Search

Clinical phenotypes of COVID-19, associated with mortality risk, have been identified in the general population. The present study assesses their applicability in solid organ transplant recipients (SOTR) hospital-admitted by COVID-19. In a cohort of 488 SOTR, nonvaccinated (n = 394) and vaccinated (n = 94) against SARS-CoV-2, we evaluated 16 demographic, clinical, analytical, and radiological variables to identify the clinical phenotypes A, B, and C. The median age was 61.0 (51-69) years, 330 (67.6%) and 158 (32.4%) were men and women, respectively, 415 (85%) had pneumonia, and 161 (33%) had SpO 2  < 95% at admission. All-cause mortality occurred in 105 (21.5%) cases. It was higher in nonvaccinated versus vaccinated SOTR (23.4% vs 13.8%, P = 0.04). Patients in the entire cohort were classified into phenotypes A (n = 149, 30.5%), B (n = 187, 38.3%), and C (n = 152, 31.1%), with mortality rates of 8.7%, 16.6%, and 40.1%, respectively, which were similar to those of nonvaccinated SOTR (9.5%, 16.7%, and 52.0%) and lower in vaccinated SOTR (4.4%, 15.8%, and 17.3%, respectively), with difference between nonvaccinated and vaccinated in the phenotype C (P < 0.001). In conclusion, COVID-19 clinical phenotypes are useful in SOTR, and all-cause mortality decreases in vaccinated patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Statement: The views expressed in this publication are the sole responsibility of the authors and the Commission is not responsible for any use that may be made of the information it contains., (© 2024. The Author(s).)

Cytomegalovirus (CMV) infection remains a significant challenge in solid organ transplantation (SOT). The last international consensus guidelines on the management of CMV in SOT were published in 2018, highlighting the need for revision to incorporate recent advances, notably in cell-mediated immunity monitoring, which could alter the current standard of care. A working group including members from the Group for the Study of Infection in Transplantation and the Immunocompromised Host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Transplantation (SET), developed consensus-based recommendations for managing CMV infection in SOT recipients. Recommendations were classified based on evidence strength and quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The final recommendations were endorsed through a consensus meeting and approved by the expert panel., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julian Torre-Cisneros reports administrative support, article publishing charges, travel, and writing assistance were provided by Spanish Society of Infectious Diseases and Clinical Microbiology. Julian Torre-Cisneros reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Julian Torre-Cisneros reports a relationship with Biotest AG that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with QIAGEN GmbH that includes: consulting or advisory, funding grants, and speaking and lecture fees. Jose Maria Aguado reports a relationship with Mundipharma International Limited that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. Sara Cantisan reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Pfizer Inc. that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with A Menarini International Pharmaceutics that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Carme Facundo reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mirian Fernandez-Alonso reports a relationship with Roche Diagnostics Corporation that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with Werfen that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with QIAGEN GmbH that includes: non-financial support. Mario Fernandez-Ruiz reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mario Fernandez-Ruiz reports a relationship with Biotech that includes: consulting or advisory. Sabina Herrera reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Sabina Herrera reports a relationship with Shionogi Inc. that includes: speaking and lecture fees. Sabina Herrera reports a relationship with Shire that includes: travel reimbursement. Sabina Herrera reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. Oscar Len reports a relationship with Pfizer that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Astellas Pharma Inc. that includes: speaking and lecture fees. Oscar Len reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Ibai Los-Arcos reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Gilead Sciences Inc. that includes: travel reimbursement. Ibai Los-Arcos reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. David Navarro reports a relationship with Roche Diagnostics Corporation that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Abbott that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with bioMérieux SA that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Beckton Dickinson that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Gilead Sciences Inc. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Pfizer Inc. that includes: consulting or advisory and speaking and lecture fees. Maricela Valerio reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Shionogi and Co Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with GSK that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Current clinical guidelines support the concomitant administration of seasonal influenza vaccines and COVID-19 mRNA boosters vaccine. Whether dual vaccination may impact vaccine immunogenicity due to an interference between influenza or SARS-CoV-2 antigens is unknown. We aimed to understand the impact of mRNA COVID-19 vaccines administered concomitantly on the immune response to influenza vaccines. For this, 128 volunteers were vaccinated during the 22-23 influenza season. Three groups of vaccination were assembled: FLU vaccine only (46, 35%) versus volunteers that received the mRNA bivalent COVID-19 vaccines concomitantly to seasonal influenza vaccines, FluCOVID vaccine in the same arm (42, 33%) or different arm (40, 31%), respectively. Sera and whole blood were obtained the day of vaccination, +7, and +28 days after for antibody and T cells response quantification. As expected, side effects were increased in individuals who received the FluCOVID vaccine as compared to FLU vaccine only based on the known reactogenicity of mRNA vaccines. In general, antibody levels were high at 4 weeks post-vaccination and differences were found only for the H3N2 virus when administered in different arms compared to the other groups at day 28 post-vaccination. Additionally, our data showed that subjects that received the FluCOVID vaccine in different arm tended to have better antibody induction than those receiving FLU vaccines for H3N2 virus in the absence of pre-existing immunity. Furthermore, no notable differences in the influenza-specific cellular immune response were found for any of the vaccination groups. Our data supports the concomitant administration of seasonal influenza and mRNA COVID-19 vaccines.

