Open access peer-reviewed chapter - ONLINE FIRST

Biology of the Human Filariases

Written By

Jesuthas Ajendra, Achim Hoerauf and Marc P. Hübner

Submitted: January 25th, 2022 Reviewed: January 28th, 2022 Published: March 25th, 2022

DOI: 10.5772/intechopen.102926

IntechOpen
Parasitic Helminths and Zoonoses - From Basic to Applied Research Edited by Jorge Morales-Montor

From the Edited Volume

Parasitic Helminths and Zoonoses - From Basic to Applied Research [Working Title]

Prof. Jorge Morales-Montor, Dr. Víctor Hugo Del Río-Araiza and Dr. Romel Hernández Bello

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Abstract

Filarial nematodes are parasitic worms transmitted by blood-feeding insects. Mainly found in tropical and subtropical areas of the developing world, diseases such as lymphatic filariasis and onchocerciasis represent major public health issues. With millions of people infected and billions at risk of infection, these diseases can stun economic growth and impair the life quality, hence the WHO classified both lymphatic filariasis and onchocerciasis as Neglected Tropical Diseases. The lesser known filarial disease loiasis is not only affecting millions of people, but represents a huge obstacle during mass drug administration programmes targeting other filarial diseases. Even less is known about mansonellosis, potentially the most widespread of the human filariases, but underestimated due to the lack of clinical symptoms. Large scale intervention as well as mass drug administration programmes are undertaken with the long term goal of eliminating the filarial diseases lymphatic filariasis and onchocerciasis. However, there is still neither a vaccination nor short term macrofilaricidal treatments available. The following chapter will encompass the different filarial diseases, the biology of the parasite and their vector, the epidemiology as well as pathology of the filariases, highlighting the impact of these diseases is still immense and further research in understanding and combating these diseases is needed.

Keywords

  • Brugia
  • filariasis
  • ivermectin
  • Loa loa
  • loiasis
  • lymphatic filariasis
  • Mansonella
  • mansonellosis
  • neglected tropical diseases
  • Onchocerca volvulus
  • onchocerciasis
  • parasitic diseases
  • Wolbachia
  • Wuchereria bancrofti

1. Introduction

Listed as a Neglected Tropical Disease (NTD) by the WHO, lymphatic filariasis (LF) is a debilitating infectious disease of the developing world. This disease is caused by three species of lymph-dwelling filarial nematodes, Wuchereria bancrofti, Brugia malayiand Brugia timori(see Table 1). These worms are transmitted by mosquitoes and infections can lead to severe clinical manifestations such as elephantiasis, hydrocele, and lymphedema. It is these serious outcomes, which makes LF one of the leading causes of disability in the endemic regions, ultimately impairing life quality and stunning economic growth. Due to the massive negative effect LF has on public health, the WHO coordinates programmes with the aim to eliminate LF as a public health problem in 80% of the endemic countries by 2030 [1].

