IdiPAZ - Instituto de Investigación Sanitaria Hospital La Paz (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16963

El Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) está constituido en 2009 por el Hospital Universitario La Paz (HULP), la Universidad Autónoma de Madrid (UAM), el Hospital Universitario de Getafe (HUG), la Universidad Europea (EU) y la Fundación para la Investigación Biomédica del Hospital Universitario La Paz (FIBHULP). IdiPAZ se concibe como un espacio de investigación biomédica multidisciplinar y trabaja para constituirse como un referente en la investigación biomédica traslacional, nacional e internacional, fomentando la investigación de calidad a nivel básico, clínico, epidemiológico y de servicios para la salud. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2010, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Suicide Among Older People in Spain: The Role of Sex and Urbanicity
(Wiley, 2025-03) Rodríguez-Rodríguez, Gabriel Jesús; Martínez-Alés, Gonzalo; Lopez-Cuadrado, Teresa; NIH - National Institute of Mental Health (NIMH) (Estados Unidos); American Foundation for Suicide Prevention
Objectives: Suicide rates are driven by availability of lethal means, increase with age, and are often higher in rural versus urban areas. This study examines temporal and geographic variations in suicides among elderly with a focus on rural-urban differences in method-specific suicide rates among people aged 65 and older in Spain, a rapidly aging country. Methods: Population-based study including all suicides among people over 65 in Spain between 2010 and 2022. We examined overall and method-specific suicide rates and their temporal and geographical variation, stratifying results by sex and urbanicity level. Time trends were estimated via joinpoint regression. Maps were created to analyze the geographical distribution of suicide rates. Results: While 2010-2022 suicide rates in people aged 65 and older remained largely stable overall, they increased by an annual 2.6% for women living in urban areas. The most common suicide methods were hanging for men living in rural and urban areas (68.5% and 47.3%, respectively) and for women living in rural areas (42.1%); for women living in urban areas jumping was the modal suicide method (46.9%). Method-specific trend analyses revealed recent increases in male suicide by poisoning and hanging in rural areas, decreases in male suicide by hanging and increases in male suicide by jumping in urban areas, and increases in female suicide by poisoning and jumping in urban areas. We identified and mapped remarkable geographic variation in overall and sex-specific suicide rates across Spain's regions. Conclusions: These results, highlighting recent increases in female suicides in urban areas and in specific method-specific male suicides both in rural and urban areas, and demonstrating geographical variation across regions, should help guide targeted suicide prevention efforts.
Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations
(Frontiers Media, 2024) Martín-Antonio, Beatriz; Blanco, Belén; González-Murillo, África; Hidalgo, Laura; Minguillón, Jordi; Pérez-Chacón, Gema; Next Generation CART MAD Consortium; Rodriguez-Milla, Miguel A; García-Rodriguez, Patricia; Somovilla-Crespo, Beatriz; Garcia-Castro, Javier; Comunidad de Madrid (España); Instituto de Salud Carlos III
Adoptive T cellular immunotherapies have emerged as relevant approaches for treating cancer patients who have relapsed or become refractory (R/R) to traditional cancer treatments. Chimeric antigen receptor (CAR) T-cell therapy has improved survival in various hematological malignancies. However, significant limitations still impede the widespread adoption of these therapies in most cancers. To advance in this field, six research groups have created the "NEXT Generation CART MAD Consortium" (NEXT CART) in Madrid's Community, which aims to develop novel cell-based immunotherapies for R/R and poor prognosis cancers. At NEXT CART, various basic and translational research groups and hospitals in Madrid concur to share and synergize their basic expertise in immunotherapy, gene therapy, and immunological synapse, and clinical expertise in pediatric and adult oncology. NEXT CART goal is to develop new cell engineering approaches and treatments for R/R adult and pediatric neoplasms to evaluate in multicenter clinical trials. Here, we discuss the current limitations of T cell-based therapies and introduce our perspective on future developments. Advancement opportunities include developing allogeneic products, optimizing CAR signaling domains, combining cellular immunotherapies, multi-targeting strategies, and improving tumor-infiltrating lymphocytes (TILs)/T cell receptor (TCR) therapy. Furthermore, basic studies aim to identify novel tumor targets, tumor molecules in the tumor microenvironment that impact CAR efficacy, and strategies to enhance the efficiency of the immunological synapse between immune and tumor cells. Our perspective of current cellular immunotherapy underscores the potential of these treatments while acknowledging the existing hurdles that demand innovative solutions to develop their potential for cancer treatment fully.
Zoonosis screening in Spanish immunocompromised children and their pets
(Frontiers Media, 2024) Garcia-Sanchez, Paula; Romero-Trancón, David; Falces-Romero, Iker; Navarro Carrera, Paula; Ruiz-Carrascoso, Guillermo; Carmena, David; Casares Jiménez, María; Rivero-Juarez, Antonio; Moya, Laura; Rodón, Jaume; Esperón, Fernando; Pérez-Hernando, Belén; Sánchez-León, Rocío; Hurtado-Gallego, Jara; Alcolea, Sonia; Sainz, Talia; Calvo, Cristina; Méndez-Echevarría, Ana; Asociación Española de Pediatría; Fundación Mapfre; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); European Society for Paediatric Infectious Diseases; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Comunidad de Madrid (España); Regional Government of Andalusia (España)
Introduction: Although pets provide several social-emotional benefits for children, the risk of zoonosis must be considered among immunocompromised individuals. Methods: A prospective study was conducted in a tertiary hospital including immunocompromised patients younger than 20 years owning dogs and/or cats. Colonization and/or infection was evaluated by stool studies, bacterial swabs, blood polymerase chain reaction and serological studies in both patients and their pets, to evaluate potential zoonotic transmission occurrence. Results: We included 74 patients and their 92 pets (63 dogs, 29 cats). Up to 44.6% of the patients and 31.5% of the pets had at least 1 positive result. Up to 18.4% of pets' fecal samples were positive (bacteria, parasites or hepatitis E virus). No helminths were observed despite the high frequency of incorrect intestinal deworming practices. Among children, gastrointestinal microorganisms were found in 37.3% (primarily Clostridium difficile). Colonization by Staphylococcus pseudintermedius was common among pets (8.0%) but not among children (0.0%). No shared colonization between owners and pets was observed, except in one case (Blastocystis in both patient and pet feces). Among patients, serologies were positive for Strongyloides stercoralis (14.8%), Toxocara canis (3.2%), Bartonella henselae (19.1%) and hepatitis E (5.6%). Serology was positive for Rickettsia spp. (22.6%) and Babesia spp. (6.5%) in dogs and for Leishmania spp. (14.3%) and Toxoplasma spp. (14.3%) in cats. Conclusion: Exposure to zoonotic agents was detected in both patients and pets; however, shared colonization events were almost nonexistent. In our cohort, dogs and cats do not appear to entail high zoonosis transmission risk for immunocompromised patients.
