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Sensitive PCR detection of viral nucleic acids plays a critical role in infectious disease research, diagnosis and monitoring. In the context of SARS-CoV-2 detection, recent reports indicate that digital PCR-based tests are significantly more sensitive than traditional qPCR tests. Numerous factors can influence digital PCR reaction sensitivity. In this review, using a model for human HIV infection and the Raindance ddPCR platform as an example, we describe technical aspects that contribute to sensitive viral signal detection in DNA and RNA from tissue samples, which often harbor viral reservoirs and serve as better predictors of disease outcome and indicators of treatment efficacy.

Infectious diseases may cause serious morbidity and mortality in pregnant women, their foetuses, and infants; the risk associated with any newly emerging infectious disease (EID) is likely unknown at the time of its emergence. While the ongoing SARS-CoV-2 pandemic shows that the development of vaccines against new pathogens can be considerably accelerated, the immunization of pregnant women generally lags behind the general population. Guided by the priority pathogen list for WHO’s R&D Blueprint for Action to Prevent Epidemics, this workshop sought to define the evidence needed for use of vaccines against EIDs in pregnant and lactating women, using Lassa fever as a model. Close to 60 maternal immunization (MI) and vaccine safety experts, regulators, vaccine developers, Lassa fever experts, and investigators from Lassa-affected countries examined the critical steps for vaccine development and immunization decisions for pregnant and lactating women. This paper reports on key themes and recommendations from the workshop. Current practice still assumes the exclusion of pregnant women from early vaccine trials. A shift in paradigm is needed to progress towards initial inclusion of pregnant women in Phase 2 and 3 trials. Several practical avenues were delineated. Participants agreed that vaccine platforms should be assessed early for their suitability for maternal immunization. It was noted that, in some cases, nonclinical data derived from assessing a given platform using other antigens may be adequate evidence to proceed to a first clinical evaluation and that concurrence from regulators may be sought with supporting rationale. For clinical trials, essential prerequisites such as documenting the disease burden in pregnant women, study site infrastructure, capabilities, and staff experience were noted. Early and sustained communication with the local community was considered paramount in any program for the conduct of MI trials and planned vaccine introduction.

mRNA vaccines have evolved from being a mere curiosity to emerging as COVID-19 vaccine front-runners. Recent advancements in the field of RNA technology, vaccinology, and nanotechnology have generated interest in delivering safe and effective mRNA therapeutics. In this review, we discuss design and self-assembly of mRNA vaccines. Self-assembly, a spontaneous organization of individual molecules, allows for design of nanoparticles with customizable properties. We highlight the materials commonly utilized to deliver mRNA, their physicochemical characteristics, and other relevant considerations, such as mRNA optimization, routes of administration, cellular fate, and immune activation, that are important for successful mRNA vaccination. We also examine the COVID-19 mRNA vaccines currently in clinical trials. mRNA vaccines are ready for the clinic, showing tremendous promise in the COVID-19 vaccine race, and have pushed the boundaries of gene therapy., Graphical abstract Unlabelled Image, Highlights • mRNA vaccines showed spectacular success in the race for COVID-19 vaccines. • Design of both mRNA and the delivery vectors help in fine-tuning efficacy. • Self-assembled mRNA delivery vectors include lipid and polymer nanoparticles. • Lipid nanoparticle mRNA vaccines have ca. 95% efficacy and earned EUA FDA approval. • These unprecedented results may pave the road for future mRNA vaccine development.

Highlights • As a counter-regulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. • The affinity of the spike protein receptor binding domain (RBD) of the SARS-CoV-2 with human ACE2 (hACE2) largely determines the degree of clinical symptoms infected by SARS-CoV-2. • Vitamin D was found to affect ACE2, the same target of SARS-CoV-2, we therefore propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 through modulating ACE2., A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed to have the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) has been found to be expressed on type II pneumocytes. As a counterregulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 with human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have revealed that regulating the ACE2/RAS system was effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor of both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.

Graphical abstract, The worldwide health crisis caused by the SARS-Cov-2 virus has resulted in>3 million deaths so far. Improving early screening, diagnosis and prognosis of the disease are critical steps in assisting healthcare professionals to save lives during this pandemic. Since WHO declared the COVID-19 outbreak as a pandemic, several studies have been conducted using Artificial Intelligence techniques to optimize these steps on clinical settings in terms of quality, accuracy and most importantly time. The objective of this study is to conduct a systematic literature review on published and preprint reports of Artificial Intelligence models developed and validated for screening, diagnosis and prognosis of the coronavirus disease 2019. We included 101 studies, published from January 1st, 2020 to December 30th, 2020, that developed AI prediction models which can be applied in the clinical setting. We identified in total 14 models for screening, 38 diagnostic models for detecting COVID-19 and 50 prognostic models for predicting ICU need, ventilator need, mortality risk, severity assessment or hospital length stay. Moreover, 43 studies were based on medical imaging and 58 studies on the use of clinical parameters, laboratory results or demographic features. Several heterogeneous predictors derived from multimodal data were identified. Analysis of these multimodal data, captured from various sources, in terms of prominence for each category of the included studies, was performed. Finally, Risk of Bias (RoB) analysis was also conducted to examine the applicability of the included studies in the clinical setting and assist healthcare providers, guideline developers, and policymakers.

