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Visceral Leishmaniasis (VL) is a vector-borne disease caused by an intracellular protozoa of the genus Leishmania that can be lethal if not treated. VL is caused by Leishmania donovani in Asia and in Eastern Africa, where the pathogens’ reservoir is represented by humans, and by Leishmania infantum in Latin America and in the Mediterranean area, where VL is a zoonotic disease and dog is the main reservoir.
- visceral leishmaniasis
- tropical diseases
- neglected diseases
- Leishmania
1. Epidemiology, Microbiology, and Transmission
Visceral leishmaniasis (VL) is a potentially fatal vector-borne disease reaching the second and seventh place among tropical diseases in mortality and loss of disability-adjusted life years, respectively [1,2]. However, being mainly considered as a disease of developing countries, the pharmaceutical industry shows little interest in investing in its research, so VL is included among “the neglected diseases” [3,4]. In addition, in the most affected areas, access to health care can be difficult and drugs are often not affordable, making the death rate even higher [5].
The term Leishmaniasis covers a wide range of clinical manifestations due to infections by protozoa of the genus Leishmania [15,16,17]. In particular, the genus includes the subgenera Leishmania and Vianna [15]. VL is mainly caused by Leishmania donovani and Leishmania infantum, the latter also called Leishmania chagasi in South America. VL due to L. donovani occurs in Southeast Asia, in particular India, Bangladesh, and Nepal, and in Eastern Africa, especially Sudan, Ethiopia, Kenya, and Somalia [3,7,8]. It can affect people of all ages, even if in endemic areas its incidence is higher among children due to the acquired immunity of adults [8]. In both regions, VL exhibits cyclical patterns of occurrence: in particular, the incidence increases over 2 to 5 years with a peak and then drops for some years [18]. In 2014, Sudan, South Sudan, and Ethiopia reported more than 14,000 cases, and about 10,000 were observed in India and Bangladesh [18].
L. infantum causes VL in the Mediterranean area, in the Middle East, Afghanistan, Iran, Pakistan, and Brazil. Rare cases have been observed in Central Asia and Latin and Central America excluding Brazil [19], where 90% of reported VL cases in the Americas occur [9]. Children aged less than 10 years and immunosuppressed individuals are more likely to manifest a clinical disease due to L. infantum than immunocompetent adults [8].
2. Diagnosis
Overall, the clinical diagnosis of VL is difficult because its presentation overlaps with other infections like typhoid fever, tuberculosis, brucellosis, malaria, or some hematologic malignancies [21]. Traditionally, in a child with clinical suspicion of VL (febrile splenomegaly, hepatomegaly, loss of weight, and laboratory signs such as pancytopenia and hypergammaglobulinemia or hemophagocytic syndrome), diagnosis can be confirmed by direct demonstration of Leishmania in tissue specimens or cultures, or by serologic testing. However, these techniques have limitations in terms of low sensitivity in general and poor performance in immunocompromised patients, respectively. Further diagnostic options have arisen, such as rapid diagnostic kits and polymerase chain reaction (PCR) tests. In general, the use of multiple diagnostic approaches is recommended to increase the likelihood of a positive result [15,46].
2.1. Direct Visualization of the Amastigote
Amastigotes, which are round or oval bodies 1–4 μm in diameter with a typical rod-shaped kinetoplast or circular nucleus, can be detected by direct microscopic observation with a sensitivity that depends on the collected tissue: above 90% for the spleen, 50–80% for bone marrow, and lower values for lymph node aspirates [7,15,46,47]. Blood samples have low sensitivity, except for HIV patients who exhibit higher parasitemia [7]. Tissue aspirates or biopsy specimens for smears, histopathology, parasite culture, and molecular testing are recommended; in general, bone marrow aspiration is the preferred first source of a diagnostic sample [15]. However, the need for invasive procedures to obtain a tissue specimen is an important limitation of microscopic examination for VL diagnosis [46]. Spleen aspirates, which are considered the gold standard, have an incidence of hemorrhage of up to 1/1000 procedures [48] and are routinely performed only in eastern Africa and in the Indian subcontinent [47]; bone marrow aspiration is more commonly done in Europe, Brazil, and in the United States [47].
