Asociación de comorbilidades con infección sintomática y síndrome inflamatorio multisistémico por SARS-CoV-2 en niños / Association of comorbidities and symptomatic infection and multisystemic inflammatory syndrome due to SARS-CoV-2 in children

INTRODUCCIÓN: En niños, la infección por el nuevo coronavirus (SARS-CoV-2) habitualmente cursa asintomática o con síntomas leves; sólo una proporción menor presenta síntomas graves o un conjunto de signos y síntomas postinfecciosos descritos como síndrome inflamatorio multisistémico pediátrico (SIMP). OBJETIVO: Describir la asociación de comorbilidades con la infección sintomática y SIMP por SARS-CoV-2 en niños. PACIENTES Y MÉTODOS: Estudio transversal analítico, se incluyeron pacientes pediátricos hospitalizados. Mediante reacción de la polimerasa en cadena y/o pruebas antigénicas se diagnosticó la infección activa y con la definición propuesta por la Organización Mundial de la Salud se identificaron pacientes con SIMP. RESULTADOS: Se estudiaron 375 pacientes, la mediana de edad fue de 3,8 años. El 47,7% (n: 179) presentó comorbilidades, siendo las más frecuentes: neoplasias sólidas y/o enfermedades hematológicas 17,1% (n: 64), obesidad 13,3% (n: 48) y neumopatías crónicas 9,3% (n: 35). Presentaron infección por SARS-CoV-2 el 16,5% (n: 62/375) y SIMP el 10,4% (n. 39/375). Los niños con obesidad mostraron mayor riesgo de infección sintomática (OR 2,21, IC 95% 1,05-4,6) y en aquellos con cáncer (OR 0,15, IC 95% 0,03-0,68) el riesgo de SIMP fue menor. CONCLUSIONES: La presencia de comorbilidades modifica el riesgo de infección por SARS-CoV-2 y SIMP.

BACKGROUND: In children, infection by the new coronavirus (SARS-CoV-2) usually occurs asymptomatic or with mild clinical data, only a minor proportion have severe symptoms or a set of post-infectious signs and symptoms described as Pediatric Inflammatory Multisystemic Syndrome (PIMS). AIM: To describe the association of comorbidities with symptomatic infection and PIMS due to SARS-CoV-2 in children. METHODS: Analytical cross-sectional study, pediatric patients hospitalized were included. Active infection was diagnosed by polymerase chain reaction and/or antigenic tests. Patients with PIMS were identified by the definition proposed by the World Health Organization. RESULTS: 375 patients were studied, the median age was 3.8 years. 47.7% (n: 179) had comorbidities, the most frequent were: solid neoplasms and/or hematological diseases 17.1% (n: 64), obesity 13.3% (n: 48) and chronic pneumopathies 9, 3% (n: 35). SARS-CoV-2 infection was present in 16.5% (n: 62/375) and PIMS in 10.4% (n. 39/375). Children with obesity showed a higher risk of infection (OR 2.21, 95% CI 1.05-4.6) and in those with cancer (OR 0.15, 95% CI 0.03-0.68) the PIMS risk was lower. CONCLUSIONS: The presence of comorbidities modifies the risk of infection by SARS-CoV-2 and PIMS.

[Association of comorbidities and symptomatic infection and multisystemic inflammatory syndrome due to SARS-CoV-2 in children]. / Asociación de comorbilidades con infección sintomática y síndrome inflamatorio multisistémico por SARS-CoV-2 en niños.

