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Visceral Leishmaniasis: A Brazilian Perspective

Andréia Patrícia Gomes1*, Paulo Sérgio Balbino Miguel1, Rodrigo Roger Vitorino2, Marisa Dibbern Lopes Correia3, Ronny Francisco de Souza4, Rodrigo de Barros Freitas4, Juliana Lopes Rangel Fietto5, Luiz Alberto Santana1, Mauro Geller6 and Rodrigo Siqueira-Batista7

1Laboratório de Agentes Patogênicos (LAP), Departamento de Medicina e Enfermagem, Universidade Federal de Viçosa (UFV), Viçosa, MG, Brazil.

2Curso de Medicina, Centro Universitário Serra dos Órgãos (UNIFESO), Teresópolis, RJ, Brazil.

3Departamento de Medicina e Enfermagem, Universidade Federal de Viçosa (UFV), Viçosa, MG, Brazil.

4Curso de Ciências Biológicas, Centro Universitário de Caratinga (UNEC), Caratinga, MG, Brazil.

5Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa (UFV), Viçosa, MG, Brazil.

6School of Medicine, New York University (NYU), NY, USA. Curso de Medicina, Centro Universitário Serra dos Órgãos (UNIFESO), Teresópolis, RJ, Brazil.

7Laboratório de Métodos Epidemiológicos e Computacionais em Saúde (LMECS), Departamento de Medicina e Enfermagem, Universidade Federal de Viçosa (UFV), Viçosa, MG, Brasil. Curso de Medicina, Faculdade Dinâmica do Vale do Piranga (FADIP), Ponte Nova, MG, Brazil. Programa de Pós-graduação em Bioética, Ética Aplicada e Saúde Coletiva (PPGBIOS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.

*Corresponding Author:
Prof. Andréia Patrícia Gomes
Universidade Federal de Viçosa
Departamento de Medicina e Enfermagem
Laboratório de Agentes Patogênicos. Avenue
PH Rolfs s / n, University Campus
Viçosa, MG, CEP 36571-000, Brazil
Tel: + 55 3138993978
Fax: + 55 31 38994083
E-mail: [email protected]

Received Date: December 04, 2016; Accepted Date: January 28, 2016; Published Date: February 04, 2016

Citation: Gomes AP, Miguel PSB, Vitorino RR, Correia MDL, Souza RFD, et al. (2016) Visceral Leishmaniasis: A Brazilian Perspective. J Trop Dis 4: 202.doi:10.4172/2329-891X.1000202

Copyright: © 2016 Gomes AP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Objective: The scope of this paper is to present the main aspects related to the causative agent of visceral leishmaniasis and implications of this interaction with the human host, allowing the improvement of health care actions.
Methods:
The paper was put together based on a literature review with a defined search strategy. To obtain the articles we consulted the Scientific Electronic Library Online (SciELO) and the U. S. National Library of Medicine (PubMed).
Results: The leishmaniases are a group of diseases that pose a serious public health problem in at least 88 countries, and are included among the six priority endemic diseases in the world, according to the World Health Organization (WHO). In this scenario the visceral form stands out kala-azar (visceral leishmaniasis) which, despite its endemic nature, has been reported in different areas of Latin America associated with the process of expansion and urbanization, as well as the unchecked deforestation.
Conclusion: The importance of this discussion of the clinical and diagnostic aspects of VL relates particularly to delayed diagnosis of cases by professionals unfamiliar with the disease – which is becoming quite common due to the intense flow of people in the world resulting in the delayed initiation of therapy.

Keywords

Visceral leishmaniasis; Epidemiology; Diagnosis; Treatment; Control

Introduction

Visceral leishmaniasis (VL) or kala-azar, also known as dumdum fever, is an overlooked tropical, systemic infectious, non-contagious, potentially serious disease. It is vector transmitted and evolves chronically with pathologicalalterations in the mononuclear phagocyte system, and can occur systemically or endemically [1,2]. It includes a broad spectrum of clinical manifestations whose course may vary from acute to sub-acute, to chronic, with an incubation period that varies from weeks to years. The disease is transmitted by female sandflies members of the Psychodidae family, subfamily Phlebotominae, gena Phlebotomus (Old World) and Lutzomyia (America) [1].

