Corrigendum: Impaired antigen-specific B-cell responses after Influenza vaccination in kidney transplant recipients receiving co-stimulation blockade with Belatacept.

[This corrects the article DOI: 10.3389/fimmu.2022.918887.].

miRNome Profiling of Extracellular Vesicles in Patients With Severe COVID-19 and Identification of Predictors of Mortality.

BACKGROUND: Extracellular vesicles (EVs), containing microRNAs (miRNAs) and other molecules, play a central role in intercellular communication, especially in viral infections caused by SARS-CoV-2. This study explores the miRNA profiles in plasma-derived EVs from patients with severe COVID-19 vs controls, identifying potential mortality predictors. METHODS: This prospective study included 36 patients with severe COVID-19 and 33 controls without COVID-19. EV-derived miRNAs were sequenced, and bioinformatics and differential expression analysis between groups were performed. The plasma miRNA profile of an additional cohort of patients with severe COVID-19 (n = 32) and controls (n = 12) was used to compare with our data. Survival analysis identified potential mortality predictors among the significantly differentially expressed (SDE) miRNAs in EVs. RESULTS: Patients with severe COVID-19 showed 50 SDE miRNAs in plasma-derived EVs. These miRNAs were associated with pathways related to inflammation and cell adhesion. Fifteen of these plasma-derived EV miRNAs were SDE in the plasma of severe cases vs controls. Two miRNAs, hsa-miR-1469 and hsa-miR-6124, were identified as strong mortality predictors with an area under the receiver operating characteristic curve of 0.938. CONCLUSIONS: This research provides insights into the role of miRNAs within EVs in severe COVID-19 and their potential as clinical biomarkers for mortality.

Human T-lymphotropic virus-1 infection among Latin American pregnant women living in Spain.

Objectives: Human T-lymphotropic virus (HTLV) antenatal screening is not mandatory in Spain. Surveys conducted decades ago reported HTLV-1 seroprevalence rates of 0.2% among foreign pregnant women in Spain. The migrant flow to Spain from HTLV-1 endemic regions in Latin America and sub-Saharan Africa has increased during the last decade. Currently, 25% of pregnant women in Spain are foreigners. Methods: From January 2021 to October 2023 a cross-sectional study was carried out in all consecutive pregnant women attended at eleven Spanish clinics. A commercial enzyme immunoassay (EIA) was used for screening of serum HTLV-1/2 antibodies. Reactive samples were confirmed by immunoblot. Results: A total of 9813 pregnant women with a median age of 34 years-old were examined. Native Spaniards were 6977 (76.5%). Of 2147 foreigners (23.5%), 903566 (9.9%) were Latin Americans, 416 (4.5%) North Africans, 293 (3.2%) from Romania, and 196 (2.1%) from sub-Saharan Africa. A total of 47 samples were EIA reactive but only five were confirmed as HTLV-1 positive using immunoblot. Infected women came from Paraguay, Colombia, the Dominican Republic, Venezuela and Peru. All but one were primigravida, with ages ranging from 20 to 33 years-old. One was HIV-1 positive, and another was infected with Chlamydia trachomatis. Conclusion: The overall seroprevalence for HTLV-1 among pregnant women in Spain is 0.05% but rises ten-fold (0.55%) among Latin Americans. This rate is higher than in surveys conducted decades ago. Our results support that anti-HTLV testing should be part of antenatal screening in Spain in pregnant women coming from Latin America, as it is already done with Chagas disease.

Synergistic impact of N-antigenemia profiled by a rapid antigen test and low anti-S1 antibodies on the risk of hospitalization in COVID-19.

