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.

Plasmodium vivax and Mansonella ozzardi co-infection in north-western Argentina.

A case of co-infection with Plasmodium vivax and Mansonella ozzardi was detected in a blood sample from a person who had shown symptoms of malaria and lived in a city that was close to the Argentina/Bolivia border. The case was detected during a random revision of thick and thin smears from patients diagnosed with malaria from various towns and cities located in north-western Argentina between 1983 and 2001. Trophozoites of P. vivax were observed in the thin blood smear along with M. ozzardi microfilaria (larval form), which presented a long, slender, pointed anucleate tail and the absence of the sheath. This last characteristic is shared with Mansonella perstans, Mansonella streptocerca and Onchocerca volvulus. More rigorously controlled studies to detect other co-infection cases in the area as well as the possibility of importation from Bolivia into Argentina are currently ongoing. The relationship between the malaria parasite and microfilaria, the potential effect of malaria treatment on the development of M. ozzardi, and the possible impact of this microfilaria on the immunity of a person against P. vivax are all still unknown. This contribution constitutes a point of focus for future studies involving the interaction between the parasites and the potential risk that humans are exposed to.

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.)

Plasmodium falciparum and helminth coinfection in a semi urban population of pregnant women in Uganda.

BACKGROUND: Helminth infections and malaria are widespread in the tropics. Recent studies suggest helminth infections may increase susceptibility to Plasmodium falciparum infection. If confirmed, this increased susceptibility could be particularly important during pregnancy-induced immunosuppression. OBJECTIVE: To evaluate the geographical distribution of P. falciparum-helminth coinfection and the associations between P. falciparum infection and infection with various parasite species in pregnant women in Entebbe, Uganda. METHODS: A cross-sectional study was conducted at baseline during a trial of antihelminthic drugs during pregnancy. Helminth and P. falciparum infections were quantified in 2,507 asymptomatic women. Subjects' socioeconomic and demographic characteristics and geographical details were recorded. RESULTS: Hookworm and Mansonella perstans infections were associated with P. falciparum infection, but the effect of hookworm infection was seen only in the absence of M. perstans infection. The odds ratio [OR] for P. falciparum infection, adjusted for age, tribe, socioeconomic status, HIV infection status, and location was as follows: for individuals infected with hookworm but not M. perstans, 1.53 (95% confidence interval [CI], 1.09-2.14); for individuals infected with M. perstans but not hookworm, 2.33 (95% CI, 1.47-3.69); for individuals infected with both hookworm and M. perstans, 1.85 (CI, 1.24-2.76). No association was observed between infection with Schistosoma mansoni, Trichuris, or Strongyloides species and P. falciparum infection. CONCLUSIONS: Hookworm-P. falciparum coinfection and M. perstans-P. falciparum coinfection among pregnant women in Entebbe is more common than would be expected by chance. Further studies are needed to elucidate the mechanism of this association. A helminth-induced increase in susceptibility to P. falciparum could have important consequences for pregnancy outcome and responses to P. falciparum infection in infancy.

Onchocerca volvulus-specific antibody and cytokine responses in onchocerciasis patients after 16 years of repeated ivermectin therapy.

The recommended control option against onchocerciasis is repeated ivermectin treatment, which will need to be implemented for decades, and it remains unknown how repeated ivermectin therapy might affect immunity against Onchocerca volvulus in the long term. O. volvulus-specific antibody reactivity and cellular cytokine production were investigated in onchocerciasis patients receiving ivermectin (150 microg/kg) annually for 16 years. In treated patients, the T helper type 2 (Th2) cytokine interleukin (IL)-5 and T regulatory IL-10 in response to O. volvulus antigen (OvAg) and bacteria-derived Streptolysin O (SL-O) diminished to levels found in infection-free endemic controls; also, cellular release of Th1-type interferon (IFN)-gamma at 16 years post initial ivermectin treatment (p.i.t.) approached control levels. In ivermectin-treated onchocerciasis patients, IL-5 production in responses to the mitogen phytohaemagglutinin (PHA) decreased, but IL-10 in response PHA increased, and neither attained the cytokine production levels of endemic controls. At 16 years p.i.t., O. volvulus-specific IgG1 and IgG4 subclass reactivity still persisted at higher levels in onchocerciasis patients than in O. volvulus exposed but microfilariae-free endemic controls. In addition, cytokine responses remained depressed in onchocerciasis patients infected concurrently with Mansonella perstans and Necator americanus or Entamoeba histolytica/dispar. Thus, long-term ivermectin therapy of onchocerciasis may not suffice to re-establish fully a balanced Th1 and Th2 immune responsiveness in O. volvulus microfilariae-negative individuals. Such deficient reconstitution of immune competence may be due to an as yet continuing and uncontrolled reinfection with O. volvulus, but parasite co-infections can also bias and may prevent the development of such immunity.