The main parasitic reservoirs are foxes, dogs, and opossums [1]. It is considered an emerging or re-emerging illness with worsening incidence in various parts of the world, especially in tropical areas [3]. In Brazil, despite underreporting, there has been a significant increase in the number of cases of visceral leishmaniasis [4-6] owing to several reasons including precarious economic and social conditions [7] including the nutritional status of the exposed population [8], migratory movement, urbanization, and predatory occupation of previously preserved areas associated with poor health care, which may have favored the peridomiciliary movement of the vector Lutzomyia longipalpis [9,10] and the expansion to infected dogs [11,12] transforming VL into a previously unheard of urban disease [13].

Additionally, failures in disease control strategies based on:

• Early detection and treatment in human cases;

• Control of domestic reservoirs; and

• Control of vectors [14] contribute to the spread of the disease [15,16].

Another factor that has been gaining importance is the increased incidence of co-infection with human immunodeficiency virus (HIV) [17,18].

The disease presents significant clinical and epidemiological diversity arising from the multiplicity of possible ecological relations, with the involvement of different species of Leishmania, sandflies, and hosts, with zoonoticand anthroponotic cycles [4]. Most transmission processes are classified as zoonotic, with the exception of the anthroponotic cycles of Leishmania donovani in Southeast Asia and West Africa and Leishmania tropica. Some cycles, previously thought to be exclusively zoonotic, may in fact also are anthroponotic, and vice-versa. This phenomenon has its origins in environmental [19] and epidemiological [5] alterations.

VL is a chronic and systemic disease whose characteristics include: irregular long term fever, weight loss, asthenia, adynamia, anemia with visible cutaneous and mucosal pallor, splenomegaly, hepatomegaly, leucopenia, thrombocytopenia and complications of bacterial infections. Malnutrition is also common, noted by cachexy upon physical examination as well as laboratory evidence of hypoalbuminemia associated with hypergammaglobulinemia [20]. As a result of various anthropic, environmental, political, economic, and social factors, VL is no longer an illness typical of isolated rural areas, and is now present in urban areas in a pattern of frank geographicexpansion [13].

The importance of publicizing this infectious disease lies in the difficulty of unfamiliarized physicians to recognize this illness, especially given its oligosymptomatic characteristics and also because of the existence of effective and easily accessed treatment, allowing for a considerable reduction in fatalities. Furthermore, the disease is difficult to control and causes epidemic outbreaks, which makes it an important public health issue [20].

The objective of this paper is to present the principal aspects of Leishmania species that cause VL and the clinical and therapeutic implications of its interaction with the human host, emphasizing the aspects of the VL in Brazil.

Methods

The paper was written based on a literature review with a defined search strategy. To obtain reference material we consulted the Scientific Electronic Library Online (SciELO) and the U. S. National Library of Medicine (PubMed), up to the date of 20/01/2016. The search terms used were:

Strategy 1 – visceral leishmaniasis + epidemiology

Strategy 2 – visceral leishmaniasis + diagnosis

Strategy 3 – visceral leishmaniasis + treatment

Strategy 4 – visceral leishmaniasis + control

In addition to the papers, we also consulted Internal Medicine and Infectious Diseases textbooks as an integral part of the bibliographic search.

The search yielded citations distributed as shown in (Table 1). Of the total manuscripts consulted, after reading the abstracts, we selected 102 texts opting for those focused primarily on the clinical approach to the patient, which subsidized the present work.

Results and Discussion

The genus Leishmania

The species belonging to Leishmania are included in the kingdom Protozoa, phylum Mastigophora; order Kinetoplastida; family Trypanosomatidae (as Trypanosoma cruzi) [21]. The genus Leishmania is subdivided into three sub-genera (Leishmania, Viannia e Sauroleishmania), the first two according of the location of the promastigote forms in the vector intestine. The addition of Sauroleishmania, a parasite exclusive to lizards, is more recent. The species belonging to the subgenus Leishmania are limited to the midgut and anterior intestine of the sandfly, while the Viannia develop in the large intestine [22,23].

The genus unites species of unicellular protozoa, obligate intracellular parasites with a heteroxenous life cycle, with one vertebrate and one invertebrate host, in which reproduction occurs by simple binary division [22]. In mammalian hosts, represented in nature by numerous orders and species, including Homo sapiens sapiens, we find the amastigote form – round, immobile, and reproducing obligatorily within the cells of the monocyte phagocytic system. The invertebrate hosts are represented exclusively by small insects belonging to the order Diptera, family Psychodidae and genus Lutzomyia, in whose digestive tract are found the mobile promastigote: the extracellular, flagellated and infectious form [24].