OBJECTIVES: Identifying patients with COVID-19 who are at risk of poor evolution is key to early decide on their hospitalization. We evaluated the combined impact of nucleocapsid (N)-antigenemia profiled by a rapid test and antibodies against the S1 subunit of the SARS-CoV S protein (S1) on the hospitalization risk of patients with COVID-19. METHODS: N-antigenemia and anti-S1 antibodies were profiled at admission to the emergency department in 146 patients with COVID-19 using the Panbio® antigen Rapid Test and the SARS-CoV-2 immunoglobulin G II Quant/SARS-CoV-2 immunoglobulin G assay from Abbott. A multivariable analysis was used to evaluate the impact of these factors on hospitalization. RESULTS: Patients with a positive N-antigen test in plasma and anti-S1 levels <2821 arbitrary units/mL needed hospitalization more frequently (20 of 23, 87%). A total of 20 of 71 (28.2%) of those showing a negative N-antigen test and anti-S1 ≥2821 arbitrary units/mL were hospitalized for 18 of 52 (34.6%) of the patients with only one of these conditions. Patients with a positive N-antigen test and low antibody levels showed an odds ratio, 95% confidence interval, and P-value for hospitalization of 18.21, 2.74-121.18, and 0.003, respectively, and exhibited the highest mortality (30.4%). CONCLUSIONS: Simultaneous profiling of a rapid N-antigen test in plasma and anti-S1 levels could help to early identify patients with COVID-19 needing hospitalization.

Early estimates of nirsevimab immunoprophylaxis effectiveness against hospital admission for respiratory syncytial virus lower respiratory tract infections in infants, Spain, October 2023 to January 2024.

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.

Wastewater-based epidemiology for COVID-19 using dynamic artificial neural networks.

Global efforts in vaccination have led to a decrease in COVID-19 mortality but a high circulation of SARS-CoV-2 is still observed in several countries, resulting in some cases of severe lockdowns. In this sense, wastewater-based epidemiology remains a powerful tool for supporting regional health administrations in assessing risk levels and acting accordingly. In this work, a dynamic artificial neural network (DANN) has been developed for predicting the number of COVID-19 hospitalized patients in hospitals in Valladolid (Spain). This model takes as inputs a wastewater epidemiology indicator for COVID-19 (concentration of RNA from SARS-CoV-2 N1 gene reported from Valladolid Wastewater Treatment Plant), vaccination coverage, and past data of hospitalizations. The model considered both the instantaneous values of these variables and their historical evolution. Two study periods were selected (from May 2021 until September 2022 and from September 2022 to July 2023). During the first period, accurate predictions of hospitalizations (with an overall range between 6 and 171) were favored by the correlation of this indicator with N1 concentrations in wastewater (r = 0.43, p < 0.05), showing accurate forecasting for 1 day ahead and 5 days ahead. The second period's retraining strategy maintained the overall accuracy of the model despite lower hospitalizations. Furthermore, risk levels were assigned to each 1 day ahead prediction during the first and second periods, showing agreement with the level measured and reported by regional health authorities in 95 % and 93 % of cases, respectively. These results evidenced the potential of this novel DANN model for predicting COVID-19 hospitalizations based on SARS-CoV-2 wastewater concentrations at a regional scale. The model architecture herein developed can support regional health authorities in COVID-19 risk management based on wastewater-based epidemiology.

Quantification of bacterial DNA in blood using droplet digital PCR: a pilot study.

We used droplet digital PCR (ddPCR) assays to detect/quantify DNA from Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus spp. in blood samples. Bacterial DNA from clinical strains (4 < n < 12) was extracted, quantified and diluted (10-0.0001 ng/µL) and ddPCR assays were performed in triplicate. These ddPCR assays showed low replication variability, low detection limit (1-0.1 pg/µL), and genus/species specificity. ddPCR assays were also used to quantify bacterial DNA obtained from spiked blood (1 × 104-1 CFU/mL) of each bacterial genus/species. Comparison between ddPCR assays and bacterial culture was performed by Pearson correlation. There was an almost perfect correlation (r ≥ 0.997, P ≤ 0.001) between the number of CFU/mL from bacterial culture and the number of gene copies/mL detected by ddPCR. The time from sample preparation to results was determined to be 3.5 to 4 hours. The results demonstrated the quantification capacity and specificity of the ddPCR assays to detect/quantify 4 of the most important bloodstream infection (BSI) bacterial pathogens directly from blood. SIGNIFICANCE AND IMPACT: This pilot study results support the potential of ddPCR for the diagnosis and/or severity stratification of BSI. Applied to patients' blood samples it can improve diagnosis and diminish sample-to-results time, improving patient care.

HTLV-1-associated myelopathy in Spain.

