cord-007385-xcx4ic0s	2005	27 In a 1136 Spector J ALLERGY CLIN IMMUNOL MAY 1995 study by Sperber et al., 28 naproxen did not alter virus shedding or serum neutralizing antibody in experimental rhinovirus cold, but it had a beneficial effect on such symptoms as headache, malaise, myalgia, and cough. Although some time-honored treatments might have limited usefulness, novel attempts at ameliorating the symptoms of a common cold, such as the use of ipratropium bromide nasal spray or specific antiviral receptor therapy, might represent a significant advance. Potential role of hands in the spread of respiratory viral infections: studies with human parainfluenza virus 3 and rhinovirus 14 Development of common cold symptoms following experimental rhinovirus infection is related to prior stressful life events Analysis of nasal secretions during experimental rhinovirus upper respiratory infections Effect of experimental rhinovirus 39 infection on the nasal response to histamine and cold air challenges in allergic and nonallergic subjects
cord-007866-2d6003r9	2017	The 2016 Nobel Prize in Physiology or Medicine was awarded to Yoshinori Ohsumi, Professor at the Tokyo Institute of Technology, for ''''recycling.'''' Recycling on the cellular level is termed autophagy and is a fundamental process for degrading and recycling cellular components. A new type of vesicle was discovered and named autophagosomes, describing a process of ''''self-eating'''' to understand the mechanism of how such large cargos get into the lysosome. Although little work has been carried out in this regard thus far, there are convincing data available linking autophagy in airway epithelium, and autophagy might be essential for bronchial epithelial mucus secretion, as has been shown in an allergic asthma model. IL13 activates autophagy to regulate secretion in airway epithelial cells The complex roles of endoplasmic reticulum stress and autophagy in modulating Eotaxin-3 production and secretion from human airway epithelial cells
cord-010159-uo47oab1	2007	title: Respiratory viruses and acute asthma in children We read with great interest the article by Khetsuriani et al 1 on the prevalence of respiratory tract viruses in children with asthma. The results of PCR analysis of combined nasopharyngeal and throat swabs for 13 different viruses were positive in 63% of patients with asthma exacerbation in the 1-year study. We disagree with the low virus detection rate reported by Khetsuriani et al 1 because many studies in wheezing children have shown virus detection rates of close to 90%. 1 Interestingly, 2 or more viruses were detected in 43% of the children compared with 7% in the study by Khetsuriani et al. Our findings suggest that nearly all exacerbations of asthma in children necessitating hospitalization are associated with viral infection. Prevalence of viral respiratory tract infections in children with asthma Human bocavirus and acute wheezing in children
cord-025380-6bagohw8	2020	Globally, emerging data may identify air pollution as a modulator to DNA methylation (DNAm) disturbing the inflammation process, allergic diseases development, and exacerbation risk. Considering that SARS-CoV-2 infection involves a proinflammatory cytokine storm as IL-6 and IL-1b, a putative hypothesis could explain that populations exposed to chronic air pollution are associated with a different COVID-19 incidence in line with chronic epigenetic deregulation. Affecting the immune system and the inflammatory pathways, DNAm related to air pollution could explain the disparities in COVID-19 in geographic zones in which genetically predisposed populations were living in climate favoring SARS-CoV-2 distribution.
cord-027511-j5ayp0tv	2020	2 Globally, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has upset the lifestyle of humans, increasing sedentary behaviors with quarantine (ie, staying at home, tele-working, screen activities), the fear of contagion (ie, social connections, mass transit, and compulsive disinfecting), and probably a city dweller migration to the periphery of crowed cities and surrounding countryside. Considering that filtering face piece respirators (FFPs) reduced the penetration of fine particulates ranging from 80% (FFP1) to 99% (FFP3), their global use during the coronavirus disease 2019 pandemic could protect people against outdoor and indoor allergenic components. 4 Promoting warm and humid environment, indoor activities (ie, tele-working, cooking, and indoor sports) could improve the exposition of airborne fungal spores in damp houses, increasing the incidence of asthma and allergic diseases. 7 Because of the fear of contagion, people may avoid mass transit and increase their commuting by individual car, which may in turn promote air pollution-and the release of the highly allergenic fine particulate matter.