Among the species of Leishmania are Leishmania donovani, linked to VL in India and other eastern regions, Leishmania infantum (cause of VL in Mediterranean areas), and Leishmania chagasi (cause of american VL) [23].

The life cycle of the protozoa has two stages: one in the vertebrate host and the other in the vector. During a blood meal, the infected vector regurgitates part of the content of its intestinal tract and inoculates the infective metacyclic promastigote forms of the parasite together with its saliva – the latter with the capacity to alter the host immune response allowing for persistence of the infection [23]. The vector’s salivary proteins possess immunogenic properties, characterized by the presence of IFN-γ, and can determine outcome of the disease [25].

The promastigote (infective) forms of the protozoa bind to macrophage receptors and are quickly phagocytized. This result in reduction of the pathogen, loss of the flagella, and change to the amastigote form, which multiplies and can infect other macrophages, that when ingested together with the host’s blood by the sandfly can continue the cycle. Subsequently, there is hematogenous dissemination of the protozoa with tropism for viscera, especially the spleen and the liver. Upon biting the infected host, the vector ingests a small quantity of blood with macrophages containing amastigotes. In the digestive tract of the vector, the amastigotes transform into promastigotes, and after adhering to the intestinal epithelium of the host, differentiate into metacyclic promastigotes, completing the cycle [24,25].

Epidemiological aspects

The leishmaniases – including VL – constitute a group of diseases that represent a serious public health problem in at least 88 countries, considered one of the six priority endemic diseases in the world [20]. VL is a zoonosis typical of tropical areas, occurring in various regions of the world, however more than 90% the cases that occur in the world are registered in six countries: India, Bangladesh, Sudan, Southern Sudan, Ethiopia, and Brazil [26,27]. However, in other regions including Kenya, the Middle East, and some countries of Latin Ameria (Colombia, Venezuela, Bolivia, El Salvador, and Honduras) the disease is also present [3]. An estimated 0.2 to 0.4 million cases occur annually worldwide [26], with roughly 12 million people currently infected [27]. Specifically in the Americas, the disease has been registered in 12 countries, most recently in Paraguay and Argentina, though roughly 96% of cases are described in Brazil [26]. Although it is an epidemic disease, there have been frequent outbreaks in the five regions of Brazil, with the states of Bahia, Ceará, Rio Grande do Norte and São Luís do Maranhão having the highest recorded number of cases, especially in rural areas [1]. Children under the age of 10 are the most commonly affected (41.9%), and the male gender is proportionally more affected, with 62.8% of cases [20]. The annual mean number of new cases of VL in Brazil between 2003 and 2012 was 3,565 cases and the incidence was of 1.9 cases per 100,000 inhabitants, with a mean lethalityof 6.4% [20]. Between 2004 and 2014 Brazil experienced a process of expansion and urbanization of VL, resulting from increased proximity between dwellings, high population density, and the considerable susceptibility of the population to parasitosis [20]. In this period the main outbreaks in the country occurred in the cities of Rio de Janeiro (RJ), Belo Horizonte (MG), Araçatuba (SP), Santarém (PA), Corumbá (MS), Teresina (PI), Natal (RN), São Luís (MA), Fortaleza (CE), Camaçari (BA), and the epidemics in the municipalities of Três Lagoas (MS), Campo Grande (MS), and Palmas (TO) [20].

VL is included in the group of neglected diseases – also known as neglected tropical diseases – that share the hallmark of affecting primarily the more vulnerable populations and that contribute to the perpetuation of poverty, mainly due to their impact on infant mortality and morbidity, reduced productivity of economically active individuals, and the social stigma [8].

The sandfly vectors – in Brazil Lutzomyia longipalpis and Lutzomyia cruzi – are crepuscular and nocturnal, with L. longipalpis found intraand peridomicile [14,20]. The lifestyle of L. longipalpis, the main vector of VL, is in part responsible for the expansion process of the disease, given that it adapts to the domestic environment, where there is availability of organic residues and areas with humidity and shade, in addition to the intermediate host – the dog [20,28]. These insects are small, measuring between 1 and 3 centimeters in length, covered by light colored hairs, and are easily recognizable by their peculiar habit of flying short distances and landing with their wings open [10]. There is the possibility of a third transmitting species, Lutzoyia migonei, indicated by high density in areas absent of L. longipalpis and/or L. cruzi with consequent registration of indigenous VL cases, a fact that remains to be confirmed [20].