BACKGROUND: HTLV-1 infection is a neglected disease. Over 10 million people are infected worldwide, with hot spots of high endemicity across all continents. Roughly 5% of HTLV-1 carriers develop HTLV-1-associated myelopathy (HAM), a progressive subacute neurological disabling disease. METHODS: We report the main features of patients diagnosed with HAM up to date in Spain, a non-endemic country with a relatively high migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. RESULTS: A total of 451 cases of HTLV-1 had been recorded in Spain until the end of year 2022. HAM had been diagnosed in 58 (12.9%). The current incidence is of 2-3 new cases per year. Women represent 76%. Mean age at diagnosis is 49 years-old. Nearly 60% are Latin Americans. Although sexual transmission is the most likely route of HTLV-1 acquisition, up to 6 individuals had been infected following solid organ transplantation. Rapid onset myelopathy developed in all but one of these transplant recipients from three HTLV-1-positive donors. HTLV-1 subtype 1a transcontinental was the only variant recognized in HAM patients. HTLV-1 proviral load was significantly greater in HAM patients than in asymptomatic HTLV-1 carriers (677 vs 104 HTLV-1 DNA copies/104 PBMC; p = 0.012). Symptom relief medications and physiotherapy have been the only treatment providing some benefit to HAM patients. Neither significant clinical nor virological efficacy was noticed using antiretrovirals in at least 9 HAM patients. Two thirds of HAM patients ended up in a wheelchair and with urinary/fecal sphincter incontinence. CONCLUSION: HAM is the most frequent clinical manifestation of HTLV-1 infection in Spain, a non-endemic country. Middle aged women migrants from Latin America are the most frequently affected. Two thirds end up in a wheelchair despite using antiretroviral therapy.

Influence of Sepsis on the Middle-Term Outcomes for Urinary Tract Infections in Elderly People.

Urinary tract infection (UTI) is a common condition that predominantly affects elderly people, who are particularly susceptible to developing sepsis. Previous studies have indicated a detrimental effect of sepsis on short-term outcomes in elderly patients with UTI, but there is a lack of data about the middle-term prognosis. The aim of this study was to investigate the influence of sepsis on the middle-term prognosis of patients aged 65 years or older with complicated community-acquired UTIs. A prospective observational study of patients admitted to a hospital with UTI. We conducted a comparison of epidemiological and clinical variables between septic and nonseptic patients with UTI, as well as their 6-month case-fatality rate. A total of 412 cases were included, 47.8% of them with sepsis. Septic patients were older (83 vs. 80 years, p < 0.001), but did not have more comorbidities. The short-term case-fatality rate was higher in septic patients and this difference persisted at 6 months (34% vs. 18.6%, p = 0.003). Furthermore, age older than 75 years, Barthel index <40 and healthcare-associated UTI were also associated with the middle-term case-fatality rate. In conclusion, the detrimental impact of sepsis is maintained on the middle-term prognosis of elderly patients with UTI. Age, functional status and healthcare-associated UTIs also play significant roles in shaping patient outcomes.

Risk Factors for Bacteremia and Its Clinical Impact on Complicated Community-Acquired Urinary Tract Infection.

Bacteremia has been associated with severity in some infections; however, its impact on the prognosis of urinary tract infections (UTIs) is still disputed. Our goal is to determine the risk factors for bacteremia and its clinical impact on hospitalized patients with complicated community-acquired urinary tract infections. We conducted a prospective observational study of patients admitted to the hospital with complicated community-acquired UTIs. Clinical variables and outcomes of patients with and without bacteremia were compared, and multivariate analysis was performed to identify risk factors for bacteremia and mortality. Of 279 patients with complicated community-acquired UTIs, 37.6% had positive blood cultures. Risk factors for bacteremia by multivariate analysis were temperature ≥ 38 °C (p = 0.006, OR 1.3 (95% CI 1.1-1.7)) and procalcitonin ≥ 0.5 ng/mL (p = 0.005, OR 8.5 (95% CI 2.2-39.4)). In-hospital and 30-day mortality were 9% and 13.6%, respectively. Quick SOFA (p = 0.030, OR 5.4 (95% CI 1.2-24.9)) and Barthel Index <40% (p = 0.020, OR 4.8 (95% CI 1.3-18.2)) were associated with 30-day mortality by multivariate analysis. However, bacteremia was not associated with 30-day mortality (p = 0.154, OR 2.7 (95% CI 0.7-10.3)). Our study found that febrile community-acquired UTIs and elevated procalcitonin were risk factors for bacteremia. The outcomes in patients with bacteremia were slightly worse, but without significant differences in mortality.