1.1 Biology of the parasites

The three species of filarial nematodes causing LF are transmitted to its human host by different mosquito species. W. bancroftiis transmitted by mosquitos of the genera Aedes, Anopheles, Culexand Mansonia. B. malayiby Mansoniaand Anopheles spp., and B. timoriis transmitted by Anopheles barbirostris[2, 3, 4]. To date, no reservoir host is known, but subperiodic forms have been found in domestic and wild animals such as cats and monkeys. Development and replication of the filarial nematodes requires both the mammalian host and the arthropod vector. During the blood meal of the mosquito infective L3 larvae are transmitted into the mammalian host. These L3 larvae reach lengths up to 1.5 mm and 18–23 μm in diameter. Within their host, the L3 larvae migrate to the lymphatics, where they molt and become adult worms within 5–18 months. In these filarial nematodes display sexual dimorphism with females being longer than their male counterparts. Females of W. bancroftiare 8–10 cm long and between 0.24–0.30 mm in diameter, while males reach 4 cm in length and up to 1 mm in diameter. Compared to W. bancrofti, Brugia ssp. adult worms are smaller in length with females measuring 4.3–5.5 cm in length and 130–170 μm in diameter and males reaching 1.3–2.3 cm in length and 70–80 μm in width. When gravid, female worms release sheathed microfilaria (MF) in the lymphatic vessels that drain into the blood stream. The MF of W. bancroftiare larger in size compared to those of Brugia ssp.. W. bancroftiMF are 244–296 μm long and 7.5–10 μm wide, while BrugiaMF are 177–230 μm and 5–7 μm wide (see Table 2). MF release by female worms follows a nocturnal or diurnal periodicity that is in tune with the biting behavior of the mosquito vector in the endemic area [5]. While W. bancroftiand B. malayimostly follow a nocturnal periodicity with peak MF blood counts around midnight, diurnal patters have been observed in the Pacific regions, where Aedesmosquitoes (e.g. Aedes polynesiensis) are the common vector [6]. This coordinated behavior between parasite and vector is a great example of co-evolution. Estimations for the life span for adult female worms of the aforementioned filarial nematode species range between 5 and 10 years, MF have a lifespan of 6–24 months [7, 8]. Female worms produce up to several thousand MF per day which remain in the lymphatics or in blood vessels, preferably under the skin. During a blood meal, MF are ingested by the female mosquitos. The MF penetrate the midgut and thereby shed their sheaths and migrate on to the thoracic muscles, where they molt twice and develop to the infective L3 stage. The L3 migrate through the haemocoel to the mosquito’s proboscis and from there is transmitted to the mammalian host during a blood meal of the mosquito. The development rate of the larvae within the mosquitoes is temperature-dependent and takes between 10 and 12 days [3, 9, 10, 11]. Of note, no sexual reproduction or replication occurs within the arthropod vector.

DiseaseCausative agentVectorInfection rate (estimations)Geographical distribution
Lymphatic filariasisWuchereria bancrofti, Brugia malayi, B. timoriAedes spp., Anopheles spp., Culex spp., Mansonia spp.,65 millionAfrica, South and Southeast Asia, South America, Pacific Islands
OnchocerciasisOnchocerca volvulusSimulium spp.,20.9 millionSub-Saharan Africa, South America, Yemen
LoiasisLoa loaChrysops spp.10 millionWestern and Central Africa
MansonellosisMansonella perstans, M. streptocerca, M. ozzardiCulicoides spp., Simulium spp., Ceratopogonidae114 millionSub-Saharan African, Central and South America

Table 1.

Overview of the human filarial diseases.

Overview of the human filarial diseases, their causative agents with the nematode-transmitting arthropod vectors as well as estimations of currently infected people and the endemic regions for the disease.

SpeciesResidency of adult wormsSize of adult wormsMicrofilariaePresence of WolbachiaMajor severe forms of pathology
Wuchereria bancroftiLymphatic vessels and lymph nodes; scrotal tissue♂4 cm
♀ 8–10 cm
Blood, nocturnal, sheathed, 244–296 μmYesLymphangitis, elephantiasis, hydrocele
Brugia malayiLymphatic vessels and lymph nodes♂ 1.3–2.3 cm
♀4.3–5.5 cm
Blood, nocturnal, sheathed, 177–230 μmYesLymphangitis, elephantiasis
Brugia timoriLymphatic vessels and lymph nodes♂ 1.3–2.3 cm
♀4.3–5.5 cm
Blood, nocturnal, sheathed, 177–230 μmYesLymphangitis, elephantiasis
Onchocerca volvulusSubcutaneous nodules♂ 2–5 cm,
♀ 33–70 cm
Skin (upper dermis), unsheathed, 220–360 μmYesBlindness, dermatitis, Sowda
Loa loaSubcutaneous tissue♂ 3–3.4 cm,
♀ 4–7 cm
Blood, diurnal, sheathed, 230–300 μmNoCalabar swelling, Eye worm, Angioedema,
Mansonella streptocercaDermal skin layer♂ 1.7 cm,
♀ 2.7 cm
Skin (upper dermis), unsheathed, 180–240 μm?Mild dermatitis
Mansonella perstansPeritoneal, pleural, and pericardial cavity♂ 4.5 cm,
♀ 7–8 cm
Blood, unsheathed, 200 μmYesMainly asymptomatic
Mansonella ozzardiPeritoneal and pleural cavity♂ 2.6 cm,
♀ 3.2–6 cm
Blood and skin, unsheathed, 207–232 μmYesMainly asymptomatic

Table 2.