The Association of HIV-1 Neutralization in Aviremic Children and Adults with Time to ART Initiation and CD4+/CD8+ Ratios
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Sanchez-Merino, Victor; Martin-Serrano, Miguel; Beltran, Manuela; Lazaro-Martin, Beatriz; Cervantes, Eloísa; Oltra, Manuel; Sainz, Talia; García, Felipe; Navarro, Maria Luisa; Yuste, Eloisa; Instituto de Salud Carlos III; RETICS-Sida (RIS-ISCIII) (España); Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Fundación Banco Santander; Fundación Universidad Alfonso X el Sabio
Broadly neutralizing antibodies (bnAbs) bind and neutralize diverse HIV isolates and demonstrate protective effects in primate models and humans against specific isolates. To develop an effective HIV vaccine, it is widely believed that inducing these antibodies is crucial. However, the high somatic hypermutation in bnAbs and the limited affinity of HIV Env proteins for bnAb germline precursors suggest that extended antigen exposure is necessary for their production. Consequently, HIV vaccine research is exploring complex sequential vaccination strategies to guide the immune response through maturation stages. In this context, the exploration of the factors linked to the generation of these antibodies across diverse age groups becomes critical. In this study, we assessed the anti-HIV-1 neutralization potency and breadth in 108 aviremic adults and 109 aviremic children under 15 years of age who were receiving ART. We used a previously described minipanel of recombinant viruses and investigated the factors associated with neutralization in these individuals. We identified individuals in both groups who were capable of neutralizing viruses from three different subtypes, with greater cross-neutralization observed in the adult group (49.0% vs. 9.2%). In both groups, we observed an inverse association between neutralization breadth and the CD4+/CD8+ ratio, as well as a direct association with the time to ART initiation. However, we found no association with time post-infection, cumulative ART duration, or CD8+ cell levels. The present study demonstrates that children receiving antiretroviral therapy generate broadly neutralizing responses to HIV-1, albeit with lower magnitude compared to adults. We also observed that neutralization breadth is associated with CD4+/CD8+ levels and time to treatment initiation in both children and adults living with HIV-1. Our interpretation of these results is that a delay in ART initiation could have prolonged the antigenic stimulation associated with viral replication and thus facilitate the capacity to elicit long-lasting broadly neutralizing responses. These results corroborate prior findings that show that HIV-1-neutralizing responses can persist for years, even at low antigen levels, implying an HIV-1 vaccine may induce lasting neutralizing antibody response.
Plasma metabolomic profile is near-normal in people with HIV on long-term suppressive antiretroviral therapy
(Frontiers Media, 2024) Virseda-Berdices, Ana; Martín-Escolano, Rubén; Berenguer, Juan; González-García, Juan; Brochado-Kith, Oscar; Rojo, David; Fernandez-Rodriguez, Amanda; Pérez-Latorre, Leire; Hontañón, Víctor; Barbas, Coral; Resino, Salvador; Jimenez-Sousa, Maria Angeles; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Comunidad de Madrid (España)
Background: Combination antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection in people with HIV (PWH). However, a chronic state of immune activation and inflammation is maintained despite achieving HIV suppression and satisfactory immunological recovery. We aimed to determine whether the plasma metabolomic profile of PWH on long-term suppressive ART and immunologically recovered approximates the normality by comparison with healthy controls with similar age and gender. Methods: We carried out a cross-sectional study in 17 PWH on long-term ART (HIV-RNA <50 copies/mL, CD4+ ≥500 cells/mm3, and CD4+/CD8+ ≥1) and 19 healthy controls with similar age and gender. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and Generalized Linear Models (GLM) with a gamma distribution (log-link). Significance levels (p-value) were corrected for multiple testing (q-value). Results: PCA and PLS-DA analyses found no relevant differences between groups. Adjusted GLM showed 14 significant features (q-value<0.20), of which only three could be identified: lysophosphatidylcholine (LysoPC) (22:6) (q-value=0.148), lysophosphatidylethanolamine (LysoPE) (22:6) (q-value=0.050) and hydroperoxy-octadecatrienoic acid (HpOTrE)/dihydroperoxy-octadecatrienoic acid (DiHOTrE)/epoxy-octadecadienoic acid (EpODE) (q-value=0.136). These significant identified metabolites were directly correlated to plasma inflammatory biomarkers in PWH and negatively correlated in healthy controls. Conclusion: PWH on long-term ART have a metabolomic profile that is almost normal compared to healthy controls. Nevertheless, residual metabolic alterations linked to inflammatory biomarkers persist, which could favor the development of age-related comorbidities among this population.