Group 1 and group 2 hemagglutinin stalk antibody response according to age.

Objective: Antibodies elicited by seasonal influenza vaccines mainly target the head of hemagglutinin (HA). However, antibodies against the stalk domain are cross-reactive and have been proven to play a role in reducing influenza disease severity. We investigated the induction of HA stalk-specific antibodies after seasonal influenza vaccination, considering the age of the cohorts. Methods: A total of 166 individuals were recruited during the 2018 influenza vaccine campaign (IVC) and divided into groups: <50 (n = 14), 50-64 (n = 34), 65-79 (n = 61), and ≥80 (n = 57) years old. Stalk-specific antibodies were quantified by ELISA at day 0 and day 28 using recombinant viruses (cH6/1 and cH14/3) containing an HA head domain (H6 or H14) from wild bird origin with a stalk domain from human H1 or H3, respectively. The geometric mean titer (GMT) and the fold rise (GMFR) were calculated, and differences were assessed using ANOVA adjusted by the false discovery rate (FDR) and the Wilcoxon tests (p <0.05). Results: All age groups elicited some level of increase in anti-stalk antibodies after receiving the influenza vaccine, except for the ≥80-year-old cohort. Additionally, <65-year-old vaccinees had higher group 1 antibody titers versus group 2 before and after vaccination. Similarly, vaccinees within the <50-year-old group showed a higher increase in anti-stalk antibody titers when compared to older individuals (≥80 years old), especially for group 1 anti-stalk antibodies. Conclusion: Seasonal influenza vaccines can the induction of cross-reactive anti-stalk antibodies against group 1 and group 2 HAs. However, low responses were observed in older groups, highlighting the impact of immunosenescence in adequate humoral immune responses.

Risk Factors and the Impact of Multidrug-Resistant Bacteria on Community-Acquired Urinary Sepsis.

Risk factors for multidrug-resistant bacteria (MDRB) in nosocomial urinary tract infection (UTI) have been widely studied. However, these risk factors have not been analyzed in community-acquired urinary sepsis (US), nor have its outcomes been studied. The aim of our study is to determine risk factors for MDRB in community-acquired US and its influence on outcomes. Prospective observational study of patients with community-acquired US admitted to a university hospital. We compared epidemiological and clinical variables and outcomes of US due to MDRB and non-MDRB. Independent risk factors for MDRB were analyzed using logistic regression. A total of 193 patients were included, 33.7% of them with US due to MDRB. The median age of patients was 82 years. Hospital mortality was 17.6%, with no difference between the MDRB and non-MDRB groups. The length of hospital stay was 5 (4-8) days, with a non-significant tendency to longer hospital stays in the MDRB group (6 (4-10) vs. 5 (4-8) days, p = 0.051). Healthcare-associated US was found to be an independent risk factor for MDR bacteria by multivariate analysis. In conclusion, the impact of MDR bacteria on the outcomes of community-acquired urinary sepsis was mild. Healthcare-associated US was an independent risk factor for MDR bacteria.

Evolution of antibody profiles against SARS-CoV-2 in experienced and naïve vaccinated elderly people.

Introduction: The third dose of the COVID-19 vaccine is especially necessary in people over 65 years of age due to their lower immune response. Methods: We designed a multicentre, prospective observational study including 98 people ≤65 years old who lived in two nursing homes in Valladolid, Spain. One of the groups had previous experience with SARS-CoV-2 (n=68;69.4%) and the other was naïve (n=30;30.6%). We evaluated the response to the three doses of the Comirnaty vaccine and the dynamics of antibodies during 5 consecutive serum samplings: 2 after the first two doses of vaccination, one three months after the first dose, another at 6 months and the last one month after the third dose. IgG antibodies against SARS-CoV-2 S1, RBD and N antigens were analysed. Results: Both groups increased the level of Abs against S1 and RBD, but the experienced group showed a 130-fold higher humoral response due to hybrid immunisation (infection+vaccination). The response to vaccination with Comirnaty against COVID-19 was higher in those ≤65 years with previous experience than those who were naïve. However, the amount of antibodies against S1 and RBD equalised at 6 months. After the third dose, both groups raised the amount of antibodies to a similar level. The reinfections suggested by the analysis of antibodies against N were frequent in both groups. Discussion: The third dose showed a clear benefit for elderly people, with the reinforcement of the antibody levels after the decline suffered after six months of the first two doses.