The novel betacoronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread across the globe at an unprecedented rate since its first emergence in Wuhan City, China in December 2019. Scientific communities around the world have been rigorously working to develop a potent vaccine to combat COVID-19 (coronavirus disease 2019), employing conventional and novel vaccine strategies. Gene-based vaccine platforms based on viral vectors, DNA, and RNA, have shown promising results encompassing both humoral and cell-mediated immune responses in previous studies, supporting their implementation for COVID-19 vaccine development. In fact, the U.S. Food and Drug Administration (FDA) recently authorized the emergency use of two RNA-based COVID-19 vaccines. We review current gene-based vaccine candidates proceeding through clinical trials, including their antigenic targets, delivery vehicles, and route of administration. Important features of previous gene-based vaccine developments against other infectious diseases are discussed in guiding the design and development of effective vaccines against COVID-19 and future derivatives., Graphical abstract Unlabelled Image

With the COVID-19 pandemic now ongoing for close to a year, people all over the world are still waiting for a vaccine to become available. The initial focus of accelerated global research and development efforts to bring a vaccine to market as soon as possible was on novel platform technologies that promised speed but had limited history in the clinic. In contrast, recombinant protein vaccines, with numerous examples in the clinic for many years, missed out on the early wave of investments from government and industry. Emerging data are now surfacing suggesting that recombinant protein vaccines indeed might offer an advantage or complement to the nucleic acid or viral vector vaccines that will likely reach the clinic faster. Here, we summarize the current public information on the nature and on the development status of recombinant subunit antigens and adjuvants targeting SARS-CoV-2 infections., Graphical abstract Unlabelled Image, Highlights • Recombinant protein vaccines constitute a proven, well-established vaccine development platform • Multiple expression systems are available to scale-up production • Various adjuvants are being used to elicit the desired immune response • Recombinant protein vaccines are suitable for production in low-resource countries • Recombinant protein COVID-19 vaccinesmay offer a better solution in the long-term

The detrimental impact of air pollution as a result of frequent exposure to fine particles posed a global public health risk mainly to the pulmonary disorders in pediatric and geriatric population. Here, we reviewed the current literature regarding the role of ginseng and/or its components as antimicrobials, especially against pathogens that cause respiratory infections in animal and in vitro models. Some of the possible mechanisms for ginseng-mediated viral inhibition suggested are improvements in systemic and mucosa-specific antibody responses, serum hemagglutinin inhibition, lymphocyte proliferation, cell survival rate, and viral clearance in the lungs. In addition, ginseng reduces the expression levels of proinflammatory cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-8) and chemokines produced by airway epithelial cells and macrophages, thus preventing weight loss. In case of bacterial infections, ginseng acts by alleviating inflammatory cytokine production, increasing survival rates, and activating phagocytes and natural killer cells. In addition, ginseng inhibits biofilm formation and induces the dispersion and dissolution of mature biofilms. Most clinical trials revealed that ginseng, at various dosages, is a safe and effective method of seasonal prophylaxis, relieving the symptoms and reducing the risk and duration of colds and flu. Taken together, these findings support the efficacy of ginseng as a therapeutic and prophylactic agent for respiratory infections. Keywords: Bacteria, Clinical trials, Ginseng, Respiratory tract infections, Virus

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:39 issue:11 pages:1171-1190 ispartof: location:United States status: published

COVID-19 is still a deadly disease that remains yet a major challenge for humans. In recent times, many large pharmaceutical and non-pharmaceutical companies have invested a lot of time and cost in fighting this disease. In this regard, today's scientific knowledge shows that designing and producing an effective vaccine is the best possible way to diminish the disease burden and dissemination or even eradicate the disease. Due to the urgent need, many vaccines are now available earlier than scheduled. New technologies have also helped to produce much more effective vaccines, although the potential side effects must be taken into account. Thus, in this review, the types of vaccines and vaccine designs made against COVID-19, the vaccination programs, as well as the delivery methods and molecules that have been used to deliver some vaccines that need a carrier will be described.

Respiratory syncytial virus (RSV)—the most common viral cause of bronchiolitis—is a significant cause of serious illness among young children between the ages of 0–5 years and is especially concerning in the first year of life. Globally, RSV is a common cause of childhood acute lower respiratory illness (ALRI) and a major cause of hospital admissions in young children and infants and represents a substantial burden for health-care systems. This burden is strongly felt as there are currently no effective preventative options that are available for all infants. However, a renaissance in RSV prevention strategies is unfolding, with several new prophylactic options such as monoclonal antibodies and maternal vaccinations that are soon to be available. A key concern is that health decision makers and systems may not be ready to take full advantage of forthcoming technological innovations. A multi-stakeholder approach is necessary to bridge data gaps to fully utilise upcoming options. Knowledge must be made available at multiple levels to ensure that parents and doctors are aware of preventative options, but also to ensure that stakeholders and policymakers are given the necessary information to best advise implementation strategies.