Mansonella perstans causing symptomatic hypereosinophilia in a missionary family.

Mansonella perstans is rarely pathogenic. The rare reports of symptomatic cases, however, include severe complications. Three cases of symptomatic hypereosinophilia with multi-organ involvement are described in a missionary family returning from tropical Africa. Pathogenicity may be related to the induction of hypereosinophilia rather than direct host-parasite interactions.

Helminth infection is not associated with faster progression of HIV disease in coinfected adults in Uganda.

BACKGROUND: We studied a cohort of human immunodeficiency virus (HIV)-infected adults in Uganda who were not receiving antiretroviral therapy, to explore the impact of helminths on HIV progression in areas where antiretrovirals are not available. METHODS: A total of 663 patients were screened for helminths, treated presumptively with albendazole and selectively with praziquantel, and monitored for 6 months. Blood samples were analyzed for CD4+ cell count and HIV-1 RNA. RESULTS: Schistosoma mansoni, hookworm, Strongyloides stercoralis, and Mansonella perstans were the most prevalent helminths. Helminth infection was not associated with higher viral load, lower CD4+ cell count, or faster decrease in CD4+ cell count preceding antihelminthic therapy. The effect of coinfection on HIV disease progression varied with species. CD4+ cell counts were highest in subjects with hookworm and Mansonella perstans infection. For most helminths, effective treatment was associated with greater decrease in CD4+ cell count than in those in whom infection was still present at follow-up. A highly significant decrease in viral load at 6 months was seen in patients with persistent Mansonella perstans infection at follow-up. Mortality was lower in subjects with hookworm infection at enrollment. CONCLUSION: Helminth infection was not associated with more-advanced HIV disease or faster disease progression. Antihelminthic therapy may not be beneficial in slowing HIV progression in coinfected adults.

Epidemiology of concomitant infections due to Loa loa, Mansonella perstans, and Onchocerca volvulus in rain forest villages of Cameroon.

An epidemiological survey was conducted in 16 remote villages of the rain forest of southern Cameroon to ascertain the prevalence and intensity of three species of filariae: Loa loa, Onchocerca volvulus, and Mansonella perstans. We examined 1458 individuals for blood-dwelling microfilariae and 1255 of these were also for the presence of palpable nodules. All the villages surveyed were found highly endemic for onchocerciasis and mansonellosis with prevalence ranging from 28.44% to 87.17% for O. volvulus and 52.48% to 100% for M. perstans. The intensities of infection were also found high for M. perstans with arithmetic means of microfilaremia ranging from 280.94 to 4947.57 mf/ml. The loiasis prevalence was relatively low with value from 2.22% to 19.23%. Males were found more infected than females for the three species of filariae, and the prevalence and intensities of microfilaremia vary differently in males and females at different ages. The three species of filariae displayed different degrees of association in the inhabitants with a low prevalence of co-occurrence between L. loa/O. volvulus and between L. loa/M. perstans. In contrast, there was a high prevalence of co-occurrence between M. perstans and O. volvulus. The implications of the co-occurrence of the three species of filariae in the populations of these remote villages on the intervention programs based on mass treatment with mectizan are discussed.

Transfusional Mansonella perstans microfilariasis.

Mansonella perstans filariasis is widely distributed across the center of Africa and equatorial America. We describe a case of post-transfusional M. perstans microfilariasis in a young child, affected with severe Plasmodium falciparum malaria, admitted in Goundi Hospital in South of Chad. A decrease of M. perstans microfilariasis in the patient's blood was observed, with no subsequent development of either clinical symptoms or eosinophilia. We suggest that, in endemic areas, transfused M. perstans microfilariae may be cleared from the blood over relatively short periods of time. It is likely that only adult worms are responsible for symptoms and eosinophilia, whereas microfilariae in the bloodstream are unable to give clinical manifestations.

