Characterizing carbapenemase-producing Escherichia coli isolates from Spain: high genetic heterogeneity and wide geographical spread.

Introduction: Carbapenemase-Producing Escherichia coli (CP-Eco) isolates, though less prevalent than other CP-Enterobacterales, have the capacity to rapidly disseminate antibiotic resistance genes (ARGs) and cause serious difficult-to-treat infections. The aim of this study is phenotypically and genotypically characterizing CP-Eco isolates collected from Spain to better understand their resistance mechanisms and population structure. Methods: Ninety representative isolates received from 2015 to 2020 from 25 provinces and 59 hospitals Spanish hospitals were included. Antibiotic susceptibility was determined according to EUCAST guidelines and whole-genome sequencing was performed. Antibiotic resistance and virulence-associated genes, phylogeny and population structure, and carbapenemase genes-carrying plasmids were analyzed. Results and discussion: The 90 CP-Eco isolates were highly polyclonal, where the most prevalent was ST131, detected in 14 (15.6%) of the isolates. The carbapenemase genes detected were bla OXA-48 (45.6%), bla VIM-1 (23.3%), bla NDM-1 (7.8%), bla KPC-3 (6.7%), and bla NDM-5 (6.7%). Forty (44.4%) were resistant to 6 or more antibiotic groups and the most active antibiotics were colistin (98.9%), plazomicin (92.2%) and cefiderocol (92.2%). Four of the seven cefiderocol-resistant isolates belonged to ST167 and six harbored bla NDM. Five of the plazomicin-resistant isolates harbored rmt. IncL plasmids were the most frequent (45.7%) and eight of these harbored bla VIM-1. bla OXA-48 was found in IncF plasmids in eight isolates. Metallo-ß-lactamases were more frequent in isolates with resistance to six or more antibiotic groups, with their genes often present on the same plasmid/integron. ST131 isolates were associated with sat and pap virulence genes. This study highlights the genetic versatility of CP-Eco and its potential to disseminate ARGs and cause community and nosocomial infections.

HBsAg level defines different clinical phenotypes of HBeAg(-) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality.

Background: HBe-antigen(Ag)-negative chronic hepatitis B virus (HBV) infection is characterized by little liver fibrosis progression and vigorous HBV-multispecific CD8+ T-cell response. Aims: To assess whether HBsAg level could discriminate different HBeAg-negative chronic HBV infection subtypes with dissimilar quality of HBV-specific CD8+ T-cell response. Methods: We recruited 63 HBeAg-negative chronic HBV infection patients in which indirect markers of liver inflammation/fibrosis, portal pressure, viral load (VL), and HBV-specific CD8+ cell effector function were correlated with HBsAg level. Results: A positive linear trend between HBsAg level and APRI, liver stiffness (LS), liver transaminases, and HBV VL, and a negative correlation with platelet count were observed. Frequency of cases with HBV-specific CD8+ T-cell proliferation against at least two HBV epitopes was higher in HBsAg < 1,000 IU/ml group. CD8+ T-cell expansion after HBVpolymerase456-63-specific stimulation was impaired in HBsAg > 1,000 IU/ml group, while the response against HBVcore18-27 was preserved and response against envelope183-91 was nearly abolished, regardless of HBsAg level. Cases with preserved HBVpolymerase456-63 CD8+ cell response had lower LS/duration of infection and APRI/duration of infection rates. HBV-polymerase456-63-specific CD8+ T-cell proliferation intensity was negatively correlated with LS/years of infection ratio. Conclusion: HBsAg > 1,000 IU/ml HBeAg-negative chronic HBV infection group shows indirect data of higher degree of inflammation, liver stiffness, and fibrosis progression speed, which are related to an impaired HBV-polymerase-specific CD8+ T-cell response.

Low peripheral blood chemokine (C-C motif) ligand 5 and tumor necrosis factor α gene expression is associated with unfavorable progression of respiratory syncytial virus bronchiolitis in infants.