In urban areas, the main reservoir is the dog – Canis familiaris – among which a high prevalence has been observed in epidemiological investigations [29,30]. In the wild, the main vertebrate hosts with an important epidemiological role are foxes – Dusicyon vetulus and Cerdocyon thous – and marsupials – Didelphis albiventris [11].

Clinical aspects

The incubation period – from 10 days to 24 months, with an average of two to six months [20] and the clinical manifestations of VL vary widely depending on the host immune response. There are often periods of fever remission and illusory improvement of the other symptoms of the morbid process, a fact that not infrequently leads to a patient seeking medical treatment only after months of disease evolution [2]. The disease can be classified into the following forms:

Asymptomatic form: Although infected, subjects do not present signs and symptoms, however it should be noted that the intradermal test is reactive and serum or polymerase chain reaction testing is positive [31].

Oligosymptomatic or subclinical form: This is the most frequent expression of the disease in endemic areas, characterized by nonspecific manifestations such as low fever, unproductive cough, diarrhea, adynamia, in some cases with the presence of discrete hepatomegaly, and palpable spleen in a minority of cases. Generally, most patients (85%) presenting both the asymptomatic and oligosymptomatic forms present spontaneous cure even without treatment after three to six months. A smaller proportion of patients (15%), especially malnourished children, evolve to the classic form [32]. Most oligosymptomatic patients harbor viable parasites throughout their lifetimes, and can develop the disease in the event of immunosuppression reactivation [33].

Acute form: Characterized by high fever, cough, and severe diarrhea without hepatosplenomegaly or important hematological alterations, with a mean duration of two months and significantly elevated anti-Lieshmania IgM and IgG (titers ≥ 1:80 considered positive) [32]. The principal differential diagnoses of this form are typhoid fever, malaria, schistosomiasis, and other acute fevers accompanied by hepatosplenomegaly [1].

Classic form: Prolonged disease progression presenting as principal characteristics protein-energy malnutrition, edema, brittle hair, and elongated eyelashes. Alopecia also occurs. The initial signs include persistent or intermittent fever, diarrhea, asthenia, adynamia, nonproductive cough, somnolence, and progressive weight loss. The disease evolves with anemia, dry and brittle hair with more than one color (flag signal), elongated eyelashes, and alopecia may be present. Edema and eventually anasarca may occur. Volumous splenomegaly, variable hepatomegaly, abdominal distention due to the hepatosplenomegaly and some degree of ascites are frequent alterations [32]. Hemorrhagic alterations (epistaxis, ecchymosis, petechia, haemorrhagia) occur in roughly 32.7% of cases [32]. Delayed puberty and growth are observed among children and adolescents, as are hypergammaglobulinemia and hypoalbuminemia. There are rare reports of neurological involvement in VL, clinically expressed primarily by extremity tremors. The reduction of cerebral volume is also described especially in the frontal lobe – evidenced by cranial computerized tomography, in addition to atrophic alterations in the white matter and increased third ventricle on magnetic resonance imaging [34].

In the final stages of this condition, patients may present dyspnea upon minimal effort and accentuated pancytopenia. The association of comorbidities such as bacterial infections – mainly by Staphylococcus aureus and Pseudomonas aeruginosa –, malnutrition, bleeding, and gangrenous stomatitis may contribute to increased lethality [35]. Although the risk factors for secondary bacterial infections are wellknown, a recent study in Brazil carried out in urban areas highlighted AIDS as the most commonly reported comorbidity among patients with VL, followed by tuberculosis, systemic lupus erythematosus, and chronic myeloid leukemia [36]. The susceptibility of HIV-positive patients to VL is attributed to reduced humoral and cellular response to Leishmania, and coinfection may accelerate disease progression and increase the pathogenic effects due to interference with macrophage function [37].

Cutaneous post-calazar form: This is a complication of visceral leishmaniasis occurring in patients who have recovered from the disease. These patients present with macular, maculopapular, cutaneous, and nodular eruptions. The eruption initially affects the area around the mouth, from where it can spread to other body regions depending on severity. This form of VL manifestation occurs primarily in the Sudan and in India [38]. Although considered rare in South America, there are reports in Brazil. In one report, the patient from an endemic area exhibited clinical manifestations of VL three years after being diagnosed with AIDS [39]. The cutaneous lesions manifested mainly on the face, abdomen, and lower extremities, as densely distributed papulonodular lesions [40].