Overview of the human-pathogenic filarial nematodes.

This table gives an overview over the discussed filarial nematodes species with facts about their biology, size and associated disease pathology.

1.2 Epidemiology

Currently, an estimated 858 million people live in 50 endemic countries [12, 13]. Of these, 65 million people are infected with LF. The majority of these infections, around 90%, are thereby caused by W. bancrofti. An estimated 19 million cases with hydrocele and 17 million lymphedema cases exist, leading to 1.3 million disability-adjusted life years (DALYs) [12, 14, 15]. Most infections with W. bancroftioccur in South and Southeast Asia as well as in Sub-Saharan Africa, but also Central and South America, the Middle East as well as the Pacific Islands are endemic regions. B. malayihas its distribution in South and Southeast Asia, found in India, Indonesia, Thailand, Vietnam, Malaysia, and the Philippines. B. timoriis limited to Eastern Indonesia and Timor-Leste. Despite the wide distribution of LF, the prevalence rate has been decreasing in many areas, mainly due to the impact of the Global Programme to Eliminate Lymphatic Filariasis (GPELF). This programme has even led to the elimination of LF in several countries including Togo, Egypt, Maldives, Sri Lanka, Thailand, Cambodia, Cook Island, Marshall Islands, Niue, Palau, Tonga, Vanuatu, Vietnam, Japan, Korea and China [16, 17]. In the last two decades, GPELF has distributed more than 8.2 billion treatments, ultimately leading to this success. GPELF has ended in 2020, but MDAs targeting LF are still ongoing in 45 endemic countries. While the initial goal to globally eliminate LF by 2020 was missed, GPELF has created a good foundation for endemic countries to achieve the goal which the WHO has stated in their NTD roadmap 2021–2030: to eliminate LF as a public health problem in 80% of the endemic countries by 2030 [14, 18, 19]. Further major challenges for the future are increasing population numbers in endemic countries and the associated unplanned urbanization combined with poor sanitary [20].

1.3 Pathology

LF is a chronic and persistent disease, but the majority of infected individuals remain asymptomatic and do not develop clinical symptoms. However, LF can cause a broad spectrum of clinical manifestations including the most severe forms seen in patients with elephantiasis or hydrocele. The most common symptoms are lymphedema of the legs, lymphangitis, elephantiasis, and only in W. bancrofti-infected individuals, hydrocele [21, 22]. Interestingly, even asymptomatic patients display some degree of subclinical disease with microscopic haematuria/proteinuria, dilated lymphatics and presence of scrotal lymphangiectasia. The most prevalent symptoms are caused by the presence of worms and their products in the lymphatic system, which leads to the induction of endothelial cell proliferation and lymphangiectasia, the dilatation of lymphatic vessels. Furthermore, host proteins such as vascular endothelial growth factors, matrix metalloproteinases and angiopoietins are involved. Studies have demonstrated that lymphedema development is associated with genetic risk factors and nucleotide polymorphisms for genes encoding for the proteins mentioned above [23, 24, 25]. The dilated lymph vessels and the associated impaired lymph function leads to lymph fluids no longer being pumped against gravity, resulting in elevated tissue pressure. Progression of lymphedema can take many years during which leg skin thickens and loses elasticity, develop deep folds accompanied with development of dermatosclerosis and skin lesions. The lesions additionally can lead to secondary bacterial and fungal infections, further accelerating the development of chronic and severe lymphedema and elephantiasis [26, 27, 28]. Hydrocele is a common clinical symptom in men infected with W. bancrofti. Hydrocele is characterized by fluid accumulation inside the tunica vaginalis and swelling of the groin and scrotal area. Acute hydrocoel is a result of worm death, both naturally and medically, leading to temporary clogging of the lymphatics due to disintegrating worms [29], whereas chronic hydrocoel develops after years of infection due to impaired lymph transport. A rare, but serious manifestation of LF is the so-called tropical pulmonary eosinophilia (TPE). TPE is caused by immunological hyperresponsiveness to MF in the lungs, associated with coughing and wheezing, extremely high eosinophil counts and high levels of serum IgE. TPE can lead to further manifestations such as lymphadenopathy as well as spleno- and hepatomegaly [30].

