LEISHMANIASIS

History

Leishmaniasis has been the cause of great suffering and death for hundreds of years. Representations of skin lesions and facial deformities have been found on pre-Inca pottery from Peru and Ecuador dating back to the first century AD. They are evidence that some forms of leishmaniasis prevailed as early as this period. The discovery of parasites in lesions of cutaneous or visceral leishmaniasis was reported in the late 1800s and early 1900s .

1756;Russel:The first description in English

1898;Borovsky noted the protozoal nature of the organism

1903;Leishman identified the parasite

1903;Donovan described identical organisms in a splenic puncture

Etiology

Leishmaniasis is the result of infection with intracellular protozoan parasites belonging to the genus Leishmania. The organisms are found in two morphologic forms during their life cycle. In humans and other mammalian hosts, they exist within macrophages as round to oval nonflagellated amastigotes and in the arthropod vectors (sandflies) the parasites exist as elongated flagellated promastigotes

About 30 species of sandflies can become infected when taking a blood meal from a reservoir host. In the old world genus Phlebotomus and in the new world genus Lutzomia are responsible for transmitting the disease. Sandflies are small mosquito-like insects 1.5 to 4 mm in length and their small size allows them to pass through ordinary mesh screens and mosquito netting.

Hosts are infected humans, wild animals, such as rodents, and domestic animals, such as dogs. Most leishmaniases are zoonotic (transmitted to humans from animals), and humans become infected only when accidentally exposed to the natural transmission cycle. However, in the anthroponotic forms (those transmitted from human to human through the sandfly vector), humans are the sole reservoir host.

Classification

Leishmaniasis presents itself in humans in four different forms with a broad range of clinical manifestations. All forms can have devastating consequences. Similar to Hansen disease, leishmaniasis is a disease in which the clinical diversity reflects a complex interplay between the virulence of the infecting species and the host's immune response. At one extreme, localized cutaneous disease demonstrates a vigorous immune response, with most cases resolving without intervention. This form of disease exhibits a helper T-cell subtype 1 (TH1) immune response, with interleukin 2, interferon g, and interleukin 12 as the prominent cytokines that induce disease resolution. At the other extreme, with visceral or diffuse cutaneous disease, patients exhibit relative anergy to the Leishmania organism and have a prominent helper T-cell subtype 2(TH2) cytokine profile.

Visceral leishmaniasis (VL), also known as kala azar, is the most severe form of the disease, which, if untreated, has a mortality rate of almost 100%. It is characterized by irregular bouts of fever, substantial weight loss, swelling of the spleen and liver, and anaemia.

Mucocutaneous leishmaniasis (MCL), or espundia, produces lesions which can lead to extensive and disfiguring destruction of mucous membranes of the nose, mouth and throat cavities.

Cutaneous leishmaniasis (CL) can produce large numbers of skin ulcers—as many as 200 in some cases—on the exposed parts of the body, such as the face, arms and legs, causing serious disability and leaving the patient permanently scarred. Diffuse cutaneous leishmaniasis (DCL) never heals spontaneously and tends to relapse after treatment. The cutaneous forms of leishmaniasis are the most common and represent 50-75% of all new cases.

Epidemiology

Geographic Distribution

• The leishmaniases are now endemic in 88 countries on five continents—Africa, Asia, Europe, North America and South America—with a total of 350 million people at risk.

• It is believed that worldwide 12 million people are affected by leishmaniasis; this figure includes cases with overt disease and those with no apparent symptoms. Of the 1.5-2 million new cases of leishmaniasis estimated to occur annually, only 600 000 are officially declared.

• Of the 500 000 new cases of VL which occur annually, 90% are in five countries: Bangladesh, Brazil, India, Nepal and Sudan.

• 90% of all cases of MCL occur in Bolivia, Brazil and Peru.

• 90% of all cases of CL occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia and Syria, with 1-1.5 million new cases reported annually worldwide.
• In Iran, CL is endemic in south, east north and some part of the center of Iran.

• The geographical distribution of leishmaniasis is limited by the distribution of the sandfly, its susceptibility to cold climates, its tendency to take blood from humans or animals only and its capacity to support the internal development of specific species of Leishmania.

Increased Prevalence

• Since 1993, regions that are Leishmania-endemic have expanded significantly, accompanied by a sharp increase in the number of recorded cases of the disease.

• The geographic spread is due to factors related mostly to development. These include massive rural-urban migration and agro-industrial projects that bring non-immune urban dwellers into endemic rural areas. Man-made projects with environmental impact, like dams, irrigation systems and wells, as well as deforestation, also contribute to the spread of leishmaniasis.

• AIDS and other immunosuppressive conditions increase the risk of Leishmania-infected people developing visceral illness. In certain areas of the world the risk of co-infection with HIV is rising due to epidemiological changes.

