The search for better treatment strategies for mansonellosis: an expert perspective.

INTRODUCTION: Four species of the Mansonella genus infect millions of people across sub-Saharan Africa and Central and South America. Most infections are asymptomatic, but mansonellosis can be associated with nonspecific clinical manifestations such as fever, headache, arthralgia, and ocular lesions (M. ozzardi); pruritus, arthralgia, abdominal pain, angioedema, skin rash, and fatigue (M. perstans and perhaps Mansonella sp. 'DEUX'); and pruritic dermatitis and chronic lymphadenitis (M. perstans). AREAS COVERED: We searched the PubMed and SciELO databases for publications on mansonelliasis in English, Spanish, Portuguese, or French that appeared until 1 May 2023. Literature data show that anthelmintics - single-dose ivermectin for M. ozzardi, repeated doses of mebendazole alone or in combination with diethylcarbamazine (DEC) for M. perstans, and DEC alone for M. streptocerca - are effective against microfilariae. Antibiotics that target Wolbachia endosymbionts, such as doxycycline, are likely to kill adult worms of most, if not all, Mansonella species, but the currently recommended 6-week regimen is relatively impractical. New anthelmintics and shorter antibiotic regimens (e.g. with rifampin) have shown promise in experimental filarial infections and may proceed to clinical trials. EXPERT OPINION: We recommend that human infections with Mansonella species be treated, regardless of any apparent clinical manifestations. We argue that mansonellosis, despite being widely considered a benign infection, may represent a direct or indirect cause of significant morbidity that remains poorly characterized at present.

A large case series of travel-related Mansonella perstans (vector-borne filarial nematode): a TropNet study in Europe.

BACKGROUND: Infection with Mansonella perstans is a neglected filariasis, widely distributed in sub-Saharan Africa, characterized by an elusive clinical picture; treatment for mansonellosis is not standardized. This retrospective study aimed to describe the clinical features, treatment schemes and evolution, of a large cohort of imported cases of M. perstans infection seen in four European centres for tropical diseases. METHODS: Mansonella perstans infections, diagnosed by identification of blood microfilariae in migrants, expatriates and travellers, collected between 1994 and 2018, were retrospectively analysed. Data concerning demographics, clinical history and laboratory examinations at diagnosis and at follow-up time points were retrieved. RESULTS: A total of 392 patients were included in the study. Of the 281 patients for whom information on symptoms could be retrieved, 150 (53.4%) reported symptoms, abdominal pain and itching being the most frequent. Positive serology and eosinophilia were present in 84.4% and 66.1%, respectively, of those patients for whom these data were available. Concomitant parasitic infections were reported in 23.5% of patients. Treatment, administered to 325 patients (82.9%), was extremely heterogeneous between and within centres; the most commonly used regimen was mebendazole 100 mg twice a day for 1 month. A total of 256 (65.3%) patients attended a first follow-up, median 3 months (interquartile range 2-12) after the first visit; 83.1% of patients having received treatment based on mebendazole and/or doxycycline, targeting Wolbachia, became amicrofilaremic, 41.1-78.4% of whom within 12 months from single treatment. CONCLUSIONS: Lack of specific symptoms, together with the inconstant positivity of parasitological and antibody-based assays in the infected population, makes the clinical suspicion and screening for mansonellosis particularly difficult. Prospective studies evaluating prevalence of infection in migrants from endemic areas, infection-specific morbidity, presence of Wolbachia endosymbionts in M. perstans populations from different geographical areas and efficacy of treatment regimens are absolutely needed to optimize the clinical management of infection.

Human Filariasis in Travelers and Migrants: A Retrospective 25-year Analysis at the Institute of Tropical Medicine, Antwerp, Belgium.

BACKGROUND: Information on human filariasis in international travelers is scarce. We describe the epidemiology, clinical presentation, and outcome of these infections in a reference travel clinic over the past decades. METHODS: We reviewed all cases of filariasis diagnosed at the Institute of Tropical Medicine, Antwerp, Belgium, from 1994 to 2018. Diagnosis was obtained by either parasitological methods (confirmed) or strict clinical case definitions (probable). We assessed the characteristics of cases at diagnosis and response to therapy within 3-12 months. RESULTS: A total of 320 patients (median age: 41 years; 71% males) were diagnosed with 327 filarial infections (Wuchereria bancrofti = 6, Onchocerca volvulus = 33, Loa loa = 150, Mansonella perstans = 130, unspecified species = 8). Diagnosis was confirmed in 213/320 (67%) patients. European long-term travelers accounted for 166 patients (52%) and visitors/migrants from tropical countries for another 110 (34%). Central Africa was the likely region of acquisition for 294 (92%) patients. The number of filariasis cases decreased from 21.5/year on average in the 1990s to 6.3/year in the past decade, when loiasis became predominant. Cases reported symptoms in >80% of all filarial infections but mansonellosis (45/123 single infections; 37%). Lymphatic filariasis and onchocerciasis cases responded well to conventional therapy. However, 30% of patients with loiasis and mansonellosis experienced treatment failure (with diethylcarbamazine and levamisole-mebendazole, respectively). CONCLUSIONS: The burden and species distribution of filariasis in travelers evolved in the past decades. Most presentations were symptomatic. Case management would benefit from more effective therapies for loiasis and mansonellosis.

