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1.
BMC Bioinformatics ; 20(1): 629, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801472

RESUMO

BACKGROUND: Advances in next-generation sequencing (NGS) of antibody repertoires have led to an explosion in B cell receptor sequence data from donors with many different disease states. These data have the potential to detect patterns of immune response across populations. However, to this point it has been difficult to interpret such patterns of immune response between disease states in the absence of functional data. There is a need for a robust method that can be used to distinguish general patterns of immune responses at the antibody repertoire level. RESULTS: We developed a method for reducing the complexity of antibody repertoire datasets using principal component analysis (PCA) and refer to our method as "repertoire fingerprinting." We reduce the high dimensional space of an antibody repertoire to just two principal components that explain the majority of variation in those repertoires. We show that repertoires from individuals with a common experience or disease state can be clustered by their repertoire fingerprints to identify common antibody responses. CONCLUSIONS: Our repertoire fingerprinting method for distinguishing immune repertoires has implications for characterizing an individual disease state. Methods to distinguish disease states based on pattern recognition in the adaptive immune response could be used to develop biomarkers with diagnostic or prognostic utility in patient care. Extending our analysis to larger cohorts of patients in the future should permit us to define more precisely those characteristics of the immune response that result from natural infection or autoimmunity.


Assuntos
Anticorpos/genética , Análise de Componente Principal , Adulto , Estudos de Coortes , Sangue Fetal/imunologia , Infecções por HIV/sangue , Infecções por HIV/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Pessoa de Meia-Idade , Vacinação
2.
Adv Exp Med Biol ; 1222: 69-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637606

RESUMO

This study seeks to define the level of antihemagglutinin antibodies, using the hemagglutination inhibition assay (HAI), in the serum of patients, stratified into seven age groups, in Poland during the influenza epidemic season of 2017/18. A quadrivalent influenza vaccine has been introduced in Poland as of this epidemic season, making it possible for the first time to conduct the analysis for four antigens: A/Michigan/45/2015 (H1N1) pdm09, A/Hong Kong/4801/2014 (H3N2), B/Brisbane/60/2008 - Victoria lineage, and B/Phuket/3073/2013 - Yamagata lineage. We found that the level of individual antihemagglutinin antibodies was different among the seven age groups studied; with the highest in patients of 5-9 years and 10-14 years of age. Interestingly, the protection factor, defined as the percentage of people with the level of antihemagglutinin antibodies of at least 1:40 after vaccination or due to a previous infection, was the highest for the antigen A/Hong Kong/4801/2014 (H3N2) in the same age groups (74% and 75%, respectively). Taking into account the dismal 3.6% of the vaccinated population in Poland, these findings point toward the sustained presence of an immune system response in patients after a prior influenza virus infection.


Assuntos
Anticorpos Antivirais/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Hemaglutininas , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Influenza Humana/sangue , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Estações do Ano , Vacinação/estatística & dados numéricos , Adulto Jovem
4.
J Prev Med Hyg ; 60(1): E1-E4, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31041403

RESUMO

Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions. In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shanghai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phylogenetic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018. Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme.


Assuntos
Doenças Transmissíveis Importadas/diagnóstico , Influenza Humana/diagnóstico , Adulto , Antivirais/uso terapêutico , China , Doenças Transmissíveis Importadas/sangue , Doenças Transmissíveis Importadas/complicações , Doenças Transmissíveis Importadas/tratamento farmacológico , Febre , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/sangue , Influenza Humana/complicações , Influenza Humana/tratamento farmacológico , Itália , Leucopenia/sangue , Leucopenia/etiologia , Masculino , Oseltamivir/uso terapêutico , Filogenia , Estações do Ano
5.
Medicine (Baltimore) ; 98(19): e15544, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083210