Objective To assess the epidemiologic association between Kawasaki disease and common pediatric infectious diseases (PIDs) identified during the coronavirus disease 2019 (COVID-19) pandemic period to confirm whether the infection-triggered theory is a plausible hypothesis for the pathogenesis of Kawasaki disease. Study design A retrospective epidemiologic study was conducted using datasets obtained from Web-based surveillance of Kawasaki disease and PIDs in Japan. We compared weekly numbers of patients who developed Kawasaki disease and specific PIDs between 2020 and 2017-2019 and evaluated the association between the percent reduction in the number of patients with these diseases. Results A total of 868 patients developed Kawasaki disease in 2020. During the social distancing period in 2020, the number of patients with Kawasaki disease was approximately 35% lower than in 2017-2019. Time from the onset of Kawasaki disease until the first hospital visit did not differ significantly among the examined years. The proportion of older children with Kawasaki disease decreased more than that of infants with Kawasaki disease (age

Graphical abstract, COVID-19 caused by SARS-CoV-2 is the latest pandemic which has thrown the world into an unprecedented social and economic uncertainties along with huge loss to humanity. Identification of the host factors regulating the replication of SARS-CoV-2 in human host may help in the development of novel anti-viral therapies to combat the viral infection and spread. Recently, some research groups used genome-wide CRISPR/Cas screening to identify the host factors critical for the SARS-CoV-2 replication and infection. A comparative analysis of these significant host factors (p

The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein.

OBJECTIVE We evaluated the incidence of influenza and non-influenza respiratory viruses (NIRVs) pre-/post-implementation of public health (PH) measures aimed to decrease COVID-19 transmission using population-based surveillance data. We hypothesized that such measures could reduce the burden of respiratory viruses (RVs) transmitting via the same routes. PATIENTS AND METHODS An interrupted time-series analysis of RV surveillance data in Alberta, Canada from May 2017 – July 2020 was conducted. The burden of influenza and NIRVs before and after intervention initiation at week 11, 2020 was compared. The analysis was adjusted for seasonality, over-dispersion, and autocorrelation. RESULTS During the study period, an average of 708 and 4056 weekly respiratory multiplex molecular panels were conducted pre-/post-intervention respectively. We found significant reductions in test positivity rates in the post-intervention period for influenza (-94.3%; 95% CI -93.8 to 97.4%, p

Highlights • Febrile seizures were reported to be associated with seasonal viral epidemics. • The seasonal distribution of febrile seizures was high from late spring to summer. • Influenza virus and enterovirus was most frequently associated with febrile seizure., Purpose The seasonal distribution patterns of febrile seizures and of respiratory and enteric viral pathogens are similar. In this study, we analyzed trends in febrile seizures and viral infection in Korean children, using big data from the Korean Health Insurance Review and Assessment Service (HIRA). Methods We analyzed children younger than 6 years who visited the hospital and were diagnosed with febrile seizures from 2009 to 2016, using medical records in the HIRA database. A total of 666,136 medical records of children with a main or subdiagnosis of febrile seizure from 2008 to 2016 were included. Of these records, patients younger than 1 month and records before 2009 were excluded. Finally, 558,130 records were extracted. Results The medical records included 315,774 male children and 242,356 (43.4%) female children, with a mean age of 2.31 ± 1.31 years. The annual incidence of febrile seizure was 25.4 per 1000 person-years (27.9 for boys and 22.7 for girls). The ratio of male to female children was 1.30: 1, and records of 1-year-old children comprised the highest proportion (n = 210,400, 33.70%). The total monthly number of patients was highest in May (n = 64,969, 11.6%), and peaks were formed from April to July. The fewest patients were seen in October (n = 34,424, 6.17%). The most common viral pathogens were influenza in April and enterovirus during May–July. Conclusion The seasonal distribution of febrile seizures was high from late spring to summer, and influenza virus and enterovirus were most frequently associated.

Highlights • We examined virus interference in a Department of Defense dependent population. • Vaccinated personnel did not have significant odds of respiratory illnesses. • Vaccinated personnel were protected against influenza. • Odds of virus interference by vaccination varied for individual respiratory viruses., Purpose Receiving influenza vaccination may increase the risk of other respiratory viruses, a phenomenon known as virus interference. Test-negative study designs are often utilized to calculate influenza vaccine effectiveness. The virus interference phenomenon goes against the basic assumption of the test-negative vaccine effectiveness study that vaccination does not change the risk of infection with other respiratory illness, thus potentially biasing vaccine effectiveness results in the positive direction. This study aimed to investigate virus interference by comparing respiratory virus status among Department of Defense personnel based on their influenza vaccination status. Furthermore, individual respiratory viruses and their association with influenza vaccination were examined. Results We compared vaccination status of 2880 people with non-influenza respiratory viruses to 3240 people with pan-negative results. Comparing vaccinated to non-vaccinated patients, the adjusted odds ratio for non-flu viruses was 0.97 (95% confidence interval (CI): 0.86, 1.09; p = 0.60). Additionally, the vaccination status of 3349 cases of influenza were compared to three different control groups: all controls (N = 6120), non-influenza positive controls (N = 2880), and pan-negative controls (N = 3240). The adjusted ORs for the comparisons among the three control groups did not vary much (range: 0.46–0.51). Conclusions Receipt of influenza vaccination was not associated with virus interference among our population. Examining virus interference by specific respiratory viruses showed mixed results. Vaccine derived virus interference was significantly associated with coronavirus and human metapneumovirus; however, significant protection with vaccination was associated not only with most influenza viruses, but also parainfluenza, RSV, and non-influenza virus coinfections.

