**4. Mansonellosis**

Mansonellosis is caused by four different species of the nematode genus *Mansonella*. Knowledge about epidemiology, pathology and even just the general biology of the parasite is very limited. Mansonellosis is not listed as a NTD and further research is urgently needed not only in understanding the immune response of infected patients, but also in developing better diagnostic tools. In contrast to the aforementioned filarial diseases, *Mansonella* infections lack a distinct clinical picture and infections appear mild or asymptomatic—a feature that probably comes with an optimal adaptation to the human host. Currently, mansonellosis can be considered the most neglected of the human filarial diseases.

#### **4.1 Biology of the parasite**

Mansonellosis is caused by four species of *Mansonella*, named *Mansonella perstans*, *M. ozzardi* and *M. streptocerca* (**Table 1**) as well as the newly discovered molecular clade of *M. perstans* named *Mansonella sp.* "DEUX" [85, 86]. Latter could represent a new species with a pathogenic role. It has been detected only in febrile children in Gabon [86]. Most of our knowledge about mansonellosis is based on *M. perstans* infections. Transmission of *M. perstans* is associated with midges of the genus *Culicoides*. *M. streptocerca* and *M. ozzardi* can also be transmitted by *Simulium* blackflies and *M. ozzardi* is additionally transmitted by *Ceratopogonidae* midges in South America and the Caribbeans [87–89]. The life cycle of the *Mansonella* species is similar to the other tissue-dwelling nematodes. L3 get transmitted onto the skin during the blood meal of the insect vector and they penetrate into the bite wound. The L3 eventually develop into adult worms which reside in body cavities like the peritoneum, the pleura and the pericardium. Female worms of *M. perstans* are 70–80 mm long and 120 μm wide, males are smaller, reaching 45 mm in length and being 60 μm wide. *M. ozzardi* is smaller and more slender than *M. perstans*, reaching 32–61 mm for females and 24–28 mm for males. *M. ozzardi* also resides in subcutaneous tissues. Gravid females release unsheated MF, which are sub-periodic for *M. perstans*, meaning they are present in the blood at all times, and non-periodic for *M. ozzardi* and *M. streptocerca* (MF size: *M. perstans;* 200 μm long and 4.5 μm wide, *M. ozzardi:* 207–232 μm long and 3–4 μm wide and *M. streptocerca:* 180–240 μm long and 3–5 μm wide, **Table 2**). The MF can be taken up again by their vectors during a blood meal and there they migrate from the midgut to the thoracic muscles to develop from L1 to L3 [85, 90–92]. MF of *Mansonella* species do not exhibit periodicity.

#### **4.2 Epidemiology**

More than 600 million people live at high risk of infection with *M. perstans* in 33 countries of sub-Saharan Africa as well as in tropical regions of Central and South America. Studies have also brought up evidence for *M. perstans* infections by migrants from Africa living in Spain [93]. It is estimated that 114 million individuals in total are infected with *M. perstans*. While only a few epidemiological studies have been carried out for *M. perstans* infections so far, it has been shown that MF prevalence rates are higher in adults than in children and that males are more frequently infected than females [94]. Endemic areas for *M. streptocerca* are the tropical rainforests of West, Central and Eastern Africa. *M. ozzardi* is found in South America and in the Caribbean. Also in these areas, a high prevalence is suggested. A recent study from Ecuador showed a high prevalence of >20% for *M. ozzardi* [95]. Although once again the actual number of infected patients is unknown, up to 70% of patients in endemic areas are MF+ [96]. Transmission of mansonellosis is strongly associated with the abundance and seasonal occurrence of the vector. The vector species themselves rely on aquatic or semi-aquatic habitats, animal dung as well as banana stems, rotting fruits or cacti that are required as breeding sites and essential for insect development [97, 98].

#### **4.3 Pathology**

Generally, mansonellosis is not associated with severe clinical symptoms and is therefore not considered a public health problem. Infections with both *M. perstans* and *M. ozzardi* are usually asymptomatic and only transient itching, skin swellings and rashes occur. *M. streptocerca* was reported to induce dermatological pathology similar to *O. volvulus* with spotty depigmentations around thorax and shoulders, coinciding with areas where MF are often detected [99]. Further clinical studies also report symptoms like fever, headache, tiredness, joint pain and lymph node enlargement [100–102]. Serological tests to diagnose *Mansonella* infections are not yet available. The current method for diagnosis is identifying the unsheated MF in blood (*M. perstans* and *M. ozzardi*) and skin biopsis (*M. streptocerca* and *M. ozzardi*).

### **5. Current treatments and future perspectives**

The United Nations Sustainable Development Goals and the WHO NTD road map 2021–2030 stated the goal of confirmed elimination of transmission for onchocerciasis and as a public health problem for LF by 2030. MDAs with ivermectin in combination with albendazole within Africa, or diethylcarbamazine (DEC) plus albendazole outside of Africa for LF and ivermectin alone for onchocerciasis were used. As mentioned above, the goal of eliminating LF by 2020 was missed by WHO's GPELF. However, over 8 billion doses of the annual MDA treatments were distributed to more than 923 million people. The result is that 17 countries are currently under surveillance to confirm the elimination of LF transmission [18, 19, 103, 104]. The main intervention strategy for LF consists of annual, single dose MDAs with ivermectin plus albendazole or DEC plus albendazole targeting the MF stage. These treatments do not efficiently kill the adult worms, but removes MF from peripheral blood and inhibit MF release for a few months [105, 106]. A new approach for LF in areas that are that are not co-endemic for onchocerciasis and loiasis, is the now WHO-recommended MDA using a triple therapy. This therapy consists of a single dose of ivermectin (200 μg/kg), DEC (6 mg/kg) and albendazole (400 mg) [107]. The triple therapy was shown to reduce microfilaremia for more than 2 years and may have some macrofilaricidal efficacy. While the triple therapy can be seen as a game changer for LF, it is not recommended in co-endemic areas for onchocerciasis and loiasis. DEC can lead to severe adverse effects in onchocerciasis patients and *L. loa*

