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An overview of paediatric leishmaniasis. DA KafetzisUniversity of Athens Second Department of Paediatrics, "P. and A. Kyriakou" Children's Hospital, Athens, 11527 Greece. , Greece
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.930
Leishmaniasis, a parasitic disease transmitted by the bite of some species of sandflies affects various age groups depending on the infecting Leishmania species, geographic location, disease reservoir, and host immunocompetence. Visceral leishmaniasis is the most severe form of the disease affecting children. The extent and presentation of the disease depend on several factors, including the humoral and cell-mediated immune response of the host, the virulence of the infecting species, and the parasite burden. Children are at greater risk than adults in endemic areas. Malnutrition contributes to the development of disease, and incomplete therapy of initial disease is a risk factor for recurrence of leishmaniasis. Children usually present with intermittent fever, paleness, refusal to feed or anorexia, weight loss, and abdominal distension. Splenomegaly, hepatomegaly, lymph node enlargement, thrombocytopaenia, anaemia, leukopaenia and hypergammaglobulinemia are the most common findings in Paediatric leishmaniasis. Molecular methods appear to offer the promise of accurate non-invasive tools for the diagnosis of Leishmaniasis. Till these methods are evaluated, definite diagnosis will rely on the demonstration of the infecting parasite in various tissues. World-wide, with the notable exception of India, pentavalent antimonial compounds remain the most effective and the most affordable therapy for this disease. Lipid formulations of amphotericin B were assessed as short duration treatment and were proved to be effective. However, their cost precludes their wide use in developing countries. Miltefosine, a new oral agent, might prove effective, safe, and affordable. Strategies aimed at control of the micro-population of sandflies, eradication of canine leishmaniasis, and offering personal protection against sandfly bites, together with health education programs in developing countries, can help control the disease. Development of an effective vaccine remains a priority. Keywords: Animal, Antiprotozoal Agents, therapeutic use,Child, Developing Countries, Human, Leishmania donovani, pathogenicity,Leishmaniasis, Visceral, diagnosis,epidemiology,therapy,Protozoan Vaccines, therapeutic use,Risk Factors,
Leishmaniasis, a vector-born disease caused by obligate intra-cellular protozoa of the genus Leishmania, is capable of causing a spectrum of clinical syndromes affecting millions of people in endemic areas of the tropics and subtropics. It affects other regions of the world as well with the only exception of Australia and Antarctica. The prevalence is the highest in central and south America, southern Europe, central Africa and parts of southern and central Asia. Leishmaniasis is transmitted by sandflies (Phlebotomus species). In the human host, Leishmania are intra-cellular parasites that infect the mononuclear phagocytes. When a vector (sandfly) transmits the parasite between vertebrate hosts, usually dogs or rodents and humans, the parasites can cause different disease manifestations. In cutaneous leishmaniasis (CL), the amastigotes replicate in the dermis and do not spread beyond the site of the vector’s bite. The lesion often heals spontaneously. In visceral leishmaniasis (VL), the amastigotes replicate in macrophages of the mononuclear phagocyte system and then spread to the entire reticuloendothelial system, resulting in “kala-azar” or they replicate and spread in the naso-oropharyngeal mucosa, resulting in mucocutaneous leishmaniasis (ML). Left untreated, these latter conditions result in high rates of mortality.[1],[2],[3],[4] Leishmaniasis affects various age groups depending on the infecting species, geographic location, disease-reservoir and host immunocompetence. Although the various species and subspecies of the genus Leishmania traditionally have been considered either viscerotropic or dermotropic, exceptions have been reported. Whether visceral involvement with some strains of Leishmania is exceptional or relatively common but only rarely recognised is unknown. It is also not known if the strains that disseminate to the viscera differ subtly from strains that do not.[5],[6],[7] Host factors, such as lack of previous exposure to the parasite and type of immune response generated, may also play a role in visceral dissemination of the various strains. Recently, visceral leishmaniasis has received increasing attention, as a result of the parasite emerging as an opportunistic pathogen among HIV-infected patients, with the recognition of imported cases after travel to endemic areas and with the adoption of these organisms as a model for the study of cell-mediated immune responses.[8],[9],[10]