Human Adenovirus (HAdV) infections in immunocompromised patients can result in disseminated diseases with high morbidity and mortality rates due to the absence of available treatments for these infections. The sponge Ircinia felix was selected for the significant anti-HAdV activity displayed by its organic extracts. Its chemical analysis yielded three novel sesterterpene lactams, ircinialactams J-L, along with three known sesterterpene furans which structures were established by a deep spectrometric analysis. Ircinialactam J displayed significant antiviral activity against HAdV without significant cytotoxicity, showing an effectiveness 11 times greater than that of the standard treatment, cidofovir®. Comparison of the antiviral evaluation results of the isolated compounds allowed us to deduce some structure-activity relationships. Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV replicative cycle before HAdV genome reaches the nucleus of the host cell. The first total synthesis of ircinialactam J was also accomplished to prove the structure and to provide access to analogues. Key steps are a regio- and stereoselective construction of the trisubstituted Z-olefin at Δ 7 by iron-catalyzed carbometallation of a homopropargylic alcohol, a stereoselective methylation to generate the stereogenic center at C18, and the formation of the (Z)-Δ 20 by stereoselective aldol condensation to introduce the tetronic acid unit. Ircinialactam J is a promising chemical lead to new potent antiviral drugs against HAdV infections., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

Objectives: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19., Methods: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated., Results: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (P = 0.009, P = 0.030 and P = 0.001, respectively). The 90-day overall survival was lower (P = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia., Conclusion: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human adenovirus (HAdV) and cytomegalovirus (HCMV) cause high morbidity and mortality in patients undergoing solid organ transplantation (SOT) and haematopoietic stem cell transplantation (HSCT). Immunosuppressors are used universally to prevent graft-vs-host disease in HSCT and graft rejection in SOT. The long-term use of these drugs is associated with a high risk of infection, but there is also evidence of their specific interference with viral infection. This study evaluated the antiviral activity of immunosuppressors commonly used in clinical practice in SOT and HSCT recipients in vitro to determine whether their use could be associated with reduced risk of HAdV and HCMV infection. Cyclophosphamide, tacrolimus, cyclosporine, mycophenolic acid, methotrexate, everolimus and sirolimus presented antiviral activity, with 50% inhibitory concentration (IC 50 ) values at low micromolar and sub-micromolar concentrations. Mycophenolic acid and methotrexate showed the greatest antiviral effects against HAdV (IC 50 =0.05 µM and 0.3 µM, respectively) and HCMV (IC 50 =10.8 µM and 0.02 µM, respectively). The combination of tacrolimus and mycophenolic acid showed strong synergistic antiviral activity against both viruses, with combinatory indexes (CI 50 ) of 0.02 and 0.25, respectively. Additionally, mycophenolic acid plus cyclosporine, and mycophenolic acid plus everolimus/sirolimus showed synergistic antiviral activity against HAdV (CI 50 =0.05 and 0.09, respectively), while methotrexate plus cyclosporine showed synergistic antiviral activity against HCMV (CI 50 =0.29). These results, showing antiviral activity in vitro against both HAdV and HCMV, at concentrations below the human C max values, may be relevant for the selection of specific immunosuppressant therapies in patients at risk of HAdV and HCMV infections., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [ Au(dpta)Cl 2 , Au(dpta)(mrdtc) , and Au(dpta)(dedtc) ] or thiophosphonamide [ Au(bpta)(dedtc) ] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-α2 alone (five patients) or with IFN-ω (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-α2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-ω. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients <70 yr of age (5.7 vs. 1.1%, P = 2.2 × 10-5), but not >70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-α2 and IFN-ω (OR = 11.7, P = 1.3 × 10-5), especially those <70 yr old (OR = 139.9, P = 3.1 × 10-10). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for ∼5% of cases of life-threatening influenza pneumonia in patients <70 yr old., (© 2022 Zhang et al.)