OBJECTIVES: We aimed to analyze whether the expression of inflammatory and antiviral genes in respiratory syncytial virus (RSV)-infected infants' peripheral blood is associated with bronchiolitis progression. METHODS: We conducted a prospective study on 117 infants between 2015 and 2023. The expression levels of nine genes were quantified by quantitative polymerase chain reaction. Infants were classified according to their clinical evolution during hospital admission: (i) non-progression (n = 74), when the RSV bronchiolitis severity remained stable or improved; (ii) unfavorable progression (n = 43), when the RSV bronchiolitis severity increased. The association analysis was performed by logistic regression, adjusted by age, gender, prematurity, and RSV bronchiolitis severity in the emergency room. RESULTS: Infants were 57.3% male, and the median age of the study population was 61 days. Thirty-five infants (30.7%) were admitted to the intensive care unit after hospital admission. Univariate logistic models showed that tumor necrosis factor (TNFα) and chemokine (C-C motif) ligand (CCL5) gene expression at baseline were inversely associated with unfavorable progression, which was confirmed by multivariate analyses: TNFα (adjusted odds ratio = 0.8 [95% confidence interval = 0.64-0.99], P-value = 0.038) and CCL5 (adjusted odds ratio = 0.76 [95% confidence interval = 0.62-0.93], P-value = 0.007). CONCLUSIONS: An inadequate immune response to RSV, characterized by reduced gene expression levels of CCL5 and TNFα in peripheral blood, was associated with an unfavorable progression of RSV bronchiolitis.

IL-15 boosts activated HBV core-specific CD8+ progenitor cells via metabolic rebalancing in persistent HBV infection.

A rebalance between energy supply and demand in HBV-specific-CD8+ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8+ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.

Adult T-cell leukemia/lymphoma in HTLV-1 non-endemic regions.

BACKGROUND: HTLV-1 infection is a neglected disease, despite producing neurological and lymphoproliferative severe illnesses and affect over 10 million people worldwide. Roughly 5% of HTLV-1 carriers develop Adult T-cell leukemia/lymphoma (ATLL), one of the most aggressive hematological malignancies. METHODS: A national HTLV-1 register exists since 1989 in Spain, a non-endemic country with a large migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. The main features of all patients diagnosed with ATLL in Spain up to date are reported. RESULTS: A total of 451 cases of HTLV-1 infection had been reported in Spain until the end of year 2022. ATLL had been diagnosed in 35 (7.8%). The current average incidence of ATLL in Spain is of two cases per year. Women represent 57% of ATLL patients. Mean age at diagnosis was 47 years-old. Roughly 57% were Latin Americans and 26% Africans. At diagnosis, the majority presented with acute or lymphoma clinical forms. Survival was shorter than one year in most of them. Mean HTLV-1 proviral load was significantly greater in ATLL patients than in asymptomatic HTLV-1 carriers (2,305 vs 104 copies/104 PBMC). HTLV-1 subtyping in 6 ATLL patients found the 1a transcontinental variant (n = 4) and the Japanese variant (n = 2). All ATLL patients were negative for HIV-1, did not develop HTLV-1-associated myelopathy and were not transplant recipients. CONCLUSION: The rate of ATLL is very low in Spain and mostly associated to migrants from HTLV-1 endemic regions. Given the poor clinical outcome of ATLL, HTLV-1 testing should be performed at least once in all migrants coming from HTLV-1 endemic countries and in natives who have lived in or had sex partners from such regions.

Influenza A(H5N1) detection in two asymptomatic poultry farm workers in Spain, September to October 2022: suspected environmental contamination.

In autumn 2022, the Spanish Influenza National Reference Laboratory (NRL) confirmed the detection of influenza A(H5N1) in samples from two asymptomatic workers linked to an outbreak in a poultry farm in Spain. Nasopharyngeal swabs were taken according to a national screening protocol for exposed workers. Absence of symptoms, low viral load and negative serology in both workers suggested environmental contamination. These findings motivated an update of the early detection strategy specifying timing and sampling conditions in asymptomatic exposed persons.

Changes in the epidemiology of hepatitis A: Clinical and preventive implications. / Cambios en la epidemiología de la hepatitis A: repercusiones clínicas y preventivas.