RESUMO

Concomitant influenza and cryptococcal infections are rare. Herein, we describe an unusual case of an avian influenza A (H7N9) infection with several severe mixed bacterial infections and systemic super-infection with Cryptococcus neoformans presenting as ventilator-associated pneumonia (VAP) and bloodstream infection in a previously immunocompetent man during hospitalization.A 58-year-old man was admitted to our hospital complaining of hyperpyrexia, dyspnoea, cough, and phlegm with blood. A chest computed tomography scan revealed multiple ground-glass opacities and consolidation in both lungs with right pleural effusion. An initial sputum test was positive for influenza A (H7N9) virus. After antiviral treatment and other supportive measures, the patient's condition improved. However, the patient's condition deteriorated again approximately 2 weeks after admission, and bronchoalveolar lavage fluid (BALF) and blood cultures were positive for C. neoformans. Therapy with intravenous liposomal amphotericin B and fluconazole was started. After a 2-week antifungal treatment, BALF and blood cultures were negative for C. neoformans. However, the patient had persistent lung infiltrates with severe pulmonary fibrosis with a prolonged course of disease. On hospital day 40, BALF and blood cultures were both positive for multidrug-resistant Stenotrophomonas maltophilia. Finally, the patient developed septic shock, disseminated intravascular coagulation and multi-organ failure and succumbed to treatment failure.Cryptococcal infection can occur in patients with severe influenza during hospitalization with a more severe condition, and the clinician should be aware of this infection.


Assuntos
Coinfecção , Criptococose/complicações , Cryptococcus neoformans , Influenza Humana/complicações , Coinfecção/sangue , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Criptococose/sangue , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Influenza Humana/sangue , Influenza Humana/diagnóstico , Influenza Humana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade
6.
mBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088926

RESUMO

In this study, we examined the relationships between anti-influenza virus serum antibody titers, clinical disease, and peripheral blood leukocyte (PBL) global gene expression during presymptomatic, acute, and convalescent illness in 83 participants infected with 2009 pandemic H1N1 virus in a human influenza challenge model. Using traditional statistical and logistic regression modeling approaches, profiles of differentially expressed genes that correlated with active viral shedding, predicted length of viral shedding, and predicted illness severity were identified. These analyses further demonstrated that challenge participants fell into three peripheral blood leukocyte gene expression phenotypes that significantly correlated with different clinical outcomes and prechallenge serum titers of antibodies specific for the viral neuraminidase, hemagglutinin head, and hemagglutinin stalk. Higher prechallenge serum antibody titers were inversely correlated with leukocyte responsiveness in participants with active disease and could mask expression of peripheral blood markers of clinical disease in some participants, including viral shedding and symptom severity. Consequently, preexisting anti-influenza antibodies may modulate PBL gene expression, and this must be taken into consideration in the development and interpretation of peripheral blood diagnostic and prognostic assays of influenza infection.IMPORTANCE Influenza A viruses are significant human pathogens that caused 83,000 deaths in the United States during 2017 to 2018, and there is need to understand the molecular correlates of illness and to identify prognostic markers of viral infection, symptom severity, and disease course. Preexisting antibodies against viral neuraminidase (NA) and hemagglutinin (HA) proteins play a critical role in lessening disease severity. We performed global gene expression profiling of peripheral blood leukocytes collected during acute and convalescent phases from a large cohort of people infected with A/H1N1pdm virus. Using statistical and machine-learning approaches, populations of genes were identified early in infection that correlated with active viral shedding, predicted length of shedding, or disease severity. Finally, these gene expression responses were differentially affected by increased levels of preexisting influenza antibodies, which could mask detection of these markers of contagiousness and disease severity in people with active clinical disease.


Assuntos
Anticorpos Antivirais/sangue , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Influenza Humana/imunologia , Leucócitos/imunologia , Neuraminidase/imunologia , Doença Aguda , Adolescente , Adulto , Convalescença , Proteção Cruzada , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Testes de Inibição da Hemaglutinação , Experimentação Humana , Humanos , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/sangue , Masculino , Pessoa de Meia-Idade , Eliminação de Partículas Virais , Adulto Jovem
7.
Nat Commun ; 10(1): 1780, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992428