Three epidemiological forms affecting children have been recognised. In India and Brazil where an animal reservoir has not been identified, visceral leishmaniasis is found in all age groups. This epidemiological form was first described in India, and is known as the Indian type of visceral leishmaniasis. In this form of the disease, children between 5 and 15 years of age are affected. L. donovani is the predominant parasite of this form of Leishmaniasis in India, while in the New World, the disease is predominantly caused by L. chagasi. In areas with animal reservoirs, such as the Mediterranean Basin, visceral leishmaniasis mainly affects children of 1 to 4 years of age; it is caused mainly by L. infantum, transmitted by phlebotomine sandflies, and dogs are the most important reservoir. The African type of VL is again caused by L. infantum affecting older children and young adults and rodents are the reservoir hosts.[1],[2],[11] Visceral disease (classically known as “kala azar”) is the most devastating form of the disease and if left untreated, is fatal. It results from systemic infection of the liver, spleen, and bone marrow. The syndrome is characterised by the pentad of fever, hepatosplenomegaly, pancytopenia, hypergammaglobu-linemia and weight loss. However, after infection most cases remain asymptomatic or are associated with symptoms that eventually resolve spontaneously.[1],[2],[11],[12],[13],[14],[15]
Leishmania species exist as extra-cellular flagellated promastigotes in the guts of female sandflies, and transform to the amastigote form in animal and human hosts. In this form, the protozoa resist phagolysosomal enzymes and replicate within the macrophages. This allows them to spread throughout the reticuloendothelial system of the host and live within the intra-cellular lysosomal organelle of macrophages. It has recently been recognised that sandfly components may enhance the ability of the promastigotes to enter macrophages and thus increase its virulence.[2],[16] Pathogenesis appears related to T-cell cytotoxicity, and control of visceral leishmaniasis depends on the magnitude of T helper 1 and multicytokine responses early in the course of infection. During progressive Leishmania infection in mice, Th2-type CD4 T cells expand and secrete interleukin-4, resulting in polyclonal B-cell activation.[17] Fully established visceral leishmaniasis is associated with cellular anergy, as indicated by negative skin tests to Leishmania antigens and in-vitro lymphocyte transformation, which reverse to positive several months after successful treatment. Inappropriate antigen presentation and communication between the antigen-presenting cells and T cells, as well as the induction of interleukins 10 and 4 may explain this anergy. Interleukins 10 and 4 suppress, whereas interleukin-12 promotes, interferon-? responses. The fact that interleukin-12 and interferon-? appear to be important in order to achieve a favourable outcome after leishmanial infection renders them potential adjuvants for the development of vaccines and therapeutic regimens.[18],[19],[20],[21],[22],[23] Current data indicate that susceptibility to leishmaniasis is genetically determined.[19],[21] The extent and presentation of the disease depend on several factors, including the humoral and cell-mediated immune response of the host, the virulence of the infecting species, and the parasite burden.[2] However, it has been shown that children are at a greater risk than adults in endemic areas. Malnutrition seems to contribute to the development of the disease, and incomplete therapy of initial disease predisposes to recurrence of leishmaniasis.[1],[2],[3] Infections may heal spontaneously or may progress to chronic disease, often resulting in death from secondary infection. If spontaneous recovery occurs, the patient’s cell- mediated immunity increases. Such patients will develop a delayed hypersensitivity response resembling the tuberculin reaction upon intra-dermal injection of a suspension of killed promastigotes. This is known as the leishmanin or Montenegro test. If the individual is unable to mount an appropriate immune response, the parasite disseminates in the reticuloendothelial cells of the body. Alternately, the parasite may remain dormant and not present itself until one’s immune system becomes compromised.[24]
