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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.
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COVID-19 , Epidemias , Anticorpos Antivirais , Doadores de Sangue , Brasil/epidemiologia , COVID-19/epidemiologia , Humanos , Imunoglobulina G , SARS-CoV-2 , Estudos SoroepidemiológicosRESUMO
The SARS-CoV-2 virus has infected and killed millions of people, but little is known about the risk factors that lead to the development of severe, mild or asymptomatic conditions after infection. The individual immune response and the balance of cytokines and chemokines have been shown to be important for the prognosis of patients. Additionally, it is essential to understand how the production of specific antibodies with viral neutralizing capacity is established. In this context, this study aimed to identify positive individuals for IgG anti-SARS-CoV-2 in a large population of blood donors (n = 7837) to establish their immune response profile and to evaluate its viral neutralization capacity. The prevalence found for IgG anti-SARS-CoV-2 was 5.6% (n = 441), with male blood donors (61.9%) being more prevalent among the positive ones. The results showed that positive individuals for IgG anti-SARS-CoV-2 have high serum concentrations of chemokines, TNF, IFN-γ and IL-10. The analyses showed that the positivity index for IgG anti-SARS-CoV-2 is associated with the neutralizing capacity of the antibodies, which, in turn, is significantly related to lower serum concentrations of CCL5 and CXCL10. The results allow us to hypothesize that the development and maintenance of IgG anti-SARS-CoV-2 antibodies in infected individuals occurs in a pro-inflammatory microenvironment well regulated by IL-10 with great capacity for recruiting cells from the innate and adaptive immune systems.
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Anticorpos Antivirais , Doadores de Sangue , COVID-19 , Imunoglobulina G , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/imunologia , Quimiocinas , Feminino , Humanos , Imunoglobulina G/sangue , Interferon gama , Interleucina-10 , Masculino , SARS-CoV-2 , Fator de Necrose Tumoral alfaRESUMO
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.
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Armazenamento de Sangue , COVID-19 , Humanos , Armazenamento de Sangue/métodos , COVID-19/epidemiologia , Pandemias , Brasil/epidemiologia , SARS-CoV-2 , Estudos Retrospectivos , Estudos TransversaisRESUMO
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.
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Doadores de Sangue , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2 , Carga Viral , Adulto , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , Coinfecção/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , SARS-CoV-2/fisiologia , Estudos SoroepidemiológicosRESUMO
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.
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Proteína ADAMTS13/sangue , Anemia Falciforme/sangue , Fator de von Willebrand/metabolismo , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Estudos Transversais , Feminino , Humanos , Hidroxiureia/administração & dosagem , Masculino , Trombose Venosa/sangue , Trombose Venosa/etiologiaRESUMO
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.
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Bancos de Sangue/provisão & distribuição , Doadores de Sangue/provisão & distribuição , COVID-19/epidemiologia , SARS-CoV-2 , Bancos de Sangue/estatística & dados numéricos , Remoção de Componentes Sanguíneos/estatística & dados numéricos , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Doadores de Sangue/estatística & dados numéricos , Brasil/epidemiologia , COVID-19/mortalidade , Estudos Transversais , Humanos , PandemiasRESUMO
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.
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Hemofilia A/complicações , Hemofilia A/epidemiologia , Hepatite C/complicações , Adolescente , Adulto , Brasil/epidemiologia , Estudos de Coortes , Seguimentos , Humanos , Masculino , Análise Multivariada , Prevalência , Encaminhamento e Consulta , Fatores de Risco , Adulto JovemRESUMO
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.
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Variação Genética , Doença de von Willebrand Tipo 2/genética , Fator de von Willebrand/genética , Adulto , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Desamino Arginina Vasopressina/metabolismo , Éxons , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto Jovem , Doença de von Willebrand Tipo 2/patologiaRESUMO
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.
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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.
Assuntos
Infecções Assintomáticas , Portador Sadio/imunologia , Quimiocinas/sangue , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Adulto , Idoso , Portador Sadio/virologia , Quimiocina CCL2/sangue , Quimiocina CCL2/imunologia , Quimiocina CXCL9/sangue , Quimiocina CXCL9/imunologia , Quimiocinas/imunologia , Estudos de Coortes , Feminino , Infecções por HTLV-I/diagnóstico , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/imunologia , Paraparesia Espástica Tropical/fisiopatologia , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Prediction of inhibitor development in patients with hemophilia A (HA) remains a challenge. OBJECTIVES: To construct a predictive model for inhibitor development in HA using a network of clinical variables and biomarkers based on the individual similarity network. METHODS: Previously untreated and minimally treated children with severe/moderately severe HA, participants of the HEMFIL Cohort Study, were followed up until reaching 75 exposure days (EDs) without inhibitor (INH-) or upon inhibitor development (INH+). Clinical data and biological samples were collected before the start of factor (F)VIII replacement (T0). A predictive model (HemfilNET) was built to compare the networks and potential global topological differences between INH- and INH+ at T0, considering the network robustness. For validation, the "leave-one-out" cross-validation technique was employed. Accuracy, precision, recall, and F1-score were used as evaluation metrics for the machine-learning model. RESULTS: We included 95 children with HA (CHA), of whom 31 (33%) developed inhibitors. The algorithm, featuring 37 variables, identified distinct patterns of networks at T0 for INH+ and INH-. The accuracy of the model was 74.2% for CHA INH+ and 98.4% for INH-. By focusing the analysis on CHA with high-risk F8 mutations for inhibitor development, the accuracy in identifying CHA INH+ increased to 82.1%. CONCLUSION: Our machine-learning algorithm demonstrated an overall accuracy of 90.5% for predicting inhibitor development in CHA, which further improved when restricting the analysis to CHA with a high-risk F8 genotype. However, our model requires validation in other cohorts. Yet, missing data for some variables hindered more precise predictions.