Imported Mansonella perstans infection in Spain.

BACKGROUND: Mansonella perstans infection can be considered one of the most neglected tropical infectious diseases. Very few studies have reported on the clinical picture caused by infection with this nematode. Therefore, our study was aimed to describe the clinical patterns and treatment of imported M. perstans infection by migrants from Africa. METHODS: The present study evaluated a large cohort of migrants who have been diagnosed, examined and treated for imported M. perstans infection at a Spanish reference center (Hospital Carlos III Tropical Medicine Unit, Madrid, Spain) over a 19-year period. Most patients voluntarily attend the emergency unit or are referred from primary care or general hospitals in Madrid. Chi-square test was used to compare the association between categorical variables. The continuous variables were compared by Student's t-test or the Mann-Whitney test. The corresponding regression models were used for multivariate analysis. RESULTS: Five hundred three cases of migrants from tropical and subtropical areas with M. perstans infection were identified. Two hundred sixty-four patients were female (52.5%). The mean age (± SD) was 44.6 ± 18.2 years (range: 16-93 years). The mean time (± SD) between the arrival in Spain and the first consultation was 8.6 ± 18.0 months. The major origin of the patients was Equatorial Guinea (97.6%). Regarding the clinical picture, 257 patients were asymptomatic (54.7%) and 228 were symptomatic (45.3%); 190 patients had pruritus (37.8%), 50 (9.9%) had arthralgia, 18 patients had Calabar-like swelling (3.6%), and 15 (3%) had abdominal pain. Four hundred forty-two (87.9%) migrants had hyper-IgE, and 340 (67.6%) had eosinophilia. One hundred ninety-five patients had coinfections with other filarial nematodes (38.8%), and 308 migrants had only M. perstans infection (61.2%). Four hundred thirty-seven cases (86.9%) had been treated with anti-filarial drugs; 292 cases were treated with one anti-filarial drug, and 145 cases were treated with combined anti-filarial therapy. Additionally, 20 (4%) cases received steroids and 38 (7.6%) cases received antihistamines. CONCLUSIONS: A long series of M. perstans infections is presented in sub-Saharan immigrants whose data indicate that it should be included in the differential diagnosis in patients with pruritus or analytical alterations such as eosinophilia or hyper-IgE presentation, and they also have a high number of coinfections with other microorganisms whose treatment needs to be protocolized.

The Efficacy of Doxycycline Treatment on Mansonella perstans Infection: An Open-Label, Randomized Trial in Ghana.

Treating Mansonella perstans is challenged by the low efficacy of registered antihelminthics. Wolbachia endobacteria provide an alternative treatment target because depletion results in amicrofilaremia in filarial infections with Wuchereria bancrofti and Onchocerca volvulus infections. This open-label, randomized study sought to confirm that i) Wolbachia are present in M. perstans in Ghana and ii) doxycycline treatment will deplete Wolbachia and cause a slow, sustained decline in microfilariae (MF). Two hundred and two Ghanaians with M. perstans infection were randomized into early (immediate) and delayed (6 months deferred) treatment groups, given doxycycline 200 mg/day for 6 weeks, and monitored for MF and Wolbachia levels at baseline, 4, 12, and 24 months after the study onset (= time of randomization and start of treatment for the early group). Per protocol analysis revealed that the median MF/mL in the early group declined from 138 at baseline to 64 at month 4 and further to 0 at month 12. In the delayed group, MF load did not change from a baseline median of 97 to 102 at month 4 but declined to 42 at month 12, that is, 6 months after receiving treatment, trailing the early group as expected. By month 24, both treatment groups had reached a median MF level of 0. After treatment, Wolbachia were depleted from MF by ≥ 1-log drop compared with baseline levels. We conclude that M. perstans in Ghana harbor Wolbachia that are effectively depleted by doxycycline with subsequent reduction in MF loads, most likely because of interruption of fertility of adult worms.

Laboratory Parameters after Treatment for Loa loa and Mansonella perstans: The Experience of a Single Referral Center for Tropical Diseases in a Non-Endemic Area.

