Early identification of patients at higher risk of progressing to severe disease and death is crucial for implementing therapeutic and preventive measures; this could reduce the morbidity and ...mortality from kala-azar. We describe a score set composed of four scales in addition to software for quick assessment of the probability of death from kala-azar at the point of care.
Data from 883 patients diagnosed between September 2005 and August 2008 were used to derive the score set, and data from 1,031 patients diagnosed between September 2008 and November 2013 were used to validate the models. Stepwise logistic regression analyses were used to derive the optimal multivariate prediction models. Model performance was assessed by its discriminatory accuracy. A computational specialist system (Kala-Cal(r)) was developed to speed up the calculation of the probability of death based on clinical scores.
The clinical prediction score showed high discrimination (area under the curve AUC 0.90) for distinguishing death from survival for children ≤2 years old. Performance improved after adding laboratory variables (AUC 0.93). The clinical score showed equivalent discrimination (AUC 0.89) for older children and adults, which also improved after including laboratory data (AUC 0.92). The score set also showed a high, although lower, discrimination when applied to the validation cohort.
This score set and Kala-Cal(r) software may help identify individuals with the greatest probability of death. The associated software may speed up the calculation of the probability of death based on clinical scores and assist physicians in decision-making.
Since the early 1980s, visceral leishmaniasis (VL) which is, in general, a rural zoonotic disease, has spread to the urban centers of the north, and now the south and west of Brazil. The principal ...drivers differ between cities, though human migration, large urban canid populations (animal reservoir), and a decidedly peripatetic and adaptable sand fly vector are the primary forces. The exact number of urban cases remains unclear as a result of challenges with surveillance. However, the number of urban cases registered continues to increase annually. Most control initiatives (e.g. culling infected dogs and household spraying to kill the sand fly) could be effective, but have proven hard to maintain at large scales due to logistical, financial and other reasons. In this article, the urbanization of VL in Brazil is reviewed, touching on these and other topics related to controlling VL within and outside Brazil.
Visceral leishmaniasis (VL) is a life-threatening disease caused by the protozoa Leishmania donovani and L. infantum. Likely, L. infantum was introduced in the New World by the Iberic colonizers. Due ...to recent introduction, the genetic diversity is low. Access to genomic information through the sequencing of Leishmania isolates allows the characterization of populations through the identification and analysis of variations. Population structure information may reveal important data on disease dynamics. Aiming to describe the genetic diversity of L. infantum from the Middle-North, Brazil, next generation sequencing of 30 Leishmania isolates obtained in the city of Teresina, from where the disease dispersed, was performed. The variations were categorized accordingly to the genome region and impact and provided the basis for chromosomal ploidy and population structure analysis. The results showed low diversity between the isolates and the Iberic reference genome JPCM5. Most variations were seen in non-coding regions, with modifying impact. The ploidy number analysis showed aneuploid profile. The population structure analysis revealed the presence of two L. infantum populations identified in Teresina. Further population genetics studies with a larger number of isolates should be performed in order to identify the genetic background associated with virulence and parasite ecology.
There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option.
A ...multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption.
378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003).
Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738.
ClinicalTrials.gov NCT01310738.
Visceral leishmaniasis (VL), or kala-azar, is a common comorbidity in patients with AIDS in endemic areas. Many patients continue to experiences relapses of VL despite virological control, but with ...immunological failure. These patients remain chronically symptomatic with hypersplenism, for example with anemia, leukopenia, and thrombocytopenia, and are at risk of severe co-infection due to low CD4+ count. Therefore, in this study, splenectomized patients with VL and HIV infection were investigated to understand why the CD4+ count fails to recover in these patients, evaluating the importance of spleen mass for hypersplenism and immunological failure.
From a retrospective open cohort of 13 patients who had previously undergone splenectomy as salvage therapy for relapsing VL, 11 patients with HIV infection were investigated. This study compared the patients' complete blood cell count (CBC) and CD4+ and CD8+ cell counts before and after splenectomy with respect to spleen weight.