Background Respiratory viruses, air pollutants, and aeroallergens are all implicated in worsening pediatric asthma symptoms, but their relative contributions to asthma exacerbations are poorly understood. A significant decrease in asthma exacerbations has been observed during the COVID-19 pandemic, providing a unique opportunity to study how major asthma triggers correlate with asthma activity. Objective To determine whether changes in respiratory viruses, air pollutants, and/or aeroallergens during the COVID-19 pandemic were concomitant with decreased asthma exacerbations. Methods Health care utilization and respiratory viral testing data between January 1st, 2015 and December 31st, 2020 were extracted from the Children's Hospital of Philadelphia (CHOP) Care Network's electronic health record. Air pollution and allergen data were extracted from U.S. Environmental Protection Agency public databases and a National Allergy Bureau-certified station, respectively. Pandemic data (2020) were compared to historical data. Results Recovery of in-person asthma encounters during phased re-opening (June 6th - November 15th, 2020) was uneven: primary care well and specialty encounters reached 94% and 74% of pre-pandemic levels, respectively, while primary care sick and hospital encounters reached 21% and 40% of pre-pandemic levels, respectively. During the pandemic, influenza A and influenza B decreased to negligible frequency when compared to pre-pandemic cases, while RSV and rhinovirus infections decreased to low (though non-negligible) pre-pandemic levels, as well. No changes in air pollution or aeroallergen levels relative to historical observations were noted. Conclusions Our results suggest that viral respiratory infections are a primary driver of pediatric asthma exacerbations. These findings have broad relevance to both clinical practice and the development of health policies aimed at reducing asthma morbidity.

Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.

Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.

Epidemiological evidence suggests that Bacille Calmette-Guerin (BCG) vaccine induced trained immunity protects against non-specific infections including coronavirus disease 2019 (COVID-19). A recent clinical trial has also supported BCG protection in viral respiratory infections in general, with multiple COVID-19 specific trials currently ongoing. The durability and mechanism of BCG trained immunity however remain unclear. An integrative analysis of available epidemiological transcriptomic data related to BCG vaccination and viral respiratory infections, along with transcriptomic alterations reported in COVID-19, is presented here toward addressing this gap. Results show that BCG vaccination leads to a very long-lasting transcriptomic changes which mimic viral infections by upregulated antiviral defense response, and oppose viral infections by downregulated myeloid cell activation mediated immune response. Antiviral defense upregulation is consistent with the present concept of trained immunity, whereas downregulation of myeloid cell activation seems directionally inconsistent, with enhancement of innate immune response considered to characterize trained immunity. The present finding is however in consonance with recent retrospective cohort study and clinical trial evidence that shows no association of BCG vaccination with systemic inflammation, alleviating the concern that the vaccine may add to inflammatory response and worsen severe COVID-19. In conclusion, the present analysis offers transcriptomic support to the existing epidemiological evidence of lower prevalence and mortality of COVID-19 in countries with childhood BCG vaccination policy.

Due to the high prevalence and long incubation periods often without symptoms, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions of individuals globally, causing the coronavirus disease 2019 (COVID-19) pandemic. Even with the recent approval of the anti-viral drug, remdesivir, and Emergency Use Authorization of monoclonal antibodies against S protein, bamlanivimab and casirimab/imdevimab, efficient and safe COVID-19 vaccines are still desperately demanded not only to prevent its spread but also to restore social and economic activities via generating mass immunization. Recent Emergency Use Authorization of Pfizer and BioNTech’s mRNA vaccine may provide a pathway forward, but monitoring of long-term immunity is still required, and diverse candidates are still under development. As the knowledge of SARS-CoV-2 pathogenesis and interactions with the immune system continues to evolve, a variety of drug candidates are under investigation and in clinical trials. Potential vaccines and therapeutics against COVID-19 include repurposed drugs, monoclonal antibodies, antiviral and antigenic proteins, peptides, and genetically engineered viruses. This paper reviews virology and immunology of SARS-CoV-2, alternative therapies for COVID-19 to vaccination, principles and design considerations in COVID-19 vaccine development, and the promises and roles of vaccine carriers in addressing the unique immunopathological challenges presented by the disease., Graphical abstract Unlabelled Image

Background Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma. Objectives In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma. Methods Children participating in the Childhood Origins of Asthma study (n=285) provided nasopharyngeal mucus samples in the first two years of life, during routine healthy study visits (2, 4, 6, 9, 12, 18 and 24 months of age) and episodes of respiratory illnesses, which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and correlated these with presence of asthma at 6, 8, 11, 13 and 18 years of age. Results Of the four microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood. Conclusion In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma. Clinical Implication Identifying factors that promote early colonization with S. aureus may lead to future interventional studies to prevent childhood asthma., Capsule summary: In a birth cohort study, early colonization of the upper airway with Staphylococcus aureus and detection of rhinoviruses and Moraxella catarrhalis during illnesses were associated with subsequent childhood asthma.

Background Studies have reported an increased risk for asthma following lower respiratory tract infections, but few studies have specifically assessed this risk in children diagnosed with pneumonia in infancy. Furthermore, it is not fully understood whether this association is indicative of a causal relationship or if certain children have a predisposition for both diseases. Research Question Are children diagnosed with pneumonia in infancy at increased risk for asthma, and what is the role of familial confounding and pneumococcal conjugate vaccine immunization on the association? Study Design and Methods This study was a nationwide register-based cohort analysis of > 900,000 Swedish children to assess the association between pneumonia in infancy and prevalent asthma at 4 years. A secondary aim was to assess if the association has changed after the introduction of nationwide pneumococcal conjugate vaccine (PCV) immunization as this has led to a shift in pneumonia etiology. The study controlled for important confounders, including shared environmental and familial confounding, by using sibling analyses. Results There was a strong association between pneumonia diagnosis in infancy and prevalent asthma at 4 years (adjusted OR, 3.38; 95% CI, 3.26-3.51), as well as in the full sibling analyses (adjusted OR, 2.81; 95% CI, 2.58-3.06). The risk for asthma following pneumonia diagnosis in infancy was slightly higher for those born in the PCV period compared with the pre-PCV period (adjusted OR, 3.80 [95% CI, 3.41-4.24] vs 3.28 [95% CI, 3.15-3.42]) when the proportion of viral pneumonia etiology was also higher (14.5% vs 10.7%, respectively) and the overall asthma prevalence was lower (5.3% vs 6.6%). Interpretation Children diagnosed with pneumonia in infancy have a highly increased risk for prevalent asthma at 4 years, which might have implications for future asthma preventive measures and needs to be considered when assessing the morbidity that can be attributed to pneumonia., Graphical abstract

