Leishmaniasis in travelers: A literature review

Summary

Leishmaniasis is a vector-borne protozoan infection whose clinical spectrum ranges from asymptomatic infection to fatal visceral leishmaniasis. Over the last decades, an increase in imported leishmaniasis cases in developed, non-endemic countries, have been pointed-out from a review of the international literature. Among the possible causes are increasing international tourism, influx of immigrants from endemic regions and military operations. The main area for the acquisition of cutaneous leishmaniasis, especially for adventure travelers on long-term trips in highly-endemic forested areas, is represented from South America, whereas popular Mediterranean destinations are emerging as the main areas to acquire visceral variant. Leishmaniasis should be considered in the diagnostic assessment of patients presenting with a compatible clinical syndrome and a history of travel to an endemic area, even if this occurred several months or years before. Adventure travelers, researchers, military personnel, and other groups of travelers likely to be exposed to sand flies in endemic areas, should receive counseling regarding leishmaniasis and appropriate protective measures.

Introduction

Leishmaniasis (or ‘leishmaniosis’) is a vector-borne obligate intracellular protozoan infection (Kinetoplastida, Trypanosomatidae) whose clinical spectrum, depends largely both on parasite species and host immune response. The disease ranges from asymptomatic infection to three main clinical syndromes: visceral leishmaniasis (VL) also known as ‘kala-azar’, cutaneous leishmaniasis (CL), and mucosal or mucocutaneous leishmaniasis (ML) also known as ‘espundia’. Although the disease has been known and studied for a long time, it remains a public health problem worldwide, affecting approximately 12 million people in 88 countries (350 million inhabitants, mainly in remote rural areas and underserved urban areas. Based on geographical distribution, leishmaniasis is divided into ‘Old World’ (southern Europe, Mediterranean basin, Middle East, Asia, and Africa) and ‘New World’ (Latin America) leishmaniasis. The means of leishmaniasis transmission are hematophagous female sand flies (order Diptera, family Psychodidae, subfamily Phlebotominae) of the Phlebotomus genus in the Old World, and of the Lutzomyia genus in the New World. Nevertheless, fewer than 50 of the approximately 1000 species of sand flies worldwide are vectors of leishmaniasis. This could be attributable to the inability of some sand fly species to support the development of parasite infective stages in their gut, and/or a lack of ecological contact with reservoir hosts [1]. Other possible means of transmission of lesser importance are blood transfusions, or in immune-depressed intravenous-drug users, as a result of needle sharing, or following organ transplantation, or via congenital transmission, vertically or mother to child [2]. There are more than 20 Leishmania species known to infect humans. A female sand fly ingests Leishmania amastigotes while blood-feeding, and then transmits the parasite in infective stages (usually assumed to be the metacyclic promastigotes) during a subsequent blood meal. The infective promastigotes inoculated by the sand fly are phagocytosed in the mammalian host by macrophages and related cells, within those cell promastigotes transform into amastigotes and often provoke a cutaneous ulcer at the site of the bite [3].

In the last decade leishmaniasis expanded or emerged in several foci worldwide due to climate and human factors (e.g. deforestation, urbanization) [4], and some models predict that sand flies will further expand with global warming [5]. In addition, the widespread emergence of Leishmania species resistant to pentavalent antimonials in India, where half of VL cases occur globally, as well as the HIV co-infection (in Northwest Ethiopia up to 30% of VL cases are HIV-co-infected), leishmaniasis has become the third most frequent opportunistic parasitic disease after toxoplasmosis and cryptosporidiosis, which compromises control of the disease [6], [7], [8].