RESUMO

Influenza infection increases the incidence of myocardial infarction but the reason is unknown. Platelets mediate vascular occlusion through thrombotic functions but are also recognized to have immunomodulatory activity. To determine if platelet processes are activated during influenza infection, we collected blood from 18 patients with acute influenza infection. Microscopy reveals activated platelets, many containing viral particles and extracellular-DNA associated with platelets. To understand the mechanism, we isolate human platelets and treat them with influenza A virus. Viral-engulfment leads to C3 release from platelets as a function of TLR7 and C3 leads to neutrophil-DNA release and aggregation. TLR7 specificity is confirmed in murine models lacking the receptor, and platelet depletion models support platelet-mediated C3 and neutrophil-DNA release post-influenza infection. These findings demonstrate that the initial intrinsic defense against influenza is mediated by platelet-neutrophil cross-communication that tightly regulates host immune and complement responses but can also lead to thrombotic vascular occlusion.


Assuntos
Plaquetas/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Ativação Plaquetária/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Complemento C3/imunologia , Complemento C3/metabolismo , Modelos Animais de Doenças , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/sangue , Influenza Humana/virologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo
8.
PLoS One ; 14(3): e0213290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30849093

RESUMO

Frequent typing and molecular characterization of influenza A (IAV) strains are crucial for the identification of circulating subtypes and for the selection of the subtypes' lineages to be included in the annually prepared vaccine cocktail. We investigated IAV sampled from an underrepresented population from Palestine. 200 nasopharyngeal aspirates (NPA) were collected between February and May of 2015 from Palestinians in East Jerusalem and the West Bank suffering from mild to severe symptoms of upper respiratory infections. NPA were screened for the presence of IAV using RT-PCR. Epidemiological data, hemagglutinin (HA) and neuraminidase (NA) gene sequences were analyzed in IAV positive samples. 50 samples tested positive for IAV; 48% of which were identified as A(H1N1)pdm09 and 52% as A(H3N2), respectively. Infection with A(H1N1)pdm09 occurred mainly in April, while A(H3N2) infections were mainly detected in March. Most IAV infections in 6-year-olds and below were attributed to subtype A(H3N2), while A(H1N1)pdm09 was responsible for most infections in adults above 18-year-olds. Analyses of HA and NA amino acid sequences revealed numerous substitutions. Thereafter, and based on the HA analysis, the Palestinian A(H1N1)pdm09 isolates fell into clade 6B, while the A(H3N2) isolates fell into clades 3C.2 and 3C.3, respectively. This study is significant in providing the first insight into the epidemiology and genetic properties of IAV circulating in Palestine. In contrast to international reports for the same season, A(H3N2) was not the dominant subtype as in northern hemisphere, nor was A(H1N1)pdm09 as in WHO reports for the Middle East, however genetic properties of Palestinian A(H3N2) and A(H1N1)pdm09 were in line with global isolates.


Assuntos
Variação Genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A/isolamento & purificação , Influenza Humana/epidemiologia , Epidemiologia Molecular , Neuraminidase/genética , RNA Viral/genética , Adolescente , Árabes/estatística & dados numéricos , Criança , Pré-Escolar , Monitoramento Epidemiológico , Evolução Molecular , Feminino , Humanos , Lactente , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Influenza Humana/sangue , Influenza Humana/virologia , Israel/epidemiologia , Masculino , Oriente Médio/epidemiologia , Filogenia , RNA Viral/sangue , Inquéritos e Questionários
9.
Influenza Other Respir Viruses ; 13(1): 64-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30156030

