Leishmaniases and Schistosomiasis Comorbidity Potential in Kenya: The Need for Follow Up Studies

There are potential overlapping distributions of the protozoan parasite Leishmania and the parasitic helminth Schistosoma mansoni in eastern Africa most notably in endemic regions in the Sudan and Kenya. In murine model studies, the Th1-Th2 model of CD4+ T helper cell differentiation is a well-established paradigm for understanding the basis of protective versus pathogenic immune responses in the concomitance state that result in enhanced pathological changes and impaired parasite resolution. In complementation to the experimental studies, the concern for presages of human leishmaniases and schistosomiasis co-infections occurring is increased by their chronicity, displacement of people between endemic areas owing to conflict, climatic changes due to human activities, the spread through irrigation, pisciculture, water conservation schemes and human mobility in pursuit of economic dynamics and resources. Based on diseases prevalence, epidemiology and analyzing the associated risk factors undercurrents, several portents of comorbidity in Kenya are pinpointed. Taking into consideration the limited local resources and diminished surveillance of the areas affected by the two neglected tropical diseases, the discourse concludes that elimination of the diseases is still a challenge. There is need for pilot studies and/or elaborate field surveillance of concomitance and development strategies to mitigate the impending defy in Kenya and beyond.


Introduction
In the developing world, leishmaniases, caused by obligate intracellular kinetoplastid protozoa of the genus Leishmania, are endemic [1,2] and schistosomiasis, caused by parasitic trematodes (schistosomes) have widely been reported [3][4][5]. Infection by Leishmania can result to visceral leishmaniasis (VL) or kala-azar, mucocutaneous leishmaniasis (MCL) and cutaneous leishmaniasis (CL) depending on the infecting species [6]. Statistical reports indicate that more than 12 million people are estimated to have leishmaniases worldwide. There are 2 million new cases every year, a number that is growing, and 350 million people are considered to be at risk [7]. The disease affects the poorest populations in 88 countries, majority being in the developing nations [7]. Schistosomiasis is the collective name for infection by one or more of five Schistosoma species adapted to humans namely S. mansoni, S. japonicum, S. haematobium, S. mekongi and S. intercalatum or by species adapted to other mammals which can occasionally infect humans which include S. matheei and S. magrobowei [8,9]. Majority of schistosomiasis cases worldwide are attributed to three species: S. mansoni and S. japonicum (which cause the intestinal disease) or S. haematobium (responsible for the urinary form of the disease), named according to the site preferred by the adult worms [8]. It is estimated that over 600 million people worldwide are at risk of schistosomiasis whereas close to 200 million are actually infected continuously or intermittently mainly in rural agricultural and periurban areas [8]. The need for frequent re-treatment limits success of control efforts with core concern in Sub-Saharan Africa, which harbours about 85% of all schistosomiasis in the world [9].
One line of argument indicates that the interactions between the helminth and protozoan parasites could affect both entities [18], while others argue that the helminth/protozoan coinfection prompts leishmaniases development without any effect on the helminth parasite [19][20][21]. This bias may reflect the greater human disease burden imposed by leishmaniases compared to helminths [22], and the ongoing need to understand and evaluate what causes variability in leishmaniases infection outcomes.
Interactions among parasitic agents commonly alter disease severity and transmission dynamics [23][24][25]. Co-infecting parasites may interact either positively (facilitation) or negatively (competition) via a range of mechanisms including resource competition, immune-mediated interactions and direct interference [16,22,23]. To date, studies of helminth-protozoa concomitance have focused largely on immune-mediated mechanisms, no doubt largely due to the known immunomodulatory effects of helminths. Using the immune response mechanism, two major pathways have been proposed by which helminths might release parasites from immune pressure and thereby facilitate their replication, both of which involve the dampening of pro-inflammatory immune responses [26][27][28][29][30][31]. Thus it has been suggested that by polarizing immune responses towards Th2-type effector mechanisms, helminths will diminish the proinflammatory Th1-type mechanisms needed to down modulate Leishmania in concomitance.
These suggest that helminth co-infection might thus impair the mechanisms necessary to control and/or modulate leishmaniasis. The current immunomodulatory account is in concurrence with observation in murine models, where comorbidity of L. major and S. mansoni exacerbated lesions development compared to mice infected with L. major alone [18][19][20]32]. The action of helminth infection affecting the immune response of the host, may increase protozoa multiplication significantly thus enhancing leishmaniasis severity [19,20,22].
As yet, the concern for portents of leishmaniases and schistosomiasis co-infections occurring is prompted by their chronicity, displacement of people between endemic areas due to conflict, climatic changes due to human activity, the spread through irrigation, pisciculture, water conservation schemes and human mobility in pursuit of economic dynamics and resources [11,14,23,24]. Based on the diseases pathognomonic implications in concomitance, prevalence, epidemiology and analyzing the associated risk factors undercurrents, portents of comorbidity in Kenya are pinpointed.

