Risk factors associated with severe dengue in Latin America: A systematic review and meta-analysis.

OBJECTIVE: Severe dengue is a significant health problem in Latin America, with children being the most affected. Understanding risk factors for severe dengue is crucial for enhancing patient care. Therefore, this study aims to systematically review the literature to identify the risk factors associated with severe dengue in Latin America through systematic review and meta-analysis. METHODS: PubMed, SciELO, LILACS and EMBASE databases were used to search for eligible scientific articles for the review. The outcomes considered were symptoms of severe dengue, hospitalisation and death. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess the quality of the studies. Data analysis was performed using STATA v 13.0 software. The degree of heterogeneity between studies was quantified using the I2 measure, and statistically significant results were defined as those with p values <0.05. RESULTS: Of the 1876 articles screened, 47 articles were included in the systematic review and 45 articles were analysed through meta-analysis. Identified risk factors associated with severe dengue included secondary dengue infection, female sex, white or Caucasian ethnicity and specific signs and symptoms such as headache, myalgia and/or arthralgia, vomiting/nausea, abdominal pain or tenderness, diarrhoea, prostration, lethargy, fatigue or similar. For the death outcome, respiratory symptoms and age <18 years were identified as risk factors. On the other hand, in women, the diagnosis of positive tourniquet test, platelet count <100,000 per µL and symptoms of capillary fragility were associated with a lower probability of death. These data highlight the importance of early screening of patients, to identify possible haemorrhagic signs and reduce deaths from dengue. This study has limitations, including possible publication bias, heterogeneity of results and study design biases. CONCLUSION: These findings are significant for shaping strategies, management approaches and identifying high-risk groups, which will help establish future guidelines.

Imbalanced IL10/TGF-ß production by regulatory T-lymphocytes in patients with HTLV-1-associated myelopathy/ tropical spastic paraparesis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-ß. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. METHODS: Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-ß-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. RESULTS: Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. CONCLUSIONS: A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-ß may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.

Molecular characterization of HTLV-1 genomic region hbz from patients with different clinical conditions.

The human T-cell lymphotropic virus type-1 (HTLV-1) is associated with severe pathologies, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), adult T-cell leukemia-lymphoma (ATLL), and infective dermatitis associated with the HTLV-1 (IDH). Interestingly, HTLV-1 infection does not necessarily imply the development of pathological processes and it is unknown why some patients remain asymptomatic carriers (AC). Despite some mutations in the HTLV-1 genome appear to influence the outcome of HTLV-1, there are few studies that characterize molecularly the hbz region. This study aimed to perform the molecular characterization of hbz gene isolated from patients with different clinical outcomes. A total of 15 sequences were generated and analyzed with 571 sequences previously published. The analises showed that the R119Q mutation seems to be related to HTLV-1 clinical conditions since the frequency of this HBZ mutation is significantly different in comparison between AC with HAM/TSP and ATLL. The R119Q mutation is possibly a protective factor as the frequency is higher in AC sequences.

An overview of sequencing technology platforms applied to HTLV-1 studies: a systematic review.

Human T-lymphotropic virus type 1 (HTLV-1) was the first human retrovirus described. The viral factors involved in the different clinical manifestations of infected individuals are still unknown, and in this sense, sequencing technologies can support viral genome studies, contributing to a better understanding of infection outcome. Currently, several sequencing technologies are available with different approaches. To understand the methodological advances in the HTLV-1 field, it is necessary to organize a synthesis by a rigorous review. This systematic literature review describes different technologies used to generate HTLV-1 sequences. The review follows the PRISMA guidelines, and the search for articles was performed in PubMed, Lilacs, Embase, and SciELO databases. From the 574 articles found in search, 62 were selected. The articles showed that, even with the emergence of new sequencing technologies, the traditional Sanger method continues to be the most commonly used methodology for generating HTLV-1 genome sequences. There are many questions that remain unanswered in the field of HTLV-1 research, and this reflects on the small number of studies using next-generation sequencing technologies, which could help address these gaps. The data compiled and analyzed here can help research on HTLV-1, assisting in the choice of sequencing technologies.

Decreased memory T-cell response and function in human immunodeficiency virus-infected patients with tegumentary leishmaniasis.