RESUMO

OBJECTIVES: The goal of this investigation was to determine if acute influenza infection is associated with depletion of CoQ10 compared to healthy controls and to determine any associations between CoQ10 levels and illness severity and inflammatory biomarkers. PATIENTS AND METHODS: We analyzed serum CoQ10 concentrations of patients with acute influenza enrolled in a randomized clinical trial prior to study drug administration. Patients were enrolled at a single urban tertiary care center over 3 influenza seasons (December 27, 2013 to March 31, 2016). Wilcoxon rank sum test was used to compare CoQ10 levels between influenza patients and healthy controls. Correlations with inflammatory biomarkers and severity of illness were assessed using Spearman correlation coefficient. RESULTS: We analyzed CoQ10 levels from 50 patients with influenza and 29 controls. Overall, patients with acute influenza had lower levels of CoQ10 (.53 µg/mL, IQR .37-.75 vs .72, IQR .58-.90, P = .004). Significantly more patients in the influenza group had low CoQ10 levels (<.5 µg/mL) compared to controls (48% vs 7%, P < .001). Among influenza patients, there were significant but weak correlations between CoQ10 levels and IL-2 (r = -.30, P = .04), TNF-alpha (r = -.35, P = .01) and VEGF (r = .38, P = .007), but no correlation with IL-6, IL-10, VCAM or influenza severity of illness score (all P > .05). CONCLUSIONS: We found that CoQ10 levels were significantly lower in patients with acute influenza infection and that these levels had significant although weak correlations with several inflammatory biomarkers.


Assuntos
Influenza Humana/sangue , Ubiquinona/análogos & derivados , Doença Aguda , Adulto , Atorvastatina/uso terapêutico , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Inflamação/sangue , Influenza Humana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Centros de Atenção Terciária , Ubiquinona/sangue , Adulto Jovem
10.
Adv Exp Med Biol ; 1150: 77-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30276725

RESUMO

The diagnostic of influenza virus infections is possible using molecular biology methods as well as the analysis of anti-hemagglutinin (anti-HA) antibodies in the blood serum. The aim of this study was to determine the level of anti-HA antibodies in 7 age groups of patients during the 2015/2016 epidemic season in Poland. A total of 1050 serum samples were tested using the hemagglutination inhibition (HAI) assay. We confirmed the presence of anti-HA antibodies for the influenza virus strains: A/California/7/2009(H1N1)pdm09, A/Switzerland/9715293/2013(H3N2), and B/Phuket/3073/2013, which were the components of the influenza vaccine for the 2015/2016 epidemic season. The level of specific anti-HA antibodies was different in each age group. The geometric mean titers were highest at age 5-9 years, where the antibody protection level reached 61.3% against B/Phuket/3073/2013 and 52.7% for A/Switzerland/9715293/2013(H3N2) antigen. The antibody level amounted to 56.7% against for antigen B at age 45-64. In the remaining age groups, the protection levels for all hemagglutinin types did not exceed 50%. These findings confirm the urgent need to increase a persistently low influenza vaccination coverage in the Polish population, which may have had its part in the noticeable increase in the confirmed cases of influenza and influenza-like virus infection during the season.


Assuntos
Anticorpos Antivirais/imunologia , Epidemias , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vacinas contra Influenza , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/sangue , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Estações do Ano
11.
Inflamm Res ; 68(1): 39-46, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30288556

RESUMO

BACKGROUND: C-reactive protein (CRP) is an acute-phase reactant downstream of the pro-inflammatory cytokines released during influenza infection. However, the role of this inflammatory marker in influenza severity and complications is yet to be elucidated. OBJECTIVES: We aim to systematically review and evaluate the levels of CRP in severe and non-severe H1N1 influenza cases and assess its utility as a biomarker in predicting the severity of infection. METHODS: We conducted a comprehensive search in Ovid MEDLINE, Ovid MEDLINE (R) Epub ahead of Print, Embase and Embase Classic to identify human studies reporting measurements of CRP levels in patients infected with H1N1 influenza at various levels of disease severity. RESULTS: Our search identified ten studies eligible for inclusion in this systematic review. The results of the data analysis show that the average CRP levels upon diagnosis were significantly higher (P < 0.05) in patients who developed severe H1N1 influenza compared to their counterparts with a no severe disease. Furthermore, levels of CRP were associated with the degree of H1N1 severity. Subjects with H1N1-related pneumonia and patients who were hospitalized or died of the disease complications, respectively, had 1.4- and 2.5-fold significantly higher CRP levels (P < 0.05) than those with no severe disease outcome. CONCLUSION: CRP levels have been consistently shown to be significantly higher in H1N1 influenza patients who develop a severe disease outcome. The resuts of the present study suggest that serum CRP can be employed-in combination with other biomarkers-to predict the complications of H1N1 influenza.