Immunogenicity of the Conjugate Meningococcal ACWY-TT Vaccine in Children and Adolescents Living with HIV
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Berzosa, Arantxa; Guillen, Sara; Epalza, Cristina; Escosa, Luis; Navarro, Maria Luisa; Prieto, Luis M; Sainz, Talia; Jimenez de Ory, Santiago; Montes Mota, Marina; Abad, Raquel; Vazquez-Moreno, Julio Alberto; Serrano García, Irene; Ramos-Amador, José Tomás; Fundación Familia Alonso; RETICS-Sida (RIS-ISCIII) (España); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); European Society for Paediatric Infectious Diseases
Background: Children and adolescents living with HIV (CALHIV) are at high risk of meningococcal infections and may present lower immune responses to vaccines. The objectives of this study were to assess the immunogenicity of the quadrivalent Men ACWY-TT vaccine (Nimenrix®) in CALHIV after a two-dose schedule and to describe possible HIV-related factors that may affect the immunogenic response. Methods: A multicenter prospective study was designed, including CALHIV followed in five hospitals in Madrid, between 2019 and 2021. Two doses of the Men ACWY-TT vaccine were administered. Serum bactericidal antibody (SBA) assays using rabbit complement (rSBA) against serogroups C, W, and Y were used to determine seroprotection and vaccine response (the proportion achieving a putative protective titer of ≥eight or a ≥four-fold rise in titer from baseline). Serum was collected at baseline, and at 3 and 12 months after vaccination. Results: There were 29 CALHIV included, 76% of whom were perinatally infected. All were receiving TAR and presented a good immunovirological and clinical status overall. At baseline, 45% of CALHIV had seroprotective titers to at least one serogroup, with individual seroprotection rates of 24%, 28%, and 32% against C, W, and Y, respectively. After a two-dose schedule, vaccine response was 83% for each serogroup, eliciting a vaccine response to all serogroups in 69% of them. One year after vaccination, 75% of CALHIV maintained seroprotective titers against the C serogroup, and 96% against W and Y. None of the HIV-related characteristics analyzed could predict vaccine response or antibody duration. Conclusions: CALHIV who received effective TAR and presented a good immuno-virological situation achieved an appropriate vaccine response after two doses of the Men ACWY-TT vaccine, and antibody-mediated protection against serogroups C, W, and Y was maintained in more than 70% of the patients one year after vaccination.
Assessment of twelve echovirus virus-neutralisation assays in Europe: recommendations for harmonisation of non-polio enterovirus sero-surveillance studies
(Microbiology Society, 2024-09) Couderé, Karen; Benschop, Kimberley SM; Koen, Gerrit; van Eijk, Hetty; Harvala, Heli; Bailly, Jean-Luc; Bessaud, Maël; Kamau, Everlyn; Simon, Isabelle; Joffret, Marie-Line; Nikolaeva-Glomb, Lubomira; Georgieva, Irina; Stoyanova, Asya; Diedrich, Sabine; Böttcher, Sindy; Cabrerizo, Maria; Tabain, Irena; Hruškar, Željka; Stevanović, Vladimir; Susi, Petri; Hietanen, Eero; Palminha, Paula; Rainetová, Petra; Baicus, Anda; Kristensen, Maartje; PajkrtJean-Luc Murk, Dasja; Wolthers, Katja C; European Non-Polio Enterovirus Network; Ministry of Health Welfare and Sport (Países Bajos); Instituto de Salud Carlos III
Non-polio enteroviruses (NPEV) cause significant disease worldwide. Population-based sero-surveillance, by measuring antibodies against specific NPEV types, provides additional information on past circulation and the prediction for future upsurges. Virus neutralisation assays (VNA), the current method of choice for measuring NPEV type specific antibodies, are not entirely standardised. Via the European Non-Polio Enterovirus Network, we organised a VNA quality assessment in which twelve laboratories participated. We provided five echovirus (E) types (E1, E18, E30 G2, E30 G6 and E6) and intravenous immunoglobulins (IVIG) as a sample for the NPEV VNA quality assessment. Differences in VNA protocols and neutralising Ab (nAb) titres were found between the participating laboratories with geometric coefficients of variation ranging from 10.3-62.9 %. Mixed-effects regression analysis indicated a small but significant effect of type of cell line used. Harmonisation of cell line passage number, however, did not improve variation between laboratories. Calibration by making use of a reference sample, reduced variation between laboratories but differences in nAb titres remained higher than two log2 dilution steps. In conclusion, sero-surveillance data from different laboratories should be compared with caution and standardised protocols are needed.
Sustained Long-Term Decline in Anti-HCV Neutralizing Antibodies in HIV/HCV-Coinfected Patients Five Years after HCV Therapy: A Retrospective Study
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-08-30) Sepulveda-Crespo, Daniel; Volpi, Camilla; Amigot-Sánchez, Rafael; Yélamos, María Belén; Díez, Cristina; Gómez, Julián; Hontañón, Víctor; Berenguer, Juan; González-García, Juan; Martín-Escolano, Rubén; Resino, Salvador; Martinez, Isidoro; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: This study evaluated titers and amplitudes of anti-E2 antibodies (anti-E2-Abs) and neutralizing antibodies against hepatitis C virus (HCV; anti-HCV-nAbs) in HIV/HCV-coinfected individuals over five years after successful HCV treatment completion. Methods: We retrospectively analyzed 76 HIV/HCV-coinfected patients achieving sustained virologic response post-HCV treatment. Plasma levels of anti-E2-Abs and anti-HCV-nAbs against five HCV genotypes (Gt1a, Gt1b, Gt2a, Gt3a, and Gt4a) were determined using ELISA and microneutralization assays, respectively. Statistical analyses comparing the three follow-up time points (baseline, one year, and five years post-HCV treatment) were performed using generalized linear mixed models, adjusting p-values with the false discovery rate (q-value). Results: Compared to baseline, anti-E2-Abs titers decreased at one year (1.9- to 2.3-fold, q-value < 0.001) and five years (3.4- to 9.1-fold, q-value < 0.001) post-HCV treatment. Anti-HCV-nAbs decreased 2.9- to 8.4-fold (q-value < 0.002) at one year and 17.8- to 90.4-fold (q-value < 0.001) at five years post-HCV treatment. Anti-HCV-nAbs titers against Gt3a were consistently the lowest. Nonresponse rates for anti-E2-Abs remained low throughout the follow-up, while anti-HCV-nAbs nonresponse rates increased 1.8- to 13.5-fold (q-value < 0.05) at five years post-HCV treatment, with Gt3a showing the highest nonresponse rate. Conclusions: Humoral immune responses against HCV decreased consistently one and five years post-HCV treatment, regardless of HCV genotype and previous HCV therapy or type of treatment (IFN- or DAA-based therapy). This decline was more pronounced for anti-HCV-nAbs, particularly against Gt3.