Infection in immunocompromised patients (HIV): coinfection presents peculiar characteristics in clinical manifestations, diagnostic laboratory findings, and treatment response [36,41]. The clinical findings are generally not characteristic; however there may be a rapid, sometimes fatal progression, with T CD4+ cells as important prognostic factor [42,43]. Usually, the classic triad of febrile hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia are the most frequently observed alterations, occurring in approximately 75% of patients [37,44]. In some cases in which the T CD4+ count is below 200 cells/ mm3, digestive, pulmonary, and cutaneous manifestations may be observed [44,45]. In cases of coinfection with HIV, there is a persistent doubt of whether it is a primary infection or reactivation, considering the immunosuppression triggered by the HIV [40,46]. The risk of acquiring VL in endemic areas is roughly one hundred times higher in a patient infected with HIV, a context in which the virus acts as an opportunist infective agent. Coinfection with HIV also compromises the therapeutic response, and increases the probability of relapse given that both conditions compete for immune system depletion [47]. This group of patients also presents the possibility of visceralization of cutaneous and mucocutaneous leishmaniasis, and thus it is important to focus on establishment of the differential diagnosis [42]. Other opportunistic infections may often be associated, including esophageal candidiasis, Pneumocystis jiroveci pneumonia, tuberculosis, and criptococosis of the central nervous system [44]. Therefore, when considering the high rates of mortality, all patients VL patients should be checked for HIV and the pathogens involved in possible bacterial infections [36]. Table 2 summarizes the clinical manifestations of VL in potentially immunodeficient patients, for whom HIV serum testing should be requested.

Diagnosis

Diagnosis of human VL is still challenging for physicians given the wide variety of clinical signs common to other diseases [48]. Furthermore, the methods used in VL diagnosis are not 100% sensitive and specific. Routine diagnosis is usually based on clinical, epidemiological, and serological parameters; however, evidence of the protozoa via parasitological methods or DNA testing – by molecular methods – is required for definitive diagnosis [48,49].

For the purpose of reducing mortality rates, Table 3 lists the criteria which may be used for the definition of suspected and confirmed cases, as well as warning signs or disease severity, according to the Ministério da Saúde (Ministry of Health) of Brazil.

The disease should always be investigated in patients presenting a history of prolonged fever associated with hepatosplenomegaly, especially if coming from endemic areas, and also in cases of travelers who have returned from such regions and present prolonged febrile conditions [19].

Parasitological diagnosis: Parasitological diagnosis confirms infection [20]. This may be performed by stained smears of peripheral blood, in which the amastigote forms of Leishmania can be seen [50]. However, splenic fine needle aspiration is the most sensitive (90% to 95%) method to detect the parasite. Other sites such as the bone marrow and liver may also be aspirated, taking into account that in HIV positive patients the parasite may be located in unusual locations such as the gastrointestinal tract. Because it is considered a safer procedure, bone marrow aspiration is recommended, and the material obtained should be examined in the following order [51]:

• Direct examination: A smear is made of a drop of aspirated material on at least four slides. Using Giemsa, Wright, Leishman or Panoptic stains, it is possible to view the amastigote forms of the parasite. Under light microscope oil immersion magnification, smears stained with panoptic acid show elliptical or rounded amastigotes, measuring 3-4μm in diameter, as shown in Figure 1.

• Isolation in culture medium (in vitro): Special culture mediums, especially NNN (Novy-MacNeal-Nicolle), are used to inoculate amastigote forms of the parasite, which transform into promastigote. The cultures are observed weekly over four weeks using light microscopy. When positive, the tubes should be sent to reference laboratories for species identification.

Parasite DNA detection methods: The molecular techniques used after DNA extraction were developed for more precise detection and identification of the protozoa that cause VL, without the need for isolation of the pathogen in culture [52]. As in the parasitological investigation, various biological materials can be used in these reactions: aspirate from lymph nodes, bone marrow, spleen, total blood, culture, and blood collected on filter paper [53]. These methods are highly sensitive and include polymerase chain reaction (PCR), realtime PCR, reverse transcriptase associated PCR (RT-PCR) for RNA detection, nucleic acid sequence based amplification (NASBA), and loop-mediated isothermal amplification (LAMP) [53] and sequencing [54]. The targets for the PCRs have been primarily repeated sequences of conserved mitochondrial or kinetoplast DNA (conserved region of kDNA DNA) [55]. Other studies identify additional targets for pathogen detection, such as the small-subunit ribosomal RNA (SSUrRNA), internal transcribed spacer 1 (ITS1), cysteine protease B (cpb), cytochrome b (cyt b), and heat shock protein 70 (HSP70), among others [54].