Assuntos
Proteína C-Reativa/análise , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/sangue , Biomarcadores/sangue , Humanos , Índice de Gravidade de Doença
12.
PLoS One ; 13(12): e0208028, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30507951

RESUMO

BACKGROUND AND AIM: The majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model. METHODS AND RESULTS: Ferrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages. CONCLUSIONS: In this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.


Assuntos
Proteção Cruzada/imunologia , Imunogenicidade da Vacina , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Vacinação/métodos , Administração Intranasal , Animais , Anticorpos Antivirais/sangue , Proteção Cruzada/genética , Modelos Animais de Doenças , Feminino , Furões , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza B/genética , Vírus da Influenza B/imunologia , Vírus da Influenza B/patogenicidade , Vacinas contra Influenza/administração & dosagem , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia
13.
Rev Esp Quimioter ; 31(6): 542-545, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30421883

RESUMO

OBJECTIVE: The role of tumor necrosis factor (TNF), interleukin (IL)-1ß and IL-6 in the pathogenicity of seasonal flu is unknown. METHODS: We analyzed the profiles of these cytokines in 77 flu patients and 17 controls with non-flu respiratory infection, using molecular biology techniques (real-time polymerase chain reaction). RESULTS: Flu patients had lower monocyte counts (p=0.029) and a slightly lower median level of IL-6 (P=0.05) than the control group. Twenty-four flu patients (31.2%) had pneumonia; this group had higher C-reactive proteins (p=0.01) and monocyte levels (p=0.009). Pro-inflammatory cytokines levels did not rise in patients with pneumonia complicating seasonal influenza. CONCLUSIONS: IL-6 levels were lower in adults with influenza.


Assuntos
Influenza Humana/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Humanos , Influenza Humana/complicações , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Pneumonia/sangue , Pneumonia/complicações , Pneumonia/etiologia
14.
Cell Host Microbe ; 24(4): 558-568.e7, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30269969

RESUMO

H7N9 low pathogenic influenza viruses emerged in China in 2013 and mutated to highly pathogenic strains in 2017, resulting in human infections and disease in chickens. To control spread, a bivalent H5/H7 inactivated vaccine was introduced in poultry in September 2017. To monitor virus evolution and vaccine efficacy, we collected 53,884 poultry samples across China from February 2017 to January 2018. We isolated 252 H7N9 low pathogenic viruses, 69 H7N9 highly pathogenic viruses, and one H7N2 highly pathogenic virus, of which two low pathogenic and 14 highly pathogenic strains were collected after vaccine introduction. Genetic analysis of highly pathogenic strains revealed nine genotypes, one of which is predominant and widespread and contains strains exhibiting high virulence in mice. Additionally, some H7N9 and H7N2 viruses carrying duck virus genes are lethal in ducks. Thus, although vaccination reduced H7N9 infections, the increased virulence and expanded host range to ducks pose new challenges.


Assuntos
Doenças Transmissíveis Emergentes/virologia , Evolução Molecular , Subtipo H7N9 do Vírus da Influenza A/genética , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , Animais , Galinhas , China , Doenças Transmissíveis Emergentes/sangue , Doenças Transmissíveis Emergentes/imunologia , Doenças Transmissíveis Emergentes/mortalidade , Patos , Feminino , Humanos , Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Influenza Aviária/sangue , Influenza Aviária/imunologia , Influenza Aviária/mortalidade , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Organismos Livres de Patógenos Específicos , Vacinas de Produtos Inativados/imunologia , Virulência/genética
15.
Clin Drug Investig ; 38(12): 1189-1196, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30288682

