Clinical Forms

Clinical forms of leishmaniasis are diverse, representing a complex of diseases:

• visceral leishmaniasis (VL) which affects internal organs and can be fatal;

• post kala‐azar dermal leishmaniasis (PKDL), which arises after visceral infection (Ameen 2007);

• muco‐cutaneous leishmaniasis (MCL), which is a mutilating disease affecting mucous membranes;

• diffuse cutaneous leishmaniasis (DCL), which is a long lasting disease due to a deficient cellular mediated immune response;

• cutaneous leishmaniasis (CL), which is confined to the skin and which can be disfiguring (Desjeux 2004).

Cutaneous leishmaniasis, the most common form and therefore the main focus of this review, also includes zoonotic cutaneous leishmaniasis (ZCL) where the reservoir is a non‐human mammal. Cutaneous leishmaniasis can show at least three clinical forms including acute cutaneous leishmaniasis (ACL), chronic cutaneous leishmaniasis (CCL) and occasionally leishmaniasis recidivans (LR) (Dowlati 1979).

Cutaneous leishmaniasis usually produces skin ulcers on the exposed parts of the body such as the arms, legs and especially the face (WHO 2005). Over 90% of cases of cutaneous leishmaniasis heal spontaneously within 3 ‐18 months (Davies 2003).

In ZCL many patients with acute myeloid leukaemia were reported to have multiple lesions, up to two hundred in number, and one patient had 384 lesions (Dowlati 1979).

In 2 ‐ 5% of cases, ACL becomes chronic or can develop into LR (leishmaniasis recidivans), a persistent presence of parasites that are able to expand and drive a cutaneous lesion around the original lesions during the course of the primary lesions or long after healing (Modabber 2007).

Leishmaniasis recidivans is difficult to treat and leaves extensive scars (Alvar 2006).

Cutaneous leishmaniasis is endemic in more than 70 countries worldwide (Reithinger 2007). The annual incidence of CL is estimated to be 1 to 1.5 million cases with an estimated prevalence of 12 million cases (Ameen 2007). However, it is likely that the number of cases occurring around the world is considerably greater than that officially reported. One reason for this is under‐reporting by affected people who are not accessing or not seeking medical or diagnostic facilities (Desjeux 2004). In several areas of the world there is a clear increase in the number of cases; eg Brazil, Kabul (Afghanistan) and Ouagadougou (Burkina Faso) (Desjeux 2004). Many endemic areas have reported a 500% increase over the past seven years (Roberts 2006). Such increases can be explained in part by improved diagnosis and case notification, but are also a result of inadequate vector or reservoir control, increased detection of cutaneous leishmaniasis associated with opportunistic infections (eg, HIV/AIDS), and the emergence of anti‐leishmanial drug resistance (Reithinger 2007).

Causes and Natural History

The leishmaniases are caused by 20 species of parasites belonging to the genus Leishmania, which are pathogenic for humans. The protozoa are transmitted by the bite of a tiny two to three millimetre‐long insect vector, the Phlebotomine sandfly (WHO 2005) in the Old World and Lutzomyia in the New World (Markle 2004). Approximately thirty sandfly species are proven vectors (Desjeux 2004) with more than 40 additional species probably involved in transmission (Reithinger 2007). Biting an infected animal or human will infect the sandfly and the organisms are passed on when the sandfly bites its next victim (Desjeux 2004; WHO 2005). Humans are usually accidental hosts of these flies; natural hosts include a variety of rodents, small mammals, and dogs (Roberts 2006).

A striking difference occurs between the so‐called Old World (ie, Africa, Europe, and Asia) and New World (ie, the Americas) cutaneous leishmaniases in the ecological context of their respective transmission cycles. Old World cutaneous leishmaniasis usually occurs in open semi‐arid or even desert conditions but New World cutaneous leishmaniasis is still mostly associated with forests (Reithinger 2007).

These sandflies are able to pass through the usual netting used for mosquitoes. Sandflies are found around human habitations and breed in specific organic wastes such as feces, manure, rodent burrows and leaf litter (Markle 2004).

Each species of Leishmania favours one or more animal reservoirs, except Leishmania donovani (Klaus 2003) and Leishmania tropica (Alvar 2006) in which the reservoir is human.

The Leishmania parasite has different life cycle forms called promastigote (with flagellum) and amastigote (without flagellum). Parasites, in the form of amastigotes are taken up from the infected tissues or blood of a mammalian host during feeding by female sandflies. Within the midgut of the sandflies the parasites undergo a change to the promastigote form and multiply. Once the promastigotes are fully developed they migrate from the gut to the sandfly pharynx and proboscis (the insect's tubular feeding organ), where they remain until they are injected into a new mammalian host during a subsequent blood meal. Between 10 to 200 promastigotes enter the skin during each feeding by an infected sandfly. Some of the promastigotes are taken up by the macrophage cells (cells related to the immune system) in the host skin. Within the macrophages the promastigotes transform into amastigotes. When a macrophage becomes filled with amastigotes the macrophage is disrupted. The amastigotes re‐enter the extracellular space and are then taken up again by other macrophages (Klaus 2003).

The incubation period of CL is usually measured in months, but ranges from a few days to over a year (Bryceson 1998). The disease begins as a small red swelling (papule) at the site of the sandfly bite. The papule increases in size and becomes a nodule which eventually ulcerates and crusts over. The ulcer is typically painless unless there is secondary bacterial or fungal infection (Markle 2004). Sometimes, the ulcer is associated with bleeding and itching. Many people think that covering the ulcer delays its healing, and allow it to be exposed to the air. However, this may facilitate transmission of leishmaniasis to others.

