Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

High levels of anti-factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors.

Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

A potent inflammatory response is triggered in asymptomatic blood donors with recent SARS-CoV-2 infection.

BACKGROUND: The inflammatory response plays a significant role in the outcome of coronavirus disease (COVID-19). METHODS: We investigated plasma cytokine and chemokine concentrations in non-infected (NI), asymptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected blood donors (AS), and patients with severe COVID-19 (SC). RESULTS: The SC group showed significantly higher levels of interleukin 6 (IL-6), IL-10, and CCL5 than the AS and NI groups. The SC and AS groups had considerably greater CXCL9 and CXCL10 concentrations than the NI group. Only NI and infected people showed separate clusters in the principal component analysis. CONCLUSIONS: SC, as well as AS was characterized by an inflammatory profile.

Impact of COVID-19 on the efficacy of meeting the transfusion demand by a Brazilian blood banks network.

One of the effects of the pandemic in the hemotherapy services was the reduction in the attendance of blood donors and production of blood components. It is relevant to investigate how the capacity to meet the demand for blood components was affected, especially in blood centers located in the regions most affected by the pandemic, such as Brazil. This study aimed to describe the impact of the pandemic on the capacity to meet the demand for different types of blood components by a Brazilian blood center in 2020, compared to the historical series of 2016-2019 and to discuss the measures adopted to mitigate the effects of the pandemic. Retrospective cross-sectional study was carried out with comparative analysis of the blood components requested and attended in the period from 2016 to 2020. Data analysis was performed by Graphpad Prism 5. The spread of COVID-19 cases since March 2020 had impact on the blood components production and transfusions. The reduction in the production of blood components was observed prior to the restriction measures, in March 2020. In comparison to 2016-2019, there was a reduction in the number of transfusions performed in all months of 2020. The results suggest that the measures adopted in a Brazilian blood center to face the COVID-19 pandemic resulted in reasonable regularity in the supply of blood components. The sharing of experiences between blood banks in different regions, social and epidemiological contexts can contribute to the improvement of strategies to reduce the impact of COVID-19 in transfusion medicine.

SARS-CoV-2 IgG Seroprevalence among Blood Donors as a Monitor of the COVID-19 Epidemic, Brazil.

During epidemics, data from different sources can provide information on varying aspects of the epidemic process. Serology-based epidemiologic surveys could be used to compose a consistent epidemic scenario. We assessed the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG in serum samples collected from 7,837 blood donors in 7 cities of Brazil during March-December 2020. Based on our results, we propose a modification in a compartmental model that uses reported number of SARS-CoV-2 cases and serology results from blood donors as inputs and delivers estimates of hidden variables, such as daily values of SARS-CoV-2 transmission rates and cumulative incidence rate of reported and unreported SARS-CoV-2 cases. We concluded that the information about cumulative incidence of a disease in a city's population can be obtained by testing serum samples collected from blood donors. Our proposed method also can be extended to surveillance of other infectious diseases.

A potent inflammatory response is triggered in asymptomatic blood donors with recent SARS-CoV-2 infection

ABSTRACT Background: The inflammatory response plays a significant role in the outcome of coronavirus disease (COVID-19). Methods: We investigated plasma cytokine and chemokine concentrations in non-infected (NI), asymptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected blood donors (AS), and patients with severe COVID-19 (SC). Results: The SC group showed significantly higher levels of interleukin 6 (IL-6), IL-10, and CCL5 than the AS and NI groups. The SC and AS groups had considerably greater CXCL9 and CXCL10 concentrations than the NI group. Only NI and infected people showed separate clusters in the principal component analysis. Conclusions: SC, as well as AS was characterized by an inflammatory profile.

Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol.

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

Analysis of current SARS-CoV-2 infection in a large population of blood donors evidenced that RNAemia is rare in plasma.

BACKGROUND: Transmission of SARS-CoV-2 by asymptomatic individuals and by blood transfusion are important issues to understand to control the viral spread. In this work, we estimated the current SARS-CoV-2 infection rate in blood donors from Belo Horizonte, Brazil. STUDY DESIGN AND METHODS: Saliva and blood samples were collected from 4103 blood donors from June 15 to September 30, 2020. Saliva samples were tested by real-time RT-PCR for SARS-CoV-2 in mini-pools of four samples. Individual samples were tested for positive or inconclusive pools, and positive donors had their plasma tested. RESULTS: Twenty-seven (0.66%) blood donors were positive for SARS-CoV-2 in their saliva, but their plasma was negative, except for one, who presented a high viral load in saliva and nasopharyngeal samples and RNAemia in the plasma close to the limit of detection. Fourteen (56%) positive blood donors reported mild symptoms related to COVID-19 after donation, but the viral load levels were not statistically different between symptomatic and asymptomatic individuals. DISCUSSION: Despite the measures taken by Blood Centers to avoid blood donors with SARS-CoV-2 infection, asymptomatic or presymptomatic carriers are able to donate. The risk of the virus transmission by transfusion seems to be negligible since plasma RNAemia was seen at a very low level in only one (3.7%) of the positive donors, but other studies must be performed to confirm this finding.

Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL Study.

Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.

ADAMTS-13-VWF axis in sickle cell disease patients.

Sickle cell disease (SCD) comprises a group of genetic disorders characterized by the presence of the hemoglobin (Hb) S in homozygosis or in heterozygosis with some other Hb variant or in interaction with thalassemia. SCD is characterized by a very complex pathophysiology, which determines a wide variability of clinical manifestations, including a chronic state of hypercoagulability responsible for the increased risk of thromboembolic events. ADAMTS13 and von Willebrand factor (VWF) play an important role in arterial and venous thrombosis. Thus, the aim of this study was to understand how the ADAMTS13-VWF axis behaves in sickle cell disease, as well as whether there is an association of these markers with the use of hydroxyurea (HU). This is a cross-sectional study conducted with 40 patients diagnosed with SCD and 40 healthy individuals. The analysis of the ADAMTS13-VWF axis was comparatively performed between groups of patients and controls and, afterwards, between patients with SCD who were users and non-users of HU. ADAMTS13 activity, ADAMTS13 activity/VWF:Ag, and ADAMTS13:Ag/VWF:Ag ratios were significantly lower and VWF:Ag levels significantly higher in SCD patients when compared to the controls. There was no statistically significant difference in ADAMTS13:Ag and VWF collagen binding (VWF:CB) levels between the groups evaluated. Among the categories of HU use, there was no statistically significant difference in any of the evaluated markers. As a conclusion, we could observe that the ADAMTS13-VWF axis is altered in SCD when compared to healthy individuals and that there is no association between these markers and the use of HU.

Impact of COVID-19 in the attendance of blood donors and production on a Brazilian Blood Centres.

BACKGROUND: One of the effects of the coronavirus disease 2019 (COVID-19) pandemic is the risk of shortages in Blood Centres. OBJECTIVES: To verify the impact of the COVID-19 pandemic on the blood donor's attendance and production of blood components in Fundação Hemominas, a Brazilian public institution was formed by several Blood Centres. METHODS: A cross-sectional study was carried out from January to June 2020. Data collected were compared to a historical series from 2016 to 2019. RESULTS: The study showed a reduction in the attendance of blood donors, whole blood collections and blood component production from March 2020, when the first case of COVID-19 was notified in Minas Gerais, Brazil. The results evidenced that Hemominas Blood Centres were affected in a very distinct way by the pandemic with a general mean reduction around 17% in attendance of blood donors and in production of blood components in the period of March to June. On the other hand, the return of blood donors rate increased. CONCLUSION: The reduction in blood donation during the pandemic period was significant, despite the measures adopted. Still, the recruitment of return donors appears to be an important measure to be considered to decrease the pandemic's effect on blood stocks.

Genetic variants of VWF gene in type 2 von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. AIM: This study aimed to identify variants associated with type 2 VWD. METHODS: We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. RESULTS: We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as "likely causative" in 17/40 patients (42.5%), according to the ISTH-SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as "likely pathogenic" (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. CONCLUSION: In conclusion, we identified 19 variants, of which 14 are "likely pathogenic" and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.

Prevalence and risk factors associated with hepatitis C among Brazilian male patients with haemophilia: A long-term follow-up.

People with haemophilia represent a population with a high prevalence of HCV infection due to the use of blood components and plasma-derived clotting factor concentrates before the introduction of viral-inactivating procedures (in the 1980s) and screening for HCV (in the 1990s). About 80% of HCV-infected patients have chronic HCV infection, and at least 20% develop end-stage liver disease. The aim of the study was to assess current anti-HCV positivity in a large cohort of Brazilian haemophilia patients and to determine associated factors with HCV exposure. The study retrospectively analysed medical records of all male haemophilia patients attended the main public referral blood centre in Belo Horizonte, Brazil, from January 1985 to January 2015. Sociodemographic, epidemiological and serological characteristics were collected of all participants tested for anti-HCV. Among 724 patients enrolled in the study, anti-HCV was positive in 259 resulting in a seroprevalence of 35.8% (95% CI: 32.3%-39.3%). Factors independently associated with previous exposure to HCV were as follows: age older than 30 years, moderate to severe haemophilia, detection of inhibitor at least once in lifetime and previous exposure to hepatitis B virus (HBV) infection or HIV infection. Otherwise, exclusive previous use of inactivated clotting factors resulted in a significant decrease in the chance of positivity for anti-HCV. At the end of cohort period, patients with positive anti-HCV had a 3-fold higher risk of death. This study showed that hepatitis C infection remains a critical problem for Brazilian haemophilia patients and reinforced the need to unify efforts to eradicate it.