cord-032811-sdbj26ca	2020	They suggest that suppression of angiotensin-converting enzyme-2 (ACE-2) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could impair the hydrolysis of des-Arg 9 -bradykinin and stimulate the bradykinin receptor type 1 (BKB1) pathway to induce leakage of fluid into the lungs. 4 However, other studies suggest that SARS-CoV-2 may upregulate the expression of ACE-2 in patients with coronavirus disease 2019 (COVID-19) or influenza pneumonia in alveolar epithelial cells, endothelial cells, and lymphocytes in perivascular tissue than in uninfected control autopsy lung. 7 We favor a third hypothesis, where excessive and prolonged secretion of type I and type III IFNs in the airways contributes to loss of lung epithelial barrier function during COVID-19 and other RNA virus infections (Fig 1, A) . Because IFN-l contributes to loss of lung epithelial barrier function, 8 we hypothesize that entry of SARS-CoV-2 via ACE-2 can stimulate secretion of IFN-l and induce leakage of fluid into the lungs (Fig 1, A) .
cord-034640-ygtbuy4k	2020	key: cord-034640-ygtbuy4k authors: nan cord_uid: ygtbuy4k This is highlighted by preliminary findings in a recent study demonstrating the efficacy of dexamethasone in reducing mortality in critically ill patients with COVID-19, but showing no benefit in those not requiring respiratory support. 4 Furthermore, our study 5 demonstrated a ''''dose-response,'''' with greater degrees of respiratory allergy being associated with larger reductions in angiotensin-converting enzyme 2 gene expression in the nasal epithelium, and the impact of suppressing type 2 inflammation in these individuals is not currently known. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2 The names were shown as Gregori Silvia, PhD, and Aiuti Alessandro, MD, PhD. The first and last names of both authors were inadvertently reversed and should be Silvia Gregori
cord-252950-eiphxwmn	2020	COVID patients in ICU present a high mortality rate and immunoprofiling reveals heterogeneous IFN-α2 production with about 20% of critically-ill patients unable to produce IFN-α2, highlighting the immune response heterogeneity and opening avenues for targeted therapies. 42 Capsule summary: 43 COVID patients in ICU present a high mortality rate and immunoprofiling reveals heterogeneous α2 production with about 20% of critically-ill patients unable to produce IFN-α2, highlighting the 45 immune response heterogeneity and opening avenues for targeted therapies. Various immunosuppressive drugs, including IL-6 blockers or JAK-STAT signaling inhibitors have been 56 suggested for the treatment of SARS-COV-2 infection 2 whereas additional clinical trials are evaluating 57 the use of recombinant interferon to foster host antiviral response. To date, IFN-I response has not been evaluated in COVID-19 60 patients and its contribution to the viral control and inflammation is unknown. We further explored a larger cohort of 26 critically ill COVID patients from one of the intensive care 75 unit (ICU) at Hospices Civils de Lyon (Lyon, France).
cord-255794-55ubow92	2020	Since 120 interleukin-6 (IL-6) is a relevant cytokine in ARDS, the blockade of its receptor with 121 Tocilizumab (TCZ) could reduce mortality and/or morbidity in severe Objective 123 To determine whether baseline IL-6 serum levels can predict the need for IMV and the 124 response to TCZ. Retrospective observational study performed in hospitalized patients diagnosed of Clinical information and laboratory findings, including IL-6 levels, were collected 128 approximately 3 and 9 days after admission to be matched with pre-and post-administration The recent exponential increase in cases of severe acute respiratory syndrome caused by 181 coronavirus 2 (SARS-CoV-2) has led the World Health Organization to declare a pandemic. To determine the variables associated with the need for IMV, we performed a multivariable 296 logistic regression analysis that was first modeled by adding all the variables with a p value 297 lower than 0.15 in the bivariable analysis, namely total lymphocyte count, D-dimer, LDH, 298 PaO 2 /FiO 2 , COPD, obesity, hypertension, C-reactive protein, and IL-6 (high vs low).
cord-256788-h4iv8crq	2012	9 In that regard a decrease in IFN-g production from cord blood mononuclear cells (CBMCs) stimulated by PHA or allergens has been associated with increased risk for acute respiratory tract illness during infancy. We assessed whether each of these immune end points could predict the development of respiratory tract illness during the first year of life in a prospective birth cohort of children at high risk for asthma and allergic disease. Together, these findings reinforce the association of a decreased IFN-g response to RSV with the development of increased viral respiratory tract infections in the first year of life. In this study we provide evidence that a decreased antiviral interferon response at the time of birth is selectively associated with an increase in acute respiratory tract infections in the first year of life among infants at high risk for asthma and allergic disease.
