The 7 Cardinal Sins of COPD in Spain.

Chronic obstructive pulmonary disease (COPD) is a public health problem due to its high prevalence (11% in the adult population in Spain), increasing incidence, and great social and economic impact. Despite this, it is underdiagnosed (and, therefore, undertreated) at a rate of around 80%. In this paper, a group of respiratory physicians specializing in COPD discuss 7 fundamental problems ("cardinal sins") that contribute to this situation, with the explicit aim of proposing specific solutions that may help to improve this unfavorable state of affairs.

Determinants of early antibody responses to COVID-19 mRNA vaccines in exposed and naive healthcare workers

BackgroundTwo doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naive adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. MethodsWe measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. FindingsVaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects. A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with lower neutralization and antibody levels. Among fully vaccinated, 6.3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. InterpretationOur data support administering a single-dose in pre-exposed healthy individuals. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. FundingThis work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clinic de Barcelona, the Fundacio Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.

Antibody Conversion rates to SARS-CoV-2 in Saliva from Children Attending Summer Schools in Barcelona, Spain

Surveillance tools to estimate infection rates in young populations are essential to guide recommendations for school reopening and management during viral epidemics. Ideally, field-deployable non-invasive, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We determined SARS-CoV-2 antibody conversion by high-throughput Luminex assays in saliva samples collected weekly in 1,509 children and 396 adults in 22 Summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29th to July 31st 2020, between the first and second COVID-19 pandemic waves. Saliva antibody conversion defined as [≥]4-fold increase in IgM, IgA and/or IgG levels to SARS-CoV-2 antigens between two visits over a 5-week period was 3.22% (49/1518), or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. To conclude, saliva antibody profiling including three isotypes and multiplexing antigens is a useful and more user-friendly tool for screening pediatric populations to determine SARS-CoV-2 exposure and guide public health policies during pandemics.

Multiplex Antibody Analysis of IgM, IgA and IgG to SARS-CoV-2 in Saliva and Serum from Infected Children and their Close Contacts

COVID-19 affects children to a lesser extent than adults but they can still get infected and transmit SARS-CoV-2 to their contacts. Field deployable non-invasive sensitive diagnostic techniques are needed to evaluate the infectivity dynamics of the coronavirus in pediatric populations and guide public health interventions. We evaluated the utility of high-throughput Luminex-based assays applied to saliva samples to quantify IgM, IgA and IgG antibodies against five SARS-CoV-2 spike (S) and nucleocapsid (N) antigens in the context of a contacts and infectivity longitudinal study. We compared the antibody levels obtained in saliva versus serum/plasma samples from a group of children and adults tested weekly by RT-PCR over 35 days and diagnosed as positive (n=58), and a group of children and adults who consistently tested negative over the follow up period (n=61), in the Summer of 2020 in Barcelona, Spain. Antibody levels in saliva samples from individuals with confirmed RT-PCR diagnosis of SARS-CoV-2 infection were significantly higher than in negative individuals and correlated with those measured in sera/plasmas. Higher levels of anti-S IgG were found in asymptomatic individuals that could indicate protection against disease in infected individuals. Higher anti-S IgG and IgM levels in serum/plasma and saliva, respectively, in infected children compared to infected adults could also be related to stronger clinical immunity in them. Among infected children, males had higher levels of saliva IgG to N and RBD than females. Despite overall correlation, individual clustering analysis suggested that responses that may not be detected in blood could be patent in saliva, and vice versa, and therefore that both measurements are complementary. In addition to serum/plasma, measurement of SARS-CoV-2-specific saliva antibodies should be considered as a complementary non-invasive assay to better estimate the percentage of individuals who have experienced coronavirus infection. Saliva antibody detection could allow determining COVID-19 prevalence in pediatric populations, alternative to bleeding or nasal swab, and serological diagnosis following vaccination.