Of all the forms of leishmaniasis, CL is the most common. A review of international literature show that in the published cases of imported travel-related leishmaniasis over the past 25 years nearly 80% have concerned CL [9]. According to recent estimates, CL is endemic in 88 different countries, 72 of which are developing nations, placing nearly 350 million people at risk of infection and disease, 1.5 million new cases each year. More than 90% of cases occur in five countries in the Old World (Algeria, Saudi Arabia, Iran, Iraq, and Afghanistan) and two countries in the New World (Brazil and Peru) [2]. CL is more common in rural areas, in settings ranging from rainforests (jungle environments) to arid regions; however it is increasingly reported in urban and suburban areas of the Old and New World, where a number of opportunistic hosts, such as dogs and donkeys, have become the reservoirs of infection, reproducing a pattern similar to the VL caused by Leishmania infantum in the Mediterranean basin [10]. Main species involved in CL are: Leishmania tropica, Leishmania aethiopica, Leishmania major, and L. infantum in the Old World, and parasites belonging to the Leishmania (Leishmania [L.] amazonensis, Leishmania [L.] mexicana, Leishmania [L.] venezuelensis), and Viannia (the Leishmania braziliensis complex, with two species, L. [V.] braziliensis and Leishmania [V.] peruviana, the Leishmania guyanensis complex, with three species, L. [V.] guyanensis, Leishmania [V.] shawi, and Leishmania [V.] panamensis), the Leishmania naiffi complex, with one species, L. [V.] naiffi, and the Leishmania lainsoni complex, with one species, L. [V.] lainsoni) subgenus in the New World (the so-called New World or American CL, ACL). While most of the Old World species cause benign cutaneous disease, New World species cause a spectrum of disease, ranging from mild cutaneous disease to severe mucosal lesions, depending to multiple parameters, including immune status of the host and the infecting species [2]. More in details, manifestations of ACL include acute/localized cutaneous leishmaniasis (LCL), anergic diffuse cutaneous leishmaniasis (DCL), also referred to as disseminated cutaneous leishmaniasis in literature, and mucocutaneous leishmaniasis (ML, see below). In the middle of this broad clinical spectrum is LCL, the most common form of ACL. Whenever Leishmania infection is not controlled (i.e. inadequate treatment, poor compliance, or development of an immunosuppressive state), it can progress to one of two polar forms, either exhibiting cellular hyposensitivity, as in the cases of DCL, or cellular hypersensitivity, as in ML. Additionally, an intermediate/borderline disseminated cutaneous leishmaniasis (ICL or BDCL) pattern has recently been identified as a distinct nosological entity, representing an intermediate between LCL and either of the extreme forms, DCL and ML, similar to DCL for its chronic evolution, tendency to relapse, and partial resistance to standard antileishmanial therapy. Cell-mediated immunity, particularly T-cell-mediated one, plays an important part in the immunologic response to Leishmania infection. A type 1 T helper (T_H1) predominant response is related to cure, while a T_H2 predominant response or the lack of an adequate T_H1 response are both associated with worsening of disease and/or treatment failure. Individuals affected by ACL who manifest with LCL are characterized as immune responders, whereas those who manifest with disseminated disease (i.e., DCL) are described as non-responders. Those who manifest with ICL have an intermediate degree of responsiveness. Looking at the immune response, if LCL develops a T_H1 predominant response, with production of T_H1-related cytokines (mainly IFN-γ and TNF-α), DCL has a T_H2 predominant one, with production of T_H2-related cytokines (mainly IL-4 and IL-10). In contrast, as would be expected, in the ICL subset there is a mixed cytokine profile, with at least partially preserved T_H1 immune response. Any member of the subgenera Leishmania and Viannia represents the possible etiologic agents of LCL. However, L. [V.] braziliensis is regarded as the most important parasite associated with this form of disease in the Americas. In cases of LCL caused by L. [V.] braziliensis the histopathology of the lesions proves a modest infiltration in the skin bordering the ulcerated lesion, and scanty macrophages and parasites, whereas lymphocytes and plasma cells are more frequent in the infiltrate, which has the characteristics of an epithelioid granuloma, similar to that of Old World CL. More rarely, if LCL is due to L. [L.] amazonensis, pathologists can highlight a large infiltration at the edge of lesion, and a dense infiltrate of vacuolated macrophages in the dermis, which are full of amastigotes and give the infiltrate the appearance of a macrophagic granuloma. In cases of DCL, L. [L.] amazonensis and L. [L.] mexicana are the main causative agents. In the dermis, the histopathological feature is a severe infiltration of macrophages containing abundant amastigotes, whereas lymphocytes and plasma cells are rare, giving also to DCL lesion the typical aspect of a macrophagic granuloma. Finally, parasites of the subgenus Viannia, especially L. [V.] braziliensis, have been identified as the major etiologic agent of ICL. The histology of this picture normally shows a nodular infiltration of lymphocytes and plasma cells in the dermis, with rare macrophages and parasites (Table 1) [11], [12].