INTRODUCTION AND OBJECTIVES: Hepatitis A Virus Infection (HAI) has been related to the hygienic-sanitary situation of an area, the changes in the epidemiology of HAI in the province of Guadalajara between 1991 and 2017 are analyzed. MATERIALS AND METHODS: Cases of HAI declared between 1991 and 2017 in Guadalajara were included. The variables analyzed were age, sex, environment, risk factors for HAI and need for hospitalization. The incidence was compared in three periods: 1991-1999, 2000-2008 and 2009-2017. RESULTS: Two hundred and thirty-three cases of HAI were declared, the average incidence rate was 4.27 cases/100,000 inhabitants, highest between 1991 and 1999 (6.93) and lowest between 2009 and 2017 (1.92), with an increment in 2017 (5.5). The median age was 16 years (IR: 8.5-28.5 years), 58.4% were male, and the highest incidence occurred between 5 and 14 years in both sexes. The most frequent risk factors were family and non-family contact and trips to endemic areas (18.6%, 17.3% and 18.2%, respectively). The last risk factor increased after 2000 (P=.001), as did the incidence in urban areas. The MSM group showed an increase in the last period (P<.001). Hospital admissions increased progressively from the first to the third period studied (P=.001). CONCLUSIONS: HAI has a low incidence in our area. More cases related to travel or sexual practices are observed. This should be considered when establishing prevention policies, including vaccination of the most exposed people.

Brote de sarampión en el área sanitaria de Guadalajara (España): dificultad en el diagnóstico microbiológico en la era de su eliminación / Measles outbreak in the sanitary area of Guadalajara (Spain): Difficulty in microbiological diagnosis in the era of its elimination

Introducción: En España, al igual que en otros países donde el sarampión endémico ha sido eliminado, es necesario utilizar de forma rutinaria las herramientas diagnósticas que confirmen los casos para su prevención y control de la diseminación. Se describen los diferentes ensayos microbiológicos utilizados para su diagnóstico durante un brote de sarampión en 2019 en la provincia de Guadalajara (España). Métodos: Las pruebas serológicas y moleculares se realizaron en el laboratorio de Microbiología del Hospital Universitario de Guadalajara y en el Centro Nacional de Microbiología del Instituto de Salud Carlos III (Majadahonda, España). Los datos de los pacientes se obtuvieron del sistema epidemiológico de vigilancia. Resultados: Se diagnosticaron de sarampión un total de 43 pacientes por métodos microbiológicos: 29 casos por PCR (exudado faríngeo u orina) junto con IgM específica positiva, 11 pacientes solamente por PCR, y 3 pacientes exclusivamente por presencia de IgM. El genotipo D8 fue identificado en 35 pacientes y el genotipo A en 2 casos descartados como postvacunal. La PCR en suero fue positiva en 11 de 14 pacientes con ausencia de IgM en su primera muestra recogida de suero. Once casos confirmados habían recibido una o 2 dosis de la vacuna. Doce adultos fueron ingresados, todos diagnosticados de hepatitis. Conclusiones: La combinación de pruebas moleculares y la presencia de IgG e IgM específicas son necesarias para un diagnóstico correcto y la clasificación de los pacientes como fallo vacunal (primario o secundario). El genotipado es una herramienta fundamental para la correcta clasificación de los pacientes en el contexto de un programa de eliminación del sarampión.(AU)

Introduction: In Spain, like in other countries where endemic measles has been eliminated, there is a need for available diagnostic tools for confirming any cases in order to prevent and control its transmission. We describe the different microbiological tests used for the diagnosis of measles during an outbreak that occurred in 2019 in the province of Guadalajara (Spain). Methods: Serological and molecular tests were performed at the Microbiology laboratory of the Guadalajara University Hospital and at the National Center for Microbiology of the Carlos III Health Institute (Majadahonda, Spain). Patient data were obtained from the surveillance system. Results: A total of 43 patients had a laboratory diagnosis of measles: 29 cases by PCR (pharyngeal exudate or urine) and positive specific IgM, 11 cases by PCR, and 3 cases only by a positive IgM. Genotype D8 was identified in 35 confirmed cases and genotype A in 2 that were discarded as post-vaccination cases. PCR was positive in the acute sera of 11 out of 14 patients with a negative IgM. Eleven confirmed cases had recieved one or 2 vaccine doses. Twelve adult patients were hospitalizated, all of them with a diagnostic of hepatitis. Conclusions: The combination of molecular tests and the presence of specific IgG and IgM are necessary for a correct diagnosis of measles and also to classify patients with a breakthrough infection or vaccine failures (primary or secondary). Genotyping is essential for the correct classification of the patients in the context of a measles elimination program.(AU)

Measles outbreak in the sanitary area of Guadalajara (Spain): difficulty in microbiological diagnosis in the era of its elimination.