Epidemiology and distribution of leishmaniases in Kenya
In Kenya the leishmaniases have been known to be endemic in some parts as far back as early in the 20 th century where both CL and VL have been identified [6,[33][34][35]. The visceral form is present in 70 countries, with East Africa having approximately 30,000 cases per year, while new foci are appearing at an alarming rate and incidences are on the increase within the region [7]. A lack of surveillance systems and the frequency of misdiagnosis especially confusion with malaria mean that true incidence is underestimated [2,5]. The expected annual cases in Kenya average 600 annually though in epidemic years caseloads can rise to over 1,000 [33,36]. The sandfly vectors Phlebotomus martini and P. orientalis have been identified in endemic areas [6,33] [6,33,37,38]. The majority of patients in these foci were nomads who grazed their cattle over the border area however Somali refugees in Kenyan refugee camps were also affected [39,40].
There are reports of post kala-azar dermal leishmaniasis (PKDL) that can occur in patients who have been successfully treated and recovered from kala-azar [9,10]. Increased cases of PKDL were reported at Kacheliba health centre in West Pokot county between 2007 and 2009 [33,38].
Cutaneous leishmaniasis is present in at least 88 countries, with an estimated annual incidence of 1.5 million cases worldwide [7]. It was first described in Kenya in 1969 and its distribution is diverse ranging from semi-arid lowlands, river valleys and highland plateaus. The aetiological agents for CL include L. major which has been reported in Baringo; L. tropica in Laikipia, Samburu, Isiolo, Nakuru and Nyandarua counties while L. aethiopica has been reported in the Mt Elgon area [6,37,38,[41][42][43]. In Kenya, P. duboscqi and P. guggisbergi have been identified to be the vectors of L. major and L. tropica respectively while P. pediffer, P. longipes and P. elgonensis have been implicated as vectors of L. aethiopica [6,33]. CL has been described to be more endemic in Naivasha, Nakuru county and in Laikipia county, and an outbreak of at least 50 cases of CL was reported from Gilgil (Nakuru county) in April 2009 [36,38]. Baringo county is a unique foci as both VL and CL are known to occur in the area [6,38,42].

Epidemiology and distribution of schistosomiasis in Kenya
In Sub-Saharan Africa, human schistosomiasis (bilharziasis) is caused mainly by S. mansoni and S. haematobium whose intermediate hosts are freshwater snails in the genera Biomphalaria and Bulinus, respectively [8,9]. In humans, these blood flukes reside in the mesenteric and vesical venules and have a life span of many years and daily produce large numbers of eggs, which must traverse the gut and bladder tissues on their way to the lumens of the excretory organs [8,9].
Many of the eggs remain in the host tissues, inducing immunologically mediated granulomatous inflammation and fibrosis while heavy worm burdens may produce hepatosplenic disease in S. mansoni (and S. japonicum in China and southeast Asia), and urinary tract disease in S. haematobium [8,9].
In Kenya schistosomiasis is endemic along the coastal belt, Lake Victoria regions of western, Machakos and Kitui counties [44,45]. It has been estimated that over 3.5 million people are infected with S. mansoni in endemic areas of Taita-Taveta, Kitui, Machakos, Homa Bay, Siaya and Kisumu counties particularly along the shore of Lake Victoria (lake Victoria basin) for the later three [38,[46][47][48][49]. In Taveta (Taita-Taveta

The paradigm of immunology in concomitance
The Th 1 -Th 2 classic of CD4+ T helper cell differentiation is a well-established paradigm for understanding the basis of defensive versus pathogenic immune response in L. major and S. mansoni co-infections. In these studies L. major is considered as an amenable model for studying  [53][54][55][56]. The progressive shift towards Th 2 is believed to down modulate the inflammatory response induced by egg deposition mainly in the liver that causes granuloma formation and tissue damage [54]. In laboratory animal studies, mice co-infected with S. mansoni/L. major or L. donovani showed impaired ability to resolve L. major or L. donovani infections, respectively [53,57,58]. In the co-infected mice, Th 1 and Th 2 responses were counter-regulatory by focusing on disease progression and responses development [53,58]. Thus concomitant infection of S. mansoni/L. major or L. donovani suggests that Th 2 immune response induced by S. mansoni is protective for S. mansoni infection while the same response is associated with disease exacerbation in L. major or L. donovani infection, as Th 1 immune response induced by L. major or L. donovani does not appear to alter Th 2 response to S. mansoni [6,7,53,57,58]. The resolution mechanism is majorly characterized by induction of specific IFN-γ releasing CD4+ T cells while the failure to cure is associated with elevated levels of IL-4, IL-10 and IL-13 with low IFN-γ responses from Leishmania-specific CD4+ T cells in complementation of other immunological dynamics [56,59,60,61].
In studies on mammalian immunology to leishmaniases the role for IFN-γ as evidence in the control of Leishmania infection emanates from research demonstrating that IFN-γ knockout (KO) mice fail to cure infection [62]. In experimental studies it has been revealed that L. major infections genetically resistant mice develop a dominant CD4+ T helper 1 (Th 1 ) response which is characterized by IFN-γ secretion, whereas in susceptible mice the dominant response is a CD4+ T helper 2 (Th 2 ) as described by levels of interleukin (IL)-4, IL-5 and IL-13 secretion [55,56]. In studies between coinfection of leishmaniases and schistosomiasis the immune response and infection consequence led to the conception that the balance of Th 1 to Th 2 responses determines the outcome of the disease progression [55,63]. The peril modeled by the concept provided the basis for studies of co-infections between leishmaniases and schistosomiasis [53,54,57,58].