#### *Biology of the Human Filariases DOI: http://dx.doi.org/10.5772/intechopen.102926*

patients with high MF loads can experience severe adverse effects due to ivermectin [107]. In loiasis co-endemic areas, people with high MF loads have to be identified and excluded from treatment, or pretreated with albendazole. In onchocerciasis co-endemic areas the MDAs consist of a combination of ivermectin and albendazole. A treatment that can be used safely in patients with LF and *L. loa* co-infection is doxycycline. A treatment for four weeks with 200 mg/kg of doxycycline is sufficient to clear the *Wolbachia* endosymbionts, leading to a permanently inhibited filarial embryogenesis. *L. loa* worms are not affected by this treatment since they do not harbor *Wolbachia*. Doxycycline also slowly kills the adult worms [108]. Furthermore, doxycycline treatment has been shown to improve lymphedema pathology, probably due to its immunomodulatory and anti-inflammatory properties. For the treatment of lymphedema, doxycycline should be given daily at 200 mg/kg for 6 weeks, with intervals every 12–24 months [109].

Targeting the *Wolbachia* endosymbionts using doxycycline is also a proven treatment for *O. volvulus* patients. Similar to LF, depleting *Wolbachia* in *O. volvulus* leads to permanent inhibition of filarial embryogenesis and death of adult worms after 1.5–2 years [110–112]. No MF-induced adverse effects are observed and MF clearance happens over time due to natural removal of MF combined with the lack of filarial embryogenesis. Macrofilaricidal efficacy is achieved with 200 mg/day for 6 weeks. In order to accelerate the clearance of MF, doxycycline treatment can be combined with a single dose of ivermectin. The disadvantage of doxycycline is that its use is not recommended in pregnant as well as breast-feeding women and in children below the age of 8. Current research is focused on identifying anti-wolbachials with shorter treatment regimens. As such, the tylosin analogue ABBV-4083 is currently tested in phase 2 clinical studies with onchocerciasis patients [113, 114]. Current WHO supported MDA for onchocerciasis rely on ivermectin [1]. Treatment with this macrocyclic lactone (150 μg/kg) leads to clearance of MF and a temporary inhibition of female embryogenesis [115]. This results in interruption of transmission for several months [116]. However, ivermectin has no macrofilaricidal effect and has to be repeated every 6–12 months for the fecund life span of *O. volvulus*, which means for 10 years or more. Additionally, ivermectin treatment is—similar to doxycycline—not indicated in pregnant and breast-feeding women as well as in little children, although circumstantial evidence suggests that it has been inadvertently administered millionfold in early yet undetected pregnancies without overt pathologies [117]. Furthermore, side effects caused by ivermectin-induced dying MF can lead to inflammatory immune responses resulting in rashes, fever, and itching skin. Yet, in comparison to DEC, adverse effects caused by ivermectin treatment are less severe as compared to permanent visual impairment which has been reported following DEC treatment [118]. More recently, another macrocyclic lactone has been registered for onchocerciasis treatment—moxidectin. It works similar to ivermectin with clearing MF and inhibiting filarial embryogenesis. However, moxidectin leads to an extended absence of lasting up to one year [119], so that it may replace ivermectin in some settings in the future. Another drug which has successfully passed the clinical phase I trials and is currently evaluated for its macrofilaricidal and long-term sterilizing activity in onchocerciasis patients is emodepside [120].

In contrast to LF and onchocerciasis, loiasis cannot be treated with anti-wolbachials such as doxycycline due to the lack of *Wolbachia* in *L. loa* [59]. The standard treatment is DEC, given at 5–10 mg/kg for 2–4 weeks, clearing microfilaremia with some macrofilaricidal efficacy. A single oral treatment of ivermectin also clears microfilaremia. However, both these treatments can lead to severe adverse effects associated with

high MF counts in patients [121]. Adverse effects range from fever, nausea and itching (especially with DEC) to life-threatening events such as neurological symptoms, encephalopathy, coma and even death after ivermectin treatment. Therefore it is recommend that patients with more than 20,000 MF/ml are not treated with ivermectin. Patients with high MF loads can instead be treated with 200 mg albendazole twice a day for 21 days [122]. The risk of these aforementioned serious adverse effects is also one of the major obstacles during onchocerciasis elimination programs. Before treatment with ivermectin, patients require a so-called "test-and-not-treat" measure [123]. MDA activities are still continuing in *L. loa* co-endemic areas, but the co-infection represents a major challenge going forward. For mansonellosis, treatment and success of treatment differs between the three *Mansonella* species. *M. ozzardi* MF are not susceptible for DEC treatment, but a single ivermectin dose leads to reduction of MF counts [124]. For *M. streptocerca*, DEC was demonstrated to eliminate both MF and adult worms, but side effects such as severe pruritus and urticaria has been reported [125]. A single treatment of ivermectin has led to long-lasting reduction of *M. streptocerca* MF load [99]. On the other hand, single treatment of ivermectin or albendazole had very small or no effect on *M. perstans* microfilaremia [94, 126]. MF were however cleared in clinical trials using 200 mg doxycycline for 6 weeks [127].