Assuntos
Fator VIII , Hemofilia A , Aprendizado de Máquina , Índice de Gravidade de Doença , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/sangue , Hemofilia A/diagnóstico , Criança , Pré-Escolar , Fator VIII/genética , Masculino , Valor Preditivo dos Testes , Fatores de Risco , Adolescente , Reprodutibilidade dos Testes , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fatores de Tempo , Lactente , Medição de Risco , Biomarcadores/sangue , Resultado do TratamentoRESUMO
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.
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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.
Assuntos
Anticorpos Antivirais/sangue , Hemofilia A/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Interleucina-10/sangue , Interleucina-4/sangue , Proteínas do Core Viral/imunologia , Adulto , Anticorpos Antivirais/imunologia , Microambiente Celular/imunologia , Feminino , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Humanos , Imunidade Inata , Interleucina-10/imunologia , Interleucina-12/sangue , Interleucina-12/imunologia , Interleucina-4/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. Patients with the severe form of the disease may present considerable heterogeneity in the occurrence of bleeding episodes and some of them have a mild hemophilia A phenotype. This study aimed to evaluate the association of biomarkers and coagulation parameters to the differential hemorrhagic profile of severe hemophilia A patients. Polymorphisms in the genes of proteins C and S, factors V and VII and prothrombin were evaluated in a group of severe hemophilia A patients with a broad spectrum of bleeding profile. Plasma levels of coagulation factors and thrombin generation were also analyzed. This study included 59 Brazilian hemophilia A patients who were allocated into low bleeding profile (LBP; nâ=â33) and high bleeding profile (HBP; nâ=â26) groups based on their joint and muscle bleeding episodes requiring treatment in the 5 years before inclusion in the study. Results evidenced that endogenous thrombin potential (ETP) and plasma factor VII levels were significantly higher in the LBP group. Results indicate a prominent importance of FVII plasma activity and endogenous thrombin potential on the differential bleeding phenotype of hemophilia A patients.
Assuntos
Fator VII , Hemofilia A , Humanos , Hemofilia A/complicações , Trombina/metabolismo , Testes de Coagulação Sanguínea , Hemorragia/etiologia , Variação Biológica da PopulaçãoRESUMO
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.
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COVID-19 , Humanos , SARS-CoV-2 , Interleucina-10 , Interleucina-6 , Doadores de Sangue , Quimiocinas , CitocinasRESUMO
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.
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Anticorpos Biespecíficos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Fator VIII/genética , Hemofilia A/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Biomarcadores/sangue , Brasil/epidemiologia , Fator VIII/imunologia , Feminino , Hemofilia A/sangue , Hemofilia A/genética , Hemofilia A/imunologia , Humanos , Tolerância Imunológica/imunologia , Masculino , Fatores de RiscoRESUMO
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.
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Biomarcadores/sangue , Quimiocina CXCL10/sangue , Fator VIII/administração & dosagem , Hemofilia A/sangue , Hemofilia A/imunologia , Anticorpos Neutralizantes/química , Quimiocina CXCL9/sangue , Quimiocinas/metabolismo , Citocinas/metabolismo , Hemostáticos , Humanos , Sistema Imunitário , Imunoglobulina G/sangue , Lactente , Inflamação , Isoanticorpos/química , MasculinoRESUMO
This illustrated review focuses on the development of inhibitors in patients with congenital hemophilia, which is the most serious treatment-related complication in these patients. Hemophilia A (HA) is an inherited X-linked bleeding disorder affecting 1:5000-10 000 newborn males worldwide. It results from the deficiency of coagulation factor VIII (FVIII), due to mutation(s) in its coding gene (F8). Treatment requires administration of FVIII-containing products either on demand or as prophylaxis, which can induce inhibitor development in 20%-35% of patients. Inhibitors are alloantibodies that neutralize the procoagulant activity of exogenous FVIII. During the initial administration of FVIII-containing products, patients with HA can develop a proinflammatory immune response with synthesis of anti-FVIII IgG1, which has no FVIII inhibitory activity. However, in patients with inhibitors, immune response shifts toward an anti-inflammatory/regulatory pattern favoring the synthesis of anti- FVIII IgG4 antibodies. Patients with inhibitors present with bleeding episodes that are difficult to control, and they have reduced response to FVIII replacement. Currently, immune tolerance induction is the available treatment for eradication of persistent high-titer inhibitors. Despite the clinical relevance, the immunological mechanisms for inhibitor development in patients with HA remains unexplained.
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Plasmodium vivax has been reported to cause severe malaria, and one of the main resulting complications is anemia. Considering that P. vivax infects only young erythrocytes, anemia has been associated with the destruction of infected and non-infected erythrocytes. However, few studies have focused on understanding the relationship between the pathogenesis of P. vivax malaria and human genetic polymorphisms. Although ABO groups seem to influence the outcome of Plasmodium falciparum malaria, the association between P. vivax and ABO blood groups has been minimally investigated. Thus, we investigate the correlation between ABO blood groups and anemia induced by P. vivax infection. Five single nucleotide polymorphisms at the ABO gene were genotyped by PCR-RFLP and Real-Time PCR in P. vivax-infected subjects. The ABO blood types were associated with the hematological data of the patients. Our main finding was that type O infected-individuals showed lower levels of hemoglobin and hematocrit compared to type A-infected individuals. The correlation between ABO blood groups and hemoglobin levels remained significant when a multiple linear regression was applied with the possible confounding effects of clinical-epidemiologic variables taken into account. The finding that type O individuals have a higher frequency of anemia is a first step to understand the mechanisms involved in malaria anemia, which could be associated to increased destruction of type O erythrocytes.