Effects of thiabendazole in Mansonella perstans filariasis.

Mansonella perstans is a human filarial parasite distributed across the center of Africa and equatorial America. Although M. perstans infection is asymptomatic in most individuals, a variety of symptoms have been described, including angioedema, pruritus, fever, ocular involvement, and serous cavities pain. Eosinophilia is found in many cases. Treatment with diethyl-carbamazine or mebendazole is often ineffective. We present a study on the effects of thiabendazole in the treatment of symptomatic M. perstans filariasis. Twenty-five patients were treated with thiabendazole at a single dose of 50 mg/kg for children and 3 g for adults. Sixteen out of 25 subjects repeated a second dose a week later. Parasite density, eosinophilia, and symptoms were significantly reduced after both one and two-step therapy in most patients. This study shows that thiabendazole may be effective in M. perstans infection. More studies are needed to determine a more effective dosage, or a putative combination treatment.

Case report: intraocular localization of Mansonella perstans in a patient from south Chad.

A case of Mansonella perstans infection with visual impairment and a retinal lesion is described. After a course of diethylcarbamazine and a further course of mebendazole the symptoms improved and the microfilariae blood concentration decreased. The symptoms and response to antifilarial treatment strongly suggested the intraocular localization of an M. perstans worm.

The prevalence of parasite infestation and house dust mite sensitization in Gabonese schoolchildren.

BACKGROUND: Allergic diseases seem less prevalent in communities in less developed parts of the world, where parasite infections are highly prevalent. Altogether not much is known about the association between chronic infections with tissue and blood-dwelling parasites and atopy. METHODS: In an area in Gabon endemic for blood and tissue parasites, 520 schoolchildren were parasitologically examined and skin prick-tested for a set of common environmental aeroallergens. Levels of allergen-specific IgE and polyclonal IgE were measured. RESULTS: In schoolchildren schistosome and filarial infections increased with age, whereas malaria was more prevalent in younger children. In contrast to allergen sensitization that increased with age, skin test reactivity tended to decline. The number of children with mite-specific IgE antibodies (47%) by far exceeded the number responding to skin prick testing (11%). Mite sensitization was found to be the highest in children infected with schistosomes and/or filariae whereas skin test reactivity was lowest. The multiple logistic regression showed that the risk of a positive skin test was 8-fold higher with increasing levels of mite-specific IgE but was reduced by 72% when infected with blood stage helminths. CONCLUSIONS: Chronic blood and tissue parasite infections that are often capable of modulating immune responses in the host are negatively associated with skin test reactivity in a sensitized population.

Lymphatic filariasis in Uganda: baseline investigations in Lira, Soroti and Katakwi districts.

Baseline epidemiological investigations on lymphatic filariasis were conducted for the first time in Uganda in 3 communities in the districts of Lira (Alebtong area), Soroti (Lwala area) and Katakwi (Obalanga area), located to the north of Lake Kyoga at an altitude of 1000-1100 m above sea level. Individuals from the communities were examined, in April-August 1998, for Wuchereria bancrofti specific circulating antigen (by ICT card test), microfilaraemia (by counting chamber and stained blood-smear techniques) and chronic clinical manifestations of lymphatic filariasis. Endophilic mosquitoes were sampled and dissected for filarial larvae. Prevalences of circulating filarial antigen positivity were 29%, 18% and 30% in the Alebtong, Lwala and Obalanga communities, respectively. Microfilaria (mf) prevalences were 18%, 9% and 21%, and geometric mean mf intensities among mf-positive individuals were 306, 171 and 402 mf/mL blood, in the same communities. Examination of stained blood smears revealed mf of both W. bancrofti and Mansonella perstans, but more than 80% of mf-positive individuals harboured the first of these parasites. Prevalences of hydrocoele in adult (> or = 20 years) males were 28%, 7% and 17%, and prevalences of limb elephantiasis in adults were 9%, 4% and 4%, in the Alebtong, Lwala and Obalanga communities, respectively. Anopheles gambiae s.l. (mainly An. gambiae s.s.) and An. funestus were common in all 3 communities, and showed W. bancrofti infectivity rates of 1.1-1.7% and 1.3-2.9%, respectively. It is concluded that lymphatic filariasis is highly endemic in these high-altitude areas of Uganda, with An. gambiae s.l. and An. funestus being the main vectors.

The diverse expression of immunity in humans at distinct states of Onchocerca volvulus infection.