Agreement between commercially available ELISA and in-house Luminex SARS-CoV-2 antibody immunoassays

AO_SCPLOWBSTRACTC_SCPLOWSerological diagnostic of the severe respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is a valuable tool for the determination of immunity and surveillance of exposure to the virus. In the context of an ongoing pandemic, it is essential to externally validate widely used tests to assure correct diagnostics and epidemiological estimations. We evaluated the performance of the COVID-19 ELISA IgG and IgM/A (Vircell, S.L.) against a highly specific and sensitive in-house Luminex immunoassay in a set of samples from pregnant women and cord blood. The agreement between both assays was moderate to high for IgG but low for IgM/A. Considering seropositivity by either IgG and/or IgM/A, the technical performance of the ELISA was highly imbalanced, with 96% sensitivity at the expense of 22% specificity. As for the clinical performance, the negative predictive value reached 87% while the positive predictive value was 51%. Our results stress the need for highly specific and sensitive assays and external validation of diagnostic tests with different sets of samples to avoid the clinical, epidemiological and personal disturbances derived from serological misdiagnosis.

Seven-month kinetics of SARS-CoV-2 antibodies and protective role of pre-existing antibodies to seasonal human coronaviruses on COVID-19

Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and its determinants, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 and four HCoV antigens were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed-up for 6 months. Seroprevalence increased over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, were stable over time, except IgG to nucleocapsid antigen and IgM levels that waned. After the peak response, anti-spike antibody levels increased from [~]150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. Pre-existing antibodies to alpha-HCoV were lower in individuals who subsequently seroconverted for SARS-CoV-2. IgG and IgA to HCoV were significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

Immunogenicity and crossreactivity of antibodies to SARS-CoV-2 nucleocapsid protein

COVID-19 patients elicit strong responses to the nucleocapsid (N) protein of SARS-CoV-2 but binding antibodies are also detected in prepandemic individuals, indicating potential crossreactivity with common cold human coronaviruses (HCoV) and questioning its utility in seroprevalence studies. We investigated the immunogenicity of the full-length and shorter fragments of the SARS-CoV-2 N protein, and the crossreactivity of antibodies with HCoV. We indentified a C-terminus region in SARS-CoV2 N of minimal sequence homology with HCoV that was more specific and highly immunogenic. IgGs to the full-length SARS-CoV-2 N also recognised N229E N, and IgGs to HKU1 N recognised SARS-CoV-2 N. Crossreactivity with SARS-CoV-2 was stronger for alpha-rather than beta-HCoV despite having less sequence identity, revealing the importance of conformational recognition. Higher preexisting IgG to OC43 N correlated with lower IgG to SARS-CoV-2 in rRT-PCR negative individuals, reflecting less exposure and indicating a potential protective association. Antibodies to SARS-CoV-2 N were higher in patients with more severe and longer symptoms and in females. IgGs remained stable for at least 3 months, while IgAs and IgMs declined faster. In conclusion, N is a primary target of SARS-CoV-2-specific and HCoV crossreactive antibodies, both of which may affect the acquisition of immunity to COVID-19.