BACKGROUND: In children, infection by the new coronavirus (SARS-CoV-2) usually occurs asymptomatic or with mild clinical data, only a minor proportion have severe symptoms or a set of post-infectious signs and symptoms described as Pediatric Inflammatory Multisystemic Syndrome (PIMS). AIM: To describe the association of comorbidities with symptomatic infection and PIMS due to SARS-CoV-2 in children. METHODS: Analytical cross-sectional study, pediatric patients hospitalized were included. Active infection was diagnosed by polymerase chain reaction and/or antigenic tests. Patients with PIMS were identified by the definition proposed by the World Health Organization. RESULTS: 375 patients were studied, the median age was 3.8 years. 47.7% (n: 179) had comorbidities, the most frequent were: solid neoplasms and/or hematological diseases 17.1% (n: 64), obesity 13.3% (n: 48) and chronic pneumopathies 9, 3% (n: 35). SARS-CoV-2 infection was present in 16.5% (n: 62/375) and PIMS in 10.4% (n. 39/375). Children with obesity showed a higher risk of infection (OR 2.21, 95% CI 1.05-4.6) and in those with cancer (OR 0.15, 95% CI 0.03-0.68) the PIMS risk was lower. CONCLUSIONS: The presence of comorbidities modifies the risk of infection by SARS-CoV-2 and PIMS.

Cerebrospinal fluid neopterin as a biomarker of neuroinflammatory diseases.

The elevation of neopterin in cerebrospinal fluid (CSF) has been reported in several neuroinflammatory disorders. However, it is not expected that neopterin alone can discriminate among different neuroinflammatory etiologies. We conducted an observational retrospective and case-control study to analyze the CSF biomarkers neopterin, total proteins, and leukocytes in a large cohort of pediatric patients with neuroinflammatory disorders. CSF samples from 277 subjects were included and classified into four groups: Viral meningoencephalitis, bacterial meningitis, acquired immune-mediated disorders, and patients with no-immune diseases (control group). CSF neopterin was analyzed with high-performance liquid chromatography. Microbiological diagnosis included bacterial CSF cultures and several specific real-time polymerase chain reactions. Molecular testing for multiple respiratory pathogens was also included. Antibodies against neuronal and glial proteins were tested. Canonical discriminant analysis of the three biomarkers was conducted to establish the best discriminant functions for the classification of the different clinical groups. Model validation was done by biomarker analyses in a new cohort of 95 pediatric patients. CSF neopterin displayed the highest values in the viral and bacterial infection groups. By applying canonical discriminant analysis, it was possible to classify the patients into the different groups. Validation analyses displayed good results for neuropediatric patients with no-immune diseases and for viral meningitis patients, followed by the other groups. This study provides initial evidence of a more efficient approach to promote the timely classification of patients with viral and bacterial infections and acquired autoimmune disorders. Through canonical equations, we have validated a new tool that aids in the early and differential diagnosis of these neuroinflammatory conditions.

Development of an antibody cocktail for treatment of Sudan virus infection.

Antibody-based therapies are a promising treatment option for managing ebolavirus infections. Several Ebola virus (EBOV)-specific and, more recently, pan-ebolavirus antibody cocktails have been described. Here, we report the development and assessment of a Sudan virus (SUDV)-specific antibody cocktail. We produced a panel of SUDV glycoprotein (GP)-specific human chimeric monoclonal antibodies (mAbs) using both plant and mammalian expression systems and completed head-to-head in vitro and in vivo evaluations. Neutralizing activity, competitive binding groups, and epitope specificity of SUDV mAbs were defined before assessing protective efficacy of individual mAbs using a mouse model of SUDV infection. Of the mAbs tested, GP base-binding mAbs were more potent neutralizers and more protective than glycan cap- or mucin-like domain-binding mAbs. No significant difference was observed between plant and mammalian mAbs in any of our in vitro or in vivo evaluations. Based on in vitro and rodent testing, a combination of two SUDV-specific mAbs, one base binding (16F6) and one glycan cap binding (X10H2), was down-selected for assessment in a macaque model of SUDV infection. This cocktail, RIID F6-H2, provided protection from SUDV infection in rhesus macaques when administered at 50 mg/kg on days 4 and 6 postinfection. RIID F6-H2 is an effective postexposure SUDV therapy and provides a potential treatment option for managing human SUDV infection.

Assessment of DSMs Using Backpack-Mounted Systems and Drone Techniques to Characterise Ancient Underground Cellars in the Duero Basin (Spain).