INTRODUCTION: In Spain, like in other countries where endemic measles has been eliminated, there is a need for available diagnostic tolos for confirming any cases in order to prevent and control its transmission. We describe the different microbiological tests used for the diagnosis of measles during an outbreak that occurred in 2019 in the province of Guadalajara (Spain). METHODS: Serological and molecular tests were performed at the Microbiology laboratory of the Guadalajara University Hospital and at the National Center for Microbiology of the Carlos III Health Institute (Majadahonda, Spain). Patient data were obtained from the surveillance system. RESULTS: A total of 43 patients had a laboratory diagnosis of measles: 29 cases by PCR (pharyngeal exudate or urine) and positive specific IgM, 11 cases by PCR, and 3 cases only by a positive IgM. Genotype D8 was identified in 35 confirmed cases and genotype A in two that were discarded as post-vaccination cases. PCR was positive in the acute sera of 11 out of 14 patients with a negative IgM. Eleven confirmed cases had recieved one or two vaccine doses. Twelve adult patients were hospitalizated, all of them with a diagnostic of hepatitis. CONCLUSIONS: The combination of molecular tests and the presence of specific IgM is necessary for a correct diagnosis of measles and also to classify patients with a breakthrough infection or vaccine failures (primary or secondary). Genotyping is essential for the correct classification of the patients in the context of a measles elimination program.

Pertactin-Deficient Bordetella pertussis with Unusual Mechanism of Pertactin Disruption, Spain, 1986-2018.

Bordetella pertussis not expressing pertactin has increased in countries using acellular pertussis vaccines (ACV). The deficiency is mostly caused by pertactin gene disruption by IS481. To assess the effect of the transition from whole-cell vaccine to ACV on the emergence of B. pertussis not expressing pertactin in Spain, we studied 342 isolates collected during 1986-2018. We identified 93 pertactin-deficient isolates. All were detected after introduction of ACV and represented 38% of isolates collected during the ACV period; 58.1% belonged to a genetic cluster of isolates carrying the unusual prn::del(-292, 1340) mutation. Pertactin inactivation by IS481 insertion was identified in 23.7% of pertactin-deficient isolates, arising independently multiple times and in different phylogenetic branches. Our findings support the emergence and dissemination of a cluster of B. pertussis with an infrequent mechanism of pertactin disruption in Spain, probably resulting from introduction of ACV.

Model to predict on-treatment restoration of functional HBV-specific CD8+ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV)-specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off-treatment HBV control in e-antigen-negative chronic hepatitis B (CHBe(-)). AIM: To predict this response with variables involved in T-cell exhaustion for use as a treatment stopping tool. METHODS: In NUC-treated CHBe(-) patients, we considered a functional response in cases with HBV-specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off-treatment follow-up according to LRM likelihood. RESULTS: We developed an LRM that predicted the presence of a proliferative type I cytokine-secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off-treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. CONCLUSIONS: Short-term low-level antigen exposure and early long-term NUC treatment influence the restoration of a functional HBV-specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off-treatment HBV control and HBsAg decline and loss.

Measles outbreak in the sanitary area of Guadalajara (Spain): Difficulty in microbiological diagnosis in the era of its elimination. / Brote de sarampión en el área sanitaria de Guadalajara (España): dificultad en el diagnóstico microbiológico en la era de su eliminación.