Estudo da associação entre talassemia alfa e doença falciforme em pacientes do hemocentro regional de Montes Claros / Study of the association between alpha thalassemia and falciform disease in patiensts of the hemocentro regional de Montes Claros

OBJETIVO: Avaliar a coexistência da talassemia alfa (a-Tal) e sua interferência no curso clínico dos pacientes com Doença Falciforme no Hemocentro Regional de Montes Claros-MG. Metodologia: Estudo transversal analítico, com amostra aleatorizada, na qual foram incluídos pacientes triados pelo Programa Estadual de Triagem Neonatal de Minas Gerais e encaminhadas ao Hemocentro Regional de Montes Claros, com perfil eletroforético compatível com anemia falciforme, nascidos no período entre 26/01/2000 e 13/05/2014. Os dados clínicos dos pacientes foram coletados nos prontuários médicos do Ambulatório do Hemocentro Regional de Montes Claros. A genotipagem de a-Tal foi realizada por PCR multiplex (alelos: -a3.7; -a4.2; --SEA; --FIL; --MED; -(a) 20.5 e --THAI) no Serviço de Pesquisa Serviço de Pesquisa da Fundação Hemominas. Os dados foram analisados em teste estatísticos qui-quadrado em Software SPSS versão 16.0. Resultados: Foram estudados 50 pacientes, sendo 25 (50%) do sexo masculino e 25 (50%) do sexo feminino. A idade dos pacientes variou de 9 meses a 15 anos de idade. A prevalência da a-Tal foi de 30%. Não houve associação estatística significativa entre a presença de a-Tal e infecção, internação, crises álgicas, sequestro esplênico, esplenectomia, transfusão sanguínea e Acidente Vascular Cerebral (AVC). No entanto, a frequência de crises álgicas, esplenectomia e AVC foi menor nos pacientes que apresentavam coexistência da a-Tal. Conclusões: A prevalência de a-Tal em indivíduos com anemia falciforme no nosso estudo foi 30%. Algumas manifestações graves da AF ocorreram de forma menos frequente nos pacientes com a interação da a-Tal/anemia falciforme. (AU)

Objective: To evaluate the coexistence of alpha thalassemia (a-Tal) and its interference in the clinical course of patients with sickle cell disease at Hemocentro Regional de Montes Claros-MG. Methodology: This is a cross-sectional, analytical study with a randomized sample carried out with patients screened by the State Neonatal Screening Program of Minas Gerais and referred to the Hemocentro Regional de Montes Claros with an electrophoretic profile compatible with sickle cell anemia, born between 01.26.2000 and 05.13.2014. The clinical data of the patients were collected in the medical records of the Outpatient Clinic of the Hemocentro Regional de Montes Claros. The a-Tal genotyping was performed by multiplex PCR (alleles: -a3.7; -a4.2; --SEA; --FIL; --MED; - (a) 20.5 and --THAI) in the Research Service Fundação Hemominas. The data were analyzed in chi-square statistical test in SPSS Software version 16.0. Results: Fifty patients were studied, 25 (50%) were male, and 25 (50%) were female. Patients´ ages ranged from 9 months to 15 years old. The prevalence of a-Tal was 30%. There was no significant statistical association between the presence of a-Tal and infection, hospitalization, painful crises, splenic sequestration, splenectomy, blood transfusion and cerebrovascular accident (CVA). However, the frequency of painful seizures, splenectomy and CVA was lower in patients with a-Tal coexistence. Conclusions: The prevalence of a-Tal in individuals with sickle cell anemia in our study was 30%. Some severe manifestations of SCA occurred less frequently in patients with a-Tal/sickle cell anemia interaction. (AU)

The Duffy null genotype is associated with a lower level of CCL2, leukocytes and neutrophil count but not with the clinical outcome of HTLV-1 infection.

