From "Immunity Debt" to "Immunity Theft"-How COVID-19 Might Be Tied to Recent Respiratory Disease Surges.

This Medical News story discusses the relationship between the COVID-19 pandemic and recent increases in other respiratory diseases.

Assessing the impact of air pollutants on clinical visits for childhood allergic respiratory disease induced by house dust mite in Shanghai, China.

BACKGROUND: The prevalence of allergic respiratory disease (ARD) is increasing worldwide during the last few decades, causing a great disease burden especially for children. Air pollution has been increasingly considered as a potential contributor to this trend, but its role in ARD induced by house dust mite (HDM-ARD) remains unclear, especially in time-series study. METHODS: A positive reporting of respiratory allergy to named allergens was included by serum specific IgE testing. A time series Quasi-Poisson regression with distributed lag non-linear model, combined with generalized linear model was used to examine the effects of air pollutants on ARD, HDM-ARD and ARD induced by non-house dust mite (NHDM-ARD). RESULTS: A total of 16,249 cases of ARD, including 8,719 HDM-ARD and 8,070 NHDM-ARD from 1 Jan 2013 to 31 Dec 2017 were involved in this study. Air pollutants were significantly associated with clinical visits for childhood ARD and HDM-ARD. Exposure to higher O3 and interquartile range (IQR) increment in O3 (40.6 µg/m3) increased the risks of clinical visits for childhood HDM-ARD (RRlag0-5 for the 95th percentile of O3: 1.26, 95% confidence interval (CI): 1.03, 1.55; RRlag0-5 for IQR increment (40.6 µg/m3): 1.09, 95% CI: 1.01, 1.17) and ARD (RRlag0-5 for the 95th percentile of O3: 1.19, 95% CI: 1.03, 1.38; RRlag0-5 for IQR increment (40.6 µg/m3): 1.06, 95% CI: 1.01, 1.12). In addition, higher O3 was associated with increased RR of boys with ARD (RRlag0-5 for the 95th percentile: 1.26, 95% CI: 1.05, 1.51; RRlag0-5 for IQR increment (40.6 µg/m3): 1.09, 95% CI: 1.02, 1.16) and HDM-ARD (RRlag0-5 for the 95th percentile: 1.36, 95% CI: 1.06, 1.75; RRlag0-5 for IQR increment (40.6 µg/m3): 1.11, 95% CI: 1.02, 1.22), but not in girls. CONCLUSIONS: Exposure to O3 appeared to be a trigger of clinical visits for childhood ARD, especially for HDM-ARD and boys. These findings provide novel evidence on the impact of air pollution on HDM-ARD, which may have significant implications for designing effective intervention programs to control and prevent childhood ARD, especially HDM-ARD, in China and other similar developing countries.

Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease.

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.

Persistence of High Levels of Serum Complement C5a in Severe COVID-19 Cases After Hospital Discharge.

Evidence supports a role of complement anaphylatoxin C5a in the pathophysiology of COVID-19. However, information about the evolution and impact of C5a levels after hospital discharge is lacking. We analyzed the association between circulating C5a levels and the clinical evolution of hospitalized patients infected with SARS-CoV-2. Serum C5a levels were determined in 32 hospitalized and 17 non-hospitalized patients from Clinica Universidad de Navarra. One hundred and eighty eight serial samples were collected during the hospitalization stay and up to three months during the follow-up. Median C5a levels were 27.71 ng/ml (25th to 75th percentile: 19.35-34.96) for samples collected during hospitalization, versus 16.76 ng/ml (12.90-25.08) for samples collected during the follow-up (p<0.001). There was a negative correlation between serum C5a levels and the number of days from symptom onset (p<0.001). C5a levels also correlated with a previously validated clinical risk score (p<0.001), and was associated with the severity of the disease (p<0.001). An overall reduction of C5a levels was observed after hospital discharge. However, elevated C5a levels persisted in those patients with high COVID-19 severity (i.e. those with a longest stay in the hospital), even after months from hospital discharge (p=0.020). Moreover, high C5a levels appeared to be associated with the presence of long-term respiratory symptoms (p=0.004). In conclusion, serum C5a levels remain high in severe cases of COVID-19, and are associated with the presence of respiratory symptoms after hospital discharge. These results may suggest a role for C5a in the long-term effects of COVID-19 infection.

Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System-Implications for Health and Disease.

The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS. It is implicated in a variety of physiological and pathological states and an attractive pharmacological target yet to reach its full potential. This review will focus on the involvement of ECS in glucose and lipid metabolism, food intake regulation, immune homeostasis, respiratory health, inflammation, cancer and other physiological and pathological states will be substantiated using freely available data from open-access databases, experimental data and literature review. Future directions should envision capturing its diversity and exploiting pharmacological options beyond the classical ECS suspects (exogenous cannabinoids and cannabinoid receptor monomers) as signaling through cannabinoid receptor heteromers offers new possibilities for different biochemical outcomes in the cell.

Mutant Mice and Animal Models of Airway Allergic Disease.

Eosinophilia is a hallmark of allergic airway inflammation, and eosinophils represent an integral effector leukocyte through their release of various granule-stored cytokines and proteins. Numerous mouse models have been developed to mimic clinical disease and they have been instrumental in furthering our understanding of the role of eosinophils in disease. Most of these models consist of intranasal (i.n.) administration of antigenic proteases including papain and house dust mite (HDM) or the neo-antigen ovalbumin, with a resulting Th2-biased immune response and airway eosinophilia. These models have been particularly informative when combined with the numerous transgenic mice available that modulate eosinophil frequency or the mechanisms involved in their migration. Here, we describe the current models of allergic airway inflammation and outline some of the transgenic mice available to study eosinophil disease.

Eosinophils in Asthma Models to House Dust Mite for Drug Development.

Murine models of asthma are developed to better understand the mechanisms of asthma including eosinophil recruitment in the airways with the aim of evaluating new therapeutic strategies. They are intended to model the typical features of human disease, in particular airway inflammation, hyperresponsiveness (AHR), and remodeling. The phenotype of inflammatory cells recovered from the bronchoalveolar lavage fluid (BAL) is studied with innovative flow cytometry techniques while airway obstruction is measured using the forced oscillation technique, and airway responsiveness approached by barometric plethysmography in awake and unconstrained animals. We here describe models of asthma of house dust mite (HDM) as a clinically relevant allergen: a short study design (8 days) model of hypereosinophilic asthma and a chronic (31 days) asthma model, both suitable to evaluate the potential of new drug candidates to prevent allergic asthma.

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities.

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.

Activation of the 15-lipoxygenase pathway in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.

Monoclonal Antibodies and Airway Diseases.

Monoclonal antibodies, biologics, are a relatively new treatment option for severe chronic airway diseases, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS). In this review, we focus on the physiological and pathomechanisms of monoclonal antibodies, and we present recent study results regarding their use as a therapeutic option against severe airway diseases. Airway mucosa acts as a relative barrier, modulating antigenic stimulation and responding to environmental pathogen exposure with a specific, self-limited response. In severe asthma and/or CRS, genome-environmental interactions lead to dysbiosis, aggravated inflammation, and disease. In healthy conditions, single or combined type 1, 2, and 3 immunological response pathways are invoked, generating cytokine, chemokine, innate cellular and T helper (Th) responses to eliminate viruses, helminths, and extracellular bacteria/fungi, correspondingly. Although the pathomechanisms are not fully known, the majority of severe airway diseases are related to type 2 high inflammation. Type 2 cytokines interleukins (IL) 4, 5, and 13, are orchestrated by innate lymphoid cell (ILC) and Th subsets leading to eosinophilia, immunoglobulin E (IgE) responses, and permanently impaired airway damage. Monoclonal antibodies can bind or block key parts of these inflammatory pathways, resulting in less inflammation and improved disease control.

Potential of electric stimulation for the management of COVID-19.