2.2. Culture
Parasitological culture increases sensitivity on top of microscopy, but it is only performed in selected laboratories, and it generally leads to a diagnostic delay [47]. The microculture of noninvasive samples (buffy coat or peripheral blood mononuclear cells) seems to have a good sensitivity and the results are available in a few days up to 2 weeks [47,49,50]. In the United States, clinicians are recommended to contact their leishmaniasis reference laboratory before collecting specimens to attempt parasite isolation [15].
2.3. Serological Assays and Rapid Diagnostic Tests (RDTs)
Several serological assays are available, including the enzyme-linked immunosorbent assay (ELISA), the indirect fluorescent antibody test (IFAT), the indirect hemagglutination assay (IHA), immunofluorescence, and western blot. In general, these procedures show reasonable sensitivity and specificity (both 80–100% depending on test type and host factors) [15,48].
However, these techniques are not specific to the VL disease stage, because antibodies decrease slowly after the infection, and they are also present in asymptomatic infected patients [7]. Moreover, they cannot be used to assess response to treatment or diagnose relapses, or in the immunocompromised host [15,51]. Guidelines suggest the use of serologic testing for patients with suspected VL in whom other tests (microscopic visualization, culture, molecular tests) cannot be conducted or have negative results [15].
The development of RDTs was a step forward for the diagnosis of VL, as they are cost-effective and fast [21,47]. rK39-RDT is an immunochromatographic test which qualitatively detects antibodies which are specific for the recombinant Leishmania antigen rK39, a part of the kinesin-related protein of Leishmania chagasi [46]. This test is easy to perform and cheap and can be used for the early diagnosis of VL [51]. Its performance is considered to be high, but it varies depending on geographical areas: a Cochrane review concluded that the sensitivity of this test is excellent in the Indian subcontinent (97%), but lower in east Africa (85%) [52]. The more recently developed rK28 antigen based RDT showed a higher sensitivity in Sudan [53]. However, RDTs have the same limitations as the other serological assays and their results should be evaluated in the clinical context.
The direct agglutination test (DAT) is another serologic test that was developed to be used in areas which are endemic for VL but have limited laboratory infrastructures. It uses whole Leishmania promastigotes as antigens and it can be falsely positive in case of Chagas disease, brucellosis, and malaria [15,47]. A metanalysis conducted in 2006 found that DAT had a sensitivity and a specificity of 95% and 86%, respectively [54].
2.4. Polymerase Chain Reaction (PCR) Tests
Molecular tests can be performed on peripheral blood, bone marrow aspirates, and buffy coat samples with high sensitivity (>95%) and are currently part of the diagnostic work-up in Europe and North America [15,51]. However, some well-designed studies found low specificity, indicating that there is a risk of missing true cases, and that in endemic areas several people with asymptomatic infection are PCR positive [7,47,55]. Sensitivity was improved to 83% with loop-mediated isothermal amplification (LAMP) assay [56]. PCR has a role in the diagnosis of VL in L. infantum-affected countries and travel clinics, but it is rarely used in resource-limited settings mainly because of its costs.
2.5. Other Tests
The latex agglutination test KAtex (KALON biological, UK) detects a heat-stable low molecular weight carbohydrate antigen in urine. Its specificity is high (93%), but sensitivity is low (64%), thus, it is rarely used in clinical practice [7,47]. More recent urine antigen tests, based on ELISA techniques, show better sensitivity [57,58].
2.6. Diagnostic Approach
There is not a suggested diagnostic approach specific to the pediatric age. In general, in the suspicion of VL, workup should take into consideration local epidemiology and the immunocompetency status of the patient [47]. A stepwise approach should be preferred, particularly for children: first, molecular and serologic tests and microscopy should be performed on peripheral blood; if these are not sufficient to confirm or rule out VL diagnosis, tissue samples such as bone marrow or lymph nodes should be collected for further examination.
3. Therapy
Treatment of VL is still very difficult and not satisfactory; chemotherapy remains the only option, with increasing drug resistances. Drugs available for this use are limited to pentavalent antimonial compounds like sodium stibogluconate (SSG) and meglumine antimoniate (MA), injectable paromomycin (PM), oral miltefosine (MF), and amphotericin B (AmpB) in two formulations (free deoxycholate, now in disuse, and lipid formulation) [59]. There are no trials investigating a therapeutic approach specific for the pediatric age: all major trials included pediatric patients and applied the same approach as for adults, or children themselves have been the main subjects of these studies [60].