The impact of COVID-19 on patients with asthma: A Big Data analysis

BackgroundFrom the onset of the COVID-19 pandemic, an association between the severity of COVID-19 and the presence of certain medical chronic conditions has been suggested. However, unlike influenza and other viruses, the burden of the disease in patients with asthma has been less evident. ObjectiveThis study aims at a better understanding of the burden of COVID-19 in patients with asthma and the impact of asthma, its related comorbidities, and treatment on the prognosis of COVID-19. MethodsWe analyzed clinical data from patients with asthma from January 1st to May 10th, 2020 using big data analytics and artificial intelligence through the SAVANA Manager(R) clinical platform. ResultsOut of 71,192 patients with asthma, 1,006 (1.41%) suffered from COVID-19. Compared to asthmatic individuals without COVID-19, patients with asthma and COVID-19 were significantly older (55 vs. 42 years), predominantly female (66% vs. 59%), had higher prevalence of hypertension, dyslipidemias, diabetes, and obesity, and smoked more frequently. Contrarily, allergy-related factors such as rhinitis and eczema were less frequent in asthmatic patients with COVID-19 (P < .001). Higher prevalence of hypertension, dyslipidemia, diabetes, and obesity was also confirmed in those patients with asthma and COVID-19 who required hospital admission. The percentage of individuals using inhaled corticosteroids (ICS) was lower in patients who required hospitalization due to COVID-19, as compared to non-hospitalized patients (48.3% vs. 61.5%; OR: 0.58: 95% CI 0.44 - 0.77). During the study period, 865 (1.21%) patients with asthma were being treated with biologics. Although these patients showed increased severity and more comorbidities at the ear, nose, and throat (ENT) level, their hospital admission rates due to COVID-19 were relatively low (0.23%). COVID-19 increased inpatient mortality in asthmatic patients (2.29% vs 0.54%; OR 2.29: 95% CI 4.35 - 6.66). ConclusionOur results indicate that the number of COVID-19 cases in patients with asthma has been low, although higher than the observed in the general population. Patients with asthma and COVID-19 were older and were at increased risk due to comorbidity-related factors. ICS and biologics are generally safe and may be associated with a protective effect against severe COVID-19 infection.

Findings and prognostic value of lung ultrasound in COVID-19 pneumonia

ObjectivesThe aim is to systematically describe the findings of lung ultrasound in patients with COVID-19 pneumonia and to analyze its prognostic value. MethodsLung ultrasound was performed to 63 patients with COVID-19 pneumonia admitted to a University Hospital. Lung involvement was evaluated using a 4-point scale with a 12-area pulmonary division (lung score -LS-). Ultrasound findings, along with clinical characteristics, were recorded. ResultsAll patients showed ultrasound involvement in at least 1 area (mean 8 {+/-} 3.5). Total LS was 15.3 {+/-} 8.1, without differences between left and right lung. Most affected regions were the lower one (95.2%) and the posterior one (73.8%). Total LS showed a strong correlation (r = -0.765) with PaO2/FiO2; by lung regions, those with a higher correlation were the LS of the anterior one (r = -0.823) and the LS of the upper one (r = -0.731). 22.2% of patients required non-invasive respiratory support (NIRS). Multivariate analysis shows that anterior region LS, adjusted for age and sex, is significant (odds ratio 2.159, 95% confidence interval 1.309 to 3.561) for the risk of requiring NIRS. Anterior region LS [≥] 4 and total LS [≥]19 have similar characteristics to predict the need for NIRS. ConclusionsUltrasound involvement in COVID-19 pneumonia is bilateral and heterogeneous. Most affected regions are the posterior and the lower ones. The anterior region has prognostic value, because its involvement strongly correlates with the risk of requiring NIRS, and an anterior region LS [≥] 4 has high sensitivity and specificity for predicting the need for NIRS.

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Reliable serological tests are required to determine the prevalence of antibodies against SARS-CoV-2 antigens and to characterise immunity to the disease in order to address key knowledge gaps in the context of the COVID-19 pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and ELISA with their higher precision, dynamic range, throughput, miniaturization, cost-efficacy and multiplexing capacity. We developed three qSAT assays to detect IgM, IgA and IgG to a panel of eight SARS-CoV-2 antigens including spike (S), nucleoprotein (N) and membrane (M) protein constructs. The assays were optimized to minimize processing time and maximize signal to noise ratio. We evaluated the performance of the assays using 128 plasmas obtained before the COVID-19 pandemic (negative controls) and 115 plasmas from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 8 were asymptomatic, 58 had mild symptoms and 49 were hospitalized. Pre-existing IgG antibodies recognizing N, M and S2 proteins were detected in negative controls suggestive of cross-reactive to common cold coronaviruses. The best performing antibody isotype/antigen signatures had specificities of 100% and sensitivities of 94.94% at [≥]14 days since the onset of symptoms and 96.08% at [≥]21 days since the onset of symptoms, with AUC of 0.992 and 0.999, respectively. Combining multiple antibody markers as assessed by qSAT assays has the highest efficiency, breadth and versatility to accurately detect low-level antibody responses for obtaining reliable data on prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity required for vaccine development to combat pandemics like the COVID-19.

