Publications by authors named "Dorcas L Costa"

12 Publications

  • Page 1 of 1

A Leishmania infantum genetic marker associated with miltefosine treatment failure for visceral leishmaniasis.

EBioMedicine 2018 Oct 27;36:83-91. Epub 2018 Sep 27.

Centre for Immunology and Infection, Department of Biology, University of York, United Kingdom.; Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, United Kingdom.. Electronic address:

Background: Miltefosine has been used successfully to treat visceral leishmaniasis (VL) in India, but it was unsuccessful for VL in a clinical trial in Brazil.

Methods: To identify molecular markers that predict VL treatment failure whole genome sequencing of 26 L. infantum isolates, from cured and relapsed patients allowed a GWAS analysis of SNPs, gene and chromosome copy number variations.

Findings: A strong association was identified (p = 0·0005) between the presence of a genetically stable L. infantumMiltefosine Sensitivity Locus (MSL), and a positive response to miltefosine treatment. The risk of treatment failure increased 9·4-fold (95% CI 2·11-53·54) when an isolate did not have the MSL. The complete absence of the MSL predicted miltefosine failure with 0·92 (95% CI 0·65-0·996) sensitivity and 0·78 (95% CI 0·52-0·92) specificity. A genotyping survey of L. infantum (n = 157) showed that the frequency of MSL varies in a cline from 95% in North East Brazil to <5% in the South East. The MSL was found in the genomes of all L. infantum and L. donovani sequenced isolates from the Old World (n = 671), where miltefosine can have a cure rate higher than 93%.

Interpretation: Knowledge on the presence or absence of the MSL in L. infantum will allow stratification of patients prior to treatment, helping to establish better therapeutic strategies for VL treatment. FUND: CNPq, FAPES, GCRF MRC and Wellcome Trust.
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http://dx.doi.org/10.1016/j.ebiom.2018.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197651PMC
October 2018

Serological Markers of Recent Infection in Patients with Guillain-Barré Syndrome in the State of Piauí, Brazil, 2014-2016.

Am J Trop Med Hyg 2018 02 4;98(2):586-588. Epub 2018 Jan 4.

Department of Arbovirology and Haemorrhagic Fevers, Evandro Chagas Institute, Ananindeua, Pará, Brazil.

In countries where poliomyelitis has been eradicated, Guillain-Barré syndrome (GBS) is the leading cause of acute flaccid paralysis. The range of infections that precede GBS in Brazil is unknown. infection is the most frequent trigger of GBS worldwide. Given the lack of systematic surveillance of diarrheal diseases, particularly in adults, the incidence of enteritis caused by in developing countries is unknown. From 2014 to 2016, pretreatment serum samples from 63 GBS patients were tested by immunoglobulin M (IgM) enzyme-linked immunosorbent assay for . IgM antibodies were detected in 17% (11/63) of the samples. There was no association between serological positivity (IgM) for and the occurrence of diarrhea among the investigated cases ( = 0.36). Hygiene measures, basic sanitation, and precautions during handling and preparation of food of animal origin may help prevent acute flaccid paralysis.
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http://dx.doi.org/10.4269/ajtmh.17-0666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929210PMC
February 2018

Evaluation of a new set of recombinant antigens for the serological diagnosis of human and canine visceral leishmaniasis.

PLoS One 2017 28;12(9):e0184867. Epub 2017 Sep 28.

Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz (Fiocruz-Pernambuco), Recife, Pernambuco, Brazil.

Current strategies for the control of zoonotic visceral leishmaniasis (VL) rely on its efficient diagnosis in both human and canine hosts. The most promising and cost effective approach is based on serologic assays with recombinant proteins. However, no single antigen has been found so far which can be effectively used to detect the disease in both dogs and humans. In previous works, we identified Leishmania infantum antigens with potential for the serodiagnosis of VL. Here, we aimed to expand the panel of the available antigens for VL diagnosis through another screening of a genomic expression library. Seven different protein-coding gene fragments were identified, five of which encoding proteins which have not been previously studied in Leishmania and rich in repetitive motifs. Poly-histidine tagged polypeptides were generated from six genes and evaluated for their potential for diagnosis of VL by ELISA (Enzyme Linked ImmunoSorbent Assay) with sera from infected humans and dogs. None of those was valid for the detection of human VL (26-52% sensitivity) although their performance was increased in the canine sera (48-91% sensitivity), with one polypeptide useful for the diagnosis of canine leishmaniasis. Next, we assayed a mixture of three antigens, found to be best for human or canine VL, among 13 identified through different screenings. This "Mix" resulted in similar levels of sensitivity for both human (84%) and canine (88%) sera. With improvements, this validates the use of multiple proteins, including antigens identified here, as components of a single system for the diagnosis of both forms of leishmaniasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184867PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619722PMC
October 2017

Causes and consequences of higher Leishmania infantum burden in patients with kala-azar: a study of 625 patients.