An external quality assessment feasibility study; cross laboratory comparison of haemagglutination inhibition assay and microneutralization assay performance for seasonal influenza serology testing: A FLUCOP study.

Introduction: External Quality Assessment (EQA) schemes are designed to provide a snapshot of laboratory proficiency, identifying issues and providing feedback to improve laboratory performance and inter-laboratory agreement in testing. Currently there are no international EQA schemes for seasonal influenza serology testing. Here we present a feasibility study for conducting an EQA scheme for influenza serology methods. Methods: We invited participant laboratories from industry, contract research organizations (CROs), academia and public health institutions who regularly conduct hemagglutination inhibition (HAI) and microneutralization (MN) assays and have an interest in serology standardization. In total 16 laboratories returned data including 19 data sets for HAI assays and 9 data sets for MN assays. Results: Within run analysis demonstrated good laboratory performance for HAI, with intrinsically higher levels of intra-assay variation for MN assays. Between run analysis showed laboratory and strain specific issues, particularly with B strains for HAI, whilst MN testing was consistently good across labs and strains. Inter-laboratory variability was higher for MN assays than HAI, however both assays showed a significant reduction in inter-laboratory variation when a human sera pool is used as a standard for normalization. Discussion: This study has received positive feedback from participants, highlighting the benefit such an EQA scheme would have on improving laboratory performance, reducing inter laboratory variation and raising awareness of both harmonized protocol use and the benefit of biological standards for seasonal influenza serology testing.

Possible Mpox Protection from Smallpox Vaccine-Generated Antibodies among Older Adults.

Smallpox vaccination may confer cross-protection to mpox. We evaluated vaccinia virus antibodies in 162 persons ≥50 years of age in Spain; 68.5% had detectable antibodies. Highest coverage (78%) was among persons 71-80 years of age. Low antibody levels in 31.5% of this population indicates that addressing their vaccination should be a priority.

Fluoroquinolones Are Useful as Directed Treatment for Complicated UTI in a Setting with a High Prevalence of Quinolone-Resistant Microorganisms.

Fluoroquinolones (FQs) have been widely used for treating urinary tract infections (UTIs); however, the increasing emergence of resistant strains has compromised their use. We aimed to know the usefulness of FQs for the treatment of community-acquired UTI in a setting with a high prevalence of fluoroquinolone-resistant microorganisms. A prospective observational study of patients diagnosed with community-acquired UTI was conducted, in which their outcomes according to whether they had FQs or not in their empirical and directed treatments were compared. A multivariate analysis was performed to identify risk factors for UTIs due to ciprofloxacin-resistant microorganisms. A total of 419 patients were included; 162 (38.7%) patients were treated with FQs, as empirical treatment in 27 (6.4%), and as directed treatment in 135 (32.2%). In-hospital mortality (2.2% vs. 6.6%, p 0.044) and 30-day mortality (4.4 vs. 11%, p 0.028) were both lower in the group of patients directly treated with FQ, while there were no differences when FQs were used as empirical treatment. A total of 37.2% of the cases were resistant to ciprofloxacin, which was associated with healthcare-associated UTI (OR 2.7, 95% CI 2-3.7) and prior exposure to FQs (OR 2.7, 95 % CI 1.9-3.7). In conclusion, our findings show that in a setting with a high prevalence of community-acquired UTI caused by quinolone-resistant microorganisms, FQs as directed treatment for community-acquired UTI were associated with better outcomes than other antibiotics, but their use as empirical treatment is not indicated, even in those cases without risk factors for quinolones resistance.

Obstructive sleep apnea: The key for a better asthma control?