INTRODUCTION: In Spain, like in other countries where endemic measles has been eliminated, there is a need for available diagnostic tools for confirming any cases in order to prevent and control its transmission. We describe the different microbiological tests used for the diagnosis of measles during an outbreak that occurred in 2019 in the province of Guadalajara (Spain). METHODS: Serological and molecular tests were performed at the Microbiology laboratory of the Guadalajara University Hospital and at the National Center for Microbiology of the Carlos III Health Institute (Majadahonda, Spain). Patient data were obtained from the surveillance system. RESULTS: A total of 43 patients had a laboratory diagnosis of measles: 29 cases by PCR (pharyngeal exudate or urine) and positive specific IgM, 11 cases by PCR, and 3 cases only by a positive IgM. Genotype D8 was identified in 35 confirmed cases and genotype A in 2 that were discarded as post-vaccination cases. PCR was positive in the acute sera of 11 out of 14 patients with a negative IgM. Eleven confirmed cases had recieved one or 2 vaccine doses. Twelve adult patients were hospitalizated, all of them with a diagnostic of hepatitis. CONCLUSIONS: The combination of molecular tests and the presence of specific IgG and IgM are necessary for a correct diagnosis of measles and also to classify patients with a breakthrough infection or vaccine failures (primary or secondary). Genotyping is essential for the correct classification of the patients in the context of a measles elimination program.

Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016.

IntroductionEnterovirus A71 (EV-A71) is an emerging pathogen that causes a wide range of disorders including severe neurological manifestations. In the past 20 years, this virus has been associated with large outbreaks of hand, foot and mouth disease with neurological complications in the Asia-Pacific region, while in Europe mainly sporadic cases have been reported. In spring 2016, however, an EV-A71 outbreak associated with severe neurological cases was reported in Catalonia and spread further to other Spanish regions.AimOur objective was to investigate the epidemiology and clinical characteristics of the outbreak.MethodsWe carried out a retrospective study which included 233 EV-A71-positive samples collected during 2016 from hospitalised patients. We analysed the clinical manifestations associated with EV-A71 infections and performed phylogenetic analyses of the 3'-VP1 and 3Dpol regions from all Spanish strains and a set of EV-A71 from other countries.ResultsMost EV-A71 infections were reported in children (mean age: 2.6 years) and the highest incidence was between May and July 2016 (83%). Most isolates (218/233) were classified as subgenogroup C1 and 217 of them were grouped in one cluster phylogenetically related to a new recombinant variant strain associated with severe neurological diseases in Germany and France in 2015 and 2016. Moreover, we found a clear association of EV-A71-C1 infection with severe neurological disorders, brainstem encephalitis being the most commonly reported.ConclusionAn emerging recombinant variant of EV-A71-C1 was responsible for the large outbreak in 2016 in Spain that was associated with many severe neurological cases.

Infectious Keratitis: Microbiological Review of 297 Cases.

Infectious keratitis is a serious ocular infection that can lead to loss of vision. The aim of this study was to investigate the microbiological characteristics of this infection at the University Hospital of Guadalajara (Spain). We retrospectively reviewed all cases diagnosed between January 2010 and December 2016. During the 7-year study period, 297 corneal scrapes corresponding to 298 patients were performed. Antibiotic treatment prior to the culture was administered in 59 cases (19.9%). Contact lens wear was the most common risk factor (33.2%). Bacterial keratitis accounted for 64.6% of cases, viral keratitis for 3.4%, and fungal keratitis for 1%. A total of 241 bacterial strains were identified. Gram-positive isolates represented 87.1%, and gram-negative 12.7%. Coagulase-negative Staphylococcus strains were the most common microorganisms isolated (30.3%). When gram-positive microorganisms were analyzed, the sensitivity prevalence rates for vancomycin (VCM), levofloxacin, gentamicin (GM), and tobramycin (TO) were 99.4%, 84.6%, 87.9%, and 88.3%, respectively. For the gram-negative organisms, the sensitivity prevalence rates for ceftazidime, ciprofloxacin, GM, and TO were 83.3%, 93.5%, 96.3%, and 100%, respectively. Our study revealed strong predominance of gram-positive microorganisms. We suggest empirically treating bacterial keratitis originating in our area with VCM and TO, especially severe bacterial keratitis and pretreated cases in the community without a clinical response.

According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1low HCV-Specific CD8+ Cell Reactivity.