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed., Graphical abstract Unlabelled Image

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years. The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits. A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments. This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Objective To summarize and evaluate current reports on community-onset severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young infants. Study design We performed a systematic review to identify reports published from November 1, 2019, until June 15, 2020, on laboratory-confirmed community-onset SARS-CoV-2 infection in infants younger than 3 months of age. We excluded studies reporting neonates with perinatal coronavirus disease 2019 (COVID-19) exposure and diagnosis before hospital discharge and hospital-onset disease, as well as clinically diagnosed cases without confirmation. Two independent reviewers performed study screening, data abstraction, and risk of bias assessment. Variables of interest included patient age, exposure to COVID-19, medical history, clinical symptoms, SARS-CoV-2 testing, laboratory findings, clinical course, and disposition. Results In total, 38 publications met inclusion criteria, including 23 single case reports, 14 case series, and 1 cohort study, describing 63 infants younger than 3 months of age with laboratory-confirmed SARS-CoV-2 infection. Most cases were mild to moderate. Fever, respiratory, gastrointestinal, cardiac, and neurologic findings were reported. Laboratory abnormalities included neutropenia, lymphopenia, and elevated serum levels of inflammatory markers and aminotransferases. Fifty-eight (92%) infants were hospitalized, 13 (21%) were admitted to the intensive care unit, and 2 (3%) required mechanical ventilation. No death was reported. Conclusions Among young infants with laboratory-confirmed SARS-CoV-2 infection, most cases were mild to moderate and improved with supportive care. Our results demonstrate a need for a high index of suspicion for SARS-CoV-2 infection in young infants presenting with generalized symptoms such as fever or decreased feeding, even in the absence of respiratory symptoms.

Receptor Interacting Protein Kinases (RIPKs) are cellular signaling molecules that are critical for homeostatic signaling in both communicable and non-communicable disease processes. In particular, RIPK1, RIPK2, RIPK3 and RIPK7 have emerged as key mediators of intracellular signal transduction including inflammation, autophagy and programmed cell death, and are thus essential for the early control of many diverse pathogenic organisms. In this review, we discuss the role of each RIPK in host responses to bacterial and viral pathogens, with a focus on studies that have used pathogen infection models rather than artificial stimulation with purified pathogen associated molecular patterns. We also discuss the intricate mechanisms of host evasion by pathogens that specifically target RIPKs for inactivation, and finally, we will touch on the controversial issue of drug development for kinase inhibitors to treat chronic inflammatory and neurological disorders, and the implications this may have on the outcome of pathogen infections.

Coronavirus disease 2019 (COVID-19) is a rapidly emerging disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease begins as an infection of lungs, which is self-limiting in the majority of infections; however, some develop severe respiratory distress and organ failures. Lung microbiome, though neglected previously have received interest recently because of its association with several respiratory diseases and immunity. Lung microbiome can modify the risk and consequences of COVID-19 disease by activating an innate and adaptive immune response. In this review, we examine the current evidence on COVID-19 disease and lung microbiome, and how lung microbiome can affect SARS-CoV-2 infection and the outcomes of this disease. To date there is no direct evidence from human or animal studies on the role of lung microbiome in modifying COVID-19 disease; however, related studies support that microbiome can play an essential role in developing immunity against viral infections. Future studies need to be undertaken to find the relationship between lung microbiome and COVID-19 disease.

Humans have been suffered from viral infections over the centuries, such as influenza, HSV, and HIV, which have killed millions of people worldwide. However, the availability of effective treatments for infectious diseases remains limited until now, as most of the viral pathogens resisted to many medical treatments. Marine microbes are currently one of the most copious sources of pharmacologically active natural products, which have constantly provided promising antivirus agents. To date, a large number of marine microbial secondary metabolites with antiviral activities have been widely reported. In this review, we have summarized the potential antivirus compounds from marine microorganisms over the last decade. In addition, the structures, bioactivities, and origins of these compounds were discussed as well., Graphical abstract Image 1, Highlights • Marine microbes-derived natural products with various antiviral activities were summarized (2009–2019). • 18 compounds demonstrated significant antivirus activities stronger than the corresponding positive drugs. • This review highlighted the potential development of these natural products as antiviral lead compounds.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected hundreds of thousands of people, including infants and children. We carried out a comprehensive literature review to identify the underlying mechanisms and risk factors for severe COVID-19 in children, in comparison with the other two coronavirus outbreaks in the past, SARS and MERS. Search in the Pubmed and Scopus databases to identify publications between February 26, 2020 and June 10, 2020 identified 23 relevant papers in English. Children have so far accounted for 1.7-2% of the diagnosed cases of COVID-19. They often have milder disease than adults, and child deaths have been rare. The documented risk factors for severe disease in children are young age and underlying comorbidities, although the potentially fatal multisystem inflammatory syndrome (MIS) occurs in older children. It is unclear whether male gender and certain laboratory and imaging findings can also be considered as risk factors, due to current insufficiency of evidence. Reports on other potential factors, such as vitamin D level, responsiveness of the immune system, co-infections and genetic polymorphisms have not yet been published.

