A widespread contention in the parasitological and medical literature is that severe disease represents a lack of coadaption between host and parasite2 because parasite species that do not harm their hosts have the best chance of long-term survival. This view has been proposed throughout this century (89, 91, 97) and was extensively developed by Dubos, who concluded: "Given enough time a state of peaceful coexistence eventually becomes established between any host and parasite" (33, p. 190). In other words, commensalism was believed to be the ideal evolutionary end point for both host and parasite. Although several authors have suggested that evolution may sometimes result in increased virulence (6, 7, 14, 27, 28, 61), the former view is often accepted as fact in current texts and. reviews (e.g. 4, 48). One of the major problems with this view, however, is that disease severity is analyzed in terms of the survival of the species or of a large subgroup of the species rather than in terms of the effects on gene frequencies within the species. Evolutionary theory, on the other hand, emphasizes that it is the effects on gene frequencies that yield the evolutionary changes within a species (10 1).

Host-Parasite Relations, Vectors, and the Evolution of Disease Severity

From the early 1900s, visceral leishmaniasis (VL; kala-azar) has been among the most important health problems in Sudan, particularly in the main endemic area in the eastern and central regions. Several major epidemics have occurred, the most recent--in Western Upper Nile province in southern Sudan, detected in 1988--claiming over 100,000 lives. The disease spread to other areas that were previously not known to be endemic for VL. A major upsurge in the number of cases was noted in the endemic area. These events triggered renewed interest in the disease. Epidemiological and entomological studies confirmed Phlebotomus orientalis as the vector in several parts of the country, typically associated with Acacia seyal and Balanites aegyptiaca vegetation. Infection rates with Leishmania were high, but subject to seasonal variation, as were the numbers of sand flies. Parasites isolated from humans and sand flies belonged to three zymodemes (MON-18, MON-30 and MON-82), which all belong to the L. donovani sensu lato cluster. Transmission dynamics have not been elucidated fully; heavy transmission in relatively scarcely populated areas such as Dinder national park suggested zoonotic transmission whereas the large numbers of patients with post kala-azar dermal leishmaniasis (PKDL) in heavily affected villages may indicate a human reservoir and anthroponotic transmission. Clinical presentation in adults and in children did not differ significantly, except that children were more anaemic. Fever, weight loss, hepato-splenomegaly and lymphadenopathy were the most common findings. PKDL was much more common than expected (56% of patients with VL developed PKDL), but other post-VL manifestations were also found affecting the eyes (uveitis, conjunctivitis, blepharitis), nasal and/or oral mucosa. Evaluation of diagnostic methods showed that parasitological diagnosis should still be the mainstay in diagnosis, with sensitivities for lymph node, bone marrow and spleen aspirates of 58%, 70% and 96%, respectively. Simple, cheap serological tests are needed. The direct agglutination test (DAT) had a sensitivity of 72%, specificity of 94%, positive predictive value of 78% and negative predictive value of 92%. As with other serological tests, the DAT cannot distinguish between active disease, subclinical infection or past infection. The introduction of freeze-dried antigen and control sera greatly improved the practicality and accuracy of the DAT in the field. An enzyme-linked immunosorbent assay using recombinant K39 antigen had higher sensitivity than DAT (93%). The polymerase chain reaction using peripheral blood gave a sensitivity of 70-93% and was more sensitive than microscopy of lymph node or bone marrow aspirates in patients with suspected VL. The leishmanin skin test (LST) was typically negative during active VL and converted to positive in c. 80% of patients 6 months after treatment. Immunological studies showed that both Th1 and Th2 cell responses could be demonstrated in lymph nodes from VL patients as evidenced by the presence of messenger ribonucleic acid for interleukin (IL)-10, interferon gamma and IL-2. Treatment of peripheral blood mononuclear cells from VL patients with IL-12 was found to drive the immune response toward a Th1 type response with the production of interferon gamma, indicating a potential therapeutic role for IL-12. VL responded well to treatment with sodium stibogluconate, which is still the first line drug at a dose of 20 mg/kg intravenously or intramuscularly per day for 15-30 d. Side effects and resistance were rare. Liposomal amphotericin B was effective, with few side effects. Control measures have not been implemented. Based on observations that VL does not occur in individuals who have a positive LST, probably because of previous cutaneous leishmaniasis, a vaccine containing heat-killed L. major promastigotes is currently undergoing a phase III trial.