The COVID-19 pandemic is the most devastating health emergency that humans have seen over the past century. The war against the disease has been handicapped by unavailability of effective therapeutic options. Till date, there is no clinically approved vaccine or drug for the treatment of COVID-19, and the ongoing search to find a novel therapy is progressing at pandemic pace. Herein, we propose a novel hypothesis based on sound research evidence that electric stimulation can be a potential adjuvant to the currently used symptomatic therapies and antiviral drugs. Based on preclinical evidence, we propose that electric stimulation can improve respiratory functions, inhibit SARS-CoV-2 growth, reduce pain, boost immunity and improve the penetration of antiviral drugs. We envisage that our hypothesis, if used clinically as an adjuvant, may significantly improve the therapeutic outcomes of the current treatment regimen being used around the globe for the management of COVID-19.

Mucosal-associated invariant T cells: new players in CF lung disease?

The past decade has witnessed a surge in research centered around exploring the role of the enigmatic innate immune-like lymphocyte MAIT cell in human disease. Recent evidence has led to the elucidation of its role as a potent defender at mucosal surfaces including lungs due to its capacity to mount a formidable immediate response to bacterial pathogens. MAIT cells have a unique attribute of recognizing microbial ligands in conjunction with non-classical MHC-related protein MR1. Recent studies have demonstrated their contribution in the pathogenesis of chronic pulmonary disorders including asthma and chronic obstructive pulmonary disease. Several cellular players including innate immune cells are active contributors in the immune imbalance present in cystic fibrosis(CF) lung. This immune dysregulation serves as a central pivot in disease pathogenesis, responsible for causing immense structural damage in the CF lung. The present review focuses on understanding the role of MAIT cells in CF lung disease. Future studies directed at understanding the possible relationship between MAIT cells and regulatory T cells (Tregs) in CF lung disease could unravel a holistic picture where a combination of antimicrobial effects of MAIT cells and anti-inflammatory effects of Tregs could be exploited in synergy to alleviate the rapid deterioration of lung function in CF lung disease due to the underlying complex interplay between persistent infection and inflammation.

Sputum biomarkers during aspirin desensitization in nonsteroidal anti-inflammatory drugs exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization (AD) is an effective and safe therapeutic option for patients with nonsteroidal anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease (N-ERD). The mechanisms driving its beneficial effects remain poorly understood. OBJECTIVE: To investigate the effect of long-term AD on clinical, biochemical and radiological changes in N-ERD patients. METHODS: The study group consisted of twenty-three individuals with N-ERD who underwent AD, followed by ingestion of 325 mg aspirin twice daily. Twenty patients completed the 52 weeks of AD. The following evaluations were conducted at baseline and in the 52nd week of AD: (i) clinical: asthma exacerbations, Asthma Control Test (ACT), Visual Analogue Scale (VAS) for the assessment of nasal symptoms; (ii) blood and induced sputum supernatant (ISS) periostin, (iii) phenotypes based on induced sputum (IS) cells, (iiii) ISS and nasal lavage (NL) concentration of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), tetranor-PGD-M, tetranor-PGE-M, 8-iso-PGE2, leukotriene B4 (LTB4), LTC4, LTD4 and LTE4, and urine LTE4. RESULTS: A significant improvement was observed in ACT (P = 0.02) and VAS score (P = 0.008) in the 52nd week of AD. ISS periostin and IS eosinophil count decreased significantly in the 52nd week of AD (P = 0.04 and P = 0.01, respectively). ISS and NL eicosanoid concentrations did not change following long-term AD. CONCLUSION: and Clinical Relevance: AD is associated with a decrease in sputum periostin biosynthesis, which may prevent the recruitment of eosinophils into respiratory tissue and be one of explanation of the clinical benefits of AD. Long-term aspirin administration does not lead to an imbalance between pro- and anti-inflammatory ISS eicosanoids.

Functional effects of the microbiota in chronic respiratory disease.

The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.

The emerging role of immunothrombosis in paediatric conditions.