This study examined the development and persistence of immunity in humans presenting defined states of Onchocerca volvulus infection, i.e. in exposed endemic control individuals without microfilaridermia and clinical disease, in patients with patent or post-patent onchocerciasis, and in patients concurrently infected with Mansonella perstans. Onchocerca volvulus antigen (OvAg)-specific cellular reactivity was significantly diminished in microfilariae (mf)-positive patients, while the highest reactivity was measured in exposed but mf-negative endemic controls, those being free of any clinical signs of onchocercal disease. In patients who became post-patent, responses to OvAg were significantly augmented, but did not approach entirely the magnitude observed in endemic controls. In onchocerciasis patients with concurrent mansonelliasis, cellular unresponsiveness to OvAg persisted, even when mf of O. volvulus were eliminated permanently by repeated ivermectin therapy. Cells from mf-positive onchocerciasis patients produced significantly less interferon-gamma (IFN-gamma) (P < 0.01) and interleukin-5 (IL-5) (P < 0.05) in response to OvAg than those taken from endemic controls or post-patent individuals in whom IFN-gamma and IL-5 production was similarly high. In contrast, both OvAg-driven as well as spontaneous IL-10 secretion was higher in mf-positive patients than in endemic controls or post-patent cases. In all individuals examined, serological recognition of OvAg by immunoglobulins was dominated by IgG4; in mf-positive patients OvAg of 205,000-12,000 molecular weight (MW) were strongly bound. In post-patent individuals, and similarly in endemic controls. OvAg recognition by IgG4 varied from intense (with numerous antigens being recognized) to weak or absent antigen binding. Significantly elevated OvAg-specific IgG isotypes were measured in mf-positive onchocerciasis patients in comparison with endemic controls or post-patent individuals (with the exception of IgG3). IgG1, IgG2 and IgE were higher, but IgG4 was lower in endemic controls compared with post-patent onchocerciasis patients. The ratios of IgG4/IgG1 differed (P < 0.001) between endemic controls and mf-positive or post-patent onchocerciasis patients, with IgG4/IgG1 ratios of R < 3.0 being characteristic for endemic controls and post-patent O. volvulus infection. In conclusion, this cross-sectional immunoepidemiological investigation showed that distinct states of O. volvulus infection correlate with a particular cellular and humoral immune response. The mf-free condition appeared to be associated with a vigorous parasite-specific cellular reactivity and a particular cytokine production profile, while concurrent M. perstans infection depressed OvAg-specific cellular responsiveness. Antibody responses, in all likelihood, reflected the intensity and state of infection, and not the degree of acquired immunity protective against parasite aggregation.

An unexpected guest in follicular fluid.

Parasitic infection as the only or concomitant cause of infertility in Caucasian women is rare. A parasitic infection may also present itself quite unexpectedly as a coincidental finding as shown with this case report. Moving microfilariae of Mansonella perstans were found in the aspirated follicular fluid of a patient who underwent in-vitro fertilization (IVF) with embryo transfer because of tubal pathology due to Chlamydia trachomatis. The patient also appeared to have a Schistosoma infection. To our knowledge, the presence of parasites in follicular fluid has never been reported before. We expect that infertility physicians may be confronted with parasitic infections more often, not only in patients originating from tropical countries but also in Western women as a result of a tendency to travel more frequently to exotic and (sub)tropical countries.

Efficacy of ivermectin in the treatment of concomitant Mansonella perstans infections in onchocerciasis patients.

As part of an ivermectin dose-ranging study of onchocerciasis patients in Togo, 55 onchocerciasis patients with concomitant mansonelliasis received single oral doses either of ivermectin (100 to 200 micrograms/kg body weight) or placebo. As expected, Onchocerca volvulus microfilariae in the skin were greatly reduced in number soon after drug treatment, but microfilariae of Mansonella perstans reacted differently. Microfilarial densities of M. perstans were assessed with a filtration technique both before, and 4 times after, treatment. In untreated patients microfilarial densities were stable until the end of the study at 6 months. In patients receiving ivermectin, microfilarial densities dropped on average to less than 60% of the pre-treatment level and remained there until the final post-treatment examination. This partial reduction was probably not caused by a microfilaricidal effect of ivermectin, but rather by an altered distribution of microfilariae in the peripheral blood and in a suspected microfilarial reservoir.