The main objective was to evaluate the viability of the SARS-CoV-2 viral particles excreted in stools. In addition, we aimed to identify clinical factors associated with the detection of SARS-CoV-2 RNA in feces, and to determine if its presence is associated with an unfavorable clinical outcome, defined as intensive care unit (ICU) admission and/or death. A prospective multicenter cohort study of COVID-19 adult patients, with confirmed SARS-CoV-2 infection by RT-PCR assay in nasopharyngeal (NP) swabs admitted to four hospitals in Spain, from March 2020 to February 2021. Sixty-two adult COVID-19 patients had stool samples collected at admission and/or during the follow up, with a total of 79 stool samples. SARS-CoV-2 RNA was detected in stool samples from 27 (43.5%) out of the 62 patients. Replicative virus, measured by the generation of cytopathic effect in cell culture and subsequent RT-PCR confirmation of a decrease in the Ct values, was not found in any of these stool samples. Fecal virus excretion was not associated with the presence of gastrointestinal symptoms, or with differences in the evolution of COVID-19 patients. Our results suggest that SARS-CoV-2 replicative capacity is null or very limited in stool samples, and thus, the fecal-oral transmission of SARS-CoV-2 as an alternative infection route is highly unlikely. In our study, the detection of SARS-CoV-2 RNA in feces at the beginning of the disease is not associated with any clinical factor nor with an unfavorable clinical outcome., (© 2022. The Author(s).)

Nowadays there is not an effective drug for the treatment of infections caused by human adenovirus (HAdV) which supposes a clinical challenge, especially for paediatric and immunosuppressed patients. Here, we describe the design, synthesis and biological evaluation as anti-adenovirus agents of a new library (57 compounds) of diester, monoester and triazole derivatives based on 3-amino-1,2-propanediol skeleton. Seven compounds (17, 20, 26, 34, 44, 60 and 66) were selected based on their high anti-HAdV activity at low micromolar concentration (IC 50 from 2.47 to 5.75 µM) and low cytotoxicity (CC 50 from 28.70 to >200 µM). In addition, our mechanistic assays revealed that compounds 20 and 44 might be targeting specifically the HAdV DNA replication process, and compound 66 would be targeting HAdV E1A mRNA transcription. For compounds 17, 20, 34 and 60, the mechanism of action seems to be associated with later steps after HAdV DNA replication., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log 10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log 10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log 10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO 2 , neutrophils > 7.5 × 10 3 /µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome.

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC 50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fluoroquinolone treatment failure has been reported in patients with nalidixic acid-resistant Salmonella infections. Both chromosomal- and plasmid-mediated quinolone-resistance mechanisms have been described. The objective of this study was to identify the prevalence of these mechanisms in a collection of 41 Salmonella spp. clinical isolates causing acute gastroenteritis, obtained in the Hospital Clinic, Barcelona. The minimum inhibitory concentrations (MICs) of nalidixic acid and ciprofloxacin were determined by Etest. Mutations in the quinolone-resistance determining regions (QRDRs) of the gyrA, gyrB, and parC genes and the presence of the qnr, aac(6')-Ib-cr, and qepA genes were detected by PCR and DNA sequencing. All isolates showed constitutive expression of an efflux pump. None of the isolates were ciprofloxacin-resistant, whereas 41.5% showed nalidixic acid resistance associated with a mutation in gyrA and overexpression of an efflux pump. Although qnrS1, qnrB6, and qepA were found in four isolates, the expression of these genes was not associated with decreased quinolone susceptibility. Mutations in the gyrA gene and overexpression of an efflux pump were critical for nalidixic acid resistance and decreased susceptibility to ciprofloxacin in these isolates. However, plasmid-mediated quinolone resistance did not seem to play a major role. To our knowledge, this is the first description of qepA in Salmonella.