Suicide Following the COVID-19 Pandemic Outbreak: Variation Across Place, Over Time, and Across Sociodemographic Groups. A Systematic Integrative Review
(Springer, 2023-07) Martínez-Alés, Gonzalo; Szmulewicz, Alejandro; Lopez-Cuadrado, Teresa; Morrison, Christopher N; Keyes, Katherine M; Susser, Ezra S; NIH - National Institute of Mental Health (NIMH) (Estados Unidos); Instituto de Salud Carlos III; Fundación Alfonso Martín Escudero; ASISA Foundation
Purpose of review: To systematically examine changes in suicide trends following the initial COVID-19 outbreak, focusing on geographical and temporal heterogeneity and on differences across sociodemographic subgroups. Recent findings: Of 46 studies, 26 had low risk of bias. In general, suicides remained stable or decreased following the initial outbreak - however, suicide increases were detected during spring 2020 in Mexico, Nepal, India, Spain, and Hungary; and after summer 2020 in Japan. Trends were heterogeneous across sociodemographic groups (i.e., there were increases among racially minoritized individuals in the US, young adults and females across ages in Japan, older males in Brazil and Germany, and older adults across sex in China and Taiwan). Variations may be explained by differences in risk of COVID-19 contagion and death and in socioeconomic vulnerability. Monitoring geographical, temporal, and sociodemographic differences in suicide trends during the COVID-19 pandemic is critical to guide suicide prevention efforts.
Gut and respiratory tract microbiota in children younger than 12 months hospitalized for bronchiolitis compared with healthy children: can we predict the severity and medium-term respiratory outcome?
(American Society for Microbiology (ASM), 2024-07-02) Cabrera-Rubio, Raul; Calvo, Cristina; Alcolea, Sonia; Bergia, María; Atucha, Jorge; Pozo Sanchez, Francisco; Casas Flecha, Inmaculada; Arroyas, María; Collado, Maria Carmen; García-García, María Luz; Fundación Universidad Alfonso X el Sabio; Merck, Sharp & Dohme; Instituto de Salud Carlos III; Generalitat Valenciana (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España)
Growing evidence indicates that gut and respiratory microbiota have a potential key effect on bronchiolitis, mainly caused by respiratory syncytial virus (RSV). This was a prospective study of 96 infants comparing infants with bronchiolitis (n = 57, both RSV and non-RSV associated) to a control group (n = 39). Gut (feces) and respiratory [nasopharyngeal aspirate (NPA)] microbial profiles were analyzed by 16S rRNA amplicon sequencing, and respiratory viruses were identified by PCR. Clinical data of the acute episode and follow-up during the first year after infection were recorded. Pairwise comparisons showed significant differences in the gut (R2 = 0.0639, P = 0.006) and NPA (R2 = 0.0803, P = 0.006) microbiota between cases and controls. A significantly lower gut microbial richness and an increase in the NPA microbial diversity (mainly due to an increase in Haemophilus, Streptococcus, and Neisseria) were observed in the infants with bronchiolitis, in those with the most severe symptoms, and in those who subsequently developed recurrent wheezing episodes after discharge. In NPA, the higher microbial richness differed significantly between the control group and the non-RSV bronchiolitis group (P = 0.01) and between the control group and the RSV bronchiolitis group (P = 0.001). In the gut, the richness differed significantly between the control group and the non-RSV group (P = 0.01) and between the control group and the RSV bronchiolitis group (P = 0.001), with higher diversity in the RSV group. A distinct respiratory and intestinal microbial pattern was observed in infants with bronchiolitis compared with controls. The presence of RSV was a main factor for dysbiosis. Lower gut microbial richness and increased respiratory microbial diversity were associated with respiratory morbidity during follow-up. Importance: Both the intestinal and respiratory microbiota of children with bronchiolitis, especially those with respiratory syncytial virus infection, are altered and differ from that of healthy children. The microbiota pattern in the acute episode could identify those children who will later have other respiratory episodes in the first year of life. Preventive measures could be adopted for this group of infants.
Executive Summary of the Spanish Guidelines for the Diagnosis and Management of Imported Febrile Illnesses from the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Imported Pathology Group of the Spanish Society of Infectious Diseases and Clinical Microbiology (GEPI-SEIMC), the Spanish Society of Family and Community Medicine (SEMFYC), the Spanish Society of Primary Care Physicians (SEMERGEN) and the Spanish Society of Emergency Medicine (SEMES)
(Elsevier, 2024) Camprubí-Ferrer, Daniel; Díaz Menendez, Marta; Crespillo-Andújar, Clara; Galparsoro, Harkaitz Azkune; Belhassen-García, Moncef; Cuadros González, Juan; Rubio Muñoz, Jose Miguel; Llenas-García, Jara; Oteo, José A; Gayoso Martín, Sara; Santos Larrégola, Laura; Salvador, Fernando; Rojo-Marcos, Gerardo; Balerdi-Sarasola, Leire; Kortajarena Urkola, Xabier; Soriano Pérez, Manuel Jesús; Onieva-García, María Ángeles; Alegría Coll, Iñaki; Arranz, Javier; Membrillo de Novales, Javier; Sociedad Española de Medicina Tropical y Salud Internacional
The Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Emergency Medicine (SEMES), the Spanish Society of Primary Care Physicians (SEMERGEN) and the Spanish Society of Family and Community Medicine (SEMFYC) have prepared a consensus statement on the diagnosis and management of patients with imported febrile illnesses. Twenty authors with different backgrounds and representing different healthcare perspectives (ambulatory primary care, travel and tropical medicine specialists, emergency medicine, hospital care, microbiology and parasitology and public health), identified 39 relevant questions, which were organised in 7 thematic blocks. After a systematic review of the literature and a thoughtful discussion, the authors prepared 125 recommendations, as well as several tables and figures to be used as a consulting tool. The present executive summary shows a selection of some of the most relevant questions and recommendations included in the guidelines.