cord-258093-6fn8ei9f	2011	The aging lung Large, longitudinal, and more complete studies to determine the effects of aging on the function of the respiratory system Improved knowledge about lung structure-function relationships in older age using techniques of imaging and measures of lung function not requiring effort (eg, high-resolution computed tomographic scanning and forced oscillation) Improved assessment of lung processes underlying airflow limitation attributable to aging versus COPD or asthma, especially in asthmatic patients who smoke Studies to examine the effects of aging in ethnic groups and the role of gender Epidemiology, effect, diagnosis, and management Determine the true prevalence and cost of asthma in the older population Develop a uniform definition of asthma to be applied to health care records that will distinguish asthma from COPD and mixed asthma/COPD Evaluate evidence-based treatment algorithms for older asthmatic patients, such as those developed by the National Heart, Lung, and Blood Institute and Global Initiative For Asthma guidelines 7 Assess the effect of asthma treatment, including direct medical costs of care, indirect costs of care, and value of treatment in improving quality of life 8, 9 Assess the effect of comorbid conditions, especially COPD and congestive heart failure, on asthma 9 Characterize phenotypes of elderly asthma with regard to responses to therapy and long-term outcomes based on age of onset, duration of disease, and environmental triggers Develop algorithms for electronic medical record systems that are asthma-specific Evaluate effects of current asthma medications in older patients compared with younger patients Identify pharmacogenetic determinants of response to asthma medications in older adults Identify simpler and safer drug delivery systems and schedules for older adults Develop simple methods to differentiate COPD from asthma exacerbations in older adults
cord-259927-xh9cw9ao	2017	When considering prevention or treatment of viral respiratory tract infections, potential targets include the causative pathogens themselves but also the immune response, disease transmission, or even just the symptoms. Here we provide an overview of the options and highlight some of the most promising approaches in vRTI treatment, including symptomatic medication, immunomodulatory drugs, antiviral agents, and natural products, as well as in vRTI prevention, ranging from vaccines to immunostimulators and public health policies. Early in vivo evidence suggested that azithromycin has anti-inflammatory and antiviral effects through induction of interferon-stimulated gene mRNA expression and reduced viral replication and release in patients with asthma and chronic obstructive lung disease. mAb therapies to viral infections, such as EBV (rituximab) or RSV (palivizumab), provide passive immunization and are licensed, whereas similar agents targeting influenza and other viruses are in preclinical development.
cord-260700-u12aa739	2010	title: Recurrent and persistent respiratory tract viral infections in patients with primary hypogammaglobulinemia OBJECTIVE: We conducted a prospective 12-month follow-up study of respiratory tract infections in 12 adult patients with primary hypogammaglobulinemia. METHODS: Nasal swab samples and induced sputum samples were taken at the onset of acute respiratory tract infection and every 3 months thereafter. CONCLUSIONS: Despite adequate immunoglobulin replacement therapy, patients with primary hypogammaglobulinemia have increased susceptibility to respiratory tract viral infections. Using modern diagnostic techniques, we wanted to study the occurrence of respiratory tract infections, especially viral infections, in patients with primary hypogammaglobulinemia who were receiving regular immunoglobulin replacement therapy. If the spouse of the patient had acute symptoms of respiratory tract infection, she or he took nasal swabs at home according to the instructions of the research nurse and sent the vials by post. First, despite adequate immunoglobulin replacement therapy, most patients with primary hypogammaglobulinemia had increased susceptibility to respiratory tract viral infections.
cord-264311-t81r2l3r	2019	To address the knowledge gap, we examined the association between rhinovirus species and the nasopharyngeal airway microbiota determined by 16S rRNA gene sequencing in 774 infants with severe bronchiolitis. Briefly, 1016 infants (age <1 year) hospitalized for bronchiolitis were enrolled in 17 sites across 14 US states (see Table E1 in this article''s Online in PBMC-engrafted mice (n 5 14-16 per group) without or with injection of neutrophils and subsequent intranasal challenge with birch pollen extract (BPE) or PBS. 7 Our observations-for example, the association between RV-C and higher likelihood of Moraxella-dominant microbiota-corroborate these earlier findings, and extend them by applying 16S rRNA gene sequencing to the airway samples of a large multicenter prospective cohort of infants with severe bronchiolitis. Despite this complexity, the identification of the association between specific virus species and airway microbiota in infants with bronchiolitis is important given their relation to subsequent respiratory health in children.
cord-265054-52eqdlef	2006	By this same theory, it has been demonstrated that chemokine levels produced during respiratory syncytial virus infection determine host responses to later immune stimuli in the lung, with the potential to augment the asthmatic response. 3 These studies are supported by clinical investigations that demonstrate that a relatively low number of influenza cases, versus RSV or rhinovirus infections, actually cause exacerbation of asthma and acute bronchiolitis in adults. A comparative study examining the effects of respiratory viruses on CXCL8 production found that although levels of CXCL8 protein in the nasal lavage fluid (NLF) of influenza virusand rhinovirus-infected patients correlated with a higher symptom score, this was not the case for RSV-infected patients. The recruitment of allergen-responsive T cells to the lung and draining lymph nodes has been linked to CCR1 in a murine model of RSV-induced exacerbation of allergic asthma (Schaller and Lukacs, unpublished data).