Prospective studies in northeastern Brazil have shown that approximately 12% of infected children develop typical visceral leishmaniasis. It was also shown that exposure to a high leishmanial burden, younger age, malnutrition, and poverty are associated with increased probability of evolution to typical symptomatic illness. Such studies have not been conducted in the areas of the Mediterranean basin. It has, however, been reported that the median age at diagnosis of Mediterranean visceral leishmaniasis is less than 3 years and that infants are frequently affected. Typical visceral leishmaniasis usually occurs after an incubation period, which can vary widely from 2 weeks to 8 months (usually 2-6 months), depending on the patient’s age and immune status, and the species of Leishmania. In developing countries, young malnourished children are extremely susceptible to develop progressive infection. In these areas, the disease has an insidious onset with pyrexia, which is continuous or remittent and becomes intermittent at a later stage. Sometimes, it is described as a “double-rise fever in 24 hours”. Occasionally, the disease may present with an acute onset. Children presenting later in the course of the disease may demonstrate oedema caused by hypoalbuminemia, haemorrhage due to thrombocytopenia or growth failure related to the presence of chronic infection. Splenic enlargement, a finding that is often quite prominent, along with accompanying hepatomegaly causes an abdominal protuberance in these patients. While the disease progresses, the spleen extends well below the costal margin; it is usually firm or hard in consistency, but soft spleen may be encountered in acute disease.[31],[32],[33],[34],[35],[36] Intermittent fever (95%), pallor (77%), refusal to feed or anorexia (40%), weight loss (18%), abdominal distension (18%), cough (16%), vomiting (15%) and diarrhoea (12%) were the commonest presenting complaints in a study we conducted in southern Greece in 82 immunocompetent children with Mediterranean leishmaniasis. Massive splenomegaly (99%) was almost universally encountered in this study population. Hepatomegaly (85%), lymph node enlargement (39%) and ecchymoses or gingival bleeding (2%) were the other common manifestations noted on physical examination. The liver and spleen were usually soft and easily palpated. The laboratory tests revealed thrombocytopenia (80%), anaemia (77%), leukopenia (62%) and hypergammaglobulinemia (100%). There was no death reported in this study.[29] Similar findings were also reported from Italy, southern France and Spain.[5],[15],[24],[28],[30] In a study conducted in Turkey, concerning 40 cases of VL in children, the findings were analogous. However, the investigators also reported certain unusual manifestations in the form of tachycardia (80%), cardiac murmur (75%), petechiae or ecchymoses (30%), and jaundice (20%). Abdominal distension was observed in 80% of their cases.[13] Late in the course, epistaxis, and gingival bleeding caused by severe thrombocytopenia may occur; oedema and ascites may also develop. Jaundice with mildly elevated enzyme levels is rarely seen and is considered to be a bad prognostic sign. As the disease progresses, children in some areas develop typical habitus: a thin and cachetic patient with abdominal distension with skin hyperpigmentation related to xerosis and melanocyte stimulation, alopecia and elongated eyelashes. Petechiae and ecchymoses may be seen in the extremities. Pedal oedema is observed more commonly in children.[31],[33],[34],[35],[36] Skin lesions, which contain parasites and appear as diffuse, warty, non-ulcerative lesions, may occur in visceral leishmaniasis. These have especially been reported from studies carried out in Africa.[35],[36] Mucosal lesions in the mouth and nose, which appear as nodules or ulcers and may lead to perforation of the nasal septum, have been described in Sudan but are rare elsewhere.[35], [36] Such findings have not been described in Greece nor have they been reported from other areas of Southern Europe. Unusual clinical presentations include pancytopenia without splenomegaly, generalised lymphadenopathy without hepatosplenomegaly, massive hepatic necrosis, and retinal haemorrhages.[1],[2],[3],[31] Commonly encountered laboratory findings include normocytic-normochromic anaemia, neutropenia, thrombocytopenia, hypergammaglobulinemia (as a result of polyclonal B cell activation) and hypoalbuminemia. Serum levels of hepatic transaminases may be elevated.[13],[14],[27],[29],[30] Circulating immune complexes and rheumatoid factor are present in the sera of most patients with visceral leishmaniasis. Rarely, immune-complex deposition in the kidneys may lead to mild glomerulonephritis. However, renal failure is not a feature of visceral leishmaniasis. Rare manifestations of visceral leishmaniasis include haemophagocytic syndrome, acute hepatitis, cholecystitis, and Guillain-Barré syndrome.[2],[37] Also, post–kala azar dermal leishmaniasis has been reported from India.