Epidemiological and Clinical Insights into the Enterovirus D68 Upsurge in Europe 2021-2022 and Emergence of Novel B3-Derived Lineages, ENPEN Multicentre Study
(Oxford University Press, 2024-10-16) Pires Simoes, Margarida; Hodcroft, Emma B; Simmonds, Peter; Albert, Jan; Alidjinou, Enagnon K; Ambert-Balay, Katia; Andrés, Cristina; Antón, Andrés; Auvray, Christelle; Bailly, Jean-Luc; Baldanti, Fausto; Bastings, Capser; Beard, Stuart; Berengua, Carla; Berginc, Natasa; Bloemen, Mandy; Blomqvist, Soile; Bosma, Froukje; Böttcher, Sindy; Bubba, Laura; Buderus, Stafan; Cabrerizo, Maria; Calvo, Cristina; Celma, Cristina; Ceriotti, Ferruccio; Clark, Gemma; Costa, Inës; Coste-Burel, Marianne; Couderé, Karen; Cremer, Jeroen; Del Cuerpo Casas, Margarita; Daehne, Theo; de Beer, Jessica; de Ceano-Vivas, Maria; De Gascun, Cillian; de Rougemont, Alexis; Dean, Jonathan; Dembinski, Jennifer L; Diedrich, Sabine; Diez-Domingo, Javier; Dillner, Lena; Dorenberg, Dagny H; Ducancelle, Alexandra; Dudman, Susanne; Dyrdak, Robert; Eis-Huebinger, Anna-Maria; Falces-Romero, Iker; Farkas, Agnes; Feeney, Susan; Fernandez-Garcia, Maria Dolores; Flipse, Jacky; Franck, Kristina T; Galli, Cristina; Garrigue, Isabelle; Geeraedts, Felix; Georgieva, Irina; Giardina, Federica; Guiomar, Raquel; Hauzenberger, Elenor; Heikens, Esther; Henquell, Cécille; Hober, Didier; Hönemann, Mario; Howson-Wells, Hannah; Hruškar, Željka; Ikonen, Niina; Imbert, Berthemarie; Jansz, Arjan R; Jeannoël, Marion; Jiřincová, Helena; Josset, Laurence; Keeren, Kathrin; Kramer-Lindhout, Naomie; Krokstad, Sidsel; Lazrek, Mouna; Le Guillou-Guillemette, Hélène; Lefeuvre, Caroline; Lind, Andreas; Lunar, Maja M; Maier, Melanie; Marque-Juillet, Stéphanie; McClure, C Patrick; McKenna, James; Meijer, Adam; Menasalvas Ruiz, Ana; Mengual-Chuliá, Beatriz; Midgley, Sofie; Mirand, Audrey; Molenkamp, Richard; Montes, Milagrosa; Moreno-Docón, Antonio; Morley, Ursula; Murk, Jean-Luc; Navascués-Ortega, Ana; Nijhuis, Roel; Nikolaeva-Glomb, Lubomira; Nordbø, Svein A; Numanovic, Sanela; Oggioni, Massimo; Oñate Vergara, Eider; Pacaud, Jordi; Pacreau, Marie L; Panning, Marcus; Pariani, Elena; Pekova, Lili; Pellegrinelli, Laura; Petrovec, Miroslav; Pietsch, Corinna; Pilorge, Léa; Piñeiro, Luis; Piralla, Antonio; Poljak, Mario; Prochazka, Birgit; Rabella, Nuria; Rahamat-Langendoen, Janette C; Rainetova, Petra; Reynders, Marijke; Riezebos-Brilman, Annelies; Roorda, Lieuwe; Savolainen-Kopra, Carita; Schuffenecker, Isabelle; Smeets, Leo C; Stoyanova, Asya; Stefic, Karl; Swanink, Caroline; Tabain, Irena; Tjhie, Jeroen; Thouault, Luc; Tumiotto, Camille; Uceda Renteria, Sara; Uršič, Tina; Vallet, Sophie; Van Ranst, Marc; Van Wunnik, Peter; Verweij, Jaco J; Vila, Jorgina; Wintermans, Bas; Wollants, Elke; Wolthers, Katja C; Xavier López-Labrador, F; Fischer, Thea Kølsen; Harvala, Heli; Benschop, Kimberley SM; Austrian Federal Ministry of Health (Austria); Ministry of Health (República Checa); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública); Santé Publique France; Unión Europea. Comisión Europea. NextGenerationEU; Ministry of Health Welfare and Sport (Países Bajos); National Institutes of Health (Estados Unidos); Slovenian Research Agency; Swiss National Science Foundation
Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 infections and its clinical impact during the fall-winter season of 2021-2022. From 19 European countries, 58 institutes reported 10 481 (6.8%) EV-positive samples of which 1004 (9.6%) were identified as EV-D68 (including 852 respiratory samples). Clinical data were reported for 969 cases; 78.9% of infections were reported in children (0-5 years); and 37.9% of cases were hospitalized. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases including 6 diagnosed with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of 2 novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale European EV-D68 upsurge with severe clinical impact and the emergence of B3-derived lineages.
Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain
(Springer, 2024-12) Salamanca-Rivera, Elena; Palacios-Baena, Zaira R; Cañada-Garcia, Javier Enrique; Moure García, Zaira; Perez-Vazquez, Maria; Calvo-Montes, Jorge; Martínez-Martínez, Luis; Cantón, Rafael; Ruiz Carrascoso, Guillermo; Pitart, Cristina; Navarro, Ferran; Bou, Germán; Mulet, Xavier; González-López, Juan José; Sivianes, Fran; Delgado-Valverde, Mercedes; Pascual, Álvaro; Oteo-Iglesias, Jesus; Rodríguez-Baño, Jesús; GEMARA/GEIRAS-SEIMC/REIPI CARB-ES-19 Study Group; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Plan Nacional de I+D+i (España); Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). Methods: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. Results: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). Conclusions: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.
Performance of the Idylla microsatellite instability test in endometrial cancer
(Elsevier, 2024-10) Mendiola, Marta; Heredia-Soto, Victoria; Ruz-Caracuel, Ignacio; Baillo, Amparo; Ramon-Patino, Jorge Luis; Berjon, Alberto; Escudero Ruiz, Francisco Javier; Peláez-García, Alberto; Hernandez, Alicia; Feliu, Jaime; Hardisson, David; Redondo, Andres; Agencia Estatal de Investigación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Context: DNA mismatch repair (MMR) deficiency (dMMR) testing is now recommended in endometrial cancer. Defect identification in the molecules participating in this pathway, or the presence of microsatellite instability, are commonly employed for this purpose. Novel methods are continuously evolving to report dMMR/microsatellite instability and to easily perform routine diagnoses. Objective: The main aim of this study was to compare the concordance of the Idylla microsatellite instability test for the identification of dMMR endometrial cancer samples defined by immunohistochemistry and MMR genomic status. Design: We applied the Idylla MSI test to 126 early-stage endometrial cancer cases with MMR testing by immunohistochemistry and genomic characterization (methylation in MLH1 and sequence alterations in MLH1, PMS2, MSH2 and MSH6). Individual markers and overall specific performance indicators were explored. Results: The Idylla platform achieved a higher global concordance rate with MMR genomic status than with immunohistochemistry (75 % and 66 %, respectively). Sensitivity and specificity are also higher (75 % vs 66 % and 96 % vs 90 %, respectively). Clustering analysis split the patients into 2 well-differentiated clusters, the pMMR and the dMMR group, represented by MLH1/PMS2 loss and the MLH1 methylated promoter. Overall, immunohistochemistry and MMR genomic status identified more dMMR cases than did the Idylla test, although correlations were improved with a modified Idylla test cut-off. Conclusions: Performance of the Idylla test was better correlated with MMR genomic status than MMR immunohistochemistry status, which improved with a modified test cut-off. Further studies are needed to confirm the cut-off accuracy.
Novel risk loci for COVID-19 hospitalization among admixed American populations
(eLife Sciences Publications, 2024-10-03) Diz-de Almeida, Silvia; Cruz, Raquel; Luchessi, Andre D; Lorenzo-Salazar, José M; López de Heredia, Miguel; Quintela, Inés; González-Montelongo, Rafaela; Nogueira Silbiger, Vivian; Porras, Marta Sevilla; Tenorio Castaño, Jair Antonio; Nevado, Julián; Aguado, José María; Aguilar, Carlos; Aguilera-Albesa, Sergio; Almadana, Virginia; Almoguera, Berta; Alvarez, Nuria; Andreu-Bernabeu, Álvaro; Arana-Arri, Eunate; Arango, Celso; Arranz, María J; Artiga, Maria-Jesus; Baptista-Rosas, Raúl C; Barreda-Sánchez, María; Belhassen-García, Moncef; Bezerra, Joao F; Bezerra, Marcos A C; Boix-Palop, Lucía; Brion, María; Brugada, Ramón; Bustos, Matilde; Calderón, Enrique J; Carbonell, Cristina; Castano, Luis; Castelao, Jose E; Conde-Vicente, Rosa; Cordero-Lorenzana, M Lourdes; Cortes-Sanchez, Jose L; Corton, Marta; Darnaude, M Teresa; De Martino-Rodríguez, Alba; Del Campo-Pérez, Victor; Diaz de Bustamante, Aranzazu; Domínguez-Garrido, Elena; Eirós, Rocío; Fariñas, María Carmen; Fernandez-Nestosa, María J; Fernández-Robelo, Uxía; Fernandez-Rodriguez, Amanda; Fernández-Villa, Tania; Gago-Dominguez, Manuela; Gil-Fournier, Belén; Gómez-Arrue, Javier; González Álvarez, Beatriz; González Bernaldo de Quirós, Fernan; González-Neira, Anna; González-Peñas, Javier; Gutiérrez-Bautista, Juan F; Herrero, María José; Herrero-Gonzalez, Antonio; Jimenez-Sousa, Maria Angeles; Lattig, María Claudia; Liger Borja, Anabel; Lopez-Rodriguez, Rosario; Mancebo, Esther; Martín-López, Caridad; Martín, Vicente; Martinez-Nieto, Oscar; Martinez-Lopez, Iciar; Martinez-Resendez, Michel F; Martinez-Perez, Angel; Mazzeu, Juliana F; Merayo Macías, Eleuterio; Minguez, Pablo; Moreno Cuerda, Victor; Oliveira, Silviene F; Ortega-Paino, Eva; Pompa-Mera, Ericka N; Parellada, Mara; Paz-Artal, Estela; Santos, Ney PC; Pérez-Matute, Patricia; Perez, Patricia; Pérez-Tomás, M Elena; Perucho, Teresa; Pinsach-Abuin, Mel·lina; Pita, Guillermo; Porras-Hurtado, Gloria L; Pujol, Aurora; Ramiro León, Soraya; Resino, Salvador; Fernandes, Marianne R; Rodríguez-Ruiz, Emilio; Rodríguez-Artalejo, Fernando; Rodriguez-Garcia, José A; Ruiz-Cabello, Francisco; Ruiz-Hornillos, Javier; Ryan, Pablo; Soria, José Manuel; Souto, Juan Carlos; Tamayo, Eduardo; Tamayo-Velasco, Álvaro; Taracido-Fernandez, Juan Carlos; Teper, Alejandro; Torres-Tobar, Lilian; Urioste, Miguel; Valencia-Ramos, Juan; Yáñez, Zuleima; Zarate, Ruth; de Rojas, Itziar; Ruiz, Agustín; Sánchez, Pascual; Real, Luis Miguel; SCOURGE Cohort Group; Guillén-Navarro, Encarna; Ayuso, Carmen; Parra, Esteban; Riancho, José A; Rojas-Martinez, Augusto; Flores, Carlos; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Banco Santander; Fundación La Caixa; Agencia Estatal de Investigación (España); Gobierno de Canarias (España); Fundación Canaria de Investigación Sanitaria; Xunta de Galicia (España); Fundación Amancio Ortega; Estrella de Levante; Colabora Mujer
