Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway

Asthma is a heterogeneous, chronic respiratory disease affecting 300 million people and is thought to be driven by different inflammatory endotypes influenced by a myriad of genetic and environmental factors. The complexity of asthma has rendered it challenging to develop preventative and disease modifying therapies and it remains an unmet clinical need. Whilst many factors have been implicated in asthma pathogenesis and exacerbations, evidence indicates a prominent role for respiratory viruses. However, advances in culture-independent detection methods and extensive microbial profiling of the lung, have also demonstrated a role for respiratory bacteria in asthma. In particular, airway colonization by the Proteobacteria species Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) is associated with increased risk of developing recurrent wheeze and asthma in early life, poor clinical outcomes in established adult asthma and the development of more severe inflammatory phenotypes. Furthermore, emerging evidence indicates that bacterial-viral interactions may influence exacerbation risk and disease severity, highlighting the need to consider the impact chronic airway colonization by respiratory bacteria has on influencing host responses to viral infection. In this review, we first outline the currently understood role of viral and bacterial infections in precipitating asthma exacerbations and discuss the underappreciated potential impact of bacteria-virus crosstalk in modulating host responses. We discuss the mechanisms by which early life infection may predispose to asthma development. Finally, we consider how infection and persistent airway colonization may drive different asthma phenotypes, with a view to identifying pathophysiological mechanisms that may prove tractable to new treatment modalities.

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The impact of certain underlying comorbidities on the risk of developing hospitalised pneumonia in England

Pneumonia ◽

10.1186/s41479-019-0063-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

J. Campling ◽

D. Jones ◽

J. D. Chalmers ◽

Q. Jiang ◽

A. Vyse ◽

...

Keyword(s):

Risk Group ◽

Risk Groups ◽

Chronic Respiratory Disease ◽

Marrow Transplant ◽

Community Acquired Pneumonia ◽

Comorbid Condition ◽

Odds Ratios ◽

Comparator Group ◽

Increased Risk ◽

The Impact

Abstract Background UK specific data on the risk of developing hospitalised CAP for patients with underlying comorbidities is lacking. This study compared the likelihood of hospitalised all-cause community acquired pneumonia (CAP) in patients with certain high-risk comorbidities and a comparator group with no known risk factors for pneumococcal disease. Methods This retrospective cohort study interrogated data in the Hospital Episodes Statistics (HES) dataset between financial years 2012/13 and 2016/17. In total 3,078,623 patients in England (aged ≥18 years) were linked to their hospitalisation records. This included 2,950,910 individuals with defined risk groups and a comparator group of 127,713 people who had undergone tooth extraction with none of the risk group diagnoses. Risk groups studied were chronic respiratory disease (CRD), chronic heart disease (CHD), chronic liver disease (CLD), chronic kidney disease (CKD), diabetes (DM) and post bone marrow transplant (BMT). The patients were tracked forward from year 0 (2012/13) to Year 3 (2016/17) and all diagnoses of hospitalised CAP were recorded. A Logistic regression model compared odds of developing hospitalised CAP for patients in risk groups compared to healthy controls. The model was simultaneously adjusted for age, sex, strategic heath authority (SHA), index of multiple deprivation (IMD), ethnicity, and comorbidity. To account for differing comorbidity profiles between populations the Charlson Comorbidity Index (CCI) was applied. The model estimated odds ratios (OR) with 95% confidence intervals of developing hospitalised CAP for each specified clinical risk group. Results Patients within all the risk groups studied were more likely to develop hospitalised CAP than patients in the comparator group. The odds ratios varied between underlying conditions ranging from 1.18 (95% CI 1.13, 1.23) for those with DM to 5.48 (95% CI 5.28, 5.70) for those with CRD. Conclusions Individuals with any of 6 pre-defined underlying comorbidities are at significantly increased risk of developing hospitalised CAP compared to those with no underlying comorbid condition. Since the likelihood varies by risk group it should be possible to target patients with each of these underlying comorbidities with the most appropriate preventative measures, including immunisations.

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Inflammatory and Epigenetic Pathways for Perinatal Depression

Biological Research For Nursing ◽

10.1177/1099800415614892 ◽

2015 ◽

Vol 18 (3) ◽

pp. 331-343 ◽

Cited By ~ 14

Author(s):

Lindsey Garfield ◽

Herbert L. Mathews ◽

Linda Witek Janusek

Keyword(s):

Early Life ◽

Infant Health ◽

Perinatal Depression ◽

Life Experiences ◽

Perinatal Period ◽

Early Life Adversity ◽

Targeted Interventions ◽

Increased Risk ◽

History Of ◽

The Impact

Depression during the perinatal period is common and can have adverse consequences for women and their children. Yet, the biobehavioral mechanisms underlying perinatal depression are not known. Adverse early life experiences increase the risk for adult depression. One potential mechanism by which this increased risk occurs is epigenetic embedding of inflammatory pathways. The purpose of this article is to propose a conceptual model that explicates the linkage between early life adversity and the risk for maternal depression. The model posits that early life adversity embeds a proinflammatory epigenetic signature (altered DNA methylation) that predisposes vulnerable women to depression during pregnancy and the postpartum period. As proposed, women with a history of early life adversity are more likely to exhibit higher levels of proinflammatory cytokines and lower levels of oxytocin in response to the demands of pregnancy and new motherhood, both of which are associated with the risk for perinatal depression. The model is designed to guide investigations into the biobehavioral basis for perinatal depression, with emphasis upon the impact of early life adversity. Testing this model will provide a better understanding of maternal depressive risk and improve identification of vulnerable women who would benefit from targeted interventions that can reduce the impact of perinatal depression on maternal–infant health.