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2. Onchocerciasis

Another neglected tropical disease caused by a filarial nematode is onchocerciasis, also known as river blindness. This disease is caused through infections with Onchocerca volvulus, a filarial nematode transmitted by bites of Simuliumblackflies (see Table 1). These blackflies breed usually along fast-flowing and oxygen-rich rivers, hence the term river blindness. Similar to LF, onchocerciasis is a major public health problem in endemic areas due to the risk to develop severe dermatitis, vision impairment and blindness. With new diagnostic tools and the aid of MDAs, onchocerciasis was successfully eliminated in many foci of its endemic region [31]. The WHO targets elimination of transmission for onchocerciasis, set for 2022 in the Americas and for 12 African countries by 2030 [31].

2.1 Biology of the parasite

The life cycle of O. volvulusis similar to the LF-causing nematodes. Humans harbor the adult worms while blood-feeding arthropod vectors transmit the larval stages. Onchocerciasis is closely associated with fast-flowing rivers that serve as breeding grounds for Simuliumblackflies. The predominant Simuliumvector in Africa is S. damnosum, with S. naeveidriving transmission in parts of East and Central Africa [32, 33, 34]. In South and Central America, the disease is transmitted mainly by S. ochraceum[35] with other species have been active in transmission before elimination of the disease in most countries [36]. Female blackflies transmit the infectious L3 stage of O. volvulusduring the blood meal into the human body. Within 10 days, the L3 larvae molt once to become L4, which then persists in the host for 6–12 months before molting into an adult worm. The adult worms reside in so called onchocercomata, subcutaneous nodules commonly located around the hip regions of an infected person, but also on head and torso [36]. Onchocercomata are granulomatous reactions around the adult worms, they are painless for the infected person and have a diameter of 0.5–3 cm. They often consist of separate chambers with thick fibrous walls and cellular infiltration around the adult worms residing in the chambers. The ratio of females and males residing in a nodule is approximately 3:1. The worms mate here and gravid females produce and subsequently release thousands of unsheated MF into the subcutaneous tissue [37]. Female worms are long-lived, with their reproductive life span being an estimated 9–11 years, in extreme cases up to 15 years [38, 39]. The MF of O. volvulusare 220–360 μm long and 5–9 μm wide, female adult worms are 33–70 cm long and 270–440 μm wide, adult males are significantly smaller with 19–42 mm length and a width of 130–210 μm (Table 2). MF migrate and reside within the host’s skin for 6–30 months and can be taken up by the aforementioned insect vector during a blood meal. MF do not exhibit any form of periodicity. Therefore skin snips for diagnostics can be collected at any time. The MF can also be found in the lymphatics, sputum, urine and blood and it is their migration into the ocular regions which causes ocular pathology. Within the blackflies, the MF penetrate the membranes of the mid gut and migrate through the haemolymph where they then settle in the syncytial cells of the thoracic longitudinal flight muscles. The MF molt twice to become the infectious L3 larvae [40]. Similar to other human-pathogenic filariae, O. volvuluscontain the endosymbiontic bacteria Wolbachia. These bacteria are found in the hypodermis and are essential for filarial development, embryogenesis and survival [41, 42]. Depleting these endosymbionts using doxycycline leads to inhibition of filarial embryogenesis and death of adult worms, currently representing the macrofilaricidal drug for onchocerciasis [43].

