Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis (original) (raw)
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Immunobiology, 2017
Visceral leishmaniasis (VL) is a potentially fatal disease, in which the treatment based on chemotherapy is considered toxic. The cure of disease is associated with the life-long Th1-type immunity against the infection. The Th1-related cytokines production by peripheral blood mononuclear cells (PBMCs) seems to be crucial for host control of parasite load and clinical cure. In the current study, we used five proteins (IgE-dependent histamine-releasing factor [HRF], LiHyD, LiHyV, LiHyT and LiHyp6) recently shown to be antigenic and/or immunogenic in the canine VL, aiming to evaluate the antigen-specific antibody levels and cytokine production in PBMCs culture supernatants collected from VL patients before and after anti-VL treatment. In the results, when PBMCs were exposed to rHRF, rLiHyD and rLiHyT, higher IFN-γ and lower IL-10 levels were observed in all patients that were treated and clinically cured. Analysis of specific antibody subclasses was in line with in vitro cellular respo...
Biomarkers in Leishmaniasis: From Basic Research to Clinical Application
Biomarker - Indicator of Abnormal Physiological Process
Leishmania is an intracellular protozoan parasite and the etiological agent of a vector-borne disease known as leishmaniasis. This neglected tropical disease exhibits high morbidity and mortality putting at risk people from multiple countries worldwide. It is endemic in 97 countries and 700,000-1 million new cases are estimated to occur each year. Leishmaniasis management is very challenging, the symptoms are non-pathognomonic (in both human and canine populations) and the treatments are associated with significant toxicity. Therefore, the need for detection in symptomatic and asymptomatic hosts is important to tackle the dissemination of infection, increasing the need for highly specific biomarkers. In this complex the available disease biomarkers will be addressed in a retrospective manner, focusing on their development from laboratory to their direct use in clinical settings.
Frontiers in cellular and infection microbiology, 2018
The parasite resides and replicates within host macrophages during visceral leishmaniasis (VL). This study aimed to evaluate neopterin, a marker of macrophage activation, as possible pharmacodynamic biomarker to monitor VL treatment response and to predict long-term clinical relapse of VL. Following informed consent, 497 plasma samples were collected from East-African VL patients receiving a 28-day miltefosine monotherapy (48 patients) or 11-day combination therapy of miltefosine and liposomal amphotericin B (L-AMB, 48 patients). Neopterin was quantified with ELISA. Values are reported as median (inter-quartile range). Baseline neopterin concentrations were elevated in all VL patients at 98.8 (63.9-135) nmol/L compared to reported levels for healthy controls (<10 nmol/L). During the first treatment week, concentrations remained stable in monotherapy patients ( = 0.807), but decreased two-fold compared to baseline in the combination therapy patients ( < 0.01). In the combinatio...
Specific antibody responses as indicators of treatment efficacy for visceral leishmaniasis
European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2015
Acute visceral leishmaniasis (VL) is caused by infection with parasites of the Leishmania donovani complex and may be fatal if not treated. Early diagnosis and efficacious treatment are the keys to effective VL management and control. Novel regimens are being developed to overcome limitations in VL treatment options, which are currently restricted by high costs, severe systemic side effects, and unresponsiveness. Although simple and accurate serological tests are available to help confirm VL, none are suitable to monitor treatment efficacy and cure. Here, we confirm that serum antibody responses to the diagnostic antigens rK39 and rK28 are unaltered by treatment, but demonstrate that antibodies produced against two antigens, rK26 and rK18, can be used as an indirect measure of parasite clearance. The levels of anti-rK18 and -rK26 antibodies were high in patients at initial diagnosis but declined in patients treated with either SSG (Ethiopia) or AmBisome™ (Bangladesh). Taken together...