cord-269776-hj1s3ipp	2004	Concerning HAE-I and HAE-II, just as variations in serum concentrations of APP appear to determine which individuals in a normal population develop angioedema with a second perturbation of kinin metabolism, such as the use of ACE inhibitors, 96 it could be speculated that variations in either kinin activation or inactivation pathways might contribute to the differences in severity of angioedema in individuals with a pre-existing perturbation in kinin metabolism, such as a mutation in C1-INH (as occurs in HAE). 13, 14, 27 This increase in plasma bradykinin was demonstrated both for patients with HAE with C1-INH deficiency and for patients with drug-associated angioedema who had an angioedematous attack in conjunction with ACE inhibitor treatment. The patient''s daughter had recurrent skin angioedema and gastrointestinal pain attacks since age 12 years; therefore, with a normal C1-INH concentration and activity in both mother and daughter, a diagnosis of HAE type III was assumed.
cord-270635-l8380adr	2020	It is generally accepted that only achieving a better understanding of the interactions between the virus and host immune response and of the pathogenesis of infection is crucial to identify valid therapeutic tools to control virus entry, replication and spread as well as to impair its lethal effects. On this basis, we also touch important aspects regarding the immune response in asymptomatic subjects, the immune-evasion of SARS-CoV-2 in severe patients and differences in disease severity by age and gender. This implies to be able to answer many questions on the virus itself, on the pathogenesis of infection, on the 81 host immune response and to identify therapeutic tools to control virus entry into the cells, its replication and 82 spread as well as its lethal effects. Humoral Immune Responses SARS-CoV 3 -Seroconversion few days after the disease onset and specific IgG detectable in most patients by 14 days.
cord-272214-rwkfev8j	2020	46 47 There are two general pathways for the production of bradykinin, the first being the release of 48 cellular tissue kallikrein which cleaves low molecular weight kininogen (LK) to release lys-49 bradykinin (Fig. 1) . An alternative process requires 85 carboxypeptidase activity (carboxypeptidase N in plasma and carboxypeptidase M on pulmonary 86 vascular endothelial cells) to first remove the C-terminal arg from either bradykinin (plasma 87 cascade) or lys-bradykinin (tissue kallikrein product) (Fig. 1) . Studies of gene expression in 97 bronchoalveolar lavage specimens of COVID-19 patients(5), when compared to normal control 98 specimens, reveal upregulation of multiple components that lead to bradykinin production and 99 expression for C1-INH was decreased 33-fold which would render the plasma bradykinin 102 cascade labile and overreactive as we see in C1-INH deficiency (types I and II HAE) in which 103 enzymes not adequately inhibited by C1-INH include both forms of activated factor XII, plasma 104 kallikrein, and C1r.
cord-281566-6v5zfue6	2013	12 Our group found that cultured airway epithelial cells from patients with CRSsNP had an exaggerated response to stimulation with the combination of double-stranded RNA (a Toll-like receptor [TLR] 3 agonist and surrogate for viral infection) plus cigarette smoke extract, with exaggerated production of RANTES and hBD-2. Ramanathan et al 3 showed that culturing human sinonasal epithelial cells in the presence of the T H 2 cytokines IL-4 or IL-13 for 36 hours reduced expression of antimicrobial innate immune genes by using real-time PCR, ELISA, and flow cytometry, including TLR9, hBD-2, and SP-A. This has been shown in cultured airway epithelial cells and dispersed T lymphocytes from NPs. Fungi are commonly detected in the attached mucus of sinus tissues in patients with CRS 47,165 and can induce eosinophil activation and degranulation. Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells
cord-284053-tna7e9dw	2020	Objective To extend our work in interleukin (IL)-13 biology to determine if airway epithelial cell expression of two key mediators critical for SARS-CoV-2 infection, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) are modulated by IL-13. Methods We determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. Here, we demonstrate that interleukin (IL)-13, a cytokine associated 115 with type 2 (T2) asthma, suppresses ACE2 receptor expression and significantly 116 increases TMPRSS2 expression in airway epithelial cells from participants with T2 117 asthma and atopy. In addition, participants who are defined as T2 high based upon three gene 246 signatures (CLCA1, POSTN, SERPINB2) (17) also demonstrate lower nasal epithelial 247 ACE2 expression compared to the T2 low and healthy control groups (Fig 2C) .