RESUMO

BACKGROUND AND OBJECTIVE: Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. This first-in-human phase I study evaluated the safety, tolerability, and pharmacokinetics of baloxavir marboxil/baloxavir acid in healthy Japanese volunteers (Study 1), while food effects were evaluated in a separate phase I, crossover study in healthy Japanese volunteers (Study 2). METHODS: Study 1 participants were randomized to single-dose oral baloxavir marboxil (6, 20, 40, 60, or 80 mg; n = 6 per dose) or placebo (n = 10), while Study 2 participants (n = 15) received single-dose oral baloxavir marboxil 20 mg in fasted, fed, and before-meal states. RESULTS: Baloxavir marboxil was well tolerated; there were few treatment-emergent adverse events and no serious adverse events/deaths. The mean plasma baloxavir acid concentration 24 h after single-dose (C24) oral baloxavir marboxil 6 mg was 6.92 ng/mL, exceeding the target C24 (6.85 ng/mL) estimated in nonclinical studies. In Study 1, baloxavir acid exposure demonstrated dose-proportional increases in the fasted state, with maximum plasma concentration generally attained within 3.5 h. Terminal elimination half-life ranged from 49 to 91 h. In Study 2, exposure was decreased and apparent clearance increased in the fed and before-meal states versus the fasted state; however, exposure exceeded the target C24 in all states. CONCLUSION: Single-dose oral baloxavir marboxil was well tolerated, had a favorable safety profile, and had favorable pharmacokinetic characteristics, including a long half-life, supporting single oral dosing. The baloxavir acid area under the plasma concentration-time curve decreased with food intake by approximately 40%.


Assuntos
Antivirais/farmacocinética , Interações Alimento-Droga/fisiologia , Oxazinas/farmacocinética , Piridinas/farmacocinética , Tiepinas/farmacocinética , Triazinas/farmacocinética , Adulto , Antivirais/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Jejum/sangue , Seguimentos , Cefaleia/sangue , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Influenza Humana/sangue , Influenza Humana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Pró-Fármacos , Piridinas/efeitos adversos , Tiepinas/efeitos adversos , Triazinas/efeitos adversos
16.
Transfusion ; 58(12): 2757-2760, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30284726

RESUMO

BACKGROUND: Heparin-induced thrombocytopenia (HIT) usually appears at 5 to 10 days after initiation of heparin. Autoimmune HIT can arise after discontinuation of heparin treatment (delayed-onset HIT) or without any preceding heparin exposure (spontaneous HIT syndrome). CASE REPORT: This case presents a course of autoimmune HIT with delayed onset. The patient was hospitalized due to influenza pneumonia and received low-molecular-weight heparin thromboprophylaxis for 9 days. Seven days after discharge, she was readmitted because of a cerebral sinus vein thrombosis and severe thrombocytopenia. Intracranial bleeding and brain infarction caused her death. DISCUSSION: Autoimmune HIT was confirmed by functional heparin-induced platelet (PLT) activation test. Intracranial bleeding prevented continuous and effective anticoagulation. PLT transfusions were given, although they are generally advised against in HIT patients due to potential risk of thromboembolic events. CONCLUSION: This case presents that testing PLT-activating antibodies both in the presence and in the absence of current heparin treatment helps to diagnose patients with autoimmune HIT. There is conflicting evidence to refuse PLT transfusion when HIT is complicated with life-threatening bleeding.


Assuntos
Autoanticorpos/sangue , Heparina de Baixo Peso Molecular , Trombose Intracraniana , Ativação Plaquetária , Púrpura Trombocitopênica Idiopática , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/química , Humanos , Influenza Humana/sangue , Influenza Humana/tratamento farmacológico , Trombose Intracraniana/sangue , Trombose Intracraniana/induzido quimicamente , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Fatores de Tempo
17.
Med. intensiva (Madr., Ed. impr.) ; 42(7): 399-408, oct. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-178658