The effects of human immunodeficiency virus (HIV) on the immune response in patients with cutaneous leishmaniasis have not yet been fully delineated. This study quantified and evaluated the function of memory T-cell subsets in response to soluble Leishmania antigens (SLA) from patients coinfected with HIV and Leishmania with tegumentary leishmaniasis (TL). Eight TL/HIV coinfected subjects and 10 HIV seronegative subjects with TL were evaluated. The proliferative response of CD4+and CD8+T-cells and naïve, central memory (CM) and effector memory (EM) CD4+T-cells in response to SLA were quantified using flow cytometry. The median cell division indices for CD4+and CD8+T-cells of coinfected patients in response to SLA were significantly lower than those in patients with Leishmania monoinfection (p < 0.05). The proportions of CM and EM CD4+T-cells in response to SLA were similar between the coinfected patients and patients with Leishmania monoinfection. However, the median CM and EM CD4+T-cell counts from coinfected patients were significantly lower (p < 0.05). The reduction in the lymphoproliferative response to Leishmania antigens coincides with the decrease in the absolute numbers of both EM and CM CD4+T-cells in response to Leishmania antigens in patients coinfected with HIV/Leishmania.

Comprehensive analysis of early T cell responses to acute Zika Virus infection during the first epidemic in Bahia, Brazil.

BACKGROUND: In most cases, Zika virus (ZIKV) causes a self-limited acute illness in adults, characterized by mild clinical symptoms that resolve within a few days. Immune responses, both innate and adaptive, play a central role in controlling and eliminating virus-infected cells during the early stages of infection. AIM: To test the hypothesis that circulating T cells exhibit phenotypic and functional activation characteristics during the viremic phase of ZIKV infection. METHODS: A comprehensive analysis using mass cytometry was performed on peripheral blood mononuclear cells obtained from patients with acute ZIKV infection (as confirmed by RT-PCR) and compared with that from healthy donors (HD). The frequency of IFN-γ-producing T cells in response to peptide pools covering immunogenic regions of structural and nonstructural ZIKV proteins was quantified using an ELISpot assay. RESULTS: Circulating CD4+ and CD8+ T lymphocytes from ZIKV-infected patients expressed higher levels of IFN-γ and pSTAT-5, as well as cell surface markers associated with proliferation (Ki-67), activation ((HLA-DR, CD38) or exhaustion (PD1 and CTLA-4), compared to those from HD. Activation of CD4+ and CD8+ memory T cell subsets, including Transitional Memory T Cells (TTM), Effector Memory T cells (TEM), and Effector Memory T cells Re-expressing CD45RA (TEMRA), was prominent among CD4+ T cell subset of ZIKV-infected patients and was associated with increased levels of IFN-γ, pSTAT-5, Ki-67, CTLA-4, and PD1, as compared to HD. Additionally, approximately 30% of ZIKV-infected patients exhibited a T cell response primarily directed against the ZIKV NS5 protein. CONCLUSION: Circulating T lymphocytes spontaneously produce IFN-γ and express elevated levels of pSTAT-5 during the early phase of ZIKV infection whereas recognition of ZIKV antigen results in the generation of virus-specific IFN-γ-producing T cells.

HTLV-1 Proviral Load in Vaginal Fluid Correlates with Levels in Peripheral Blood Mononuclear Cells.

BACKGROUND: The prevalence of human T-lymphotropic virus type-1 (HTLV-1) infection is higher in women, and sexual intercourse has been described as an important route of male-to-female transmission. The present study aimed to quantify HTLV-1 proviral load (PVL) in vaginal fluid, and to investigate correlations with PVL in peripheral blood mononuclear cells (PBMCs). In addition, cytopathological alterations and vaginal microbiota were evaluated. METHODS: HTLV-1-infected women were consecutively recruited at a multidisciplinary center for HTLV patients in Salvador, Brazil. All women underwent gynecological examinations to obtain cervicovaginal fluid and venipuncture for blood collection. PVL, as measured by real-time quantitative polymerase chain reaction (RT-qPCR), was expressed as the number of copies of HTLV-1/106 cells in blood and vaginal fluid samples. Light microscopy was used to assess cervicovaginal cytopathology and vaginal microbiota. RESULTS: In the 56 included women (43 asymptomatic carriers and 13 diagnosed with HTLV-1-associated myelopathy/tropical spastic paraparesis-HAM/TSP), mean age was 35.9 (SD ± 7.2) years. PVL was higher in PBMCs (median: 23,264 copies/106 cells; IQR: 6776-60,036) than in vaginal fluid (451.9 copies/106 cells; IQR: 0-2490) (p < 0.0001). PVL in PBMCs was observed to correlate directly with PVL in vaginal fluid (R = 0.37, p = 0.006). PVL was detected in the vaginal fluid of 24 of 43 (55.8%) asymptomatic women compared to 12 of 13 (92.3%) HAM/TSP patients, p = 0.02. Cytopathologic analyses revealed no differences between women with detectable or undetectable PVL. CONCLUSION: HTLV-1 proviral load is detectable in vaginal fluid and correlates directly with proviral load in peripheral blood. This finding suggests that sexual transmission of HTLV-1 from females to males may occur, as well as vertical transmission, particularly in the context of vaginal delivery.