cord-284576-nemh4wdo	2020	Methods Blood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with ageand sex-matched healthy controls to provide insights into differential regulation of 185 markers. Objective: To identify and characterize the host inflammatory response to SARS-CoV-2 59 infection, we assessed levels of proteins related to immune responses and cardiovascular 60 disease, in patients stratified as mild, moderate, and severe, versus matched healthy controls. Objective: To identify and characterize the host inflammatory response to SARS-CoV-2 59 infection, we assessed levels of proteins related to immune responses and cardiovascular 60 disease, in patients stratified as mild, moderate, and severe, versus matched healthy controls. Furthermore, in a limited series of patients who were sampled 69 frequently confirming reliability and reproducibility of our assays, we demonstrate that 70 intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine 71 The COVID-19 pandemic created an overwhelming need to define host-derived molecular 96 mediators of disease severity evident in hospitalized patients.
cord-286477-0euaaspo	2020	This study aims to describe and compare the 141 epidemiological, demographic, clinical, laboratory and radiological characteristics as well as the 142 complications, treatment and outcomes of hospitalized patients with nonsevere and severe 143 COVID-19. Comparison of findings between nonsevere and severe cases in 223 the patients with positive viral nucleic acid test pre-admission showed essentially the similar 224 differences to that in the total patients (see Table E1 in the Online Repository). In the follow-up period, the complications of COVID-19 were assessed , including acute 297 respiratory distress syndrome (ARDS) (38.3%), cardiac injury (21.7%), liver dysfunction (19.3%), 298 acute kidney injury (17.3%), bacteremia (7.7%), diffuse intravascular coagulation (7.7%), and 299 hyperglycemia (33.2%) ( This study provided a comprehensive data on the epidemiological, demographic, clinical, 338 laboratory, and radiological characteristics as well as the complications, treatment, and outcomes 339 of hospitalized patients with nonsevere and severe COVID-19 in Wuhan.
cord-287063-kheek4lx	2012	In this investigation that included mother-infant dyads enrolled in the Tennessee Children''s Respiratory Initiative (TCRI), we tested the hypothesis that a familial atopic predisposition was associated with viral cause and increased severity of viral acute respiratory tract infection (ARI) during infancy. In our next set of analyses we examined whether having a mother with asthma (first defined by maternal self-report and then using the atopic asthma and nonatopic asthma classifications) was associated with increased severity of the infant''s HRV-or RSV-induced ARI. [5] [6] [7] 12, 22 Because of the known differential risk of early childhood asthma after RSV-and HRV-induced infant infections, we were interested in studying whether a familial predisposition to asthma and allergies was associated with the viral cause of the infant''s ARI and the severity of the ARI.
cord-302886-5zjghwkq	2020	OBJECTIVE: Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). Although the available evidence favors the presence of severe immunopathology during COVID-19 ARDS, the compartmental transmission of immunoinflammatory processes between blood and lungs remains unexplored, and characterization of distinct leukocyte subpopulations and their cytokine mediators could thus potentially reveal both novel therapeutic targets and guide the timing of treatment. In the present study, we immunophenotyped bronchoalveolar lavage fluid (BALF) and blood of mechanically ventilated patients with moderate-to-severe COVID-19 ARDS. [33] [34] [35] A recent study performed genome-wide transcriptome sequencing of RNA obtained from BALF in 3 patients with COVID-19 with unknown disease severity; it reported different expression of 1004 genes, including a high expression of cytokines such as MCP-1, IP-10, MIP-1A, and MIP-1B. In conclusion, our study provides novel phenotypic insight into the cell composition and inflammatory mediators simultaneously present in the lungs and blood in patients with COVID-19 ARDS.