2.2 Epidemiology

As of 2017, 20.9 million individuals were infected with O. volvulus[15]. Of these, 14.6 million are cases of severe forms of skin disease and 1.2 million were suffering from visual impairment and blindness, accounting for an estimated 205 million DALYs [15, 35]. 99% of all onchocerciasis cases are found in 31 countries of tropical sub-Saharan Africa. Rigorous Ivermectin distribution programs have eliminated onchocerciasis in most areas in South and Central America. Isolated transmission sites of this disease exist in the border region of Brazil and Venezuela as well in the western parts of Yemen [1, 35]. Taken together, 218 million people live in areas that are endemic for onchocerciasis [1]. The endemicity of onchocerciasis can be classified in hypoendemic, mesoendemic and hyperendemic areas according to the MF prevalence rates. In hypoendemic areas, less than 30% of the patients have microfilaridermia [44], in mesoendemic areas microfilaridermia is 30–60% and nodules are detectable in around 20% of the patients [44]. In hyperendemic areas with more than 60% microfilaridermia, 30–40% of patients have skin pathology. This classification is a very helpful tool to predict effects of treatment and vector control programmes as well as transmission dynamics [45]. As such, the activity of the Onchocerciasis Control Programme and the African Programme for Onchocerciasis Control (APOC) focused mainly on mesoendemic to hyperendemic areas, so areas where the disease risk is the highest [44]. Since its launch in 1995, the APOC has prevented an estimated 8.2 million onchocerciasis associated DALYs from 1995 to 2010 and another 9.2 million DALYs by 2015 [46]. However, in future hypoendemic areas must be included meet the formulated goal of onchocerciasis elimination. Based on the success of APOC and the following ESPEN (the Expanded Special Programme to Eliminate Neglected Tropical Diseases) program, the WHO targets the elimination of the transmission of onchocerciasis by 2030 as part of their roadmap 2021–2030 [1, 13].

2.3 Pathology

The vast majority of individuals infected with O. volvulusare associated with mild clinical symptoms. The adult worm-containing nodules contribute little to morbidity but can be uncomfortable and cosmetically bothersome. Individuals with onchocercomata formation, high parasite burden and mild dermatitis are referred to as generalized onchocerciasis (GEO). Clinically significant onchocerciasis results from inflammatory responses to MF and its Wolbachiain the skin and the eyes. Early symptoms of O. volvulus-induced dermatitis are itching or rash due to immune responses against dead or dying MF. While the rash can disappear shortly after, in some cases the rash persists and results in intense pruritus with secondary infections with bacteria or fungi due to extensive scratching. As a consequence, repeated inflammation can lead to chronic onchodermatitis including large papules. Chronic skin inflammation can lead to severe dermatological changes including loss of elasticity, lichenification and thickening of skin (“lizard skin”) as well as depigmentation and hyperpigmentation (“leopard skin”) [47]. The most severe form of skin pathology is “Sowda”, which presents hyperpigmented papules and plaques and local lymphadenopathy, accompanied by enlarged lymph nodes with prominent follicular hyperplasia [48, 49, 50, 51]. This disease manifestation is called hyperreactive onchocerciasis (HO). interestingly, HO patients usually harbor low worm burden, but exhibit increased immune effector mechanisms [48]. These increased effector responses eliminate the MF, however simultaneously elicit dermatitis and the “Sowda” pathology [52]. Besides the skin pathology, onchocerciasis is commonly associated with blindness. In fact, onchocerciasis is the second most prominent infectious cause of blindness in the tropics. Loss of vision is due to immune responses against dead or dying MF and its exposed Wolbachiaendosymbionts in the cornea and anterior chamber with keratitis and iridocyclitis, respectively. Opacity develops from the corners of the cornea to the center and permanent exposure to inflammation can lead to irreversible sclerosing keratitis which can develop into blindness [53, 54]. Laboratory studies have demonstrated a role for the Wolbachiaendosymbionts in the ocular pathology of onchocerciasis [55]. Dying MF release Wolbachiawhich leads to infiltration and activation of fibroblasts, dendritic cells and macrophages which in turn induce neutrophil recruitment in a chemokine-dependent manner [54]. The neutrophilic responses, mostly degranulation but potentially also the release of DNA-mediated trap formation results in degradation of the corneal matrix. This leads to corneal haze, which can cause visual impairment and in worst cases blindness. The exact route of how the MF get into the eye is still unclear, but authors suggested that blood sheaths of the posterior ciliary arteries as well as cerebrospinal fluids as entry points [56, 57].