Although PCR is a sensitive method for Leishmania detection in a variety of human materials [56-59], it is more widely used in epidemiologic studies than in routine diagnosis [60], because serologic tests are still considered more advantageous in terms of cost-benefit [61]. PCR can also be used as a complementary method in the serological approach [62]. Real-time PCR (qPCR) can also be used for diagnosis [63,64]. The advantages in relation to conventional PCR include sensitivity, speed, reproducibility, quantitative ability, and better cost-benefit [65].

Serologic tests: Serologic diagnosis is performed by detection of Leishmania antigens or antibodies in serum [66]. Among the various noninvasive tests developed for VL diagnosis, those that employ antibody detection are the most widely used. In this context, it is important to note that VL is characterized by significant polyclonal B lymphocyte stimulation, which results in hypergammaglobulinemia [67]. Indeed, in serological tests the greatest problem that has been faced is the occurrence of false positive results. Several infectious diseases – such as babesiosis, borreliosis, heartworm, ehrlichiosis, and trypanosomiasis – may interfere with the analysis and yield false positive results [68,69].

Among the most commonly used tests are the indirect immunofluorescence test (IF), enzyme-linked immunosorbent assay (ELISA), direct agglutination test (DAT), and the rapid diagnostic test, based on recombinant antigen k39 protein [66]. ELISA has been used as an important tool in serum diagnosis for nearly all infections, including VL. In several studies using DAT in endemic VL areas, the specificity and sensitivity varied from 70.5-100% and 53-100%, respectively [66]. However, one of the difficulties of this method is the time required to complete the test, requiring approximately 18 hours of incubation [70]. IF is considered the gold standard of serum diagnostic tests and the sensitivity and specificity of this method vary between 85.5% and 94,7%, respectively [14].

These techniques employ soluble total antigens, but cross reactions result in numerous false positive results [68,69,71]. One solution to this problem – that has been invested in since the 90’s – are recombinant or purified antigens [72-76], especially when using recombinant or purified Leishmania molecules [72-76]. One of these is recombinant antigen k39, a member of the kinase family. This recombinant antigen is specific for the species of the L. donovani complex [75]. The added use of recombinant antigens has improved diagnostic sensitivity [73].

Nonspecific tests: Other indirect methods that may aid diagnosis include:

• Hematological evaluation: the complete blood count may reveal intense normochromic anemia (less than 3 million red blood cells/ mm3 and hematocrit between 25 and 30%), leukopenia (2000-4000 white blood cells/mm3) and thrombocytopenia below 100,000/ mm3, Rouleaux formation is common, as is absence of eosinophilia, even when associated with other parasitoses such as schistosomiasis and strongyloidiasis [77].

• Biochemical blood evaluation: the protein assay reveals hypoalbuminemia with increased globulins; cases with inversion of albumin/globulin ratios are not uncommon, and can be as accentuated as those found in multiple myeloma [20]. The aminotransferases are normal or slightly elevated, reaching up to three times the upper reference range. Hyponatremia associated with altered antidiuretic hormone (ADH) secretion [78,79].

• Urinalysis: may reveal proteinuria, hematuria, pyuria, and cylindruria, indicating subclinical glomerulonephritis caused by immune complex deposition [80].

Evaluation by complementary methods: The possible complications of the disease can be identified using some complementary methods, including renal function tests and imaging tests, electrocardiogram and stool parasitology testing. Chest x-rays may reveal interstitial condensation or infiltrate, resulting from concurrent bacterial or viral infection, or caused by the VL itself in cases of leishmaniotic pneumonitis [32,81]. Plain abdominal x-ray may reveal hepatosplenomegaly, evidenced by increased volume with hypotransparent aspect in the upper right quadrant and retraction of the hepatic flexure, with possible presence of free fluid in the peritoneal cavity [82]. Computerized tomography of the abdomen reveals a diffuse enlargement of the liver with periportal hypoattenuation following administration of venous contrast – a finding that indicates inflammation or edema, in addition to revealing ascites, thickening of vesicular wall and lymphadenopathies [83]. The spleen is markedly enlarged with hypodense diffuse nodular lesions, associated with vascular alterations such as vena cava and splenic vein dilation [84]. Doppler echocardiography has been employed to assess cardiac function of patients undergoing treatment with N-methylglucamine antimonate, demonstrating that the occurrence of pericardial effusion is associated with elevated parasitemia [84]. Any clinical manifestation that signals progression to more severe states should be observed (Table 3). These signs indicate likelihood of development of the severe, lifethreatening forms of VL.