[38] It is said to occur in approximately 10% of cases after the treatment of visceral leishmaniasis. Lesions can develop as late as 1-2 years after treatment for the original disease and manifest on the face, trunk or extremities, and may persist for as long as 20 years. In Africa, it has been reported that dermal lesions occur in only 2% of cases and tend to appear during or shortly after the treatment and persist only for a few months.[35],[38] This complication has not been reported in Mediterranean leishmaniasis. Mortality is related to immunosuppression and secondary infections and in untreated cases mortality ranges from 75-95%.[1],[2],[3],[4] Skin lesions are the hallmark of cutaneous leishmaniasis and these skin lesions heal spontaneously within 2-10 months.[11],[39],[40] In mucocutaneous leishmaniasis, known as espundia in South America, mucosal ulcerations usually develop by metastasis rather than by local spread, and causes disfiguring lesions over the face. It destroys the mucous membranes of the nose, mouth, and throat. Secondary infection plays a prominent role in the size and persistence of these ulcers. Children are rarely affected and the progression of the disease is slow and steady but it carries a significant mortality rate.[1],[2],[3],[4]
Detailed diagnostic procedures for Leishmaniasis are described in an other article in this symposium. In children, however, a definite diagnosis of visceral leishmaniasis relies on the demonstration of Leishmania in tissue specimens or tissue culture. The parasite can be demonstrated through direct evidence from peripheral blood, bone marrow, or splenic aspirates. Microscopy of bone marrow aspirates is the safest diagnostic approach for paediatric patients, with amastigotes seen in more than 90% of cases by an experienced observer.[27],[29] Repeated sampling, however, may be required. In adult patients, bone marrow microscopy is less sensitive (~70%). The higher diagnostic efficacy of the bone marrow examination in children is probably related to the heavier parasitisation encountered in children. Microscopic examination of splenic aspirates offers the highest sensitivity (up to 98%), but is associated with the risk of life-threatening haemorrhage in cases with profound thrombocytopenia.[1],[2],[3],[4] In immunocompetent individuals, serological assays (direct agglutination, enzyme-linked immunosorbent assay, and indirect immunofluorescence) are considered to be sensitive for the diagnosis of visceral leishmaniasis. In a study conducted in Brazil, the indirect immunofluorescence assay achieved sensitivity and specificity rates close to 100% for the diagnosis of visceral leishmaniasis, with immunoglobulin G antibodies significantly reduced after treatment.[40] Recently, a strip test employing the recombinant K39 antigen of L. chagasi was developed. This strip test had a sensitivity of 100% and a specificity of 98% among patients in India. [No reference cited] However, in a study from Sudan, which compared the use of the recombinant K39 strip test with that of the recombinant K39 enzyme-linked immunosorbent assay and the direct agglutination test, the former gave limited sensitivity [67% versus 100%, and 91% (at > 1:1600 cut-off), respectively].[41] The interpretation of serological results is complicated by high titres observed for months or years after successful treatment and in cases of asymptomatic infection.[41] Moreover, serological tests are positive in only half of HIV infected patients with Leishmaniasis.[10] Over the past 5 years, the value of polymerase chain reaction (PCR) for the diagnosis of visceral leishmaniasis has been assessed using different clinical specimens (peripheral blood, bone marrow, and spleen).[42],[43] The detection of persistent parasite DNA in infected tissues by means of PCR may also be used as a marker for the risk of relapse after initial cure. Currently, PCR should be regarded as a promising tool, with the potential advantage of using blood specimens rather than the conventional invasive procedures such as splenic aspirate, bone marrow aspiration and liver biopsy. Leishmanin skin test (Montenegro test) is of value for epidemiological studies. The test involves an intra-dermal injection of 0.1 ml of promastigote antigen. The reaction is interpreted after 72 hours later. It is negative during active visceral leishmaniasis, but usually becomes positive after successful treatment. This test is also positive in patients with previous asymptomatic infection[2] and in cases with dermal leishmaniasis.[44] Differential diagnosis of Visceral leishmaniasis should include other conditions associated with massive splenomegaly, such as malaria, tropical splenomegaly syndrome, typhoid, miliary tuberculosis, portal hypertension, leukemias and lymphomas, and haemolytic anaemia. Post–kala azar dermal leishmaniasis should be differentiated from yaws, syphilis, and leprosy. Sarcoidosis, midline granuloma and histoplasmosis should be differentiated from mucocutaneous leishmaniasis.