New Strategies and Biomarkers for the Control of Visceral Leishmaniasis
Trends in Parasitology, 2019
Effective diagnosis and treatment of visceral leishmaniasis, together with the study of vectors and reservoirs, can lead to a better understanding of the parasite transmission dynamics and the development of more efficient control measures. Recent studies have applied new methodologies and biomarkers, and these have contributed to the early and rapid diagnosis of the disease; assessment of success of pharmacological treatments; efficient monitoring of immunosuppressed individuals; and to population screening for field trials of vaccine efficacy. This opinion article proposes an update to the diagnostic tools for visceral leishmaniasis and their rational and combined use to establish the real prevalence of infection or of exposure to Leishmania in endemic areas. Unveiling the Complexity of Visceral Leishmaniasis Leishmaniasis is a vector-borne infectious disease caused by parasites of the genus Leishmania. Globally distributed, it is poverty-related and is among the deadliest of the neglected tropical diseases (NTDs). Visceral leishmaniasis (VL), caused by Leishmania. donovani and Leishmania infantum, is the most severe clinical form. It affects internal organs and is fatal in 95% of cases if not successfully treated. On some occasions, after an episode of VL caused by L. donovani, the patient may develop a post-kala-azar dermal leishmaniasis (PKDL). So far, little is known about the mechanism by which a patient with VL develops PKDL [1]. The overall incidence of VL has declined in recent years, mainly because of the elimination efforts carried out in South Asia [2]. However, the incidence of VL has increased alarmingly in the Americas, where the recent report by the Pan American Health Organization (PAHO) and the World Health Organization (WHO) indicates that VL is expanding geographically: the number of cases has increased by 26.4%, while the fatality rate and number of deaths have grown progressively since 2014 [3]. In addition, epidemic outbreaks have appeared in Europe, the Indian subcontinent, and Eastern Africa [4-7]. The transmission dynamics (see Glossary) of Leishmania are complex and variable, and are dependent on environmental conditions, the distribution and biology of the vector, the reservoirs involved, and on the health, social, and economic aspects that affect the human host [2]. In the absence of an effective vaccine, the control of VL has been based on the prevention of sand fly bites, the elimination of animal reservoirs (if the VL is zoonotic), and the early detection and effective treatment of human cases [8]. Nevertheless, in regions endemic for VL, most infected individuals remain asymptomatic. Their possible role as 'parasite carriers' with capacity to infect sand flies has been suggested and is under active consideration [9]. Individuals who suffered previous VL infections for which treatment was not fully effective can also remain asymptomatic and subsequently relapse later. Additionally, immunosuppressed patients can remain asymptomatic after VL therapy, because they receive secondary prophylaxis; however, they can still act as reservoirs, as confirmed by xenodiagnoses [10]. This complex scenario for the transmission dynamics of VL makes it even more difficult to establish effective control measures, and highlights the clear need for improved tests that are able to distinguish between all the different conditions (Box 1). Diagnostic tests have to provide an immediate, reliable, confirmatory diagnosis of active VL cases independently of a central laboratory. Improved tests are also necessary to assess treatment success, a fundamental measure for predicting and avoiding relapses. This requires a specific test that goes beyond the clinical recovery of the patient, and the nondetection of the parasite, and confirms cure [11,12].
Current opinion in …, 2008
Purpose of reviewTo identify recent papers showing how human and parasite genetics influence leishmaniasis, and how understanding of the immunopathology may be utilized in immunotherapy for these diseases.Recent findingsProgress has been made in recent years showing the complexity within populations of Leishmania spp. and indicating that different strains lead to diverse clinical pictures and responses to treatment. Thus detection of parasite genetic tags for the precise identification of infecting strains, and for predictive diagnosis of clinical and therapeutic fates seems now possible. Host genetic loci involved in disease outcome have been detected, which may also be explored for better case management. These developments in diagnosis will demand expanding the therapeutic arsenal to take their expected effect. This is starting to be fulfilled by immunotherapies successfully employed to treat cases refractory to standard first line drugs, as the result of a more profound comprehension of the immunopathology of the leishmaniases.SummaryThe knowledge mounting has already helped explain why different patients present different forms of leishmaniasis and respond differently to treatment, and may be on the verge of catalyzing a major change in the already over a century old paradigm of diagnosing and managing these patients.
Biomarkers of the early response to treatment of visceral leishmaniasis: A prospective cohort study
Parasite Immunology, 2020
Visceral leishmaniasis (VL), or kala-azar, caused by the viscerotropic Leishmania infantum and L donovani, intracellular protozoa transmitted by sand flies, can range from an asymptomatic infection 1 to the typical clinical picture with fever, hepatosplenomegaly, weight loss and anaemia, 2,3 and, if not properly treated, to a lethal disease. 2,4,5 In Brazil, VL has re-emerged as a serious public health issue since the 1980s, associated with urbanization 6 and HIV infection. 7-9 The disappearance of fever and hepatosplenomegaly and improvement of anaemia, leucopenia and thrombocytopenia, as well as liver function tests, are useful to assess the response to specific therapy. Because an exaggerated plasma pro-and anti-inflammatory cytokine profile has been shown in patients with VL, particularly the inflammatory interferon gamma (IFN-γ), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), tumour necrosis factor alpha (TNF-α) and the anti-inflammatory interleukin 10 (IL-10) concentration, 5 their decline also signals clinical improvement. 10-12 In this work, we re-evaluated the importance of biomarkers at the first check point of one week to assess the early response to VL therapy. Previously, only C-reactive protein (CRP) and serum amyloid A protein (SAA) have shown dramatic decreases at seven days or less after the start of therapy. 13,14 However, CRP and SAA are released by the liver as part of the acute-phase reaction secondary to the action of
Novel Antigen Detection Assay to Monitor Therapeutic Efficacy of Visceral Leishmaniasis
The American journal of tropical medicine and hygiene, 2016
Visceral leishmaniasis (VL) diagnosis is routinely performed by invasive splenic, bone marrow, or lymph node biopsies, followed by microscopic identification of the parasites. Conventional serological tests cannot distinguish active disease from asymptomatic VL or from cured infection. Here, we report the initial validation of an enzyme-linked immunosorbent assay (ELISA) assembled to detect the Leishmania infantum/donovani antigens iron superoxide dismutase 1 (Li-isd1), tryparedoxin 1 (Li-trx1), and nuclear transport factor 2 (Li-ntf2) as a tool to monitor therapeutic efficacy of VL. The assembled ELISA detected the antigens in the urine samples from seven VL patients before initiation of therapy. Importantly, the antigens were no longer detected in all patients after completion of the treatment. These preliminary observations point to a promising tool to follow treatment efficacy of VL.