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3. Loiasis

Commonly known as the “African eye-worm”, the filarial nematode Loa loais the causative agent of Loiasis (Table 1). While this disease is not yet listed as a NTD by the WHO, it still represents a public health issue in endemic regions. It especially became prominent because Ivermectin and diethylcarbamazine (DEC) treatment during MDA programmes against LF and ivermectin MDA for onchocerciasis can lead to in co-infected individuals with high L. loaMF loads. Loiasis is also known under names like Calabar swelling, fugitive swelling and filaria lacrimalis and in contrast to other filarial nematodes, L. loadoes not possess Wolbachia[58, 59].

3.1 Biology of the parasite

Like mentioned before, loiasis is caused by the tissue-dwelling nematode L. loa. This worm gets transmitted through a bite of deer fly species Chrysops silacea, C. dimidiateand C. langi, which are restricted to Africa [60, 61]. Similar to other vector species, deer flies transmit infective L3 during a blood meal into their host. Humans are the only known host for L. loaalthough in vivoexperiments are possible with Drills (Mandrillus leucophaeus)and immunocompromised mice [62, 63]. Upon entering the host, the L3 migrate through the subcutaneous tissues and molt to adult worms. Adult female of L. loacan reach lengths of 40–70 mm and are 0.5 mm wide while males are smaller with 30–34 mm lengths and 0.35–0.43 widths. Fecund females release sheathed MF (230–300 μm) that are found in peripheral blood but also in spinal fluid, urine, lung and sputum (Table 2). Lifespan estimations of adult worms are rare, but range from at least 9 years to as long as 15–21 years [64]. Adapted to their insect vectors, L. loaMF are diurnal, so appear in the peripheral blood during the day. They reside overnight in the lung tissues. During another blood meal, the deer flies ingest the MF. The MF lose their sheaths and migrate from the midgut into the thoracic muscles of the arthropods. Upon developing into the L3, the larvae migrates to the proboscis of the fly to get transmitted during the next blood meal [60, 61].

3.2 Epidemiology

Loiasis is restricted to the rain forest areas of 12 countries of Western and Central Africa. These are namely Angola, Cameroon, the Central African Republic, Chad, the Republic of Congo and the Democratic Republic of Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria, Sudan and South Sudan [65]. Although large sections of these countries have low or no prevalence of loiasis, an estimated 14 million people reside in high-risk areas, where the prevalence of L. loais greater than 40%. An estimated 10 million people are currently infected with Loa loa[64, 65]. The vector species are more common during the rainy season and usually bite during the day [66]. But these insects can also be found in rubber and palm oil plantations as well as mangrove swamps [67]. Travelers are more likely to become infected if they are exposed to bites for many months.