INTRODUCTION: Obstructive sleep apnea (OSA) is an important risk factor for poor asthma control. The objective of this study is to analyze the symptomatic control in asthmatic patients with OSA after using continuous positive airway pressure (CPAP). METHODS: Patients were collected in a monographic asthma consult and a polygraphy was performed due to clinical suspicion or poor disease control. Asthma associated pathologies, as well as clinical and patient-perceived asthma control parameters were evaluated before and after the initiation of CPAP. RESULTS: A hundred patients were included, 59% were women and 41% men. From them, 54% had severe OSA, 33% moderate OSA and 13% mild OSA, and 10% could not tolerate CPAP. Eighty four percent had a moderate or severe degree of asthma with fractional exhaled nitric oxide (FENO) 32 ± 24.6 ppm and an asthma control test (ACT) before CPAP of 19 ± 4. Asthma control before CPAP was good in 41% of patients, partial in 29%, and bad in 30%. After three or more months of CPAP, clinical asthma control was good in 70% (p < 0.001), perceived control by ACT after CPAP was 21 ± 4 (p < 0.001). When asked for their opinion, 51.5% referred clinical improvement after CPAP, no change in 46.5%. CONCLUSIONS: The use of CPAP in asthmatic patients with OSA improves both clinical and perceived asthma control in a statistically significant way. Most patients had good adaptation to CPAP (90%) and 51.5% had clinical improvement.

Sex differences in aged 80 and over hospitalized patients with community-acquired UTI: A prospective observational study.

Aim: This study aimed to evaluate clinically significant sex differences that could have an effect on the choice of treatment and outcomes of urinary tract infection (UTI) in aged 80 and over hospitalized patients with community-acquired UTI. Methods: This was a prospective study of 161 patients aged 80 and over admitted to hospital with community-acquired UTI. Epidemiological, clinical, laboratory and microbiologic variables were compared between both sexes. Multivariate analysis was performed using logistic regression to determine the variables independently associated with sex. Results: In a population of 91 (56.52%) women and 70 (43.48%) men, aged 80 and over, we found that women were more likely to have cognitive impairment (p = 0.035) and less likely to have chronic obstructive pulmonary disease (COPD) (p = 0.006) and indwelling urinary catheter (p < 0.001) than men. Levels of creatinine were higher in men than in women (p = 0.008). Septic shock at presentation was more frequent in the male group (p = 0.043). Men had a higher rate of polymicrobial infection (p = 0.035) and Pseudomonas aeruginosa infection (p = 0.003). Factors independently associated with sex by multivariate analysis were septic shock, cognitive impairment, COPD and indwelling urinary catheter. Conclusion: Men aged 80 and over with community-acquired UTI had more septic shock at admission to hospital and higher rates of indwelling urinary catheter, while women had more cognitive impairment. There were no differences in outcomes between sexes.

Immunodominance hierarchy after seasonal influenza vaccination.

Current influenza vaccines elicit humoral immune responses against the haemagglutinin (HA) protein of influenza viruses. Different antigenic sites have been identified in the HA head as the main target of haemagglutination inhibition (HAI) antibodies (Sb, Sa, Cb, Ca1 and Ca2). To determine immunodominance (ID) of each site, we performed HAI assays against a panel of mutant viruses, each one lacking one of the classically defined antigenic sites and compared it to wild type (Wt). Agglutinating antibodies were measured before and after vaccination in two different regimens: Quadrivalent Influenza Vaccine (QIV) in young adults; or Adjuvanted Trivalent influenza Vaccine (ATIV) in elderly. Our results showed abs before vaccination were significantly reduced against all antigenic sites in the elderly and only against Sb and Ca2 in young adults compared to the Wt. Humoral response to vaccination was significantly reduced against all viruses compared to the Wt for the ATIV and only against Sb and Ca2 for the QIV. The strongest reduction was observed in all cases against Sb followed by Ca2. We concluded that ID profile was clearly dominated by Sb followed by Ca2. Additionally, the antibody response evolved with age, increasing the response towards less immunodominant epitopes of HA head. Adjuvants can positively influence ID hierarchy broadening responses towards multiple antigenic sites of HA head.