Hepatitis C virus (HCV)-specific CD8+ T cells suffer a progressive exhaustion during persistent infection (PI) with HCV. This process could involve the positive immune checkpoint 4-1BB/4-1BBL through the loss of its signal transducer, TRAF1. To address this issue, peripheral HCV-specific CD8+ T cells (pentamer-positive [pentamer+]/CD8+ T cells) from patients with PI and resolved infection (RI) after treatment were studied. The duration of HCV infection and the liver fibrosis progression rate inversely correlated with the likelihood of detection of peripheral pentamer+/CD8+ cells. In PI, pentamer+/CD8+ cells had impaired antigen-specific reactivity that worsened when these cells were not detectable ex vivo Short/midduration PI was characterized by detectable peripheral PD-1+ CD127low TRAF1low cells. After triggering of T cell receptors (TCR), the TRAF1 level positively correlated with the levels of CD127, Mcl-1, and CD107a expression and proliferation intensity but negatively with PD-1 expression, linking TRAF1low to exhaustion. In vitro treatment with interleukin-7 (IL-7) upregulated TRAF1 expression, while treatment with transforming growth factor-ß1 (TGF-ß1) did the opposite, suggesting that the IL-7/TGF-ß1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, the serum TGF-ß1 concentration was higher in patients with PI than in patients with RI, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing the level of TRAF1 expression, IL-7 plus 4-1BBL treatment in vitro enhanced T cell reactivity in patients with short/midduration infection. However, in patients with long-lasting PI, anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, was necessary to reestablish T cell proliferation in individuals with slowly progressing liver fibrosis (slow fibrosers) but had no effect in rapid fibrosers. In conclusion, a peripheral hyporeactive TRAF1low HCV-specific CD8+ T cell response, restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8+ T cells are rarely detectable ex vivo, but treatment with IL-7, 4-1BBL, and anti-PD-L1 recovers their reactivity in vitro in slow fibrosers.IMPORTANCE Hepatitis C virus (HCV) infects 71 million people worldwide. Two-thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection, but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired, which could be due to the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. When the results are taken together, this work supports novel ways of restoring the specific CD8+ T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy.

Genetic Characterization of Rubella Virus Strains Detected in Spain, 1998-2014.

The National Plan for the Elimination of Rubella was implemented in Spain in 2008 using the logistics of the National Plan for the Elimination of Measles that have been employed since year 2000. Molecular characterization of rubella virus (RUBV) is important for disease surveillance and for monitoring elimination of the disease throughout the world. We describe the first complete series of data regarding the circulation of RUBV genotypes in Spain. The 739-nucleotide fragment designated by the WHO for RUBV genotyping was sequenced in 88 selected cases collected from 1998 to 2014. Five genotypes were identified: 1E, 2B, 1J, 1I, and 1a. Genotype 1E was predominant between 1998 and 2003 but was replaced by genotype 2B, which was detected in sporadic cases in 2004, 2006, 2008, 2012, 2013 and 2014. There was an outbreak of genotype 2B in Algeciras (Andalusia) in 2008. Genotype 1J caused an outbreak in Madrid in 2004/2005 and sporadic cases in 2005 and 2007. Genotype 1I was found to have infected an immune-suppressed patient with neurological symptoms in 2008. Finally, vaccine strain RA 27/3 was detected in three sporadic cases, two of them immune-suppressed and without a recent history of vaccination. This suggests that during these years there were a series of imported sporadic cases and outbreaks, confirming the findings of epidemiological data analysis. The importation sources were generally consistent with our geographic and cultural ties, mainly with Europe (genotypes 1E, 2B, 1I) and Latin America (1J).

Reemergencia de sarampión en la provincia de Guadalajara. ¿Es el momento de establecer nuevas estrategias para su eliminación? / Re-emergence of measles in the province of Guadalajara, Spain. Is it time to establish new strategies for its elimination?

INTRODUCCIÓN: El sarampión es una infección casi erradicada que en los últimos años está reemergiendo en España y en Europa. El objetivo del estudio fue describir las características microbiológicas y clínico-epidemiológicas de un brote de sarampión ocurrido en la provincia de Guadalajara de junio a agosto de 2012. MÉTODOS: Estudio descriptivo y retrospectivo. Se analizaron 117 muestras (suero, orina y exudado faríngeo) de 52 casos sospechosos de sarampión. RESULTADOS: Se confirmaron 50 casos de sarampión, 41 por laboratorio y 9 por vínculo epidemiológico, agrupados en 4 brotes comunitarios. No se observaron casos importados. La IgM y la PCR fueron positivas en 25 pacientes, solo PCR en 11 y solo IgM en 5. El genotipo fue D4 en 13/14 cepas y genotipo A en un caso posvacunal. Los grupos de edades más afectados fueron adultos entre 20 y 34 años (38%) y menores de 15 meses (26%). El 88% de pacientes no estaban vacunados (43% etnia gitana, 27% menores de 15 meses, 11% razones ideológicas), y el 6% había recibido una dosis. La clínica fue exantema y fiebre (100%), tos (82%) y conjuntivitis (50%). El 32% requirió hospitalización y el 28% presentó complicaciones. CONCLUSIÓN: Es de especial importancia intensificar la vigilancia epidemiológica en infecciones en fase de eliminación. El aumento de la incidencia de sarampión estuvo asociado a bolsas de no vacunados que representan un desafío para la salud pública, que deberá elaborar estrategias para conseguir una elevada cobertura vacunal y alcanzar la erradicación del sarampión