CBC was substantially improved after splenectomy, indicating hypersplenism. However, to the best of our knowledge, this is the first study to show that spleen mass is strongly and negatively correlated with CD4+ cell count (ρ = -0.71, P = 0.015).
This finding was unexpected, as the spleen is the most extensive lymphoid tissue and T-lymphocyte source. After reviewing the literature and reasoning, we hypothesized that the immunological failure was secondary to CD4+ loss initially by apoptosis in the spleen induced by productive HIV infection and, subsequently, by pyroptosis sustained by parasitic infection in spleen macrophages.
•Biomarkers of severe VL-HIV/AIDS are not the same as severe VL without HIV infection.•Soluble CD14, TNF, and MIF are associated with death in VL-HIV/AIDS.•The acute-phase protein sCD14 predicts ...VL/HIV severity independently of LPS levels.•sCD14 is the only independent and a powerful predictor for VL-HIV severity and death.
Visceral leishmaniasis (VL) is caused by the protozoan Leishmania spp, transmitted by sand fly bites. VL is one of the deadliest tropical infection diseases, yet the coinfection with HIV virus drastically increases relapses, treatment failure and mortality. The concomitant action of these two pathogens leads to high cellular activation independently of the progression to AIDS. In addition, microbial translocation and bacterial infections are thought to contribute worsening the clinical picture. Identifying biomarkers associated with disease severity is of interest for clinical management of patients with VL-HIV/AIDS. Thus, we analyzed in the sera several markers including interleukins (IL-1β, IL-6, IL-8, and IL-17), interferon-γ (IFN- γ), tumor necrosis factor (TNF), lipopolysaccharide (LPS), soluble CD14 (sCD14), macrophage migration inhibitory factor (MIF) and intestinal fatty acid-binding protein (IFABP). These markers were compared with disease severity in 24 patients with VL/HIV presenting different clinical outcomes. Disease severity was defined by the probability of death calculated using a score set system derived by the Kala-Cal® software. Probability of death ranged from 3.7% to 97.9%, with median of 28.8%. Five patients died (20%). At the univariate analysis, disease severity was correlated with TNF, IFN-γ and sCD14. LPS was positively correlated with sCD14 specifically in patients with low CD4+ count (CD4+ T-cell <200 cells/mL). Most importantly, the multivariate analysis including LPS, CD4+count and sCD14 showed that sCD14 was the only independent predictor for disease severity and death. Altogether, our results indicated that sCD14 is a powerful marker of pathogenicity and death for patients with VL-HIV/AIDS.
Objective.
To develop an evidence map on visceral leishmaniasis prevention, control, diagnosis, treatment, and prognosis.
Methods.
Systematic reviews on visceral leishmaniasis were searched using ...MEDLINE/PubMed and Virtual Health Library. After selection, each included systematic review was assessed, characterized, and categorized by intervention type and by outcomes, according to the methodology offered by the PAHO/WHO Latin American and Caribbean Center on Health Sciences Information (BIREME). The methodological quality was assessed using the AMSTAR2 tool to determine the confidence level of the evidence obtained.
Results.
Among the prevention and control interventions, insecticide spraying, bednets, dog collars, and dog culling were the most assessed, emphasizing that insecticidal dog collars can reduce visceral leishmaniasis incidence in dogs. Regarding diagnosis, polymerase chain reaction (PCR), rK39 immunochromatographic test (rK39 ICT), and direct agglutination test (DAT) presented high sensitivity and specificity. As for treatment, pentavalent antimonials and amphotericin B were the most analyzed drugs and showed therapeutic success; however, serious adverse events can occur due to their use. The prognostic factors identified were anemia, edema, bleeding, jaundice, age, and HIV coinfection.
Conclusions.