Trop Med Int Health 2017 06 2;22(6):679-687. Epub 2017 May 2.

Laboratório de Leishmanioses, Instituto de Doenças Tropicais Natan Portella, Universidade Federal do Piauí, Teresina, Brazil.

Background: An infected host's Leishmania infantum load in blood is considered to be an estimate of his or her total parasite burden. Therefore, the measurement of blood parasite burden is important in the identification of factors involved in parasite control.

Methods: Quantitative polymerase chain reaction was performed on blood samples from 625 patients with kala-azar consecutively admitted to a reference hospital in Teresina, Brazil. Primers were used to amplify a segment of kDNA using the TaqMan system. Non-parametric statistical tests were applied.

Results: The median blood parasite burden was 499.2 amastigote equivalents (AE)/ml. Children <1 year old (yo) had a high parasite burden, which dropped sharply after the first year of life (192.8, AE/ml at 1 < 2 yo) and remained lower until adolescence. Following adolescence, the parasite burden increased with age, peaking among elderly individuals. Men had a higher parasite burden than women. HIV-infected patients had a much higher parasite burden than non-infected patients. The parasite burden of children under 5 years with acute moderate to severe malnourishment (weight-for-age and body mass index z-scores <-2) was almost three times greater than that of better-nourished children. The parasite burden identified in deceased patients was more than twice that of surviving patients; those with a higher risk of death, sepsis, pneumonia and jaundice also had increased parasite burdens. All of these differences were statistically significant at P-values <0.05.

Conclusions: These data indicate that the parasite burden in patients with kala-azar was associated with age- and gender-associated factors and with HIV infection status. Acute malnutrition could be either a cause or a consequence of a higher parasite burden. An individual's parasite burden influences his or her clinical profile, disease severity and mortality risk. The best explanation for the presence of a higher parasite burden in individuals with these immunoregulatory conditions and severe disease is the occurrence of acquired immunosuppression followed by heightened innate immunity.
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http://dx.doi.org/10.1111/tmi.12877DOI Listing
June 2017

Comparison of optical microscopy and quantitative polymerase chain reaction for estimating parasitaemia in patients with kala-azar and modelling infectiousness to the vector Lutzomyia longipalpis.

Mem Inst Oswaldo Cruz 2016 Jul;111(8):517-22

Universidade Federal do Piauí, Departamento de Medicina Comunitária, Instituto de Doenças Tropicais Natan Portella, Laboratório de Leishmanioses, Teresina, PI, Brasil.

Currently, the only method for identifying infective hosts with Leishmania infantum to the vector Lutzomyia longipalpis is xenodiagnosis. More recently, quantitative polymerase chain reaction (qPCR) has been used to model human reservoir competence by assuming that detection of parasite DNA indicates the presence of viable parasites for infecting vectors. Since this assumption has not been proven, this study aimed to verify this hypothesis. The concentration of amastigotes in the peripheral blood of 30 patients with kala-azar was microscopically verified by leukoconcentration and was compared to qPCR estimates. Parasites were identified in 4.8 mL of peripheral blood from 67% of the patients, at a very low concentration (average 0.3 parasites/mL). However, qPCR showed 93% sensitivity and the estimated parasitaemia was over a thousand times greater, both in blood and plasma, with higher levels in plasma than in blood. Furthermore, the microscopic count of circulating parasites and the qPCR parasitaemia estimates were not mathematically compatible with the published proportions of infected sandflies in xenodiagnostic studies. These findings suggest that qPCR does not measure the concentration of circulating parasites, but rather measures DNA from other sites, and that blood might not be the main source of infection for vectors.
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http://dx.doi.org/10.1590/0074-02760160185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981120PMC
July 2016

Bone marrow parasite burden among patients with New World kala-azar is associated with disease severity.

Am J Trop Med Hyg 2014 Apr 10;90(4):621-6. Epub 2014 Mar 10.

Laboratory of Leishmaniasis, Institute of Tropical Diseases "Natan Portella", Federal University of Piauí, Teresina, PI, Brazil; Department of Biology, Federal University of Piauí, Floriano at Floriano, PI, Brazil; Maternal and Childhood Department, Federal University of Piauí, Teresina, PI, Brazil; Laboratory of Molecular Biology, Nucleus of Tropical Medicine, Federal University of Pará, Belém, PA, Brazil; Department of Community Medicine, Federal University of Piauí, Teresina, PI, Brazil.