Advances in preventive vaccine development against HTLV-1 infection: A systematic review of the last 35 years.

Introduction: The Human T-lymphotropic virus type 1 (HTLV-1) was the first described human retrovirus. It is currently estimated that around 5 to 10 million people worldwide are infected with this virus. Despite its high prevalence, there is still no preventive vaccine against the HTLV-1 infection. It is known that vaccine development and large-scale immunization play an important role in global public health. To understand the advances in this field we performed a systematic review regarding the current progress in the development of a preventive vaccine against the HTLV-1 infection. Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA®) guidelines and was registered at the International Prospective Register of Systematic Reviews (PROSPERO). The search for articles was performed in PubMed, Lilacs, Embase and SciELO databases. From the 2,485 articles identified, 25 were selected according to the inclusion and exclusion criteria. Results: The analysis of these articles indicated that potential vaccine designs in development are available, although there is still a paucity of studies in the human clinical trial phase. Discussion: Although HTLV-1 was discovered almost 40 years ago, it remains a great challenge and a worldwide neglected threat. The scarcity of funding contributes decisively to the inconclusiveness of the vaccine development. The data summarized here intends to highlight the necessity to improve the current knowledge of this neglected retrovirus, encouraging for more studies on vaccine development aiming the to eliminate this human threat. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42021270412).

Clinical and laboratory findings of acute Zika virus infection in patients from Salvador during the first Brazilian epidemic.

Several major epidemics of Zika fever, caused by the ZIKA virus (ZIKV), have emerged in Brazil since early 2015, eventually spreading to other countries on the South American continent. The present study describes the clinical manifestations and laboratory findings of patients with confirmed acute ZIKV infection during the first epidemic that occurred in Salvador, Brazil. All included patients were seen at the emergency room of a private tertiary hospital located in Salvador, Brazil from 2015 through 2017. Patients were considered eligible if signs of systemic viral febrile disease were present. All individuals were tested for ZIKV and Chikungunya infection using PCR, while rapid test was used to detect Dengue virus antibodies or, alternatively, the NS1 antigen. A diagnosis of acute ZIKV infection was confirmed in 78/434 (18%) individuals with systemic viral febrile illness. Positivity was mainly observed in blood, followed by saliva and urine. Coinfection with Chikungunya and/or Dengue virus was detected in 5% of the ZIKV-infected patients. The most frequent clinical findings were myalgia, arthralgia and low-grade fever. Laboratory analysis demonstrated normal levels of hematocrit, platelets and liver enzymes. In summary, in acute settings where molecular testing remains unavailable, clinicians face difficulties to confirm the diagnosis of ZIKV infection, as they rely only on clinical examinations and conventional laboratory tests.

Evaluation of the cervicovaginal environment in asymptomatic Human T-cell lymphotropic virus type 1 infected women.

INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) is sexually transmitted and causes persistent infection. This virus induces activation of the immune system and production of inflammatory cytokines. This study aimed to assess the cytokine profile and cytopathological findings in the cervicovaginal fluid of asymptomatic HTLV-1-infected women. METHODS: HTLV-1-infected and uninfected women were selected at the Centro de Atendimento ao Portador de HTLV in Salvador-Brazil. None of the included HTLV-1-infected women reported any HTLV-1-associated diseases. All volunteers underwent gynecological examination to collect cervicovaginal fluid. Cytokine quantification was performed using the Cytometric Bead Array (CBA) Human Th1/Th2/Th17 kit. Light microscopy was used to evaluate cervicovaginal cytopathology. In addition, proviral load in cervicovaginal fluid and peripheral blood was measured by real-time quantitative polymerase chain reaction. RESULTS: 112 women (63 HTLV-1-infected and 49 uninfected) were evaluated. No differences were found with respect to cytopathological cervicovaginal findings between the groups. IL-2, TNF, IL-4, IL-10, and IL-17 levels were significantly higher in cervicovaginal fluid of the HTLV-1-infected women than in uninfected women (p<0.05). Conversely, IFN-γ was found to be lower in the HTLV-1-infected women (p<0.001) compared to uninfected individuals. Cervicovaginal proviral load was detectable in 53% of the HTLV-1-infected women and was found to be consistently lower than the proviral load in peripheral blood. CONCLUSIONS: HTLV-1 infection induces immune activation in cervicovaginal environment, characterized by elevated concentrations of Th1, Th2, and IL17 in the cervicovaginal fluid.