Impact

A total of 11.8% of total worldwide DALYs (Disability Adjusted Life Years) by all leishmaniasis occurs in the eastern Mediterranean countries, where CL is concentrated (Modabber 2007).

There is a social stigma associated with the deformities and disfiguring scars caused by this disease that keeps affected people hidden. Victims are mostly children in endemic areas and lesions are frequently on the face. The disfigurement caused by CL scars lead to stigma, social isolation, suffering and barrier to marriage, especially for girls and young women (Modabber 2007). New World CL which is endemic in most countries of Latin America has a dreaded sequel which is mucosal/mucocutaneous leishmaniasis (ML). Unless diagnosed and treated early, this disease can progress to destroy tissues in the nose, mouth and throat and in some cases leads to death. Many suicides or attempts have been recorded due to the stigma associated with ML in Latin America (Modabber 2007).

CL also creates a burden on the national economy. Seventy‐seven percent of men in Ecuador believe CL diminishes their ability to work. The cost of treatment is high and in most cases beyond the means of affected people who are mostly poor (Modabber 2007). On several occasions, epidemics have significantly delayed the implementation of land development projects (WHO 2005). Leishmaniasis has thus become a disease that impedes socioeconomic development.

Diagnosis

For people in endemic areas, or where travellers return from endemic areas, the clinical diagnosis of typical nodules or sores is not difficult. Deeper sores from beneath the skin, sores arising from lymphatic spread or chronic sores in which scarring predominates may present diagnostic difficulties. Confirmation of diagnosis is through microscopic demonstration of the parasite (Bryceson 1998).

Samples are taken by:

• scraping the affected sore (Markle 2004);

• punch biopsy with tissue impression smears (Markle 2004);

• needle aspiration of tissue fluid from the margin of the lesion (Markle 2004).

The parasite is identified by:

• staining with Giemsa and looking under the microscope;

• cultivation of Leishmania species in specific culture media (such as Novy‐MacNeal‐Nicolle (NNN) medium, etc);

• inoculation of suspected specimens to susceptible lab animals (such as hamsters) (Bryceson 1998, Klaus 2003);

• immunological tests such as antibody detection and a highly sensitive polymerase chain reaction test (Markle 2004).

The leishmanin skin test (LST) is a highly specific test and is of great value in epidemiological studies, although it has little clinical use (Pampiglion 1976). LST can be used for epidemiologic surveys, diagnosis in nonendemic areas particularly in recidivant and mucosal forms of CL and for identification of chronic forms of CL (Dowlati 1979).

In LST a delayed hypersensitivity reaction to intradermal crude Leishmania antigen is produced in healing or cured cases of both cutaneous and visceral leishmaniasis. LST could be considered as a simple indicator for Cell Mediated Immunity reaction (Topley & Wilson 2005).

Prevention and Control

Controlling the sandflies which transmit the disease (vector control) in and around the home consists of the use of insecticides (usually pyrethroids) by house spraying or individual protection based on pyrethroid impregnated bed nets (Desjeux 2004). Various repellents, such as dimethyl‐phthalate and imidacloprid/permethrin are also used by people to discourage insect bites (Jia 1990; Mencke 2003). Animal reservoir control for CL is based on the use of poisoning baits and environmental management to control rodents (Desjeux 2004).

The complex epidemiological characteristics of the disease and its transmission have limited the success of these disease control efforts. Vector and reservoir control are not always possible or practical in the case of zoonotic diseases, or require infrastructure beyond the means of the affected population. Even if successful, these measures are not maintained because of the cost (WHO 1990; WHO 2005) and are short lived (Davies 2003).

Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. The relatively uncomplicated Leishmania life cycle and the fact that recovery from infection renders the host resistant to subsequent infection indicate that a successful vaccine is feasible. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunisation with protein or DNA vaccines (Kedzierski 2006).

Vaccination through artificial inoculation of live parasites (leishmanisation) has been used to induce protection. Though efficacious, this practice was abandoned because a small proportion of people developed severe side effects, including chronic lesions (Nadim 1988). However, this old method has been studied again recently (Khamesipour 2005). Researchers have also recently used deep‐freeze L. major promastigotes for immunisation against leishmaniasis according to the World Health Organisation (WHO) protocol in Geneva, 1997 (Mohebali 2003).

Also, attention has been turned to the use of killed (Mayrink 1979; Castes 1994; Dowlati 1996; Bahar 1996; Armijos 1998; Sharifi 1998; Momeni 1999; Velez 2000; Misra 2001; Alimohammadian 2002; Mahmoodi 2003; Mohebali 2004) or attenuated (Daneshvar 2003) parasite vaccines and defined subunit vaccines (Kahl 1989; DeLuca 1999; Kenney 1999; Rafati 2001; Follador 2002; Ivory 2004).

Leishmania are easily cultured, hence the production of vaccine using the parasite or its components are feasible (Modabber 2000). In addition for the past few decades killed parasites have been used as skin test antigens for diagnosis of leishmaniasis in humans. These killed parasites have also been used with or without adjuvants as vaccines or for immunotherapy in clinical studies (Antunes 1986).

Some evidence from experimental, clinical and field studies suggests that anti‐Leishmania vaccines based on killed whole, fractionated or recombinant parasite promastigotes are safe and capable of inducing immunity to leishmaniasis (Mayrink 1985; Antunes 1986).

However, those producing a suitable human vaccine have to consider some practical aspects. For example, the vaccine should be delivered as a single, defined molecule to facilitate compliance with regulatory and manufacturing standards and to lower the overall production costs. Ideally, the vaccine should protect against cutaneous as well as visceral leishmaniasis (Kedzierski 2006). At present there is only one prophylactic live vaccine in population use. This is a mixture of live virulent Leishmania major mixed with killed parasite registered in Uzbekistan (Khamesipour 2006).