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( and ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
Low-level HIV-1 viremia affects T-cell activation and senescence in long-term treated adults in the INSTI era
(BioMed Central (BMC), 2024-08-19) Lara-Aguilar, Violeta; Llamas-Adán, Manuel; Brochado-Kith, Oscar; Crespo-Bermejo, Celia; Grande-García, Sergio; Arca de Lafuente, Sonia; de Los Santos, Ignacio; Prado, Carmen; Alía, Mario; Sainz-Pinós, Coral; Fernandez-Rodriguez, Amanda; Martín-Carbonero, Luz; Madrid, Ricardo; Briz, Veronica; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Around 10% of people with HIV (PWH) exhibit a low-level viremia (LLV) under antiretroviral therapy (ART). However, its origin and clinical significance are largely unknown, particularly at viremias between 50 and 200 copies/mL and under modern ART based on integrase strand transfer inhibitors (INSTIs). Our aim was to characterize their poor immune response against HIV in comparison to individuals with suppressed viremia (SV) and non-HIV controls (NHC). Methods: Transversal observational study in 81 matched participants: 27 PWH with LLV, 27 PWH with SV, and 27 NHC. Activation (CD25, HLA-DR, and CD38) and senescence [CD57, PD1, and HAVCR2 (TIM3)] were characterized in peripheral T-cell subsets by spectral flow cytometry. 45 soluble biomarkers of systemic inflammation were evaluated by immunoassays. Differences in cell frequencies and plasma biomarkers among groups were evaluated by a generalized additive model for location, scale, and shape (GAMLSS) and generalized linear model (GLM) respectively, adjusted by age, sex at birth, and ART regimen. Results: The median age was 53 years and 77.8% were male. Compared to NHC, PWH showed a lower CD4+/CD8+ ratio and increased activation, senescence, and inflammation, highlighting IL-13 in LLV. In addition, LLV showed a downtrend in the frequency of CD8+ naive and effector memory (EM) type 1 compared to SV, along with higher activation and senescence in CD4+ and CD8+ EM and terminally differentiated effector memory RA+ (TEMRA) subpopulations. No significant differences in systemic inflammation were observed between PWH groups. Conclusion: LLV between 50 and 200 copies/mL leads to reduced cytotoxic activity and T-cell dysfunction that could affect cytokine production, being unable to control and eliminate infected cells. The increase in senescence markers suggests a progressive loss of immunological memory and a reduction in the proliferative capacity of immune cells. This accelerated immune aging could lead to an increased risk of developing future comorbidities. These findings strongly advocate for heightened surveillance of these PWH to promptly identify potential future complications.
A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Pain Characteristics, Cardiovascular Risk Factors, and Cardiovascular Disease.
(Oxford University Press, 2022-01-07) Rodríguez-Sánchez, Isabel; Ortolá, Rosario; Graciani, Auxiliadora; Martínez-Gómez, David; Banegas, Jose R; Rodríguez-Artalejo, Fernando; García-Esquinas, Esther; Instituto de Salud Carlos III; Plan Nacional de I+D+i (España); Unión Europea. Fondo Social Europeo (ESF/FSE); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Background: There is unclear evidence that chronic pain may increase the risk of cardiovascular disease (CVD) incidence and mortality. This work evaluated the association between chronic pain, incidence of CVD, and changes in CVD risk factors. Methods: Cohort of 1091 community-dwelling individuals of at least 60 years, free from CVD at baseline, followed up for 6 years. Data on psychosocial factors and CVD risk factors were obtained through validated questionnaires and laboratory measurements. A pain scale ranging from 0 (no pain) to 6 (worst pain) was created according to pain frequency, location, and intensity. Results: The cumulative incidence of CVD was 4.2% at 3 years and 7.7% at 5 years of follow-up. Compared to individuals without pain in the first 3 years (2012-2015), those with maintained scores of at least 2 showed a mean reduction of 3.57 (-5.77 to -1.37) METs-h/week in recreational physical activity, a 0.38-point (0.04-0.73) increase in psychological distress, and a 1.79 (1.03-3.11) higher odds of poor sleep. These associations held in the second follow-up period, when individuals with maintained pain also worsened their diet quality. A 1-point increase in the pain scale in 2012 was associated with a 1.21 (1.03-1.42) and 1.18 (0.97-1.44) increased CVD incidence in 2015 and 2017, respectively; none of the studied factors mediated this relationship. Conclusions: Older adults with chronic pain show important reductions in recreational physical activity and deterioration in mental health, sleep, and diet quality, which may well aggravate pain. Future studies should evaluate whether these factors mediate the increased risk of CVD observed in older adults with chronic pain.
Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Risk in Chronic Musculoskeletal Pain
(Oxford University Press, 2024-08-01) Pastor-Barriuso, Roberto; León-González, Rocío; Ortolá, Rosario; Carballo-Casla, Adrián; Sotos-Prieto, Mercedes; Buño-Soto, Antonio; Rodríguez-Sánchez, Isabel; Pastor-Barriuso, Roberto; Rodríguez-Artalejo, Fernando; García-Esquinas, Esther; Instituto de Salud Carlos III; Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Unión Europea. Fondo Social Europeo (ESF/FSE); Plan Nacional de Drogas (España); Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro para el Desarrollo Tecnológico Industrial (España)
Background: It is unknown whether growth differentiation factor 15 (GDF-15) is associated with chronic musculoskeletal pain (CMP) and whether or not its association with incident cardiovascular disease (CVD) changes according to CMP status. Methods: In total, 1 957 randomly selected adults aged ≥65 years without prior CVD were followed up between 2015 and 2023. CMP was classified according to its intensity, frequency, and interference with daily activities. The association between GDF-15 levels and CMP was assessed using linear models with progressive inclusion of potential confounders, whereas the association between GDF-15 and CVD risk was evaluated with Cox proportional hazard models with similar adjustment and interaction terms between GDF-15 and CMP. The incremental predictive performance of GDF-15 over standard predictors was evaluated using discrimination and risk reclassification metrics. Results: GDF-15 concentrations were 6.90% (95% confidence interval [CI]: 2.56; 11.25) higher in individuals with CMP, and up to 8.89% (4.07; 15.71) and 15.79% (8.43; 23.16) higher in those with ≥3 CMP locations and interfering pain. These increased levels were influenced by a higher prevalence of cardiometabolic risk factors, functional impairments, depressive symptoms, and greater levels of inflammation in individuals with CMP. In fully adjusted models, a twofold increase in GDF-15 was associated with a 1.49 increased risk (95% CI: 1.08; 2.05) of a CVD event in individuals with CMP, but not among those without CMP (1.02 [0.77; 1.35]); p-interaction 0.041. Adding GDF-15 to models including the Framingham Risk Score improved predictive performance among individuals with CMP. Conclusions: We provide evidence that GDF-15 could serve as a biomarker to assess CMP, as well as to predict CVD incidence in individuals with CMP.
HAE-AS: A Specific Disease Activity Scale for Hereditary Angioedema With C1-Inhibitor Deficiency
(Sociedad Española de Alergología e Inmunología Clínica (SEIAC), 2021-06-22) Forjaz, Maria João; Ayala, Alba; Caminoa, M; Prior, N; Pérez-Fernández, E; Caballero, T; DV-HAE-QoL Study Group; Instituto de Salud Carlos III
[EN] Background: The activity of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) varies between patients and within individual patients. Objective: This study aims to develop a disease activity scale for C1-INH-HAE (HAE-AS) with sound measurement properties. Methods: Eleven countries participated in a prospective multicenter cohort study. A clinical questionnaire was self-completed by 290 adult patients with C1-INH-HAE. Patients also completed 2 quality of life scales, the SF-36v2 and the HAE-QoL. Rasch analysis and classic psychometric methods were used to preselect a series of clinical items: number of attacks by location and number of treated attacks, emergency room visits, psychological/psychiatric treatment, missed school/workdays in the previous 6 months; general health; and impairment in everyday work/activities due to pain. Results: The mean (SD) age was 41.5 (14.7; range, 18-84) years, and 69% were females. The final 12-item Rasch model showed that the HAE-AS had satisfactory reliability (person separation index, 0.748), local item independence, unidimensionality, and no item bias by age or sex. The HAE-AS provided scores in a linear measure, with a mean of 10.66 (3.92; range, 0-30). Further analysis with classic psychometric methods indicated that the HAE-AS linear measure presented moderate-to-high convergent validity with quality of life scales (SF-36v2: physical component, r=–0.33; mental component, 0.555; HAE-QoL, –0.61), and good discriminative validity by age, sex, and disease severity (P<.05). Conclusions: The HAE-AS is a short, valid, reliable, and psychometrically sound measure of the activity of C1-INH-HAE that could prove useful for research studies. [ES] Antecedentes: El angioedema hereditario por déficit de inhibidor de C1 (C1-INH-HAE) muestra variabilidad en la actividad de la enfermedad entre los pacientes y en cada paciente individualmente. Objetivo: Este estudio tiene como objetivo desarrollar una escala de actividad de la enfermedad para C1-INH-HAE (HAE-AS) con propiedades sólidas de medición. Métodos: Participaron once países en un estudio multicéntrico prospectivo de cohorte. 290 pacientes adultos con C1-INH-HAE completaron un cuestionario clínico. Los pacientes también completaron dos escalas de calidad de vida (QoL), el SF-36v2 y el HAE-QoL. El análisis Rasch y los métodos psicométricos clásicos se utilizaron en una preselección de ítems clínicos: número de ataques por ubicación y número de ataques tratados, visitas a emergencias, tratamiento psicológico/psiquiátrico, días de escuela/trabajo perdidos en los últimos 6 meses; salud general; y deterioro en el trabajo/actividades cotidianas debido al dolor. Resultados: La muestra presentó una edad media de 41,5 (DE=14,7; rango: 18-84) años, con 69% de mujeres. El modelo final Rasch con 12 ítems mostró que el HAE-AS tenía una confiabilidad satisfactoria (índice de separación de personas =0,748), independencia local del ítem, unidimensionalidad y ningún sesgo de ítems por edad o género. El HAE-AS proporcionó puntuaciones en una medida lineal, con una media de 10,66 (DE=3,92; rango: 0-30). Un análisis posterior con métodos psicométricos clásicos indicó que la medida lineal HAE-AS presentaba validez convergente de moderada a alta con las escalas de calidad de vida (SF-36v2: componente físico, r=-0,33, componente mental -0,555; HAE-QoL: -0,61) y buena validez discriminativa por edad, sexo y gravedad de la enfermedad (p<0,05). Conclusiones: El HAE-AS es una medida breve, válida, confiable y psicométricamente sólida de la actividad de la enfermedad para C1-INH-HAE, que puede ser útil para estudios de investigación.

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