3.3 Pathology

The majority of infected individuals remain asymptomatic. However, clinical symptoms of loiasis may take years to develop and due to the lack of severe pathology, this disease is even more neglected [68, 69, 70, 71]. One common clinical symptom is the Calabar swelling, a localized angioedema caused by transient subcutaneous swellings which mark the migratory course of the nematode [70]. Interestingly, only around 16% of endemic patients develop this symptom, which are usually located on the face, limbs or joints [27]. It is hypothesized that these swellings are a result of an allergic reaction to the migrating adult filariae or MF [71]. Associated symptoms also include local or disseminated pruritus, urticaria and restricted movement patterns. Symptoms usually resolve after 2–4 days, but they can persist or even reoccur [71]. L. loais known as the “African eye-worm” because of its migration across the eye. This eye migration is found in 10–20% of infected individuals and can result in inflammation, itching, light sensitivity, congestion and severe pain [69]. Similar to the aforementioned symptoms, these signs of infection usually last for several days and the ensuing damage is not permanent. Due to the removal of high MF loads, patients may also present proteinuria and hematuria. Other described, but rare pathologies include inflammation of the lymph glands [72], arthritis [73], scrotal swellings [74], eosinophilic lung infiltrates [75] and endomyocardial fibrosis [71]. Attention to loiasis was raised due to reports about severe adverse effects including fatal cases of encephalopathy after ivermection or DEC treatment during MDA for LF or onchocerciasis [76, 77, 78, 79]. These serious events were connected with patients with high peripheral blood MF loads of L. loa(>30,000 MF/ml) and the associated inflammatory responses to dying MF [80, 81, 82]. Therefore, in regions where onchocerciasis and LF elimination programmes are ongoing, the co-endemicity with L. loarepresents a major obstacle [20, 83], leading to a test-and-not-treat scenario. Currently, the focus in these areas is on alternative strategies including a better understanding of the micro-epidemiology, integrated vector management and new L. loatests [84].

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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, Mansonellainfections 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. ozzardiand M. streptocerca(Table 1) as well as the newly discovered molecular clade of M. perstansnamed 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. perstansinfections. Transmission of M. perstansis associated with midges of the genus Culicoides. M. streptocercaand M. ozzardican also be transmitted by Simuliumblackflies and M. ozzardiis additionally transmitted by Ceratopogonidaemidges in South America and the Caribbeans [87, 88, 89]. The life cycle of the Mansonellaspecies 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. perstansare 70–80 mm long and 120 μm wide, males are smaller, reaching 45 mm in length and being 60 μm wide. M. ozzardiis smaller and more slender than M. perstans, reaching 32–61 mm for females and 24–28 mm for males. M. ozzardialso 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. ozzardiand 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, 91, 92]. MF of Mansonellaspecies do not exhibit periodicity.

4.2 Epidemiology

More than 600 million people live at high risk of infection with M. perstansin 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. perstansinfections 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. perstansinfections 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. streptocercaare the tropical rainforests of West, Central and Eastern Africa. M. ozzardiis 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. perstansand M. ozzardiare usually asymptomatic and only transient itching, skin swellings and rashes occur. M. streptocercawas reported to induce dermatological pathology similar to O. volvuluswith 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, 101, 102]. Serological tests to diagnose Mansonellainfections are not yet available. The current method for diagnosis is identifying the unsheated MF in blood (M. perstansand M. ozzardi) and skin biopsis (M. streptocercaand M. ozzardi).

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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. loapatients 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. loaco-infection is doxycycline. A treatment for four weeks with 200 mg/kg of doxycycline is sufficient to clear the Wolbachiaendosymbionts, leading to a permanently inhibited filarial embryogenesis. L. loaworms 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 Wolbachiaendosymbionts using doxycycline is also a proven treatment for O. volvuluspatients. Similar to LF, depleting Wolbachiain O. volvulusleads to permanent inhibition of filarial embryogenesis and death of adult worms after 1.5–2 years [110, 111, 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 Wolbachiain 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. loaco-endemic areas, but the co-infection represents a major challenge going forward. For mansonellosis, treatment and success of treatment differs between the three Mansonellaspecies. M. ozzardiMF 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. streptocercaMF load [99]. On the other hand, single treatment of ivermectin or albendazole had very small or no effect on M. perstansmicrofilaremia [94, 126]. MF were however cleared in clinical trials using 200 mg doxycycline for 6 weeks [127].

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Written By

Jesuthas Ajendra, Achim Hoerauf and Marc P. Hübner

Submitted: January 25th, 2022 Reviewed: January 28th, 2022 Published: March 25th, 2022