For more than half a century, the pentavalent antimony compounds meglumine antimonate (Glucantime; Aventis Pharma, Bridgewater, New Jersey, USA) and sodium stibogluconate (Pentostam; GlaxoSmithKline, Uxbridge, Middlesex, UK) remain the standard anti-leishmanial treatment world-wide except in India. These agents have been used extensively in children with Mediterranean visceral leishmaniasis, in doses of 20mg/kg daily for 30 days with initial response rates exceeding 90-95%. Relapse rates are low. Relapses are mainly observed among patients treated with shorter courses of therapeutic agents.[2],[14],[21],[26],[27] Most children improve and become afebrile within less than a week, whereas haematological restoration and significant subsidence of splenomegaly usually occur within 2 weeks.[27],[29] The main advantage of these agents is their low cost (A 30-day course at 20mg/kg daily in an adult: Glucantime, US: $100; Pentostam, US: $150). Disadvantages include the need for intra-muscular route of administration, lengthy hospitalisations, and non-negligible (but transient) adverse effects, such as electrocardiographic abnormalities, elevated levels of hepatic transaminases, chemical pancreatitis and pneumonitis.[2],[29],[45] In our hospital we adopted an outpatient treatment policy in selected cases, following the evidence of clinical improvement, drug tolerability, and socio-economic parameters indicative of compliance.[29] During the past decade, the large-scale failure (up to 64%) of pentavalent antimonial agents in patients from India prompted their complete abandonment as first-line agents in this area and an urgent need was felt for the development and assessment of alternative agents. Recent data indicate that resistance may also become a problem in Sudan.[46] Currently, amphotericin B and its lipid formulations amphotericin B cholesterol dispersion (Amphotec; Sequus Pharmaceuticals Inc., Menlo Park, California, USA), amphotericin B lipid complex (Abelcet; The Liposome Company Inc., Princeton, New Jersey, USA), and liposomal amphotericin B (AmBisome; Gilead, Foster City, California, USA), are highly active against visceral leishmaniasis in India, with long-term cure rates exceeding 90% to 95%. Conventional amphotericin B requires prolonged administration (1mg/kg on an alternate-day schedule over a 30-day period). It is associated with renal toxicity necessitating monitoring of renal function. The drug is expensive, too. Therefore, for areas outside India this drug does not offer any obvious advantages over pentavalent antimonial agents.[47] Several studies using the three-lipid formulations of amphotericin B have been conducted in adults and children world-wide. Some studies have indicated that even 5-10 day course of therapy may be enough for successful treatment of visceral leishmaniasis.[47],[48] In 1997, the United States Food and Drug Administration approved AmBisome (in the dose of 3 mg/kg/day on days 1-5, 14, and 21) for the treatment of visceral disease in immunocompetent children. The estimated cost for the drug itself for a 25-kg patient is US $2,068. Thus, the wide use of commercial lipid formulations of amphotericin B is prohibitively expensive in developing countries, where they are needed the most. In these countries, the simple mixing of amphotericin B with a commercially available fat emulsion was proposed (at 2 mg/kg on an alternate-day regimen for a total of 10 days), and has proved to be more affordable and equally effective.[48],[49] Amphotericin B and its lipid formulations are administered by infusion, which necessitates intravenous fluid administration through relevant equipment. Fever and chills are commonly experienced during infusion, and monitoring of renal function is required. Recently, a single-dose infusion of AmBisome (at 5 and 15 mg/kg) was assessed in patients in India, with cure rates approaching 100%[49],[50] It is, however, feared that short courses may contribute to the emergence of drug resistance.[48],[49],[50] Aminosidine was also recently evaluated in India, where a 21-day course at 16-20 mg/kg/day was associated with cure rates of up to 97%. These data make aminosidine another attractive first-line agent for this area, with a proposed cost similar to that of conventional amphotericin B. The cost of aminosidine therapy is second only to amphotericin B-fat emulsion.