Vascular risk factors for COVID-19 ARDS: endothelium, contact-kinin system

SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity–conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity

Influence of gestational and developmental age on human airway epithelial innate immune responses to Respiratory Syncytial Virus (RSV) in early life

BackgroundRSV is a major respiratory pathogen in infants, with preterm and young infants being at increased risk of severe disease. Airway epithelial cell (AEC) innate immune responses represent an important first line of defence. Development of these responses in early life is poorly understood.MethodsWell differentiated cultures were generated using nasal AECs harvested from term and preterm infants at birth and from the same infants at one-year old. Cultures were infected with RSV and resulting cytopathology and innate immune responses studied.ResultsRSV growth kinetics were similar between preterm and term newborn cohorts at birth and in the one-year-old repeat cohort. Secretion of interferon lambda-1 (IFN-l1), CXCL10 (IP-10), CCL5 (RANTES) and CXCL8 (IL-8) were similar between RSV-infected preterm and term newborn AECs. Following RSV infection, significantly higher secretion of IFN-l1 (P=0.0034), CXCL10 (P&lt;0.05) and CCL5 (P&lt;0.05) was noted in one-year-derived AECs compared to newborn AECs. We also identified differential expression of a novel endogenously expressed anti-RSV protein, pleiotrophin (PTN), which interacts with nucleolin, a cofactor for RSV entry. PTN expression/secretion was significantly decreased in preterm versus term AECs (P=0.014) and in newborn compared to one-year WD-PNECs (P=0.0008).ConclusionThese exciting findings represent the first description of age- and prematurity-related differences in AEC innate immune responses, demonstrating greater RSV-induced expression of pro-inflammatory chemokines with increasing age and developmental differences in expression of the novel anti-RSV protein PTN. These findings may, in part, explain the increased susceptibility of preterm and very young infants to severe RSV disease.<br/

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity

Characterisation of morphological differences in well-differentiated nasal epithelial cell cultures from preterm and term infants at birth and one-year

BackgroundInnate immune responses of airway epithelium are important defences against respiratory pathogens and allergens. Newborn infants are at greater risk of severe respiratory infections compared to older infants, while premature infants are at greater risk than full term infants. However, very little is known regarding human neonatal airway epithelium immune responses and whether age-related morphological and/or innate immune changes contribute to the development of airway disease.MethodsWe collected nasal epithelial cells from 41 newborn infants (23 term, 18 preterm) within 5 days of birth. Repeat sampling was achieved for 24 infants (13 term, 11 preterm) at a median age of 12.5 months. Morphologically- and physiologically-authentic well-differentiated primary paediatric nasal epithelial cell (WD-PNEC) cultures were generated and characterised using light microscopy and immunofluorescence.ResultsWD-PNEC cultures were established for 15/23 (65%) term and 13/18 (72%) preterm samples at birth, and 9/13 (69%) term and 8/11 (73%) preterm samples at one-year. Newborn and infant WD-PNEC cultures demonstrated extensive cilia coverage, mucous production and tight junction integrity. Newborn WD-PNECs took significantly longer to reach full differentiation and were noted to have much greater proportions of goblet cells compared to one-year repeat WD-PNECs. No differences were evident in ciliated/goblet cell proportions between term- and preterm-derived WD-PNECs at birth or one-year old.ConclusionWe describe the successful generation of newborn-derived WD-PNEC cultures and their revival from frozen. We also compared the characteristics of WD-PNECs derived from infants born at term with those born prematurely at birth and at one-year-old. The development of WD-PNEC cultures from newborn infants provides a powerful and exciting opportunity to study the development of airway epithelium morphology, physiology, and innate immune responses to environmental or infectious insults from birth

Correction: Characterisation of morphological differences in well-differentiated nasal epithelial cell cultures from preterm and term infants at birth and one-year

There are errors in the Author Contributions. The correct contributions are: Conceptualization: MDS, UFP, HEG. Data curation: HEG, LB, HGP. Formal analysis: HEG, LB, MDS, UFP. Funding acquisition: MDS, UFP, HEG. Investigation: HEG, HGP, LB, UFP, MDS. Methodology: HGP, HEG, LB, UFP, MDS. Supervision: MDS, UFP. Writing–original draft: HEG. Writing–review &amp; editing: HGP, LB, MDS, UFP.<br/