cord-303135-rx21ajiw	2020	This leads us to the question whether treatment in patients with allergic rhinitis, normally INCS, or in severe patients with CRSwNP, nowadays including biologics to suppress type 2 immune reactions, should be continued in case of a SARS-CoV-2 infection. SARS-CoV-2 may also infect patients with severe asthma and CRSwNP, who might be under treatment with a type 2 biologic drug such as dupilumab, omalizumab, or mepolizumab. However, we begin to recognize that diseases of the upper airways or their management by corticosteroids and biologics do not seem to increase the risk of infection nor the risk for severe COVID-19. In research perspective, because the airway passage of nose and nasopharynx is the main entry for respiratory viruses including the SARS-CoV 2, the expression and its regulation of the ACE2 receptor and the TMPRSS2 protease are key topics for research and targets for interventions. SARS-CoV-2 entry genes are most highly expressed in nasal goblet and ciliated cells within human airways
cord-304140-4l574k3q	2014	METHODS: We included 22 patients with similar RAG1 mutations (c.519delT or c.368_369delAA) resulting in N-terminal truncated RAG1 protein with residual recombination activity but presenting with different clinical phenotypes. 9 Different RAG mutations can result in a broad spectrum of clinical phenotypes, including severe combined immunodeficiency (SCID), RAG deficiency (RAGD) with skin inflammation and ab T-cell expansion (classical Omenn syndrome [OS]), RAGD with skin inflammation but without T-cell expansion (incomplete OS), RAGD with maternofetal transfusion, RAGD with gd T-cell expansion, late-onset SCID, RAGD with granulomas, and RAGD with CD4 cytopenia and thymus hypoplasia. This suggests that receptor editing in this group of patients with RAGD was slightly impaired, which can either be a result of reduced recombination activity caused by the RAG1 mutation or by low B-cell numbers leading to reduced selection against autoreactive B cells.
cord-304320-1oaobtlx	2020	One patient developed Multisystem Inflammatory Syndrome in Children (MIS-C) in the setting of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Discussion Heterozygous loss-of-function SOCS1 mutations are associated with enhanced interferon signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias. 2, 4 In a recent study detailing 88 outcomes of whole-genome sequencing for patients with primary immunodeficiency, SOCS1 89 haploinsufficiency was briefly described in two individuals with recurrent bacterial infections and 90 severe multi-systemic autoimmunity. Individuals with Evans syndrome (ES) present with immune thrombocytopenia (ITP), 93 autoimmune hemolytic anemia (AIHA), and/or immune neutropenia arising from either primary 94 or secondary causes. Patient 1 presented at five months of age with fever, otitis media, oral ulcers, and developed ITP (61 x 10 3 platelets/µL, normal 215-448 x 10 3 platelets/µL; Fig. 1A ). At two years 107 of age, in addition to ITP and immune neutropenia, he developed a warm antibody AIHA with a 108 hemoglobin of 4.4 g/dL (normal 10.5-13.0 g/dL).
cord-304549-e8q8mck4	2005	Abnormal signaling between the epithelium, which is in contact with the environment, and the underlying (myo)fibroblasts and dendritic cells indicating reactivation of the epithelial mesenchymal trophic unit, which is involved in fetal lung development and branching, provide a basis for asthma that encapsulates both T(H)2 polarization and airway wall remodeling. Asthma is a complex disorder involving a combination of genetic and environmental interactions that culminate in a specific type of inflammation involving mast cells, eosinophils, and macrophages and polarization of T cell-mediated immunity toward enhanced production of cytokines encoded in a cluster on the long arm of chromosome 5. Two fundamental approaches are being used to discover susceptibility genes in asthma and atopy: linkage analysis with functional cloning and association analysis for mutations of "candidate" genes thought to be involved in disease pathogenesis. 55 In susceptible mice genetic linkage has shown that ozone-induced lung inflammation is directed by genes encoded on chromosome 17, including the strong candidate TNF-α, a pleiotropic cytokine generated during oxidant-induced cell injury.
cord-313058-nrrl4kjc	2020	title: COVID-19 Associated Multisystem Inflammatory Syndrome in Children (MIS-C): a novel disease that mimics Toxic Shock Syndrome. As of mid-September, the novel severe acute respiratory syndrome coronavirus 2 26 (SARS-CoV-2) has infected more than 30 million people, resulting in approximately one 27 million deaths worldwide, including over 200,000 deaths in the USA alone. Exacerbation of the COVID-19 immune response manifested by extensive cytokines 33 release, called cytokine storm, may lead to multisystem inflammatory syndrome that is 34 fatal in 28% of cases 1 . Interestingly, SAg-induced TSS has been associated with long-term 94 neuropsychologic deficits in adults, including cognitive decline 10 , and we identified a 95 homology between the SAg motif of SARS-CoV-2 and neurotoxin-like sequences which 96 are able to bind the TCR 5 . Clinical 131 Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome 132 Temporally Associated With SARS-CoV-2
cord-314640-vik5rgnq	2005	Several aminopeptidase (Ap) activities were defined by (1) substrate specificity with leucine-enkephalin (leu-Ap) and alanine-nitroanilide (ala-Ap), (2) inhibitor studies with puromycin and bestatin, (3) enzyme activity histochemistry (zymography), (4) immunohistochemistry, and (5) gel electrophoresis. To begin defining the physiology of aminopeptidases in airways, we have used multiple assays to characterize aminopeptidase activity in soluble and membrane fractions of human nasal mucosa. Enkephalin-degrading aminopeptidase activity was expressed as picomoles of leuenkephalin metabolized per minute per milligram of protein for extracts, or as picomoles of leu-enkephalin metabolized per minute per milliliter for nasal lavage fluid samples. Alanine aminopeptidase (Ala-Ap) assay samples (25 µL) were added to cuvettes containing 1.65 mL of 10 mmol/L tris HCl buffer (pH 7.4), 1 µmol/L phosphoramidon, and 10 µmol/L captopril, mixed thoroughly, and incubated for 1 minute.