Kenya situational analysis on concomitance
Water resources expansion takes place in most parts of the world inclusive of Kenya, at different scales and at a rapid pace [10,11,14,50] concern is further coupled by the fact that population trends have immensely changed where Nakuru county accounts for (1,603,325) 4.15% of the republic population thus being the fifth most populated county out of the 47 counties [68]. Naivasha and its environs is a well-known agribusiness zone and a popular tourist centre attributed to its bird life, beauty and water-sport activities [50]. Cutaneous leishmaniasis has been described to be more endemic in Naivasha constituency of Nakuru county with further reports in April 2009 indicating an outbreak with at least fifty CL cases from Gilgil constituency of Nakuru County [36,38]. Based on agroindustry and tourism activities within and around Naivasha and the need for manpower either as fully employed or self-employed in a quest to promote tourism and other agricultural activities like floriculture with the aim of economic gains for life sustainance, portents for co-infections cannot be underestimated. Apparently no pilot/surveillance study has been considered to investigate possible mixed infections among the predominant groups of migrants who migrated and continue to relocate from schistosomiasis endemic areas to Naivasha and its vicinities in Nakuru county, where they have since established their economic lifeline with visits back to their ancestral land.
Reports by [6,42] 52,69]. This is in appreciation of the concern that water conservation and utilization projects have the capacity to influence human mobility and settlement patterns while providing ideal habitats for vector snails [14]. In an effort to stop desertification and make semi-arid areas more productive, small dam-building schemes are being encouraged [14,69]. Baringo county being no exception such dams have been built where Chemoron dam is outstanding as one of the most valuable. As yet, development and management of water resources in tropical and subtropical climate zones has often resulted in transmission intensification and/or introduction of schistosomiasis into previously non-endemic areas [14,22] while schistosomiasis is considered a sensitive pointer disease for monitoring ecological transformations, as it is extensively distributed and infection rates can be transformed promptly [14]. Distribution patterns and location of the two parasitic diseases in Kenya are shown in Figures 1 and 2 respectively [70][71][72][73].
Despite the geographical variability in distribution patterns of leishmaniases and schistosomiasis, the land reclamation dynamics pointed [69], would definitely lead to the presence of pockets of leishmaniases and schistosomiasis coexistence resulting impelled co-infections in and around Machakos county [14]. The concern is by the fact that leishmaniasis caused by L. donovani and schistosomiasis caused by S. mansoni are endemic in various localities of this county as previously described [32,33,36,[44][45][46]. Moreover, the imminent risk is with due regard to the geographical variability in the distribution of the two parasitic diseases where in Kenya leishmaniasis due to L. donovani is endemic in arid and semi-arid regions [36]. These are the areas known to be low lying at altitude bellow 800 metres above sea level and categorized as Agro-Ecological Zones five and six experiencing an annual precipitation that does not exceed 300mm. The areas thus stands out to be among the core zones targeted in land reclamation policy like pisciculture, irrigation schemes and construction of dams for water conservation [14,23,24,52,69]. It follows that migrants between leishmaniases and schistosomiasis endemic zones within the counties would prospectively be attracted to working and settling in these areas as a result of economic opportunities as attested by previous findings [14] hence prompting possible mixed infections. The fears for development of water utilization projects occasioning spread of schistosomiasis in an otherwise non-endemic area has been confirmed in Mwea Tebere Irrigation Schemes where S. mansoni has increased rapidly and the disease is well established.

Conclusion
The overlap in the distribution patterns of the two parasitic diseases with regard to human activities, economic factors, effects of co-infection based on mammalian immunology paradigm, parasitic burdens, pathological changes and the government projects to make arid and semi-arid