RESUMO

Introduction: Serum procalcitonin (PCT) concentration could be increased in patients with renal dysfunction in the absence of bacterial infection. Objective: To determine the interactions among serum renal biomarkers of acute kidney injury (AKI) and serum PCT concentration, in patients admitted to the intensive care unit (ICU) due to lung influenza infection. Design: Secondary analysis of a prospective multicentre observational study. Setting: 148 Spanish ICUs. Patients: ICU patients admitted with influenza infection without bacterial co-infection. Clinical, laboratory and hemodynamic variables were recorded. AKI was classified as AKI I or II based on creatinine (Cr) concentrations (≥1.60-2.50mg/dL and Cr≥2.51-3.99mg/dL, respectively). Patients with chronic renal disease, receiving renal replacement treatment or with Cr>4mg/dL were excluded. Spearman's correlation, simple and multiple linear regression analysis were performed. Interventions: None. Results: Out of 663 patients included in the study, 52 (8.2%) and 10 (1.6%) developed AKI I and II, respectively. Patients with AKI were significantly older, had more comorbid conditions and were more severally ill. PCT concentrations were higher in patients with AKI (2.62 [0.60-10.0]ng/mL vs. 0.40 [0.13-1.20]ng/mL, p=0.002). Weak correlations between Cr/PCT (rho=0.18) and Urea (U)/PCT (rho=0.19) were identified. Simple linear regression showed poor interaction between Cr/U and PCT concentrations (Cr R2=0.03 and U R2=0.018). Similar results were observed during multiple linear regression analysis (Cr R2=0.046 and U R2=0.013). Conclusions: Although PCT concentrations were slightly higher in patients with AKI, high PCT concentrations are not explained by AKI and could be warning sign of a potential bacterial infection


Introducción: Los niveles de procalcitonina (PCT) pueden elevarse en pacientes con disfunción renal aún en ausencia de infección bacteriana. Objetivos: Determinar la interacción entre los biomarcadores de disfunción renal aguda (AKI) y las concentraciones séricas de PCT en pacientes ingresados en cuidados intensivos (UCI) debido a infección por gripe. Diseño: Análisis secundario de un estudio prospectivo, multicéntrico observacional. Lugar: Ciento cuarenta y ocho UCI. Pacientes: Con infección por gripe sin co-infección bacteriana. Se registraron las variables clínicas, de laboratorio y hemodinámicas. El nivel de AKI fue definido como AKI I y II basado en la creatinina (Cr) sérica (>1,60-2,50mg/dl y >2,51-3,99mg/dl), respectivamente. Pacientes con insuficiencia renal crónica, técnicas de reemplazo renal o Cr>4mg/dl fueron excluidos. El análisis estadístico se realizó mediante correlación de Spearman y regresión linear simple y múltiple. Intervenciones: Ninguna. Resultados: De los 663 pacientes incluidos, 52 (8,2%) y 10 (1,6%) desarrollaron AKI I y II, respectivamente. Pacientes con AKI fueron más añosos, presentaron más comorbilidades y mayor nivel de gravedad. Los niveles de PCT fueron mayores en pacientes con AKI (2,62 [0,60-10,0] ng/ml vs. 0,40 [0,13-1,20] ng/ml; p=0,002). Se observaron correlaciones débiles entre Cr/PCT (rho=0,18) y PCT/U (rho=0,19). La regresión linear simple evidenció una pobre contribución tanto de Cr (R2=0,03) como de U (R2=0,018) sobre los niveles de PCT. Resultados similares fueron obtenidos con la regresión linear múltiple para Cr (R2=0,046) y U (R2=0,013). Conclusiones: Aunque los valores de PCT pueden estar elevados en pacientes con AKI, altos niveles de PCT no pueden ser explicados por la disfunción renal y podrían ser un signo de alarma de una potencial infección bacteriana


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Lesão Renal Aguda/sangue , Infecções Bacterianas/diagnóstico , Calcitonina/sangue , Coinfecção/diagnóstico , Estado Terminal/mortalidade , Influenza Humana/sangue , Lesão Renal Aguda/etiologia , Infecções Bacterianas/sangue , Infecções Bacterianas/complicações , Biomarcadores , Comorbidade , Creatinina/sangue , Influenza Humana/complicações , Unidades de Terapia Intensiva , Estudos Prospectivos , Índice de Gravidade de Doença , Ureia/sangue , Estudo Observacional
18.
Int J Mol Sci ; 19(8)2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115864