CLINICAL CHARACTERISTICS AND PROGNOSTIC FACTORS FOR ICU ADMISSION OF PATIENTS WITH COVID-19 USING MACHINE LEARNING AND NATURAL LANGUAGE PROCESSING

There remain many unknowns regarding the onset and clinical course of the ongoing COVID-19 pandemic. We used a combination of classic epidemiological methods, natural language processing (NLP), and machine learning (for predictive modeling), to analyse the electronic health records (EHRs) of patients with COVID-19. We explored the unstructured free text in the EHRs within the SESCAM Healthcare Network (Castilla La-Mancha, Spain) from the entire population with available EHRs (1,364,924 patients) from January 1st to March 29th, 2020. We extracted related clinical information upon diagnosis, progression and outcome for all COVID-19 cases, focusing in those requiring ICU admission. A total of 10,504 patients with a clinical or PCR-confirmed diagnosis of COVID-19 were identified, 52.5% males, with age of 58.2{+/-}19.7 years. Upon admission, the most common symptoms were cough, fever, and dyspnoea, but all in less than half of cases. Overall, 6% of hospitalized patients required ICU admission. Using a machine-learning, data-driven algorithm we identified that a combination of age, fever, and tachypnoea was the most parsimonious predictor of ICU admission: those younger than 56 years, without tachypnoea, and temperature <39{degrees}C, (or >39{degrees}C without respiratory crackles), were free of ICU admission. On the contrary, COVID-19 patients aged 40 to 79 years were likely to be admitted to the ICU if they had tachypnoea and delayed their visit to the ER after being seen in primary care. Our results show that a combination of easily obtainable clinical variables (age, fever, and tachypnoea with/without respiratory crackles) predicts which COVID-19 patients require ICU admission.

Specific and cross-reactive immune response against Mycobacterium tuberculosis antigens in mice immunized with proteoliposomes from Mycobacterium bovis BCG

Objective To characterize the immunogenicity and the induction of cross-reactive responses against Mycobacterium tuberculosis (M. tuberculosis) of a proteoliposome (PL) from Mycobacterium bovis Bacillus Calmette–Guérin (BCG) with and without alum hydroxide (AL) as adjuvant (PLBCG-AL and PLBCG, respectively) in BALB/c mice. Methods BALB/c mice were inoculated with phosphate buffer solution, BCG, PLBCG and PLBCG-AL. The humoral immunogenicity was determined by ELISA [immunoglobulin G (IgG), IgG1 and IgG2a] and the cellular immunogenicity was evaluated in vivo by delayed type hypersensitivity. The humoral cross-reactive response against M. tuberculosis was determined by Western blot. Results Sera from animals immunized with PLBCG-AL and PLBCG showed significant increase in specific total IgG and IgG1 antibodies and the presence of cross-reactive antibodies against M. tuberculosis antigens, which were more intense with the use of alum as adjuvant. Mice immunized with PLBCG and PLBCG-AL also showed a specific cellular response in vivo. Conclusions The cellular and humoral immunogenicity of PLBCG and the capacity to induce cross-reactive responses against M. tuberculosis is in agreement with the protective capacity previously demonstrated by this vaccine candidate and supports the continuation of its evaluation in further stages.

[Chronic obstructive pulmonary disease and cardiovascular disease]. / EPOC y enfermedad cardiovascular.

In the last decade, various studies have suggested that chronic obstructive pulmonary disease (COPD) could favor the development of ischemic heart disease. Several observational and case-control studies have confirmed that patients with COPD have a higher risk of cardiovascular disorders. However, this increased risk could be largely explained by a greater prevalence of classical risk factors. Currently, there are no data to indicate a causal relation between COPD and cardiovascular disease and the concept of systemic inflammation as a common pathogenic mechanism has not been demonstrated. Equally, there is insufficient evidence to conclude that some drugs, such as statins or inhaled corticoids, could decrease cardiovascular risk in patients with COPD by reducing systemic inflammation. Currently, these drugs should only be recommended if patients show specific indications for their use.