Infections due to Loa loa and Mansonella perstans are common yet elusive neglected filariases. Parasitological cure after treatment is very difficult to assess, as adult parasites are not accessible. Therefore, outside transmission areas, patients require a long follow-up period to ascertain the therapeutic outcome, which is impractical for non-sedentary populations such as migrants. We studied the change over time of microfilaremia, eosinophil counts, and antifilarial antibodies tested with a commercial ELISA test (Bordier Affinity Products, Crissier, Switzerland), in a retrospective cohort of patients with confirmed L. loa and M. perstans infections, to evaluate the role of serology in clinical practice. After treatment, all 22 eligible patients diagnosed in our center between 2015 and 2017 reached amicrofilaremia, with microfilarial counts decreasing sharply within 2 months. Paralleling eosinophil counts, antibodies decreased in all patients, 36% of whom reached sero-reversion or near-sero-reversion in < 20 months. These findings suggest that positive serology is not just residual from a past infection, and may be used for diagnosis even when microfilaremia is negative or cannot be performed. Interestingly, antibodies and eosinophil counts increased following some, but not all, re-treatment courses. If the rise in these parameters reflects death of macrofilariae, caution is required in interpreting high eosinophil counts and antibody titers shortly after treatment, as these may reflect no need for further treatment. To optimize patients' management, it is now pivotal to ascertain the interval between treatment and macrofilarial death and therefore whether re-treatments are required for complete clearance of parasites.

Phase III Clinical Trial to Evaluate Ivermectin in the Reduction of Mansonella ozzardi infection in the Brazilian Amazon.

The treatment of mansonelliasis is still a challenge because there are few clinical trials for the treatment of the disease. This double-blind, randomized, placebo-controlled study (phase III clinical trial) was conducted to evaluate the effectiveness of a single oral dose of ivermectin (0.15 mg/kg) in the reduction of the Mansonella ozzardi microfilaraemia and the occurrence of adverse effects in infected people compared with the control group treated with placebo. A total of 49 microfilaraemic patients were randomly selected from the municipality of Lábrea, State of Amazonas, in the Brazilian Amazon. Among them, 40 patients have concluded the study, 19 treated with ivermectin and 21 treated with placebo. In the first and third days after the treatment, all the patients were clinically evaluated, and the diagnostic and quantification of blood microfilariae through blood filtration in polycarbonate membranes was performed. A significant reduction of the microfilaraemia (99.9%) was observed in the patients who received ivermectin. Slight changes in laboratory test results, without clinical importance, were seen in treated and control groups. Our results suggest that ivermectin is effective and safe for the treatment of infections caused by M. ozzardi.

Update on the distribution of Mansonella perstans in the southern part of Cameroon: influence of ecological factors and mass drug administration with ivermectin.

BACKGROUND: Mansonellosis remains one of the most neglected of tropical diseases and its current distribution in the entire forest block of southern Cameroon is unknown. In order to address this issue, we have surveyed the distribution of Mansonella perstans in different bioecological zones and in addition, elucidated the influence of multiple rounds of ivermectin (IVM) based mass drug administration (MDA). METHODS: A mixed design was used. Between 2000 and 2014, both cross-sectional and longitudinal surveys were carried out in 137 communities selected from 12 health districts belonging to five main bioecological zones of the southern part of Cameroon. The zones comprised of grassland savanna (GS), mosaic forest savanna (MFS), forested savanna (FS), deciduous equatorial rainforest (DERF) and the dense humid equatorial rainforest (DHERF). The survey was carried out in some areas with no treatment history as well as those currently under IVM MDA. Individuals within the participatory communities were screened for the presence of M. perstans microfilariae (mf) in peripheral blood by the calibrated thick film method to determine both prevalence and geometric mean intensities at the community level. RESULTS: Apart from sporadic cases in savanna areas, distribution of M. perstans was strongly linked to the equatorial rainforest zones. Before CDTI, the highest mean prevalence (70.0 %) and intensity (17,382.2 mf/ml) were obtained in communities in Mamfes' DHERF areas followed by communities in the DHERF zone of Lolodorf (53.8 % and 7,814.8 mf/ml, respectively). A longitudinal survey in Mamfe further showed that M. perstans infections had reduced by 34.5 % in DERF (P < 0.001) but not DHERF zones after ten years of IVM MDA. Further data from the cross-sectional study revealed that there was a decrease in prevalence in DHERF zones only after ten years of MDA. In DERF zones however, the infection was relatively lower after four years of MDA. CONCLUSIONS: The distribution of M. perstans in the southern part of Cameroon varies with bioecological zones and IVM MDA history. The zones with high prevalence and intensities lie in forested areas while those with low endemicity are in the savanna areas. MDA with ivermectin induced significant reduction in the endemicity of mansonellosis in the decidious equatorial rainforest. In contrast, the prevalence and intensity remained relatively high and stable in the dense humid equatorial rainforest zones even after a decade of mass drug administration with ivermectin. Since it is known that M. perstans down-regulates host's immune system, the findings from this work would be useful in designing studies to understand the impact of M. perstans on host immune response to vaccination and co-infection with other pathogens such as Mycobacterium spp. and Plasmodium spp. in areas of contrasting endemicities.