Kala-azar or visceral leishmaniasis, found mostly throughout the Indian Subcontinent, East Africa, and Brazil, kills 20,000-40,000 persons annually. The agents, Leishmania donovani and Leishmania infantum, are obligatory intracellular protozoa of mononuclear phagocytes found principally in the spleen and bone marrow. Protracted fever, anemia, wasting, hepatosplenomegaly, hemorrhages, and bacterial co-infections are typical features. One hundred and twenty-two (122) in-hospital patients were studied to verify if higher bone marrow parasite load estimated by quantitative polymerase chain reaction is associated with severe disease. The estimated median parasite load was 5.0 parasites/10(6) human nucleated cells. It is much higher in deceased than among survivors (median 75.0 versus 4.2). Patients who lost more weight had a higher parasite burden, as well as patients with epistaxis, abdominal pain, edema, and jaundice. This study suggests that higher parasite load is influenced by wasting, which may lead to more severe disease.
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http://dx.doi.org/10.4269/ajtmh.13-0376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973504PMC
April 2014

Serum cytokines associated with severity and complications of kala-azar.

Pathog Glob Health 2013 Mar;107(2):78-87

Maternal and Childhood Department, Federal University of Piauí, Brazil.

Objectives: Recent clinical data suggest that severe kala-azar (or visceral leishmaniasis) is an exaggerated innate immune response mediated by inflammatory cytokines, leading to a systemic inflammatory syndrome similar to what is observed in malaria, sepsis and other diseases. We tested this hypothesis by measuring serum cytokines in individuals with kala-azar.

Methods: We compared patients with severe kala-azar (i.e. hemorrhagic manifestations, n = 38) with patients without evidence of hemorrhage (n = 96). We conducted a detailed clinical and laboratory evaluation, measuring serum IL-1beta, IL-6, IL-8, IL-10, IL-12, interferon-gamma, and TNF-alpha, and markers of disseminated intravascular coagulation (DIC).

Results: Infants had higher levels of inflammatory cytokines, while HIV-infected patients had lower concentrations of IL-10 and interferon-gamma. Higher levels of IL-6, interferon-gamma, and IL-8 were found among deceased patients. IL-8 and interferon-gamma were independently associated with bleeding. Several cytokines were associated with different signs of severe clinical and laboratory manifestations, including DIC. IL-6 was highly positively and independently associated with IL-1beta, IL-8, IL-10, and negatively associated with TNF-alpha. IL-1beta and TNF-alpha were also highly independently associated with disease severity.

Conclusion: In its severe form, kala-azar, a neglected tropical disease, initiates a systemic inflammatory response that leads to DIC and other manifestations. Children may have higher risk of death due to the more intense cytokine release. The data supports the notion that IL-6 is the central cytokine that is associated with lethal disease, but interferon-gamma, IL1beta, IL-8, and TNF-alpha are also involved with disease severity. Inhibition of IL-6 is a potential target of adjuvant therapy for severe or pediatric forms of this disease.
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http://dx.doi.org/10.1179/2047773213Y.0000000078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001482PMC
March 2013

Identification and diagnostic utility of Leishmania infantum proteins found in urine samples from patients with visceral leishmaniasis.

Clin Vaccine Immunol 2012 Jun 18;19(6):935-43. Epub 2012 Apr 18.

DetectoGen Inc., Grafton, Massachusetts, USA.

Despite the clear need to control visceral leishmaniasis (VL), the existing diagnostic tests have serious shortcomings. Here, we introduce an innovative approach to directly identify Leishmania infantum antigens produced in vivo in humans with VL. We combined reverse-phase high-performance liquid chromatography (RP-HPLC) with mass spectrometry and categorized three distinct L. infantum proteins presumably produced in bone marrow/spleen/liver and excreted in the urine of patients with VL. The genes coding for these proteins (L. infantum iron superoxide dismutase, NCBI accession number XP_001467866.1; L. infantum tryparedoxin, NCBI accession number XP_001466642.1; and L. infantum nuclear transport factor 2, NCBI accession number XP_001463738.1) were cloned, and the recombinant molecules were produced in Escherichia coli. Antibodies to these proteins were produced in rabbits and chickens and were used to develop a capture enzyme-linked immunosorbent assay (ELISA) designed to detect these L. infantum antigens in the urine of VL patients. Specificity of the antibodies was confirmed by a Western blot analysis using both recombinant proteins and whole parasite extract. Importantly, a urinary antigen detection assay assembled with pairs of antibodies specific for each of these antigens identified 17 of 19 patients with VL. These results indicate that an improved antigen detection assay based on L. infantum proteins present in the urine of patients with VL may represent an important new strategy for the development of a specific and accurate diagnostic test that has the potential to both distinguish active VL from asymptomatic infection and serve as an important tool to monitor therapy efficacy.
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http://dx.doi.org/10.1128/CVI.00125-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370439PMC
June 2012

Multi-centric prospective evaluation of rk39 rapid test and direct agglutination test for the diagnosis of visceral leishmaniasis in Brazil.