BACKGROUND: Immunothrombosis is a physiological process based on the release of neutrophil extracellular traps (NETs) to immobilise, contain and kill bacteria. This is an innate immune response in which the local activation of blood coagulation exerts the critical protective function during microbial infection. In recent years, there has been much interest in the adult literature about the key role of immunothrombosis in pathologic states including thrombosis, cancer, sepsis and trauma. Currently, little research has been done into its role in paediatric conditions. METHODS: We conducted a literature search of the National Library of Medicine (MEDLINE/PubMed) from the years 2000 to May 2018 and qualitatively identified 24 relevant papers. References of articles included for full-text review were checked for relevant publications. RESULTS: Our aim is to summarise the most relevant evidences regarding an excessive production or defective removal of NETs in paediatric conditions. In particular, we have divided the role of immunothrombosis into acute (sepsis, necrotising enterocolitis, otitis media, neonatal arterial ischaemic stroke, haemolytic anaemic diseases) and chronic (systemic lupus erythematous, type 1 diabetes mellitus, respiratory diseases, graft-versus-host disease) conditions to find important similarities in their pathophysiology. CONCLUSION: The field of immunothrombosis in paediatric conditions is still in its infancy. We have presented multiple pathways of NET-induced disease together with possible areas of future research and treatments.

Emerging Regulatory Roles of Dual-Specificity Phosphatases in Inflammatory Airway Disease.

Inflammatory airway disease, such as asthma and chronic obstructive pulmonary disease (COPD), is a major health burden worldwide. These diseases cause large numbers of deaths each year due to airway obstruction, which is exacerbated by respiratory viral infection. The inflammatory response in the airway is mediated in part through the MAPK pathways: p38, JNK and ERK. These pathways also have roles in interferon production, viral replication, mucus production, and T cell responses, all of which are important processes in inflammatory airway disease. Dual-specificity phosphatases (DUSPs) are known to regulate the MAPKs, and roles for this family of proteins in the pathogenesis of airway disease are emerging. This review summarizes the function of DUSPs in regulation of cytokine expression, mucin production, and viral replication in the airway. The central role of DUSPs in T cell responses, including T cell activation, differentiation, and proliferation, will also be highlighted. In addition, the importance of this protein family in the lung, and the necessity of further investigation into their roles in airway disease, will be discussed.

Impact of immunization against OxLDL on the pulmonary response to cigarette smoke exposure in mice.

BACKGROUND: Cigarette smoke exposure can affect pulmonary lipid homeostasis and cause a progressive increase in pulmonary antibodies against oxidized low-density lipoproteins (OxLDL). Similarly, increased anti-OxLDL antibodies are observed in atherosclerosis, a pathology also tightly associated with smoking and lipid homeostasis disruption. Several immunization strategies against oxidized lipid species to help with their clearance have been shown to reduce the formation of atherosclerotic lesions. Since oxidized lipids are generated during cigarette smoke exposure, we investigated the impact of a prophylactic immunization protocol against OxLDL on the pulmonary effects of cigarette smoke exposure in mice. METHODS: Mice were immunized systemically with a mixture of human OxLDL (antigen source) and AddaVax (adjuvant) or PBS alone prior to the initiation of acute (2 week) or sub-chronic (8 weeks) cigarette smoke exposure protocols. Anti-OxLDL antibodies were measured in the bronchoalveolar lavage (BAL) fluid and serum by direct ELISA. Pulmonary impacts of cigarette smoke exposure and OxLDL immunization were assessed by measuring BAL inflammatory cells, lung functions, and changes in lung structure and gene levels of matrix/matrix-related genes. RESULTS: Immunization to OxLDL led to a marked increase in circulating and pulmonary antibodies against OxLDL that persisted during cigarette smoke exposure. OxLDL immunization did not exacerbate or reduce the inflammatory response following acute or sub-chronic exposure to cigarette smoke. OxLDL immunization alone had effects similar to cigarette smoke exposure on lung functions but OxLDL immunization and cigarette smoke exposure had no additive effects on these parameters. No obvious changes in lung histology, airspace or levels of matrix and matrix-related genes were caused by OxLDL immunization compared to vehicle treatment. CONCLUSIONS: Overall, this study shows for the first time that a prophylactic immunization protocol against OxLDL can potentially have detrimental effects lung functions, without having additive effects over cigarette smoke exposure. This work sheds light on a complex dynamic between anti-OxLDL antibodies and the pulmonary response to cigarette smoke exposure.

Potential Biomarkers for NSAID-Exacerbated Respiratory Disease.

Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.