BACKGROUND: Measles is a viral infection that was almost eradicated, but it is re-emerging in Spain and Europe in recent years. The aim of this study was to describe the microbiological, clinical and epidemiological characteristics of a measles outbreak that occurred in Guadalajara (Spain) from June to August 2012. METHODS: A descriptive and retrospective study was conducted. A total of 117 samples (including serum, urine and pharyngeal swabs) from 52 patients were analyzed for measles. RESULTS: Measles was diagnosed in 50 patients, 41 of them by microbiological diagnosis, and 9 by epidemiological link. The patients were grouped in four community outbreaks. No imported cases were observed. Positive IgM and positive CRP were detected in 25 patients, positive CRP only in 11 and positive IgM only in 5. The genotype D4 was identified in 13 patients and the genotype A in a post-vaccine case. The age groups most affected were adults between 20-34 years of age (38%) and younger than 15 months (26%). The large majority (86%) of patients were unvaccinated (44% Roma population, 27% younger than 15 months, 11% ideological reasons), 6% had one vaccine dose. The signs/symptoms were: rash and fever, 100%, cough, 82%, and conjunctivitis 50%. Almost one-third (32%) of patients were hospitalized, and 28% had complications. CONCLUSIONS: It is very important to intensify the epidemiological surveillance of infections in the elimination phase. The increased incidence of measles was associated to unvaccinated pockets, presenting a challenge for Public Health Centers. These agencies should prepare strategies to obtain a higher vaccine coverage for the eradication of measles

Características de la infección aguda por el virus de la inmunodeficiencia humana en 3 áreas de salud de Castilla-La Mancha / Characteristics of acute human immunodeficiency virus infection in three areas of Castilla-La Mancha, Spain

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[Re-emergence of measles in the province of Guadalajara, Spain. Is it time to establish new strategies for its elimination?]. / Reemergencia de sarampión en la provincia de Guadalajara. ¿Es el momento de establecer nuevas estrategias para su eliminación?

BACKGROUND: Measles is a viral infection that was almost eradicated, but it is re-emerging in Spain and Europe in recent years. The aim of this study was to describe the microbiological, clinical and epidemiological characteristics of a measles outbreak that occurred in Guadalajara (Spain) from June to August 2012. METHODS: A descriptive and retrospective study was conducted. A total of 117 samples (including serum, urine and pharyngeal swabs) from 52 patients were analyzed for measles. RESULTS: Measles was diagnosed in 50 patients, 41 of them by microbiological diagnosis, and 9 by epidemiological link. The patients were grouped in four community outbreaks. No imported cases were observed. Positive IgM and positive CRP were detected in 25 patients, positive CRP only in 11 and positive IgM only in 5. The genotype D4 was identified in 13 patients and the genotype A in a post-vaccine case. The age groups most affected were adults between 20-34 years of age (38%) and younger than 15 months (26%). The large majority (86%) of patients were unvaccinated (44% Roma population, 27% younger than 15 months, 11% ideological reasons), 6% had one vaccine dose. The signs/symptoms were: rash and fever, 100%, cough, 82%, and conjunctivitis 50%. Almost one-third (32%) of patients were hospitalized, and 28% had complications. CONCLUSIONS: It is very important to intensify the epidemiological surveillance of infections in the elimination phase. The increased incidence of measles was associated to unvaccinated pockets, presenting a challenge for Public Health Centers. These agencies should prepare strategies to obtain a higher vaccine coverage for the eradication of measles.