Leishmania/HIV Co-infection

Leishmania/HIV co-infection is emerging as an extremely serious, new disease and it is increasingly frequent. Leishmania/HIV co-infections are considered a real threat, especially in south-western Europe where between 25% and 70% of adult VL cases are related to HIV

and where 1.5%to 9% of AIDS cases suffer form newly acquired or reactivated VL.

Intravenous drug users have been identified as the main population at risk.

 It is anticipated that the number of Leishmania/HIV co-infections will continue to rise in the coming years and there are indications that cases are no longer restricted to endemic areas. The overlapping geographical distribution of VL and AIDS is increasing due to two main factors: the spread of the AIDS pandemic in suburban and rural areas of the world, and the simultaneous spread of VL from rural to suburban areas.There are important clinical, diagnostic, chemotherapeutic, epidemiological and economic implications of this trend.

• Although people are often bitten by sandflies infected with Leishmania protozoa, most do not develop the disease. However, among persons who are immunosuppressed (e.g. as a result of advanced HIV infections, immunosuppressive treatment for organ transplants, haematological malignancy, auto-immune diseases), cases quickly evolve to a full clinical presentation of severe leishmaniasis.

• AIDS and VL are locked in a vicious circle of mutual reinforcement. On the one hand, VL quickly accelerates the onset of AIDS (with opportunistic diseases such as tuberculosis or pneumonia) and shortens the life expectancy of HIV-infected people. On the other hand, HIV spurs the spread of VL. AIDS increases the risk of VL by 100-1000 times in endemic areas.

This duo of diseases produces cumulative deficiency of the immune response since Leishmania parasites and HIV destroy the same cells, exponentially increasing disease severity and consequences. VL is considered a major contributor to a fatal outcome in co-infected patients. Lately, however, use of tritherapy, where it is available, has improved the prognosis for Leishmania/HIV cases.

• Leishmaniasis can be transmitted directly person to person through the sharing of needles, as is often the case among intravenous drug users. This group is the main population at risk for co-infection. Based on a study done in Spain, Leishmania spp were detected by PCR technique, in 65 (52%) of 125 syringes collected in southern Madrid,  in 1998, and in 52 (34%) of 154 collected in southwestern Madrid in 2000-01.

Specific Problems

• Leishmania/HIV co-infections impose specific difficulties in terms of diagnosis and treatment. The usual clinical features (fever, weight loss, liver and spleen enlargement, inflammation of the lymph nodes) are not always present. The clinical diagnosis can also be made difficult by associated diseases such as cryptosporidium, disseminated cryptococcosis, cytomegalovirus infection or mycobacterial infection.

• The serological diagnosis is falsely negative in 42.6% of co-infected patients. HIV-positive patients have difficulty in producing antibodies against new infectious agents, especially at a late stage or during relapses. Consequently, there is a need to use two or more serological tests and antigens freshly prepared in the laboratory to increase sensitivity.

• Although multiple localizations are frequent (blood, skin, digestive tract, lungs, central nervous system), parasitological diagnosis can be difficult and has to be repeated to orient the treatment. Bone marrow aspirate (BMA) remains the safest and most sensitive technique, but spleen aspirate and liver biopsy are also used. When BMA cannot be performed, the search for Leishmania can be conducted in peripheral blood samples.

• Treatment for co-infected patients is aimed at clinical and parasitological cures and prevention of relapses. Unfortunately, in such patients treatment failure, relapses due to drug resistance and drug toxicity are very common. In south-western Europe, follow-up studies using pentavalent antimonials, the same first-line drug used to treat classic leishmaniasis, show a positive response in 83% of cases. However, 52% of patients relapse within a period of one month to three years, with the number of relapses ranging from one to four.

The main alternative drugs include pentamidine, amphotericin B and amphotericin B encapsulated in liposomes. This encapsulation reduces the occurrence of side-effects, but relapses still occur and the drug remains extremely expensive.

Epidemiological Changes

• Leishmania/HIV co-infections can lead to epidemiological changes which modify the traditional patterns of zoonotic VL. Co-infected patients harbour a high number of Leishmania in their blood so there is also a risk of them becoming reservoirs of the disease (that is, infective for the sandfly vector) as in anthroponotic foci in Bangladesh, India, Nepal and East Africa. Consequently, there is an increased risk of future epidemics.

• Experimentally, sandflies can be infected through a blood meal containing a very small quantity of blood from co-infected patients. The quantity may be less than the content of a needle. As 71.1% of co-infected patients in south-western Europe are intravenous drug users, transmission of Leishmania has occurred through the sharing of syringes in this population group.

Clinical Patterns 

Old world cutaneous leishmaniasis begins as a small erythematous papule, which may appear immediately after the bite of the sandfly but usually appears 2 to 4 weeks later. One or more lesions occur on unclothed part of the body. Lesions may be associated with sporotrichotic spread and usually heal spontaneously. The sequence of nodule, crusting, ulceration and healing with scar formation is common to all the self-healing sores.