RESUMO

Vitamin D generates many extraskeletal effects due to the vitamin D receptor (VDR) which is present in most tissues throughout the body. The possible role of vitamin D in infections is implied from its impact on the innate and adaptive immune responses. A significant effect is also the suppression of inflammatory processes. Because vitamin D could be acknowledged as a "seasonal stimulus", as defined by R. Edgar Hope-Simpson, it would be crucial to prove it from a potential easy and cheap prophylaxis or therapy support perspective as far as influenza infections are concerned. The survey of the literature data generates some controversies and doubts about the possible role of vitamin D in the prevention of influenza virus. The most important point is to realise that the broad spectrum of this vitamin's activity does not exclude such a possibility. According to most of the authors, more randomized controlled trials with effective, large populations are needed to explore the preventive effect of vitamin D supplementation on viral influenza infections.


Assuntos
Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Vitamina D/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Suplementos Nutricionais , Humanos , Influenza Humana/sangue , Influenza Humana/epidemiologia , Vitamina D/sangue , Vitamina D/metabolismo
19.
BMC Health Serv Res ; 18(1): 651, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134892

RESUMO

BACKGROUND: The hemagglutination-inhibition (HAI) assay is a critical component for measurement of immunogenicity in influenza vaccine development. It is unknown if the results can be influenced by sample type and anticoagulants. The purpose of this study was to evaluate the influence of different sample collection methods, in particular different anticoagulants, and choice of plasma or serum, on influenza virus serological assays. METHODS: Blood samples from thirty donors previously immunized against influenza viruses were collected using six different types of blood collection tubes, two of which collect serum and four of which contain various anticoagulants for collecting plasma. Serum: (1) serum separator tubes (SST); and (2) Plus Plastic serum "red-top serum" tubes. Plasma: (3) spray-coated K2 ethylenediaminetetraacetic acid (EDTA) tubes: (4) Sodium Heparin tubes; (5) Citrate tubes with 3.2% sodium citrate solution; and (6) Glass Blood Collection tubes with acid citrate dextrose. Samples were tested against three different influenza viruses (A/California/07/2009 (H1N1pdm09), A/Texas/50/2012 (H3N2), and B/Massachusetts/2/2012) for hemagglutination inhibition titer and virus neutralization titer via a microneutralization (MN) assay, and data compared to that obtained for standard serum sample collected in SST. RESULTS: HAI and MN titers against type A viruses were within two dilutions compared to SST collection method over 96% of the time irrespective of sample type or anticoagulant. However, HAI titers for type B virus were more variable across different collection methods. EDTA plasma samples were greater than two dilutions higher than SST serum samples 70% (21 of 30 samples) of the time. In contrast, MN titers were within two dilutions over 96% of the time, with the highest deviation noted in acid citrate dextrose plasma samples (3 of 30 samples tested, 10%). CONCLUSIONS: These data provide useful guidelines for sample collection and serology testing when screening: (i) influenza vaccine immunogenicity antibody response; (ii) antibody responses to newly emerging viral strains; and (iii) clinical samples for anti-influenza antibody activity.


Assuntos
Coleta de Amostras Sanguíneas , Testes de Inibição da Hemaglutinação , Hemaglutinação/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/imunologia , Anticorpos Antivirais , Anticoagulantes , Coleta de Amostras Sanguíneas/métodos , Guias como Assunto , Humanos , Vacinas contra Influenza , Influenza Humana/sangue , Testes de Neutralização
20.
Sci Transl Med ; 10(449)2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29997249

RESUMO

Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.


Assuntos
Doenças Transmissíveis/imunologia , Everolimo/uso terapêutico , Imidazóis/uso terapêutico , Imunidade , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Quinolinas/uso terapêutico , Idoso , Anticorpos Antivirais/imunologia , Doenças Transmissíveis/sangue , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/genética , Relação Dose-Resposta a Droga , Everolimo/efeitos adversos , Everolimo/farmacologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Vacinação
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