cord-323695-jkik03lb	2020	Objective investigating the incidence of hospitalization and death for COVID-19 in a large sample of patients with plaque psoriasis receiving biologic therapies compared with the general population. Materials and methods This is a retrospective multicenter cohort study including patients with chronic plaque psoriasis (n=6,501) being treated with biologic therapy and regularly followed up at the Divisions of Dermatology of several main hospitals in the Northern Italian cities of Verona, Padua, Vicenza, Modena, Bologna, Piacenza, Turin, and Milan. Incidence rates (IR) of hospitalization and death per 10,000 person-months with exact mid-p 95% confidence intervals (CI) and standardized incidence ratios (SIR) were estimated in the psoriasis patients and compared with the general population in the same geographic areas. We would not advise biologic discontinuation in patients on treatment since more than 6 months and not infected with SARS-CoV-2 to prevent hospitalization and death from COVID-19. In this study, we evaluated the incidence of hospitalization and death for COVID-19 in a large sample of patients with plaque psoriasis receiving biologic therapies compared with the general population.
cord-327076-qq5499qg	2020	title: COVID-19 and upper respiratory tract: Collecting swab specimens from patients inhaling corticosteroids Correspondence COVID-19 and upper respiratory tract: Collecting swab specimens from patients inhaling corticosteroids Q 1 To the Editor: Jian et al 1 in a recent article refer to the immune reaction of the upper respiratory tract (URT) in patients infected by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 (coronavirus disease 2019 [COVID-19] pandemic). The authors wonder about the consequences of inhaled corticosteroids (ICSs) on immune reaction. With the URT sprayed by ICSs, we are wondering about the diagnostic accuracy of specimens collected. With this in mind, swabbing the URT of coronavirus-infected patients under an ICS regimen renders the quality of the viral load collected questionable. With all this scepticism in our minds, we are preparing ourselves to cope with the intricacies of triaging in a COVID-19 era, performing with responsibility the swabbing techniques, ensuring specimens of high diagnostic accuracy.
cord-328210-qhl429fm	2020	title: The clinical relevance of the clinical cytological grading in patients with chronic rhinosinusitis with nasal polyps The clinical relevance of the clinical cytological grading in patients with chronic rhinosinusitis with nasal polyps Smell dysfunction is a common symptom and has a diagnostic value in the workup of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) as recently outlined by Mullol et al. As a consequence, a clinical cytological grading (CCG), including the documentation of possible asthma, allergy, or aspirin sensitivity comorbidity, and the presence of eosinophils and/or mast cells in the nose, has been proposed as a precision medicine-based approach in the management of patients with CRSwNP. Non-surgical management of chronic rhinosinusitis with nasal polyps based on clinical cytological grading: a precision medicine-based approach Olfactory dysfunction in patients with chronic rhinosinusitis with nasal polyps is associated with clinical-cytological grading severity
cord-334801-p5mxc694	2020	We evaluated the accuracy of clinical signs and these biomarkers in predicting 30-day intubation/mortality, and oxygen requirement by calculating the area under the receiver operating characteristic curve (AUROC) and by classification and regression tree analysis. sTREM-1-and IL-6-based algorithms are 54 highly sensitive to identify patients with adverse outcome and could serve as early triage The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to 84 surges of patients that can overwhelm health systems (1) (2) (3) (4) . Current prediction 90 models to support clinical decision making for Coronavirus disease (COVID-19) patients 91 were developed based on demographics, clinical signs and symptoms, imaging techniques, 92 biomarkers or a combination of these variables, however most are poorly validated and at risk 93 of bias (10). 282 The CRT analysis performed with all clinical signs, severity scores and biomarkers to predict Since we could also use this triage tool to identify patients at high risk of poor outcomes, we 290 tested this algorithm to predict 7-and 30-day intubation/death.