In this study, a backpack-mounted 3D mobile scanning system and a fixed-wing drone (UAV) have been used to register terrain data on the same space. The study area is part of the ancient underground cellars in the Duero Basin. The aim of this work is to characterise the state of the roofs of these wine cellars by obtaining digital surface models (DSM) using the previously mentioned systems to detect any possible cases of collapse, using four geomatic products obtained with these systems. The results obtained from the process offer sufficient quality to generate valid DSMs in the study area or in a similar area. One limitation of the DSMs generated by backpack MMS is that the outcome depends on the distance of the points to the axis of the track and on the irregularities in the terrain. Specific parameters have been studied, such as the measuring distance from the scanning point in the laser scanner, the angle of incidence with regard to the ground, the surface vegetation, and any irregularities in the terrain. The registration speed and the high definition of the terrain offered by these systems produce a model that can be used to select the correct conservation priorities for this unique space.

Development of a Human Antibody Cocktail that Deploys Multiple Functions to Confer Pan-Ebolavirus Protection.

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates.

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.

Modeling the two- and three-dimensional displacement field in Lorca, Spain, subsidence and the global implications.

Land subsidence associated with overexploitation of aquifers is a hazard that commonly affects large areas worldwide. The Lorca area, located in southeast Spain, has undergone one of the highest subsidence rates in Europe as a direct consequence of long-term aquifer exploitation. Previous studies carried out on the region assumed that the ground deformation retrieved from satellite radar interferometry corresponds only to vertical displacement. Here we report, for the first time, the two- and three-dimensional displacement field over the study area using synthetic aperture radar (SAR) data from Sentinel-1A images and Global Navigation Satellite System (GNSS) observations. By modeling this displacement, we provide new insights on the spatial and temporal evolution of the subsidence processes and on the main governing mechanisms. Additionally, we also demonstrate the importance of knowing both the vertical and horizontal components of the displacement to properly characterize similar hazards. Based on these results, we propose some general guidelines for the sustainable management and monitoring of land subsidence related to anthropogenic activities.

Efficacy of Human Monoclonal Antibody Monotherapy Against Bundibugyo Virus Infection in Nonhuman Primates.

Background: The 2013-2016 Ebola virus disease (EVD) epidemics in West Africa highlighted a need for effective therapeutics for treatment of the disease caused by filoviruses. Monoclonal antibodies (mAbs) are promising therapeutic candidates for prophylaxis or treatment of virus infections. Data about efficacy of human mAb monotherapy against filovirus infections in preclinical nonhuman primate models are limited. Methods: Previously, we described a large panel of human mAbs derived from the circulating memory B cells from Bundibugyo virus (BDBV) infection survivors that bind to the surface glycoprotein (GP) of the virus. We tested one of these neutralizing mAbs that recognized the glycan cap of the GP, designated mAb BDBV289, as monotherapy in rhesus macaques. Results: We found that recombinant mAb BDBV289-N could confer up to 100% protection to BDBV-infected rhesus macaques when treatment was initiated as late as 8 days after virus challenge. Protection was associated with survival and decreased viremia levels in the blood of treated animals. Conclusions: These findings define the efficacy of monotherapy of lethal BDBV infection with a glycan cap-specific mAb and identify a candidate mAb therapeutic molecule that could be included in antibody cocktails for prevention or treatment of ebolavirus infections.

Therapeutic treatment of Marburg and Ravn virus infection in nonhuman primates with a human monoclonal antibody.

As observed during the 2013-2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (mAbs) are a platform technology in wide use for autoimmune and oncology indications. Previously, we described human mAbs that can protect mice from lethal challenge with Marburg virus. We demonstrate that one of these mAbs, MR191-N, can confer a survival benefit of up to 100% to Marburg or Ravn virus-infected rhesus macaques when treatment is initiated up to 5 days post-inoculation. These findings extend the small but growing body of evidence that mAbs can impart therapeutic benefit during advanced stages of disease with highly virulent viruses and could be useful in epidemic settings.

Assessment of Data Fusion Algorithms for Earth Observation Change Detection Processes.