Trans R Soc Trop Med Hyg 2011 Feb 20;105(2):81-5. Epub 2010 Oct 20.

Laboratório de Pesquisas Clínicas, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.

The diagnosis of visceral leishmaniasis (VL) is still a major problem in Brazil and several other countries where the disease is endemic. The use of an easy-to-use and interpret, sensitive, and specific method that requires no complex infrastructure or specialized professionals, such as direct agglutination test (DAT) and the rK39-based rapid immunochromatographic test may enhance the diagnosis of disease. This study evaluated the performance of a rapid test (DiaMed- IT-LEISH®) and the DAT for the diagnosis of VL in 213 parasitologically confirmed cases and 119 controls with clinical suspicion of VL and confirmation of another etiology. The sensitivities and specificities of the rapid test were 93% and 97%, respectively and those of the DAT were 90% and 96%, respectively. The positive predictive values of the rapid test and the DAT were 98% and 97%, respectively and the negative predictive values were 89% and 84%, respectively. The Kappa index showed agreement between both methods classified as substantial (0.77). This study showed that the DAT and the rapid test can be used to diagnose VL in Brazil, following a pilot study for implementation of the rapid test in the health services.
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http://dx.doi.org/10.1016/j.trstmh.2010.09.004DOI Listing
February 2011

Could the lower frequency of CD8+CD18+CD45RO+ lymphocytes be biomarkers of human VL?

Int Immunol 2009 Feb 15;21(2):137-44. Epub 2008 Dec 15.

Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.

Toward obtaining a more comprehensive understanding of factors governing activation and/or function during visceral leishmaniasis (VL), we have compared active disease (pre-treatment) versus post-chemotherapy immune response in VL patients by means of ex vivo staining with different cell markers. Our results show that during active disease, the frequency of T cells positive for CD25, CTLA-4 and CD45RO was significantly lower in VL patients compared with healthy controls, whereas cells staining positive for Annexin V and CD95 were significantly higher. In all cases, chemotherapy was able to restore these frequencies to normal levels. Interestingly, significant differences in the frequency of CD18 and in the frequency of CD45RO-positive cells were observed in the CD8+ T cell subset. These two frequencies were also significantly higher in bone marrow when compared with peripheral blood, suggesting a possible compartmentalization of certain CD8+ T cell populations during active disease. Given that CD8+ T cells have been shown to play an essential role in immunity to infection with Leishmania, our data indicate that the lower frequency of CD18+ and CD45RO+ lymphocytes in the bone marrow CD8+ T cell subset may be considered a biomarker of acute VL.
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http://dx.doi.org/10.1093/intimm/dxn131DOI Listing
February 2009

Predictors of an unsatisfactory response to pentavalent antimony in the treatment of American visceral leishmaniasis.

Rev Soc Bras Med Trop 2002 Nov-Dec;35(6):629-33. Epub 2003 Feb 26.

Departamento de Medicina Comunitária, Hospital de Doenças Infecto-Contagiosas, Universidade Federal do Piauí, Teresina, PI, Brasil.

Although treatment of visceral leishmaniasis with pentavalent antimony is usually successful, some patients require second-line drug therapy, most commonly with amphotericin B. To identify the clinical characteristics that predict an inadequate response to pentavalent antimony, a case-control study was undertaken in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in which the staff physicians of a hospital prescribed second-line therapy with amphotericin B after determining that treatment with pentavalent antimony had failed. The control group consisted of 97 patients that were successfully treated with pentavalent antimony. A chart review using univariate and multivariate analysis was performed. The cure rate was 90% with amphotericin B. The odds ratio for the prescription of amphotericin B was 10.2 for children less than one year old, compared with individuals aged over 10 years. Patients who presented coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These data support either undertaking a longer course of therapy with pentavalent antimony for children or using amphotericin B as a first-line agent for children and individuals with coinfections. It also suggests that chemoprophylaxis directed toward bacterial coinfection in small children with VL may be indicated.
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http://dx.doi.org/10.1590/s0037-86822002000600014DOI Listing
May 2003
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