cord-341650-f8orw6ro	2020	title: Regarding "Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial" Regarding ''''Ruxolitinib in Q 1 treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, singleblind, randomized controlled trial'''' Q 2 To the Editor: We read with great interest the article titled ''''Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial'''' by Cao et al. 1 The study, which finally included 41 patients, evaluated the efficacy and safety of ruxolitinib for severe COVID-19 cases. First, the duration from illness onset to randomization, 22 days for the control group and 20 days for the ruxolitinib group, was not appropriate because according to literature reports, 2-4 the course (from illness onset to discharge) of severe patients was about 27 to 30 days. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, singleblind, randomized controlled trial Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study
cord-344759-7zs389m9	2020	128 129 One hundred and five (~34%) of the 309 infants with RSV-only ARIs enrolled in INSPIRE had 130 ≥1 nasal wash with 16S rRNA sequencing and immune mediator data available -obtained as Page 7 part of separate projects 5, 6 -and were thus included in our study. Cluster #1 also mainly included 147 infants with a higher relative abundance of Haemophilus in their nasopharynx (Figure 1) In unadjusted analyses, the nasopharyngeal relative abundance of Haemophilus was positively 152 correlated with the levels of 39 (~75%) of the 52 local immune mediators after controlling for 153 multiple comparisons (Figure 2A and Table E3 in the Online Repository). 8, 9 195 196 Our study has multiple strengths, including the population-based design of the parent study, the 197 close surveillance during the infants'' first winter viral season to capture their initial RSV ARI, 198 the use of next-generation sequencing and high-throughput immune assays, and the use of 199 statistical analysis adjusting for potential confounders.
cord-346835-gg3xespb	2020	title: Will environmental impacts of social distancing due to the SARS-CoV-2 pandemic decrease allergic disease? The burden of climatic change and air pollution represents a massive challenge for Humanity, affecting the development of allergic diseases and upsetting the exposome. 1 Air pollution, a causative factor of climate change, contributes to nine million deaths by years, 2 and more than 500 million people have an allergic disease around the world. Air pollution is a causative factor for both various symptoms such as bronchospasm, rhinorrhea, eye redness, and irritation, as well as various allergic diseases such as asthma, chronic rhinitis, nasal polyposis, atopic dermatitis, seasonal or perennial allergic conjunctivitis, and vernal or atopic keratoconjunctivitis. 7 Similar decrease was measured in most megalopolis of developing countries around the world where containment was set for limiting the spreading of the SARS-CoV-2 ( Figure 1 ). Climate Change and the Impact on Respiratory and Allergic Disease Effects on asthma and respiratory allergy of Climate change and air pollution
cord-347512-veavzt6d	2020	Methods We analyzed plasma levels of myeloperoxidase (MPO, neutrophil activation), soluble (s) CD25 and soluble T cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T cell activation and exhaustion) and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19 infected patients at hospital admission and two additional times during the first 10 days in relation to the need for ICU treatment. Results Our major findings were: (i) Severe clinical outcome (ICU) was associated with high plasma levels sTIM-3 and MPO suggesting activated and potentially exhausted T cells and activated neutrophils, respectively. Patients admitted to ICU were characterized by high levels of the T cell activation marker sCD25 and sTIM-3 in à priori analysis, and for sTIM-3 also in posthoc testing. In contrast to the T cell markers and MPO, plasma levels of sCD14 and sCD163, reflecting activation of monocytes/macrophages, were similar in ICU and non-ICU patients ( Figure 1 ).
cord-349754-v6lll1xy	2020	title: Investigating asthma heterogeneity through shared and distinct genetics: insights from genome-wide cross-trait analysis The genome-wide cross-trait analysis features in several analytical aspects: genetic correlation, cross-trait meta-analysis, Mendelian randomization, polygenic risk score and functional analysis. A major advantage going from phenotypic correlations to genetic 138 correlations is to improve understanding of the mechanism(s)-shared genetic components can 139 be identified at different levels, from whole genome to individual variants, providing insights 140 into the reasons why asthma and coexistent diseases or traits are correlated. 26-29 A genome-wide cross-trait analysis features several analyses: 173 genetic correlation, cross-trait meta-analysis, Mendelian randomization, polygenic risk score, 174 and GWAS functional analysis. Of note, the human leukocyte antigen (HLA) region (chr6: 25-34Mb) was found to be 262 shared in the cross-trait meta-analysis of allergic disease and asthma as well as that between 263 major depressive disorder and asthma. Genome-wide association study (GWAS) An analytical method that tests the association between each genetic variant and a specific phenotype (a disease status or a quantitative trait).