Clinical and laboratory findings of acute Zika virus infection in patients from Salvador during the first Brazilian epidemic

Abstract Several major epidemics of Zika fever, caused by the ZIKA virus (ZIKV), have emerged in Brazil since early 2015, eventually spreading to other countries on the South American continent. The present study describes the clinical manifestations and laboratory findings of patients with confirmed acute ZIKV infection during the first epidemic that occurred in Salvador, Brazil. All included patients were seen at the emergency room of a private tertiary hospital located in Salvador, Brazil from 2015 through 2017. Patients were considered eligible if signs of systemic viral febrile disease were present. All individuals were tested for ZIKV and Chikungunya infection using PCR, while rapid test was used to detect Dengue virus antibodies or, alternatively, the NS1 antigen. A diagnosis of acute ZIKV infection was confirmed in 78/434 (18%) individuals with systemic viral febrile illness. Positivity was mainly observed in blood, followed by saliva and urine. Coinfection with Chikungunya and/or Dengue virus was detected in 5% of the ZIKV-infected patients. The most frequent clinical findings were myalgia, arthralgia and low-grade fever. Laboratory analysis demonstrated normal levels of hematocrit, platelets and liver enzymes. In summary, in acute settings where molecular testing remains unavailable, clinicians face difficulties to confirm the diagnosis of ZIKV infection, as they rely only on clinical examinations and conventional laboratory tests.

Evaluation of the cervicovaginal environment in asymptomatic Human T-cell lymphotropic virus type 1 infected women

ABSTRACT Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1) is sexually transmitted and causes persistent infection. This virus induces activation of the immune system and production of inflammatory cytokines. This study aimed to assess the cytokine profile and cytopathological findings in the cervicovaginal fluid of asymptomatic HTLV-1-infected women. Methods: HTLV-1-infected and uninfected women were selected at the Centro de Atendimento ao Portador de HTLV in Salvador-Brazil. None of the included HTLV-1-infected women reported any HTLV-1-associated diseases. All volunteers underwent gynecological examination to collect cervicovaginal fluid. Cytokine quantification was performed using the Cytometric Bead Array (CBA) Human Th1/Th2/Th17 kit. Light microscopy was used to evaluate cervicovaginal cytopathology. In addition, proviral load in cervicovaginal fluid and peripheral blood was measured by real-time quantitative polymerase chain reaction. Results: 112 women (63 HTLV-1-infected and 49 uninfected) were evaluated. No differences were found with respect to cytopathological cervicovaginal findings between the groups. IL-2, TNF, IL-4, IL-10, and IL-17 levels were significantly higher in cervicovaginal fluid of the HTLV-1-infected women than in uninfected women (p < 0.05). Conversely, IFN-γ was found to be lower in the HTLV-1-infected women (p < 0.001) compared to uninfected individuals. Cervicovaginal proviral load was detectable in 53% of the HTLV-1-infected women and was found to be consistently lower than the proviral load in peripheral blood. Conclusions: HTLV-1 infection induces immune activation in cervicovaginal environment, characterized by elevated concentrations of Th1, Th2, and IL17 in the cervicovaginal fluid.

Th1/Th2 cytokine profile in patients coinfected with HIV and Leishmania in Brazil.

To evaluate the effects of HIV on immune responses in cutaneous leishmaniasis (CL), we quantified cytokine levels from plasma and stimulated peripheral blood mononuclear cells (PBMCs) from individuals infected with HIV and/or CL. Gamma interferon (IFN-γ) and interleukin 13 (IL-13) levels and the ratio of IFN-γ to IL-10 produced in response to stimulation with soluble Leishmania antigens were significantly lower in HIV-Leishmania-coinfected patients than in CL-monoinfected patients.

Decreased memory T-cell response and function in human immunodeficiency virus-infected patients with tegumentary leishmaniasis

The effects of human immunodeficiency virus (HIV) on the immune response in patients with cutaneous leishmaniasis have not yet been fully delineated. This study quantified and evaluated the function of memory T-cell subsets in response to soluble Leishmania antigens (SLA) from patients coinfected with HIV and Leishmania with tegumentary leishmaniasis (TL). Eight TL/HIV coinfected subjects and 10 HIV seronegative subjects with TL were evaluated. The proliferative response of CD4+and CD8+T-cells and naïve, central memory (CM) and effector memory (EM) CD4+T-cells in response to SLA were quantified using flow cytometry. The median cell division indices for CD4+and CD8+T-cells of coinfected patients in response to SLA were significantly lower than those in patients with Leishmania monoinfection (p < 0.05). The proportions of CM and EM CD4+T-cells in response to SLA were similar between the coinfected patients and patients with Leishmania monoinfection. However, the median CM and EM CD4+T-cell counts from coinfected patients were significantly lower (p < 0.05). The reduction in the lymphoproliferative response to Leishmania antigens coincides with the decrease in the absolute numbers of both EM and CM CD4+T-cells in response to Leishmania antigens in patients coinfected with HIV/Leishmania.