Although ML develops in just a small number of patients with New World CL, its course is chronic and may be life-threatening. Mucocutaneous lesions are typically not seen in L. Mexicana Leishmania complex infections, except (rarely) in L. [L.] amazonensis infections. They are quite frequent complications of the L. Viannia complex infections and are seen more commonly in L. [V.] braziliensis than in L. [V.] guyanensis or L. [V.] panamensis infections [13]. In particular, as above-mentioned, three clinical outcomes may derive from L. [V.] braziliensis infection, probably due to the complex interactions with the host's imune system. In most cases a cellular immune reaction in the inoculation site could lead to the elimination of the parasites and to acquisition of immunity. Clinically, this reaction results in LCL, characterized by skin nodules, ulcers, and sometimes regional lymphadenopathy. If cellular immune response is inadequate, a cutaneous dissemination of the parasite can occur (DCL): usually these patients have lower levels of IFN-γ and TNF-α production than the ones suffering from localized forms, thereby provoking less activation of the monocyte/macrophage immune reaction. In a subset of patients, the parasites spread via hematogenous or lymphatic routes and invade the oropharyngeal mucosa, leading to ML. Here a tubercoloid granulomatous reaction, with abundant infiltrate of lymphocytes and plasma cells, with few histiocytes and scanty parasites, causes thickening of the upper airway walls, sometimes causing lumen obstruction, associated with necrosis of the cartilaginous structures (Table 1). The paucity of amastigotes in the granulomas, the strongly positive Leishmania test result, and the high level of circulating IFN-γ and TNF-α suggest an exaggerated hypersensitivity reaction to the parasite, largely the result of a prolonged antigen-specific T_H1 activation [14], [15]. As additional pathogenic mechanism, Ronet et al. reported that metastasizing, but not non-metastatic strains of L. [V.] guyanensis, have high burden of non-segmented dsRNA Leishmania viruses (Leishmania RNA Viruses, LRV). These Leishmania viruses have been classified as Totiviridae, which includes RNA viruses detected in other protozoa, such as Trichomonas vaginalis and Giardia lamblia, and a variety of fungi, including Saccharomyces cerevisiae. Totiviruses have a small unsegmented dsRNA genome, between 5 and 7 kb in length, which encodes a capsid protein and a capsid-RNA dependent RNA polymerase (RDRP) fusion protein essential for their replication. Viral dsRNA is sensed by the host Toll-like Receptor 3 (TLR3), thereby inducing, via activation of the signaling TRIF (TIR-domain-containing adapter-inducing interferon-β) cascade, a pro-inflammatory response, with production of several cytokines (IL-6, TNF-α), chemokines (CCL5 and CXCL10), and NO, by iNOS activation via NFκB, then exacerbating and diffusing the disease. In addition, the authors detected an early upregulation of IFN-β, which is typically a sign of an anti-viral immune response [16].

VL is endemic in more than 60 countries in tropical and subtropical areas, as well as in Mediterranean countries. It has an annual global incidence of approximately 2 million cases, and an increase of 500,000 cases yearly, 90% of which concern six countries only – India, Nepal, Bangladesh, Ethiopia, Sudan, and Brazil [17]. L. infantum in the Mediterranean basin, Leishmania donovani in the Indian subcontinent, Asia, and eastern Africa, and Leishmania chagasi (L. infantum MON 1) in South America are the main causes of VL. Nowadays the most widespread is L. infantum, found from the People's Republic of China to the New World [18]. In Mediterranean countries and in South America, the disease is zoonotic and affects mainly infants and young children [19]. However, in the Mediterranean basin, an increasing rate of immune-compromised and immune-suppressed adult individuals has been noted [7], [20], [21], such as HIV co-infected patients and those under any immunosuppressive therapies. In these countries stray and domestic dogs and abundant sand flies are the main reservoir for infection, and the VL cycle is sustained in well-defined foci by a high prevalence (up to 25%) of canine leishmaniasis. Consequently, in these areas there is a large market for prophylactic drugs and treatment of canine leishmaniasis [22], [23]. In the Indian subcontinent and Africa, VL is anthroponotic (human-to-human transmission through sand flies, without the involvement of a reservoir host) and affects both adults and children [2].

Over the last decade there has been an increase in imported cases in developed, industrialized, non-endemic countries, in association with increasing international tourism, military operations, influx of immigrants from endemic countries, and HIV-infected subjects [18], [24], [25], [26], [27], [28], [29], [30], [31], [32]. This article reviews travel-acquired leishmaniasis with a focus on epidemiology, clinical presentation, diagnosis, and treatment. We researched the PubMed database for the period from 1980 through December 31, 2013, using the words ‘leishmaniasis’, ‘imported’, ‘travelers’, and ‘travel-acquired’. Articles presenting original data on imported leishmaniasis cases were included in our review, and review articles were also studied. We found and examined 44 articles presenting original data on travel-acquired leishmaniasis [18], [24], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65].