Identification of Dengue-specific B-Cell Epitopes by Phage-display Random Peptide Library

Background: Dengue is the most important human viral disease transmitted by arthropod vectors. The availability of random peptide libraries (RPL) displayed on phage has provided a powerful tool for selecting sequences that mimic epitopes from microorganisms that are useful for diagnostic and vaccine development purposes. In this paper, we describe peptides that resemble the antigenic structure of B-cell epitopes of dengue virus identified from a phage-peptide library using human sera containing polyclonal antibodies against dengue virus. Materials and Methods: Eighteen phage clones were isolated from the phage-display peptide library, J404, by affinity selection using human antisera against dengue virus type 3. These clones were tested for reactivity by ELISA with a panel of hyperimmune ascitic fluids (HAFs) containing antibodies either against all four dengue serotypes, West Nile virus (WNV) or Eastern equine encephalitis virus (EEEV) with control ascitic fluid (NAF) used as a negative control. Results: Eight clones were recognized by HAFs against the four dengue serotypes, of which four significantly inhibited binding of anti-dengue antibodies to the virus. Two peptides with similar sequences to regions of NS3 and NS4B non-structural dengue virus proteins were identified. Conclusion: Our results suggest that these peptides could be used for the development of diagnostic tools for the detection of dengue virus infection and for a potential vaccine against this pathogen.

[Epidemiology of lung cancer in Spain and forecast for the future]. / Situación epidemiológica y pronóstica del cáncer de pulmón en nuestro medio.

Lung cancer, a steadily growing problem, ranks as the first cause of tumor-related deaths in developed countries. The relation between lung cancer and smoking makes it a potentially avoidable disease. Found mainly in men, it has made alarming gains among women. The main prognostic factor is the possibility of receiving curative surgery; however, in real practice the diagnosis usually comes when the disease has reached an advanced stage, when only 20% can be treated surgically. Nonsurgical treatments based on chemo- and radiotherapy have not advanced appreciably in recent years, and 5-year survival is poor, estimated at only around 7% to 12% in Spain. Attempts must be made to improve preventive measures and early diagnosis in order to improve the prognosis for lung cancer patients.

Punçöes do estroma anterior no tratamento da ceratopatia bolhosa / Anterior stromal puncture in the treatment of bullous keratopathy

Avaliar o efeito terapêutico das punçöes do estroma anterior corneal em pacientes com ceretopatia bolhosa (CB). Métodos: Vinte e cinco pacientes com CB sintomáticos, com baixa visäo, com e sem indicaçäo de transplante de córnea, foram avaliados antes, uma, 4 e 12 semanas após punçöes estromais anteriores realizadas com agulha #25 á lâmpada de fenda. Em cada visita, os pacientes foram questionados sobre a dor, fotofobia, sensaçäo de corpo estranho, além de serem subetidos a exame oftalmológico completo, estesiometria e paquimetria. Resultados: As comparaçöes realizadas entre os valores antes e após o procedimento referentes a dor (p<0,001), fotofobia (p=0,0198), sensaçäo de corpo estranho (CE)(p<0,001), insônia (p=0,0015) e estesiometria (p=0,00654) apresentaram diferenças estatisticamente significantes quanto á diminuiçäo desses sintomas e da sensibilidade corneal. A paquimetria média näo apresentou diferenças estatisticamente significantes entre as avaliaçöes antes e após as punçöes estromais (p=0,873). Näo foram observadas alteraçöes importantes nas vascularizaçäo corneal após o procedimento. Conclusäo: As punçöes do estroma anterior da córnea representam uma modalidade efetiva, simples e de baixo custo para o tratamento dos pacientes com CB sintomáticos.