Treatment

Specific treatment: Hospitalization of the patient diagnosed with VL is required in order to provide specific parenteral therapy [47]. Drugs currently recommended for treatment of the disease are pentavalent antimonial and liposomal amphotericin B [44,85], the former being the first choice due to its proven therapeutic efficacy [86]. However, pentavalent antimonial is associated with frequent toxicity [87].

It is known that recently, ever increasing doses of antimony have been recommended by the World Health Organization and the Centers for Disease Control and Prevention (USA). This dosage increase has been attributed to the resistance demonstrated by the parasites to these drugs, especially in patients in the Sudan, Kenya, and India [44]. On the other hand, in Brazil, absences of results that confirm this trend justify use of a dose of 20mg of Sb+5 kg/day. In this case, the drug is administered intravenously or intramuscularly during 20 to 40 days and cure rates are considered satisfactory [44].

In cases of treatment failure, gestation, contra-indication, need for suspension of pentavalent antimony, or acquired infection in areas of resistance, amphotericin B [47] or miltefosine [88] should be used (however, the cure rate of infection by L. chagasi in the treatment with mitefosine is approximately 50%). Treatment using liposomal amphotericin B (LAMB) is very effective and is the most widely used [89]. Table 4 summarizes treatment options for VL.

Treatment of VL can be complicated in cases where the patient develops tumor lysis-like syndrome (TLLS), a metabolic disorder generally manifested after the start of chemotherapy [90]. This syndrome is triggered by “massive death of parasites and amastigotecontaining mononuclear phagocytes after the initiation of treatment for visceral leishmaniasis” [91]. The complications are more pronounced among patients with high parasite loads, who may present residual kidney damage within 30 days of starting treatment [90,91]. On the fourth post-treatment day, there are increases in serum levels of uric acid, phosphate, creatinine, and urea. In these cases, metabolic recovery is obtained by hydration, urine alkalinization, and use of allopurinol, and in some cases tissue damage was observed. Awareness of this condition is important, to adopt prophylactic measures and also for early recognition and adequate medication [91].

Use of immunomodulators: The therapeutic approach is being reconsidered using the idea of enhanced immunity, and immunomodulators associated with chemotherapy drugs seems promising as the most effective therapeutic alternative in the future [92,93].

Granulocyte and macrophage colony stimulating factors – G-CSF and GM-CSF – have been used in the treatment of hematological disorders in patients with VL and neutropenia. The exogenous anti-Leishmania effect of GM-CSF is accompanied not only by early macrophage and neutrophil mobilization, but also by the influx of myelocytic cells to the affected organ [93]. Immunotherapy with interferon gamma (IFN-γ) in acute or refractory VL patients under treatment with Sb+5 showed encouraging results [93]. The use of this therapy in patients with the severe forms of the disease and important neutropenia (<1,500 neutrophils/mm3) significantly reduces mortality – usually associated with bacterial or viral infections and septic complications [95].

Support measures: Blood transfusion represents an important therapeutic measure in VL. Referral to a hemotherapy service is indicated for patients with evidence of serious or significant laboratory alterations, including leucopenia <1,000/mL, neutrophils <500/mm3, thrombocytopenia <50,000/mL, serum hemoglobin <7 g/dL, serum creatinine greater than two times upper reference range, prothrombin activity less than 70%, serum bilirubins above reference range, hepatic enzyme greater than five times reference range, albumin <2.5 mg/ mL, and chest X-ray with image suggestive of infection or pulmonary edema [47,85].

Based on the presence of neutropenia – typical of VL in its classic form – the patient is presenting a decreased inflammatory response and is at risk of manifesting bacterial infections, especially on the skin, respiratory tract, and middle ear, with Pseudomonas aeruginosa and Staphylococcus aureus the most commonly involved agents [95]. Thus, fever has little diagnostic value in secondary infection, and there is no secure method to identify bacterial infection. Since there is no consensus in the literature on the antimicrobial approach in these patients, a prudent approach would be to follow the recommendations outlined for the febrile neutropenic cancer patient [47,95], as summarized in Table 5.