The evidence map developed shows rK39 ICT and DAT as promising diagnostic alternatives and reinforces the efficacy of liposomal amphotericin B and pentavalent antimonials. Insecticide-impregnated dog collars appear as a promising measure for the control of visceral leishmaniasis, but there is also a need for future studies and reviews with higher methodological quality, especially on prevention and control interventions.
Influence of sex hormones on the immune response to leishmaniasis Araújo Albuquerque, Layana Pachêco; Silva, Amanda Miranda; Araújo Batista, Francisca Miriane ...
Parasite immunology,
October/November 2021, 2021-10-00, 20211001, Letnik:
43, Številka:
10-11
Journal Article
Recenzirano
The differences in morbidity and mortality patterns and life expectancy between the sexes are well established in different infectious and parasitic conditions, such as in leishmaniases, in which ...biological, genetic, sexual and hormonal variations can modulate the immune response indicating greater infectivity, prevalence and clinical severity in men. In this regard, in seeking the understanding of factors related to protection and susceptibility to infection, this review aimed to discuss the influence of sex hormones on the immune response to leishmaniases. In the literature, sex hormone variations promote differences in the innate, humoral and cell‐mediated immune response, leading to greater susceptibility, mortality and complications in males. Epidemiological estimates confirm these results, showing a predominance of the disease, in its different clinical forms, in men and suggesting that sexual variations influence immunomodulatory mechanisms since the prevalence of cases comprises the post‐puberty and adulthood period. In this perspective, the action of sex hormones has been investigated in different clinical models, highlighting the potential of testosterone in immunosuppression, given its association with greater susceptibility and poor control of parasite load and the induction of cell apoptosis and attenuation of pro‐inflammatory signalling pathways. Therefore, hormonal variations influence the immune response among males and females against leishmaniases, in which androgens may present immunosuppressive potential, while steroids present immunomodulatory characteristics.
Background
Early biomarkers of the response to treatment are lacking and may help to reduce mortality by the vector‐borne disease visceral leishmaniasis (VL).
Methods
A prospective cohort study was ...conducted to investigate plasma cytokines and clinical laboratory data as biomarkers of the early response to specific treatment for VL in 36 patients.
Results
The mean interleukin 6 (IL‐6) concentration on the 7th day was 2.3% of the pre‐treatment concentration, interleukin 10 (IL‐10) was 8.0%, and interleukin 8 (IL‐8) was 8.2%. On the 7th day, IL‐10 was below half of the pre‐treatment concentration in 100.0%, IL‐8 in 95.5% and IL‐6 in 90.9%. The spleen and liver sizes, haemoglobin, interleukin 1 beta (IL‐1β) and tumour necrosis factor alpha (TNF‐α) showed a slower recovery. Fever disappeared in 91% on the 7th day, 69.4% had a normal white cell count, and 77.8% had a normal platelet value by this time.
Conclusions
The plasma cytokines IL‐6, IL‐10 and IL‐8 were demonstrated to be excellent markers of the early response to VL treatment and if tested before the 7th day, will likely prove to be better than fever measurement.
In India, visceral leishmaniasis (VL) caused by
has been successfully treated with miltefosine with a cure rate of > 90%. To assess the efficacy and safety of oral miltefosine against Brazilian VL, ...which is caused by
, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2-12 years) and adolescent-adults (aged 13-60 years). Definitive cure was assessed at a 6-month follow-up visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment of 42 days. The in vitro miltefosine susceptibility profile of intracellular amastigote stages of the pretreatment isolates, from cured and relapsed patients, showed a positive correlation with the clinical outcome. The IC
mean (SEM) of eventual cures was 5.1 (0.4) µM, whereas that of eventual failures was 12.8 (1.9) µM (
= 0.0002). An IC
above 8.0 µM predicts failure with 82% sensitivity and 100% specificity. The finding of
amastigotes resistant to miltefosine in isolates from patients who eventually failed treatment strongly suggests natural resistance to this drug, as miltefosine had never been used in Brazil before this trial was carried out.