The global pandemic caused by the newly described severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused worldwide suffering and death of unimaginable magnitude from coronavirus disease 2019 (COVID-19). The virus is transmitted through aerosol droplets, and causes severe acute respiratory syndrome. SARS-CoV-2 uses the receptor-binding domain of its spike protein S1 to attach to the host angiotensin-converting enzyme 2 receptor in lung and airway cells. Binding requires the help of another host protein, transmembrane protease serine S1 member 2. Several factors likely contribute to the efficient transmission of SARS-CoV-2. The receptor-binding domain of SARS-CoV-2 has a 10- to 20-fold higher receptor-binding capacity compared with previous pandemic coronaviruses. In addition, because asymptomatic persons infected with SARS-CoV-2 have high viral loads in their nasal secretions, they can silently and efficiently spread the disease. PCR-based tests have emerged as the criterion standard for the diagnosis of infection. Caution must be exercised in interpreting antibody-based tests because they have not yet been validated, and may give a false sense of security of being "immune" to SARS-CoV-2. We discuss how the development of some symptoms in allergic rhinitis can serve as clues for new-onset COVID-19. There are mixed reports that asthma is a risk factor for severe COVID-19, possibly due to differences in asthma endotypes. The rapid spread of COVID-19 has focused the efforts of scientists on repurposing existing Food and Drug Administration-approved drugs that inhibit viral entry, endocytosis, genome assembly, translation, and replication. Numerous clinical trials have been launched to identify effective treatments for COVID-19. Initial data from a placebo-controlled study suggest faster time to recovery in patients on remdesivir; it is now being evaluated in additional controlled studies. As discussed in this review, till effective vaccines and treatments emerge, it is important to understand the scientific rationale of pandemic-mitigation strategies such as wearing facemasks and social distancing, and implement them.

Background Throughout the 5000-year history of China, more than 300 epidemics were recorded. Traditional Chinese herbal medicine (TCM) has been used effectively to combat each of these epidemics’ infections, and saved many lives. To date, there are hundreds of herbal TCM formulae developed for the purpose of prevention and treatment during epidemic infections. When COVID-19 ravaged the Wuhan district in China in early January 2020, without a deep understanding about the nature of COVID-19, patients admitted to the TCM Hospital in Wuhan were immediately treated with TCM and reported later with >90% efficacy. Approach We conducted conduct a systematic survey of various TCM herbal preparations used in Wuhan and to review their efficacy, according to the published clinical data; and, secondly, to find the most popular herbs used in these preparations and look into the opportunity of future research in the isolation and identification of bioactive natural products for fighting COVID-19. Results Although bioactive natural products in these herbal preparations may have direct antiviral activities, TCM employed for fighting epidemic infections was primarily based on the TCM theory of restoring the balance of the human immune system, thereby defeating the viral infection indirectly. In addition, certain TCM teachings relevant to the meridian system deserve better attention. For instance, many TCM herbal preparations target the lung meridian, which connects the lung and large intestine. This interconnection between the lung, including the upper respiratory system, and the intestine, may explain why certain TCM formulae showed excellent relief of lung congestion and diarrhea, two characteristics of COVID-19 infection. Conclusion There is good reason for us to learn from ancient wisdom and accumulated clinical experience, in combination with cutting edge science and technologies, to fight with the devastating COVID-19 pandemic now and emerging new coronaviruses in the future.

Highlights • An HA-based vaccine candidate, created by DNA shuffling (HA-113), can be immunogenic when the recombinant antigen is expressed by PIV5 (PIV5-113). • Immunity induced by the PIV5-113 vaccine can protect mice against infection with 4 of 5 parental HAs used to create the vaccine. • Immunity induced by PIV5-113 can protect pigs against infection with an influenza virus isolate that is known to be infectious in pigs., Pigs are an important reservoir for human influenza viruses, and influenza causes significant economic loss to the swine industry. As demonstrated during the 2009 H1N1 pandemic, control of swine influenza virus infection is a critical step toward blocking emergence of human influenza virus. An effective vaccine that can induce broadly protective immunity against heterologous influenza virus strains is critically needed. In our previous studies [McCormick et al., 2015; PLoS One, 10(6):e0127649], we used molecular breeding (DNA shuffling) strategies to increase the breadth of the variable and conserved epitopes expressed within a single influenza A virus chimeric hemagglutinin (HA) protein. Chimeric HAs were constructed using parental HAs from the 2009 pandemic virus and swine influenza viruses that had a history of zoonotic transmission to humans. In the current study, we used parainfluenza virus 5 (PIV-5) as a vector to express one of these chimeric HA antigens, HA-113. Recombinant PIV-5 expressing HA-113 (PIV5-113) were rescued, and immunogenicity and protective efficacy were tested in both mouse and pig models. The results showed that PIV5-113 can protect mice and pigs against challenge with viruses expressing parental HAs. The protective immunity was extended against other genetically diversified influenza H1-expressing viruses. Our work demonstrates that PIV5-based influenza vaccines are efficacious as vaccines for pigs. The PIV5 vaccine vector and chimeric HA-113 antigen are discussed in the context of the development of universal influenza vaccines and the potential contribution of PIV5-113 as a candidate universal vaccine.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