Mansonelliasis, a neglected parasitic disease in Haiti.

Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting-midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised.

Mansonelliasis, a neglected parasitic disease in Haiti

Reported in Haiti as early as 1923, Mansonella ozzardi is still a neglected disease ignored by the health authorities of the country. This review is an update on the geographic distribution of the coastal foci of mansonelliasis in Haiti, the epidemiological profile and prevalence rates of microfilariae in people living in endemic areas, the clinical impact of the parasite on health and the efficiency of the transmission of the parasite among three Culicoides biting-midge species identified as vectors in Haiti. Additionally, interest in establishing a treatment programme to combat this parasite using a single dose of ivermectin is emphasised.

Sustained clearance of Mansonella ozzardi infection after treatment with ivermectin in the Brazilian Amazon.

Therapy for mansonelliasis is challenging because there is no standard drug recommended for its treatment. This non-randomized study was conducted to evaluate the effectiveness of a single dose of 0.15 mg/kg of ivermectin to reduce Mansonella ozzardi microfilaraemia in infected persons. A total of 74 patients were studied within the municipality of Lábrea, which is located in Amazonas State, Brazil. The patients were treated with ivermectin after detection of the parasite by blood examination. Significant microfilaraemia reduction was observed and its residual effect was maintained for at least 12 months. There was no significant change in the laboratory blood count, hepatic metabolites, and nitrogen-bounding compound excreta dosage values that could compromise the use of this drug, demonstrating that ivermectin has a low toxicity level.

Ivermectin-related adverse clinical events in patients treated for Mansonella ozzardi infections.

We report the occurrence of serious reactions after treatment with oral ivermectin in two patients with Mansonella ozzardi infections. Both had systemic and respiratory symptoms and recovered without sequelae. Follow-up revealed clearance of microfilaremia in both cases, with relapse in one of them. These reactions are well described in the treatment of other filarial infections, but have not yet been reported in the treatment of M. ozzardi. We are now reporting the first such known reactions with this helminthiasis.

Mansonella perstans filariasis in Africa.

Mansonella perstans is a vector-borne human filarial nematode, transmitted by tiny blood-sucking flies (biting midges). It is widespread in many parts of Sub-Saharan Africa and also occurs in parts of Central and South America. Despite the commonness of this parasite very few studies have been carried out on its epidemiology and on the morbidity resulting from it, and only few thorough drug trials have been conducted to look for effective and suitable drugs and drug regimens for treatment and control. Here, we review currently available knowledge on M. perstans infections in Africa, including documented aspects of biology, vectors, transmission, diagnosis, epidemiology, morbidity and treatment. It is concluded that there is an urgent need for more research on this widespread but greatly neglected infection in order to properly assess its public health significance and as a background for identifying and recommending optimal means and strategies for treatment and control.

A randomized trial of doxycycline for Mansonella perstans infection.

BACKGROUND: Mansonella perstans infection is common in areas of Africa where Wuchereria bancrofti, a causative agent of lymphatic filariasis, is endemic. M. perstans is refractory to standard antifilarial therapies. The recent discovery of bacterial endosymbionts (e.g., wolbachia) in most filarial species, including M. perstans, provides new therapeutic options for reducing microfilaremia. METHODS: In an open-label, randomized trial, we recruited subjects with M. perstans microfilaremia, with or without concomitant W. bancrofti infection, from four villages in Mali and randomly assigned them to receive doxycycline, at a dose of 200 mg daily for 6 weeks (106 subjects), or no treatment (110). At 6 months, subjects who were coinfected with W. bancrofti underwent a second random assignment, to treatment with a single dose of albendazole (400 mg) and ivermectin (150 microg per kilogram of body weight) or no treatment. Subjects were monitored daily during the first 6-week study period for adverse events. M. perstans and W. bancrofti microfilarial levels were assessed at 6, 12, and 36 months. RESULTS: At 12 months, 67 of 69 subjects who had received treatment with doxycycline only (97%) had no detectable M. perstans microfilariae per 60 microl of blood, as compared with 10 of 63 subjects who had received no treatment (16%) (relative risk, 6.18; 95% confidence interval, 3.63 to 11.89; P<0.001). At 36 months, M. perstans microfilaremia remained suppressed in 48 of 64 subjects who had received treatment with doxycycline only (75%), a finding that was consistent with a macrofilaricidal effect of doxycycline. Vomiting was more frequent in the doxycycline-treated group than in the untreated group (17% vs. 4%). CONCLUSIONS: These results are consistent with previous findings that M. perstans harbors the intracellular endosymbiont, wolbachia, and suggest that doxycycline is an effective therapy for M. perstans infection. (ClinicalTrials.gov number, NCT00340691.)