[47] Out-patient treatment with one of the aforementioned regimens appears to be feasible for those patients who manifest clinical improvement and tolerate therapy, but always bear the risk of non-compliance and partial treatment. Oral treatment for visceral leishmaniasis has only recently become a reality, with the introduction of miltefosine. Treatment with this agent (at 100-150 mg/day for 28 days) has been almost 100% effective and well-tolerated in phase I/II studies conducted in India among newly diagnosed patients or patients unresponsive to pentavalent antimonial agents. Studies of miltefosine in young children are underway.[47] The preferred anti-leishmanial agent as well as the optimal duration of treatment in HIV-co-infected patients has not yet been established. A successful clinical response is achieved in up to two-thirds of cases, regardless of the agent used (pentavalent antimonial agents, conventional or lipid formulations of amphotericin B). The management of such patients is further complicated by the fact that most of the initially cured patients are likely to relapse within the following 6-12 months. To date there are no uniform guidelines regarding the use of maintenance regimens to prevent relapse[2],[10] In recent trials, daily interferon-? injections combined with pentavalent antimonial agents were shown to accelerate the clinical response and achieve a long-term cure in approximately two-thirds of cases unresponsive to treatment with pentavalent antimonial compounds alone. However, in a randomised, controlled study conducted in India, where resistance to pentavalent antimonial agents is high, the same combination given for 28 days failed to show such adjunctive activity in terms of long-term cure.[47] Again, the cost of approaches including cytokine immunotherapy is prohibitive in developing areas. Several vaccines against leishmaniasis are being tested; however, none of them is in routine use. Vaccines using killed or live-attenuated parasites or recombinant DNA-derived components, such as antigens and peptides, have been tested with varying success.[20],[21],[51] A recent approach is the development of a vaccine using sandfly salivary gland proteins, capable of inducing strong protection in the skin against leishmanial infection. Data from mouse models are promising.[52] Ideally, sandfly components could be incorporated in a vaccine, together with parasite antigens. The presence of numerous parasite and sandfly species constitutes the main setback of such a strategy. Of equal significance is the definition of the population that is unable to elicit a protective immune reaction against leishmanial infection, where a vaccination policy is needed the most.[20],[21] In the developing countries, the use of personal protection with repellants, permethrin-impregnated bed nets, and suitable clothing significantly reduced the domestic transmission of leishmanial infection[53],[54] Also, individuals are advised to, ideally, sleep on the second floor of a building, since the flight of the sandfly is limited to 10 feet. The eradication of all stray and domestic infected dogs is also required for a successful intervention on the reservoir-vector-host chain.[28] Noxious plants are also harmful to sandflies, and may provide local protection against sandfly bites.[55]
The number of cases of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. The recent increase in the canine population because of socio-cultural changes, and the movement of susceptible populations into endemic areas also contribute to the increased incidence.[56] Visceral leishmaniasis should be suspected in children who present with specific manifestations, no matter where they live, and even without a history of travel to an endemic area. The diagnosis should be established, mainly by the demonstration of Leishmania in tissue specimens. Molecular techniques could soon change this situation considering the promise they have shown in the diagnosis of other infectious diseases. Several advances in the treatment of visceral leishmaniasis have been accomplished during the past few years. The management of each case depends on the efficacy and toxicity profile of the therapeutic agents that are affordable within a specific area and also on host factors. Control of sandflies through residual insecticides spraying, and improved environmental sanitation and personal protective measures, have been proved essential.
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