Highlights • Proteomic studies have uncovered more than a thousand cellular proteins that are present in the particles of RNA viruses. • Strikingly, nearly four hundred of these are RNA-binding proteins (RBPs). • Several virion-incorporated RBPs have been shown to regulate viral particle assembly and the initial steps of infection. • These host RBPs with regulatory roles in infection represent potential targets for antiviral therapy., RNA is a central molecule in RNA virus biology due to its dual function as messenger and genome. However, the small number of proteins encoded by viral genomes is insufficient to enable virus infection. Hence, viruses hijack cellular RNA-binding proteins (RBPs) to aid replication and spread. In this review we discuss the ‘knowns’ and ‘unknowns’ regarding the contribution of host RBPs to the formation of viral particles and the initial steps of infection in the newly infected cell. Through comparison of the virion proteomes of ten different human RNA viruses, we confirm that a pool of cellular RBPs are typically incorporated into viral particles. We describe here illustrative examples supporting the important functions of these RBPs in viral particle formation and infectivity and we propose that the role of host RBPs in these steps can be broader than previously anticipated. Understanding how cellular RBPs regulate virus infection can lead to the discovery of novel therapeutic targets against viruses.

Highlights • Winter was the season with the least number of pneumonia-related admissions. • Half of the children presented with a normal chest radiography. • Non-contaminated bacterial growth was detected in 5.3% of blood cultures. • At least one virus was detected in the respiratory secretions of most children (89.6%). • Case fatality rate was 3.2%., Objectives The study aim was to describe the etiological profile and clinical characteristics of pneumonia among children hospitalized in Thimphu, Bhutan. Methods This prospective study enrolled children aged 2–59 months admitted to the Jigme Dorji Wangchuck National Referral Hospital with World Health Organization (WHO)-defined clinical pneumonia. Demographic and clinico-radiological data were collected through questionnaires, physical examination, and chest radiography. Blood samples and nasopharyngeal washing were collected for microbiological analysis including culture and molecular methods. Results From July 2017 to June 2018, 189 children were enrolled, of which 53.4% were infants. Pneumonia-related admissions were less frequent over the winter. Chest radiographies were obtained in 149 children; endpoints included pneumonia in 39 cases (26.2%), other infiltrates in 31 (20.8%), and were normal in 79 children (53.0%). Non-contaminated bacterial growth was detected in 8/152 (5.3%) blood cultures, with only two cases of Streptococcus pneumoniae. Viral detection in upper respiratory secretions was common, with at least one virus detected in 103/115 (89.6%). The three most-commonly isolated viruses were respiratory syncytial virus (52/115; 45.2%), rhinovirus (42/115; 36.5%), and human parainfluenza virus (19/115; 16.5%). A third of patients with viral infections showed mixed infections. Case fatality rate was 3.2% (6/189). Conclusion Respiratory viral infections predominated among this cohort of WHO-defined clinical pneumonia cases, whereas bacterial aetiologies were uncommon, highlighting the epidemiologic transition that Bhutan seems to have reached.

Highlights • Potentially effective chemical drugs, including their chemical structures, pharmacological actions, adverse reactions, advance on COVID-19 treatment, and the general usage, against SARS-CoV-2 are summarized. • Various TCMs with practical effects, including Chinese herbal compound prescriptions, injection preparations, and active ingredients of TCMs, on the treatment of COVID-19 are reviewed. • Biological products, such as interferon-α, vaccines, stem cells, and convalescent plasma, are concluded to treat COVID-19., The fight against the novel coronavirus pneumonia (namely COVID-19) that seriously harms human health is a common task for all mankind. Currently, development of drugs against the novel coronavirus (namely SARS-CoV-2) is quite urgent. Chinese medical workers and scientific researchers have found some drugs to play potential therapeutic effects on COVID-19 at the cellular level or in preliminary clinical trials. However, more fundamental studies and large sample clinical trials need to be done to ensure the efficacy and safety of these drugs. The adoption of these drugs without further testing must be careful. The relevant articles, news, and government reports published on the official and Preprint websites, PubMed and China National Knowledge Infrastructure (CNKI) databases from December 2019 to April 2020 were searched and manually filtered. The general pharmacological characteristics, indications, adverse reactions, general usage, and especially current status of the treatment of COVID-19 of those potentially effective drugs, including chemical drugs, traditional Chinese medicines (TCMs), and biological products in China were summarized in this review to guide reasonable medication and the development of specific drugs for the treatment of COVID-19.

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory Syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.

Viruses reshape the organization of the cell interior to achieve different steps of their cellular cycle. Particularly, viral replication and assembly often take place in viral factories where specific viral and cellular proteins as well as nucleic acids concentrate. Viral factories can be either membrane-delimited or devoid of any cellular membranes. In the latter case, they are referred as membrane-less replication compartments. The most emblematic ones are the Negri bodies, which are inclusion bodies that constitute the hallmark of rabies virus infection. Interestingly, Negri bodies and several other viral replication compartments have been shown to arise from a liquid-liquid phase separation process and, thus, constitute a new class of liquid organelles. This is a paradigm shift in the field of virus replication. Here, we review the different aspects of membrane-less virus replication compartments with a focus on the Mononegavirales order and discuss their interactions with the host cell machineries and the cytoskeleton. We particularly examine the interplay between viral factories and the cellular innate immune response, of which several components also form membrane-less condensates in infected cells., Highlights • Viral factories harbor essential steps of the viral cycle. • Some viral factories are devoid of membranes and have liquid organelle properties. • Liquid viral factories concentrate cellular factors required for replication. • Innate immunity sensors and several ISGs are found in membrane-less condensates. • A subtle interplay exists between liquid viral factories and innate immunity actors.