Purpose. Chemokines are important in the immune response against viral infections, and may play a role in human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) pathogenesis. Polymorphisms in the Duffy antigen receptor for chemokines (DARC), such as rs12075 (A>G; FY*B>FY*A) and rs281477 (-46T>C; GATA-1 box) may influence circulating concentrations of proinflammatory chemokines. We investigate whether Duffy genotypes influence the HTLV-1 proviral load (PVL) level, HTLV-1 infection outcome and chemokine concentrations in HTLV-1 asymptomatic carriers (AC=162), HAM/TSP patients (HAM=135) and seronegative individuals (SN=71).Methodology. Quantification of plasmatic IL8, CCL2 and CCL5 were performed by flow cytometry and Duffy genotypes were investigated by real-time PCR. HTLV-1 PVL was quantified in peripheral blood. To control for spurious association, individual ancestry profiles in AC and HAM groups were investigated.Results/Key findings. PVL and IL8 level were significantly higher in the HAM group than in the AC group, but were not associated with Duffy genotypes. The highest CCL2 and CCL5 levels were seen in the SN group, and there was no difference when comparing the infected groups. The level of CCL5 was not associated with Duffy genotypes. The polymorphism -46 C/C that abrogates the DARC expression on the erythrocytes was significantly associated with lower levels of CCL2, neutrophil and white blood cell (WBC) counts in HTLV-1-infected individuals.Conclusion. We conclude that although the Duffy null genotype was associated with leukopenia, neutropenia and lower levels of CCL2, the data do not suggest the influence of Duffy genotypes on the neurologic outcome of HTLV-1 infection, but may be a confounding factor in comparison HTLV-1-infected populations with different ancestries, especially when defining inflammatory biomarkers.

Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals.

BACKGROUND: Immunosenescence is associated with several changes in adaptive and innate immune cells. Altered cytokine production is among the most prominent of these changes. The impact of age-related alterations on cytokine global profiles produced by distinct populations of leukocytes from healthy Brazilian individuals was studied. We analysed frequencies of cytokine-producing lymphocytes and innate immune cells from individuals at several ages spanning a lifetime period (0-85 years). RESULTS: Healthy adult individuals presented a balanced profile suggestive of a mature immune system with equal contributions of both innate and adaptive immunity and of both categories of cytokines (inflammatory and regulatory). In healthy newborns and elderly, innate immune cells, especially neutrophils and NK-cells, contributed the most to a balanced profile of cytokines. CONCLUSIONS: Our results support the hypothesis that ageing is not associated with a progressive pro-inflammatory cytokine production by all leukocytes but rather with distinct fluctuations in the frequency of cytokine-producing cells throughout life.

Plasmatic proinflammatory chemokines levels are tricky markers to monitoring HTLV-1 carriers.

The human T-cell leukemia virus type 1 (HTLV-1) is present throughout the world and is associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory conditions. The pathogenesis of HAM/TSP involves a chronic inflammatory response in central nervous system (CNS), with the presence of HTLV-1 infected cells and HTLV-1-specific CD8+ lymphocytes. Chemokines may have a role in the infiltration of these cells into the CNS. In this context, the present study analyzed the level of plasmatic chemokines CCL2 (MCP-1), CCL5 (RANTES), IL8 (CXCL8), CXCL9 (MIG), and CXCL10 (IP-10) and HTLV-1 proviral load from peripheral blood in 162 asymptomatic carriers and 136 HAM/TSP patients to determine the differences that be associated with the clinical status of the HTLV-1 infection. The results showed that patients with HAM/TSP have significantly higher levels of IL8 and CXCL9, and that the level of IL8, CXCL9 and CXCL10 was significantly greater in HTLV-1 infected individuals with high (>1%) than those with low proviral load (<1%). However, the levels of the chemokines tested have not showed high sensitivity to discriminate HAM/TSP patients from asymptomatic carriers. In addition, chemokine profiles in asymptomatic carriers and HAM/TSP groups were similar, with no significant increased frequency of higher producers of chemokines in HAM/TSP individuals. Results indicate that the heterogeneity of the individuals in the groups regarding time of infection, duration of disease, proviral load level and other possible confound factors may impair the use of chemokines levels to monitor HTLV-1 carriers in clinical practice. J. Med. Virol. 88:1438-1447, 2016. © 2016 Wiley Periodicals, Inc.

Anti-inflammatory/regulatory cytokine microenvironment mediated by IL-4 and IL-10 coordinates the immune response in hemophilia A patients infected chronically with hepatitis C virus.

In the past decades patients with hemophilia were infected commonly by hepatitis C virus (HCV) and a significant number of patients are infected chronically. Focusing on the role of the immune system for controlling and or maintaining HCV infection, the leukocyte and cytokine profiles of peripheral blood from hemophilia A patients and other patients with and without HCV infection were studied. The results demonstrated that hemophilia A is characterized by a general state of circulating leukocytes activation along with an overall increase in the frequency of IL-6 and IL-10 with decrease of IL-8 and IL-12. HCV infection of patients with hemophilia A does not influence further the activation state of circulating leukocytes but is accompanied by lower levels of alanine transaminase (ALT) and a prominent anti-inflammatory/regulatory serum cytokine pattern, mediated by IL-4 and IL-10. Additionally, the results demonstrated that hemophilia A patients infected with HCV displaying No/Low antibody response to C33c and C22 have significant lower viral load and higher serum levels of IL-12 and IL-4. This finding suggests that the differential RIBA reactivity to C33c/C22 HCV core proteins may have a putative value as a prognostic biomarker for the infection in hemophilia A patients.