Recent epidemiologic studies indicate that leishmaniasis in the Americas is far more abundant and of greater public health importance than was previously recognized. The disease in the New World is caused by a number of different parasite species that are capable of producing a wide variety of clinical manifestations. The outcome of leishmanial infection in humans is largely dependent on the immune responsiveness of the host and the virulence of the infecting parasite strain. This article reviews current concepts of the clinical forms, immunology, pathology, laboratory diagnosis, and treatment of the disease as well as aspects of its epidemiology and control. Recommendations for future research on the disease and its control are made.

Leishmaniases of the New World: current concepts and implications for future research.

One of the more serious clinical forms of leishmaniasis occurs in espundia when the mucosae of the upper respiratory passages are inflamed. This complication is a metastasis from a skin lesion caused by Leishmania braziliensis braziliensis (Lbb) although cases have been described associated with other leishmanial species. Epidemiological data suggest that a detectable mucosal metastasis occurs in fewer than 5% of patients infected with Lbb in our study area. The determinants of this complication are still largely obscure. The granuloma usually commences on the nasal septum. In about two-thirds of our patients the lesion remained restricted to the nose. In the rest the pharynx, palate, larynx and lips were involved, in this order. It is often difficult to isolate the parasite and for routine diagnosis the leishmanin skin reaction and serological tests are helpful. Although a serious condition, with possible mutilation and even death as subsequent complications, treatment is still mainly with pentavalent antimonials, introduced 40 years ago. These are most unsatisfactory for field use, being given parenterally and relatively toxic. In mucosal leishmaniasis, if sufficient antimony can be administered in a regular daily dose, the relapse rate is small (3 of 42 patients followed for a mean of 5 years). Also, antimony treatment of the initial skin ulcer due to Lbb followed for a mean of 4 years of 83 patients resulted in subsequent mucosal metastasis in only 2. Since espundia is relatively rare, specific treatment targeted to this specific problem is the efficient short term solution. At present there is no satisfactory alternative drug to those in current use.

Mucosal leishmaniasis ("espundia" Escomel, 1911).

Publisher Summary This chapter discusses the role of the immune response to Leishmania, with particular reference to the cutaneous disease caused by L. major. Leishmaniasis is caused by species of the intracellular protozoan parasite belonging to the genus Leishmania. There are three main categories of leishmaniasis: cutaneous leishmaniasis (oriental sore), mucocutaneous leishmaniasis (espundia), and visceral leishmaniasis (kala-azar). In humans, infection with Leishmania results in a spectrum of disease dependent upon the species involved and the efficiency of the host's immune response to the parasite. Diagnosis of active leishmaniasis is based primarily on the demonstration of the parasite in biopsies. A skin test using a killed whole parasite preparation (leishmanin) is used as a presumptive test. Genetic regulation of leishmaniasis is discussed in reference to mouse and humans, and the concept of suppressor T cells is reviewed. The various cytokines in leishmaniasis, including interferon (IFN) γ and interleukin (IL)-4, IL-10, IL-1, and IL-2 are also discussed.

Immunology of Leishmaniasis

Publisher Summary Although there are several reports of Leishmania parasitizing cells other than macrophages or even existing extracellularly in mammalian tissue, it is generally acknowledged that in the vertebrate host these organisms normally reside within cells of the macrophage lineage. The first description of this particular host cell–parasite interaction can probably be attributed to Cunningham, who examined biopsy material, stained with gentian violet, from a patient with “Delhi boil.” Given the now well-documented multifaceted role of macrophages in the immune response, the parasite's interplay with its host cell poses many intriguing problems for researchers. This chapter intends to update the progress that has been made in recent years in understanding the biology of the leishmania– macrophage interaction and how the parasite can attach to and enter the host cell and survive in the intracellular environment. The chapter also discusses the implications of these interactions in the induction of specific immune responses and on disease progression. It also describes those areas where future research may be of value in the rational development of new chemical and immunological therapies and vaccines.

The interaction of Leishmania species with macrophages.

Summary The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine—the first oral drug for visceral leishmaniasis—is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.

W Peters

Papers

Therapy in man.