Pentavalent antimonials, such as SSG, are parenteral drugs that are given in doses of 20 mg/kg for 28–30 days when used as monotherapy; their mechanism of action is still poorly understood [61]. Despite the need for prolonged parenteral treatment and the risk of adverse affects, including cardiotoxicity (ventricular tachycardia, prolonged QTc interval, ventricular fibrillation, torsades de pointe), pancreatitis, pancytopenia, and nephrotoxicity, since their discovery in 1923, these drugs have been used for decades for the treatment of VL in the vast majority of endemic regions [7,62,63]. This probably happened because of the affordability and the time-tested effectiveness of this drug [64].
PM, an aminoglycoside antibiotic which blocks protein synthesis, was shown to be a cheap and effective parenteral drug easily administered intramuscularly with a dosage of 15 mg/kg/day, but it requires a 21-days course. Moreover, it is potentially nephrotoxic and ototoxic [51,63].
MF, the only oral medication against VL, is an alkyl phospholipid compound developed as an antineoplastic agent against breast cancer. It had high efficacy at a dose of 2–2.5 mg/kg for 28 days when initially introduced after the first antimonial-resistant cases. It induces an increase in nitric oxide production in the macrophages that kills the parasite, alters its plasma membrane composition, and damages its mitochondria. It has a long half-life and this, together with inadequate use, unfortunately led to the induction of resistance in the protozoan. It is a teratogenic compound so it cannot be used for pregnant females. Its main adverse effects are diarrhea, vomiting, and dehydration [63,65,66]
AmpB is an antifungal drug with high affinity binding to ergosterol, the major component of the leishmanial cell membrane; it causes the formation of aqueous pores that ultimately lead to cell death [67]. AmpB deoxycholate has major side effects including nephrotoxicity, hypokalemia, infusion reactions, and myocarditis [65,66]. This is why Liposomal AmpB (LAMB), a lipid formulation, has been developed: it has reduced toxicity, targeted drug delivery, and better pharmaco-kinetics and bioavailability. LAMB, known as Ambisome, is the only AmpB preparation approved by the Food and Drug Administration (FDA). It is expensive and requires a good cold chain, and there is remarkable geographical variation regarding the total dose administered [63,65,67]
The latter problem does not affect only this drug: unfortunately, clinical trials showed that the same therapeutic protocol could not be equally effective everywhere, with big differences based on geographical area and protozoan epidemiology [59]. At present, multidrug therapy seems to be the most promising path in many regions of the world, as it allows reduction in the duration of therapy, drug doses, and, consequently, adverse effects and costs; another advantage of this approach is that it also limits the development of drug resistances [65].
LAMB constituted a breakthrough. The price of this drug was initially too high, but, after the WHO defined guidelines on the use of LAMB depending on geographical zones in 2005, a price reduction was obtained [59,69]. Moreover, in 2010, Sundar et al. demonstrated the effectiveness of a single dose of LAMB of 10 mg/kg against L. donovani in patients between the ages of 2 and 65, with 95.7% efficacy and a comparable cure rate with respect to the previous treatment regimen, lasting about a month. The single dose of 10 mg/kg of LAMB is currently the first option treatment regimen in the Indian Subcontinent where a cold chain is available, while the combination therapy with PM and MF is the second choice for remote areas [65,70,71]. A recent study carried out in Bangladesh confirmed the appropriateness but also the ease of use at the level of primary care [72]. Furthermore, LAMB was donated to WHO in 2012 for 10 years, and this has been fundamental for reduction of the cases [59].
At present there is no vaccine approved for the prevention of Leishmania infections. The only promising candidate is ChAd63-KH, a third-generation vaccine encoding two antigens of L. donovani, KMP-11 and HASPB [84]. It was tested in patients with PKDL and proved to be safe and immunogenic, but there is need for further studies before it can be commercialized.
This entry is adapted from the peer-reviewed paper 10.3390/microorganisms10101887
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