Special circumstances: In the treatment of Leishmania and HIV coinfection, the drugs used are the same as those for immunocompetent patients, with the recommended drug of choice being pentavalent antimonial. Alternately, amphotericin B and pentamidine isethionate can be used [47].

During pregnancy, treatment aims to cure the pregnant patient and to prevent transplacental transmission. Because of their teratogenicity, antimonials should not be used, nor should amphotericin B (it is cardiotoxic and nephrotoxic); as such, the drug of choice is aminosidine (12 to 16 mg/kg/day, intramuscularly, for 15 to 20 days) [96].

In patients presenting the cutaneous form post-kala-azar, the drug typically used is sodium stibogluconate (20mg/kg/day for two months) [88].

Cure control: Assessment of cure depends on monitoring of clinical criteria: fever drop (the first symptom to disappear, after the second to fifth day of specific medication), hepatosplenomegaly regression, overall patient improvement and appetite restoration (seen during the first week of treatment, weight gain, urinary volume, lymph node size, increased albumin and decreased serum gamma globulins. Following treatment, the presence of eosinophils in peripheral blood is a marker of a favorable prognosis [47,85].

Nursing care: The change in the epidemiological characteristic of VL points to a need for integration among healthcare workers in treating affected individuals. In this context, physicians, nurses, and other professionals should be aware of the characteristics of the disease, its transmissibility, and be able to recognize new cases. In the case of the supporting healthcare staff, they should follow the steps of the healthcare process proposed by the nurse, the professional who should guide their practice based on care planning.

Among the models proposed for this purpose are those outlined by Wanda de Aguiar Horta [97] in the Theory of Basic Human Needs associated with the North American Nursing Diagnosis Association (NANDA) taxonomy [98] and the use of the Nursing Interventions Classification (NIC) that guides interventions based on the proposed diagnoses [99], as shown in Table 6. The term nursing diagnosis is defined by NANDA as “a clinical judgment about human experience/ responses to health conditions/life processes that exist in an individual, family, or community that provide the foundation for definitive therapy aiming to achieve results in which the nurse is required” [100]. On the other hand, according to NIC, the nursing intervention consists of “any treatment based on the judgment and clinical knowledge by a nurse to improve patient/client outcomes” [100].

Prophylaxis and Recommendations for Travelers

There are some behavioral measures that considerably reduce the risk of contracting VL [28] which apply to humans, to the vector, and to other animals (Table 7).

At the moment there are no vaccines or drugs with proven efficacy in immunoprophylaxis or chemoprevention of visceral leishmaniasis in humans.

Based on the insufficient knowledge of the VL transmission chain, strategies for disease control are centered on early detection and treatment of affected patients, reduction of vector population, elimination of sandfly reservoirs, and continuing education of healthcare professionals. A study carried out in the state of Bahia between 1995 and 2000 demonstrated the validity of control actions with the percentage of visited and sprayed buildings [101].

To date there are no available vaccines for the leishmaniasis. However, research has been carried out that may in the near future lead to the development of vaccines for human visceral leishmaniasis. Among the promising results aimed at prevention and control of VL are first, second, and third generation vaccines. The first are based on the attenuated parasite; the second on antigenic or recombinant proteins; and the third are derived from DNA plasmids encoding the antigen. Some of these, such as Leishmune®, Eishtec, and CaniLeish® have already been licensed for the prevention of canine VL [102].

Epidemiologic Surveillance

Epidemiologic surveillance of VL is part of the Brazilian Visceral Leishmaniasis Control Program (Programa de Controle da Leishmaniose Visceral – PCLV), whose priority is to reduce morbidity and mortality rates through early diagnosis. It includes entomological surveillance and monitoring of human and canine cases, as summarized in Table 8.

In this way, epidemiological surveillance may indicate signs for actions and preventions to be adopted in humans. The first goal of the PCLV is to incorporate regions including those that have no recorded cases of this disease.

Final Considerations

Visceral leishmaniasis is a serious public health problem that was previously restricted to rural areas but is currently associated with the process of urbanization. The disease is potentially fatal if not diagnosed in time, but fully curable if detected, in the absence of co-morbidities that may impact overall patient condition. It is therefore important that healthcare professionals possess the capacity to identify a suspected VL case – especially those among patients in non-endemic areas – in order to reduce the morbidity and mortality associated with the disease through surveillance measures, prevention, and control.

Acknowledgements

The authors are grateful to CNPq and FAPEMIG for financial support for research.

References

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