for the treatment of onchocerciasis. However, there have been reports of persistent microfilaridermia in individuals from an endemic area in Ghana after many rounds of IVM, raising concerns of suboptimal response or even the emergence of drug resistance. Because it is considered risky to continue relying only on IVM to combat this phenomenon, we assessed the effect of targeting the Onchocerca volvulus Wolbachia endosymbionts with doxycycline for these individuals with suboptimal response. Methods. One hundred sixty-seven patients, most of them with multiple rounds of IVM, were recruited in areas with IVM suboptimal response and treated with 100 mg/day doxycycline for 6 weeks. Three and 12 months after doxycycline treatment, patients took part in standard IVM treatment. Results. At 20 months after treatment, 80% of living female worms from the placebo group were Wolbachia positive, whereas only 5.1% in the doxycycline-treated group contained bacteria. Consistent with interruption of embryogenesis, none of the nodules removed from doxycycline-treated patients contained microfilariae, and 97% of those patients were without microfilaridermia, in contrast to placebo patients who remained at pretreatment levels (P < .001). Moreover, a significantly enhanced number of dead worms were observed after doxycycline. Conclusions. Targeting the Wolbachia in O. volvulus is effective in clearing microfilariae in the skin of onchocerciasis patients with persistent microfilaridermia and in enhanced killing of adult worms after repeated standard IVM treatment. Strategies can now be developed that include doxycycline to control onchocerciasis in areas where infections persist despite the frequent use of IVM. Clinical Trials Registration. ISRCTN 66649839.

Clinical manifestations in onchocerciasis range from generalized onchocerciasis (GEO) to the rare but severe hyperreactive (HO)/sowda form. Since disease pathogenesis is associated with host inflammatory reactions, we investigated whether Th17 responses could be related to aggravated pathology in HO. Using flow cytometry, filarial-specific cytokine responses and PCR arrays, we compared the immune cell profiles, including Th subsets, in individuals presenting the two polar forms of infection and endemic normals (EN). In addition to elevated frequencies of memory CD4⁺ T cells, individuals with HO showed accentuated Th17 and Th2 profiles but decreased CD4⁺CD25^hiFoxp3⁺ regulatory T cells. These profiles included increased IL-17A⁺, IL-4⁺, RORC2⁺ and GATA3⁺CD4⁺ T cell populations. Flow cytometry data was further confirmed using a PCR array since Th17-related genes (IL-17 family members, IL-6, IL-1β and IL-22) and Th2-related (IL-4, IL-13, STAT6) genes were all significantly up-regulated in HO individuals. In addition, stronger Onchocerca volvulus-specific Th2 responses, especially IL-13, were observed in vitro in hyperreactive individuals when compared to GEO or EN groups. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network instigating the development of severe onchocerciasis. Onchocerciasis, also known as river blindness is a tropical disease causing health and socioeconomic problems in endemic communities especially sub-Saharan Africa. The disease is transmitted by a filarial nematode called Onchocerca volvulus, which is spread by the bite of infected Simulium black flies. Characteristic disease symptoms include dermatological disorders and eye lesions that can lead to blindness. Two polar forms of clinical manifestations can occur: generalized onchocerciasis (GEO) presenting mild skin disease or the hyperreactive form (HO) exhibiting severe skin disorders and inflammation. The immunological determinants behind such disease polarization are still not fully clarified. Here, we compared the immune profiles of individuals presenting these two polar forms with those of endemic normals (EN): individuals who have no clinical or parasitological evidence of infection despite ongoing exposure to the infectious agent. We could show that HO individuals, in contrast to GEO and EN, simultaneously presented elevated Th17 and Th2 profiles which were accompanied by reduced numbers of Foxp3⁺ regulatory T cells. This study provides initial evidence that elevated frequencies of Th17 and Th2 cells form part of the immune network associated with severe onchocerciasis.

In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF⁺) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF⁺) or latent (n = 67 MF⁻) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF⁺ patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF⁺ individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission. The tropical helminth infection lymphatic filariasis affects more than 120 million people worldwide and is considered a major public health concern. Over 90% of infections are elicited by Wucheria bancrofti and adult worms reside in the lymphatic system releasing millions of microfilariae (MF), which periodically circulate in the blood. New diagnostic tools have provided a method to determine asymptomatic patients that are amicrofilaremic: a subset of individuals that have so far been neglected but are of special interest since these patients represent a dead end in terms of parasite transmission. Therefore, we were interested in determining whether the absence of MF was associated with distinct immunological profiles and observed that indeed responses in MF⁺ patients were dampened. From the viewpoint of the helminth such overall suppression of immune responses may facilitate MF transmission. Latent individuals however, presented elevated filarial specific responses and extrapolating these findings to the host provides novel insight into possible protective mechanisms which either actively hinders the release of MF from worms or their travel to the periphery. Further research into these aspects may broaden the range of strategies currently employed to reduce transmission and in turn eliminate bancroftian filariasis.

There is compelling evidence that not only do anti-filarials significantly reduce larval forms, but that host immune responses also contribute to the clearance of filarial parasites; however, the underlying mechanisms have not been fully elucidated. Filarial infections caused by Wuchereria bancrofti and Brugia species (lymphatic filariasis) and Onchocerca volvulus (onchocerciasis) affect almost 200 million individuals worldwide and pose major public health challenges in endemic regions. Indeed, the collective disability-adjusted life years for both infections is 3.3 million. Infections with these thread-like nematodes are chronic and, although most individuals develop a regulated state, a portion develop severe forms of pathology. Mass drug administration (MDA) programmes on endemic populations focus on reducing prevalence of people with microfilariae, the worm's offspring in the blood, to less than 1 %. Although this has been successful in some areas, studies show that MDA will be required for longer than initially conceived. This paper highlights the mode of action of the various antifilarial treatment strategies and role of host immune response.

Background: Human lymphatic filarial pathology is the leading cause of disability and poverty among people living with the infection. The second goal of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) is to manage the disease’s morbidity to improve patients’ quality of life. Consequently, the current study assessed the overall quality of life of lymphatic filariasis (LF) pathology patients in some selected endemic communities in rural Ghana. Method: In the present study, the Lymphatic Filariasis Quality of Life Questionnaire (LFSQQ) was used to evaluate the effect of lymphatic filariasis on the quality of life of people, with the disease in nine (9) communities in the Ahanta West District of the Western Region of Ghana where mass drug administration is being implemented for the past twenty years. Pearson’s correlation, linear regression, and one-way analysis of variance (ANOVA) analyses were used to assess the associations between the LFSQQ instrument domains. Results: Of the 155 study participants recruited, 115 (74.19%) were females, and 40 (25.81%) males. A greater proportion of the study participants (40, 25.8%) were presented with stage two (2) lymphoedema, while only two patients had stage seven (7) lymphoedema. The average of the overall quality of life scores of study participants was 68.24. There was a negative Pearson correlation (r = − 0.504, p-value < 0.001) between the stage of lymphoedema (severity of the disease) and the quality of life of the LF patients. In addition, a clear pattern of positive correlation (r = 0.71, p-value < 0.001) was observed between the disease burden and pain/discomfort domains of the study participants. Whereas the highest domain-specific score (85.03) was observed in the domain of self-care, we noted that the environmental domain, which consists of the financial status, was the lowest (45.94) among the study participants. Conclusion: Our findings support previous works on the reduced quality of life among lymphatic filariasis patients with pathology. In this study, our results reveal a depressing financial condition among people presenting with late stages of LF pathologies, which eventually reduces their well-being.