Leishmaniasis in Sudan. 3. Visceral leishmaniasis

Publisher Summary This chapter is concerned with the immunological concepts in leprosy leading to a discussion of the analogous states now recognized in other infectious diseases. The typical nodular form of leprosy, associated with massive infiltration of the tissues with histiocytcs packed with colonies of mycobacteria and an apparent inability of the body to eliminate the organism is one of the two main types of the disease. The other, the anesthetic or maculoanesthetic form, is associated with the peripheral nerve damage with or without cutaneous lesions. Here, the microorganisms may be scanty or difficult to demonstrate, and the skin lesions may come to resemble those in lupus vulgaris. Tuberculoid has, therefore, been used as a generic term to describe the second form of the disease; the nodular form of leprosy is now referred to a lepronzatous. Leishmaniasis is a spectral disease similar to leprosy, in which the clinical features of the disease depend on the cell-mediated immunity (CMI) response of the host toward the parasite. When this response is deficient, diffuse cutaneous leishmaniasis (DCL) results. The possible reasons for such deficiency in CMI is also discussed with their nature and specificity of the defect.

Immunological phenomena in leprosy and related diseases.

Knowledge of the immunological basis of the leishmaniases and of the host's response is fragmentary and largely pragmatic. This paper reviews certain conceptual and clinical aspects of the immunology of these diseases. Consideration is given to man's natural resistance and his ability to acquire resistance from natural infections and from vaccination. The age-distribution of infection in different populations is discussed in relation to the effects that interaction between the parasite and its intermediate host may have on its infection characteristics and virulence.Studies in the USSR of differences in virulence among 30 human strains and 39 rodent strains are reported. The rodent strains showed a broader range of virulence than did the human isolates. Serological tests for determining species relationships among the leishmaniae are generally nonspecific, but work concerned with the development of the antiserum-culture test is reviewed. Species identification and the recognition of new forms, perhaps with different infection characteristics, is, nevertheless, of the utmost importance in the prevention and treatment of the disease.The review concludes with a discussion of functional immunity and hypotheses of the immune process in leishmaniasis.

Immunology of leishmaniasis.

Coccidial parasites of the genus Isospora cause intestinal disease in several mammalian host species. These protozoal parasites have asexual and sexual stages within intestinal cells of their hosts and produce an environmentally resistant cyst stage, the oocyst. Infections are acquired by the ingestion of infective (sporulated) oocysts in contaminated food or water. Some species of mammalian Isospora have evolved the ability to use paratenic (transport) hosts. In these cases, infections can be acquired by ingestion of an infected paratenic host. Human intestinal isosporiasis is caused by Isospora belli. Symptoms of I. belli infection in immunocompetent patients include diarrhea, steatorrhea, headache, fever, malaise, abdominal pain, vomiting, dehydration, and weight loss, blood is not usually present in the feces. The disease is often chronic, with parasites present in the feces or biopsy specimens for several months to years. Recurrences are common, Symptoms are more severe in AIDS patients, with the diarrhea being more watery. Extraintestinal stages of I. belli have been observed in AIDS patients but not immunocompetent patients. Treatment of I. belli infection with trimethoprim-sulfamethoxazole usually results in a rapid clinical response. Maintenance treatment with trimethoprim-sulfamethoxazole is needed because relapses often occur once treatment is stopped.

Biology of Isospora spp. from humans, nonhuman primates, and domestic animals.

Sudanese strains of Leishmania isolated from 2 human cases of kala-azar, 3 human cases of cutaneous leishmaniasis, 2 naturally infected sandflies ( P. orientalis ), naturally infected specimens of Rattus rattus, Arvicanthis niloticus luctuosus, Acomys albigena, Genetta genetta senegalensis and Felis serval philipsi , were examined serologically by growth on medium containing immune serum. With this method all these strains were indistinguishable from each other and are considered to belong to the same species. 3 cases of cutaneous leishmaniasis from which strains were studied are considered to have either abortive kala-azar or primary leishmaniomas. These findings add to the existing epidemiological evidence that kala-azar in the Sudan is a zoonosis, and that L. donovani is propagated in an animal reservoir by cyclical transmission through a sandfly, P. orientalis .

Ann Foner

Papers

The Relationship between Human and Animal Strains of Leishmania from the Sudan.

An attempt to infect animals with Isospora belli

2,2'-hydrazobis(5-nitrothiazoles) and analogs, a new type of antiprotozoal agents.