In this work a parametric multi-sensor Bayesian data fusion approach and a Support Vector Machine (SVM) are used for a Change Detection problem. For this purpose two sets of SPOT5-PAN images have been used, which are in turn used for Change Detection Indices (CDIs) calculation. For minimizing radiometric differences, a methodology based on zonal "invariant features" is suggested. The choice of one or the other CDI for a change detection process is a subjective task as each CDI is probably more or less sensitive to certain types of changes. Likewise, this idea might be employed to create and improve a "change map", which can be accomplished by means of the CDI's informational content. For this purpose, information metrics such as the Shannon Entropy and "Specific Information" have been used to weight the changes and no-changes categories contained in a certain CDI and thus introduced in the Bayesian information fusion algorithm. Furthermore, the parameters of the probability density functions (pdf's) that best fit the involved categories have also been estimated. Conversely, these considerations are not necessary for mapping procedures based on the discriminant functions of a SVM. This work has confirmed the capabilities of probabilistic information fusion procedure under these circumstances.

Monoclonal antibody therapy for Junin virus infection.

Countermeasures against potential biothreat agents remain important to US Homeland Security, and many of these pharmaceuticals could have dual use in the improvement of global public health. Junin virus, the causative agent of Argentine hemorrhagic fever (AHF), is an arenavirus identified as a category A high-priority agent. There are no Food and Drug Administration (FDA) approved drugs available for preventing or treating AHF, and the current treatment option is limited to administration of immune plasma. Whereas immune plasma demonstrates the feasibility of passive immunotherapy, it is limited in quantity, variable in quality, and poses safety risks such as transmission of transfusion-borne diseases. In an effort to develop a monoclonal antibody (mAb)-based alternative to plasma, three previously described neutralizing murine mAbs were expressed as mouse-human chimeric antibodies and evaluated in the guinea pig model of AHF. These mAbs provided 100% protection against lethal challenge when administered 2 d after infection (dpi), and one of them (J199) was capable of providing 100% protection when treatment was initiated 6 dpi and 92% protection when initiated 7 dpi. The efficacy of J199 is superior to that previously described for all other evaluated drugs, and its high potency suggests that mAbs like J199 offer an economical alternative to immune plasma and an effective dual use (bioterrorism/public health) therapeutic.

3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×10(6) PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment.

Adrenomedullin is a useful biomarker for the prognosis of critically ill septic children.

AIM: To measure midregional pro-adrenomedullin (MR-pro-ADM) in critically ill septic patients to determine its prognostic usefulness as compared with other used biomarkers in pediatric intensive care units, C-reactive protein (CRP) and procalcitonin (PCT). MATERIALS & METHODS: Prospective observational study conducted on 95 patients. RESULTS: Mean levels of MR-pro-ADM were significantly higher when patients needed mechanical ventilation (3.2 ± 4.3 vs 1.6 ± 2.4) and inotropes (4.4 ± 5.2 vs 1.3 ± 1.2). Receiver operating characteristic curves of mortality were higher for MR-pro-ADM (cut-off value of 2.2). This marker showed higher positive predictive prognostic value than PCT and CRP (31 vs 21.6% and 15.8%, respectively). CONCLUSION: MR-pro-ADM levels are good indicators of disease severity and show better reliability than PCT and CRP for predicting in-hospital mortality.

A tripartite cocktail of chimeric monoclonal antibodies passively protects mice against ricin, staphylococcal enterotoxin B and Clostridium perfringens epsilon toxin.

Due to the fast-acting nature of ricin, staphylococcal enterotoxin B (SEB), and Clostridium perfringens epsilon toxin (ETX), it is necessary that therapeutic interventions following a bioterrorism incident by one of these toxins occur as soon as possible after intoxication. Moreover, because the clinical manifestations of intoxication by these agents are likely to be indistinguishable from each other, especially following aerosol exposure, we have developed a cocktail of chimeric monoclonal antibodies that is capable of neutralizing all three toxins. The efficacy of this cocktail was demonstrated in mouse models of lethal dose toxin challenge.

Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp.

Without an approved vaccine or treatments, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.

Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy.

Respiratory syncytial virus (RSV) can cause devastating lower respiratory tract infections in preterm infants or when other serious health problems are present. Immunoprophylaxis with palivizumab (Synagis), a humanized IgG1 mAb, is the current standard of care for preventing RSV infection in at-risk neonates. We have explored the contribution of effector function to palivizumab efficacy using a plant-based expression system to produce palivizumab N-glycan structure variants with high homogeneity on different antibody isotypes. We compared these isotype and N-glycoform variants with commercially available palivizumab with respect to both in vitro receptor and C1q binding and in vivo efficacy. Whereas the affinity for antigen and neutralization activity of each variant were indistinguishable from those of palivizumab, their Fcγ receptor binding profiles were very different, which was reflected in either a reduced or enhanced ability to influence the RSV lung titer in challenged cotton rats. Enhanced Fcγ receptor binding was associated with reduced viral lung titers compared with palivizumab, whereas abrogation of receptor binding led to a drastic reduction in efficacy. The results support the hypotheses that classic antibody neutralization is a minor component of efficacy by palivizumab in the cotton rat and that antibody-dependent cell-mediated cytotoxicity activity can significantly enhance the efficacy of this antiviral mAb.

Chimeric plantibody passively protects mice against aerosolized ricin challenge.

Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation.

Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model.

Severe lower respiratory tract infection in infants and small children is commonly caused by respiratory syncytial virus (RSV). Palivizumab (Synagis(®)), a humanized IgG1 monoclonal antibody (mAb) approved for RSV immunoprophylaxis in at-risk neonates, is highly effective, but pharmacoeconomic analyses suggest its use may not be cost-effective. Previously described potent RSV neutralizers (human Fab R19 and F2-5; human IgG RF-1 and RF-2) were produced in IgG format in a rapid and inexpensive Nicotiana-based manufacturing system for comparison with palivizumab. Both plant-derived (palivizumab-N) and commercial palivizumab, which is produced in a mouse myeloma cell line, showed protection in prophylactic (p < 0.001 for both mAbs) and therapeutic protocols (p < 0.001 and p < 0.05 respectively). The additional plant-derived human mAbs directed against alternative epitopes displayed neutralizing activity, but conferred less protection in vivo than palivizumab-N or palivizumab. Palivizumab remains one of the most efficacious RSV mAbs described to date. Production in plants may reduce manufacturing costs and improve the pharmacoeconomics of RSV immunoprophylaxis and therapy.

Production of pharmaceutical-grade recombinant aprotinin and a monoclonal antibody product using plant-based transient expression systems.

Plants have been proposed as an attractive alternative for pharmaceutical protein production to current mammalian or microbial cell-based systems. Eukaryotic protein processing coupled with reduced production costs and low risk for mammalian pathogen contamination and other impurities have led many to predict that agricultural systems may offer the next wave for pharmaceutical product production. However, for this to become a reality, the quality of products produced at a relevant scale must equal or exceed the predetermined release criteria of identity, purity, potency and safety as required by pharmaceutical regulatory agencies. In this article, the ability of transient plant virus expression systems to produce a wide range of products at high purity and activity is reviewed. The production of different recombinant proteins is described along with comparisons with established standards, including high purity, specific activity and promising preclinical outcomes. Adaptation of transient plant virus systems to large-scale manufacturing formats required development of virus particle and Agrobacterium inoculation methods. One transient plant system case study illustrates the properties of greenhouse and field-produced recombinant aprotinin compared with an US Food and Drug Administration-approved pharmaceutical product and found them to be highly comparable in all properties evaluated. A second transient plant system case study demonstrates a fully functional monoclonal antibody conforming to release specifications. In conclusion, the production capacity of large quantities of recombinant protein offered by transient plant expression systems, coupled with robust downstream purification approaches, offers a promising solution to recombinant protein production that compares favourably to cell-based systems in scale, cost and quality.