Clinical variants of CL:

Diffuse cutaneous leishmaniasis (DCL): Analogous to lepromatous leprosy, individuals with DCL fail to mount a cell-mediated immune response to the Leishmania parasite. Consequently, patients develop multiple widespread cutaneous papules and nodules and are anergic to leishmanin skin testing.

Recidivans cutaneous leishmaniasis (RCL): A relatively uncommon clinical         variant of leishmaniasis, RCL presents as a recurrence of lesions at the site of apparently healed disease years after the original infection.Typically, RCL lesions occur on the face, and RCL presents as an enlarging papule, plaque, or coalescence of papules that heals with central scarring. Relentless expansion at the periphery may cause significant facial destruction similar to the lupus vulgaris variant of cutaneous tuberculosis.

Post kala azar dermal leishmaniasis (PKDL): Endemic to India and the Sudan, this form of leishmaniasis develops months to years after the patient’s recovery from visceral leishmaniasis. Cutaneous lesions demonstrate great variability, ranging from hypopigmented macules to erythematous papules and from nodules to plaques. As in leprosy, the wide clinical spectrum of PKDL reflects the immune response of the individual to the Leishmania organism. Lesions may be numerous and persist for decades. Isolated parasites from the lesions are identical to those causing the original visceral disease.

Diagnosis

Differential diagnosis of LCL is extensive and includes impetigo, pyoderma gangrenosum, deep fungal infection, mycobacterial infection, sarcoidosis, and squamous cell carcinoma. In the endemic areas the clinical diagnosis is not difficult but the definite diagnosis rests on finding parasites in the skin. Usually, making a smear of material from the sore and staining it with Wright’s, Giemsa or Leishman’s stain on a microscope slide best achieve this. In addition, Polymerase chain reaction (PCR) is one of the newest techniques used to identify leishmaniasis and shows significant promise as a method applicable for both detection and speciation. Most research laboratories have reported higher sensitivity and specificity with PCR than with other currently available diagnostic methods.

Treatment

The treatment of leishmaniasis depends on the clinical form of the disease. For 50 years, the mainstay of antileishmanial therapy has been pentavalent  antimony (sodium stibogluconate or meglumine antimonate).

Other measures include freezing, local heat, oral ketoconazole, rifampicin and topical paromomycin. Surgical excision usually is not recommended because of the risk of relapse and cosmetic disfigurement.

To date, no vaccines are available commercially.

The World Health Organization Response

WHO has set the following objectives:

1. To provide early diagnosis and prompt treatment;

2. To control the sandfly population through residual insecticide spraying of houses

and through the use of insecticide-impregnated bed nets;

3. To provide health education and produce training materials;

4. To detect and contain epidemics in the early stages;

5. To provide early diagnosis and effective management for Leishmania/HIV coinfections.

 

Because of the anticipated substantial increase in Leishmania/HIV co-infections, they are among the priorities for WHO's Department of Communicable Disease Surveillance and Response (CSR).

• In 1996, WHO established an initial surveillance system, comprised of 14 institutions in 10 countries. A standardized Case Report Form was elaborated and endorsed by the members of the network, and a Central International Registry was set up within WHO to centralize, process and disseminate information on co-infections.

• In 1998, a new WHO/Joint United Nations Programme on HIV/AIDS (UNAIDS) initiative was launched which helped strengthen the surveillance network; it has been expanded to include 28 institutions, especially in East Africa and the Indian subcontinent (India, Nepal). All member institutions of the network report to WHO on an annual basis. A computerized Geographic Information System (GIS) is used to map and monitor co-infections in a way that permits easy visualization and analysis of epidemiological data.

The evolution of Leishmania/HIV co-infection is being closely monitored by extending the geographic coverage of the surveillance network and by improving case reporting. WHO encourages active medical surveillance, especially in south-western Europe, of intravenous drug users, the main population at risk. Finally, because case notification of leishmaniasis is compulsory in only 40 of the 88 endemic countries, WHO strongly suggests the remaining 48 endemic countries follow suit.

Summery

Leishmaniasis is a disease caused by protozoa, and it affects as many as 12 million people worldwide, with 1.5-2 million new cases each year. Transmitted by the bite of a sandfly, the clinical spectrum of leishmaniasis ranges from a self-resolving cutaneous ulcer, to a mutilating mucocutaneous disease, to a fatal systemic illness. The global incidence of this infectious disease has been increasing during recent years because of increased international travel, human alteration of vector habitats, and concomitant factors that result in increased susceptibility such as HIV infection and malnutrition. Many Leishmania species transmit the disease, and the clinical spectrum, although once believed to be predictable, continues to evolve. Diagnosis may be difficult because of the small size of the protozoa sequestered within macrophages of the skin, bone marrow, and reticuloendothelial system. Therapy has long been a challenge for the more severe forms of the disease and is made more difficult by the emergence of drug resistance. No effective vaccine is available for leishmaniasis.

Bibliography

 

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