Graphical abstract, Glucocorticosteroids are the first-line therapy for controlling airway inflammation in asthma. They bind intracellular glucocorticoid receptors to trigger increased expression of anti-inflammatory genes and suppression of pro-inflammatory gene activation in asthmatic airways. In the majority of asthma patients, inhaled glucocorticoids are clinically efficacious, improving lung function and preventing exacerbations. However, 5–10 % of the asthmatic population respond poorly to high dose inhaled and then systemic glucocorticoids. These patients form a category of severe asthma associated with poor quality of life, increased morbidity and mortality, and constitutes a major societal and health care burden. Inadequate therapeutic responses to glucocorticoid treatment is also reported in other inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease; however, asthma represents the most studied steroid-refractory disease. Several cellular and molecular events underlying glucocorticoid resistance in asthma have been identified involving abnormalities of glucocorticoid receptor signaling pathways. These events have been strongly related to immunological dysregulation, genetic, and environmental factors such as cigarette smoking or respiratory infections. A better understanding of the multiple mechanisms associated with glucocorticoid insensitivity in asthma phenotypes could improve quality of life for people with asthma but would also provide transferrable knowledge for other inflammatory diseases. In this review, we provide an update on the molecular mechanisms behind steroid-refractory asthma. Additionally, we discuss some therapeutic options for treating those asthmatic patients who respond poorly to glucocorticoid therapy.

Graphical abstract, Highlights • Naturally-occurring antibodies were more resistant to degradation than monoclonal antibodies. • Monoclonal sIgA was more resistant to degradation than IgG and IgA. • Monoclonal antibodies may need to be provided at a higher dose to compensate for digestive losses., To help rationally design an antibody for oral administration, we examined how different isotypes (IgG, IgA and sIgA) with the same variable sequence affect antibody stability across digestion. We compared the degradation of recombinant palivizumab (IgG1), and recombinant IgA and sIgA versions of palivizumab spiked in human milk to the degradation of naturally-occurring anti-respiratory syncytial virus (RSV) sIgA/IgA and IgG in human milk from four donors across gastric and intestinal phases of an in vitro model of infant digestion via a validated RSV F protein ELISA. Palivizumab IgG and IgA formats were less stable than the sIgA version after complete simulated gastrointestinal digestion: palivizumab IgG, IgA and sIgA decreased across complete simulated gastrointestinal digestion by 55%, 48% and 28%, respectively. Naturally-occurring RSV F protein-specific IgG was stable across digestion, whereas naturally-occurring sIgA/IgA was stable in the gastric phase but decreased 33% in the intestinal phase of simulated digestion.

Background Literature describing triggers of GFAP astrocytopathy (GFAP-A) is limited. We report a case of GFAP-A in a patient with recent messenger ribonucleic acid (mRNA) severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) vaccination and discuss the possible pathogenesis. Case description A 45-year-old gentleman presented with features of meningoencephalitis 31 days after the first dose and 4 days after the second dose of mRNA SARS-CoV-2 vaccination. He sequentially developed brainstem/cerebellar, autonomic and cord dysfunction. Cerebrospinal fluid was positive for GFAP autoantibody. Clinical improvement occurred after intravenous methylprednisolone and immunoglobulins. Conclusion Although we are uncertain of a causal link of GFAP-A to mRNA vaccine, indirect activation of an underlying dysregulated immune milieu is plausible.

Highlights • Seasonal viral respiratory illnesses overburden emergency department resources. • Current viral testing practices are ineffective for patient management in the ED. • Triage viral testing can reduce transmission risk & optimize antimicrobial therapy., Background Acute respiratory illnesses (ARI) are mostly viral in etiology and cause significant morbidity and mortality. Point of care PCR (POC-PCR) is a promising new technology for rapid virus identification but utility in the Emergency Department (ED) is not yet defined. Objectives Primarily, to investigate the value of POC-PCR in rapidly identifying RSV and influenza in the setting of ED triage. Additionally, to assess whether rapid knowledge of accurate test results would improve patient management by preventing nosocomial transmission and optimizing the prescription of antimicrobials for ARIs. Study Design A prospective cohort study of consecutive ED patients with ARI symptoms during peak flu season was conducted. Patient nasopharyngeal swabs were collected and tested using a POC-PCR device; physicians and patients were blinded to results. Virus positive and negative groups were compared by ED patient room placement and antimicrobial therapy ordered. Specificity and sensitivity were calculated using laboratory-PCR as the gold standard. Results Of 119 participants, 52.9% were POC-PCR positive - Influenza A (42.9%), RSV (41.3%), influenza B (15.9%). Nearly 70% of virus positive patients were placed rooms shared with non-ARI patients. Antibiotics were prescribed for 27.3% of virus positive patients, and 77.8% of oseltamivir-eligible patients did not receive therapy. POC-PCR was 100% sensitive (95% CI, 80.5–100.0%) and 95.2% specific (95% CI, 76.2–99.9%). Conclusions Rapid POC-PCR for influenza and RSV in ED triage has excellent sensitivity and specificity and the potential to improve social distancing practices through better triage and increase appropriate prescription of antimicrobials.