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Early life bacterial airway colonization, local immune mediator response and risk of otitis media

Journal of Medical Microbiology ◽

10.1099/jmm.0.001227 ◽

2020 ◽

Vol 69 (8) ◽

pp. 1124-1131

Author(s):

Emil Dalgaard Christensen ◽

Jonathan Thorsen ◽

Jakob Stokholm ◽

Tine Marie Pedersen ◽

Susanne Brix ◽

...

Keyword(s):

Otitis Media ◽

Early Life ◽

Type Species ◽

Bacterial Colonization ◽

Acute Otitis Media ◽

Immune Mediator ◽

Content Type ◽

Link Type ◽

Increased Risk ◽

Airway Colonization

Introduction. Acute otitis media (AOM) is the most common bacterial infection in early childhood, but the underlying mechanisms making some children more susceptible are poorly understood. Aim. To examine the associations between bacterial airway colonization in early life and the risk of AOM and tympanostomy tube insertion (TTI), and whether such associations are modulated by an insufficient local immune mediator response to bacterial colonization. Methodology. Bacterial cultures from hypopharyngeal samples were obtained at 1 week, 1 month and 3 months of age in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising 700 children. Twenty immune mediators were quantified from airway mucosal lining fluid sampled at 1 month. AOM symptoms were registered in a daily diary until 3 years. Information on TTI in the first 3 years was obtained from national registers. Results. Children colonized with Streptococcus pneumoniae at 1 month of age had increased incidence of AOM [aIRR 2.43 (1.14–5.21)] and children colonized with Moraxella catarrhalis at 1 month or Haemophilus influenzae at 3 months had an increased risk of TTI [aHR 1.45 (1.00–2.10) and 1.73 (1.10–2.71)]. There were no associations between the local immune mediator response to colonization and risk of AOM or TTI. Conclusion. Pathogenic bacterial airway colonization in early life was found to be associated with an increased risk of otitis media, albeit not consistently. These associations were independent of the local immune response to colonization.

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Early life adversity, dispositional mindfulness, and longitudinal stress experience during the COVID-19 pandemic

10.31234/osf.io/5kt6z ◽

2020 ◽

Author(s):

Annika Benz ◽

Maria Meier ◽

Ulrike U. Bentele ◽

Stephanie J. Dimitroff ◽

Bernadette Denk ◽

...

Keyword(s):

Perceived Stress ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Dispositional Mindfulness ◽

Early Life Adversity ◽

Stress Buffering ◽

Psychopathological Symptoms ◽

Increased Risk ◽

The Impact

Experiencing severe or prolonged stressors in early life is associated with increased risk for mental and physical disorders in adulthood. Further, individuals who experienced early life stress (ELS) may use dysfunctional coping strategies like stress-related eating, in contrast to more beneficial stress buffering mechanisms e.g. based on mindfulness. Whether these mechanisms contribute to increased levels of perceived stress and symptoms of mental disorders in individuals with ELS in times of crisis is yet unclear. As part of a larger project, we assessed changes in perceived stress and psychopathological symptoms in a sample of N=102 participants (81% female; meanage=23.49, SDage= 7.11, range 18–62) from October/December 2019 (prior to the Covid-19 pandemic) to April/June 2020 (after the German government introduced Covid-19 related restrictions). Additionally, we assessed ELS and dispositional mindfulness.Perceived stress and depression significantly increased while anxiety levels decreased. No significant change was observed for somatization. ELS and dispositional mindfulness were not associated with change scores, but with perceived stress and psychopathological symptoms at both assessments. The increase in perceived stress during the pandemic in a majority of participants demonstrates the impact of the pandemic in the general population.

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Interaction of Macrophages and Cholesterol-Dependent Cytolysins: The Impact on Immune Response and Cellular Survival

Toxins ◽

10.3390/toxins12090531 ◽

2020 ◽

Vol 12 (9) ◽

pp. 531 ◽

Cited By ~ 1

Author(s):

Roshan Thapa ◽

Sucharit Ray ◽

Peter A. Keyel

Keyword(s):

Bacterial Infections ◽

Myeloid Cells ◽

Adaptive Immune System ◽

Host Responses ◽

Membrane Repair ◽

Cellular Survival ◽

Protein Map ◽

Mitogen Activated Protein ◽

Necrotizing Soft Tissue Infections ◽

The Impact

Cholesterol-dependent cytolysins (CDCs) are key virulence factors involved in many lethal bacterial infections, including pneumonia, necrotizing soft tissue infections, bacterial meningitis, and miscarriage. Host responses to these diseases involve myeloid cells, especially macrophages. Macrophages use several systems to detect and respond to cholesterol-dependent cytolysins, including membrane repair, mitogen-activated protein (MAP) kinase signaling, phagocytosis, cytokine production, and activation of the adaptive immune system. However, CDCs also promote immune evasion by silencing and/or destroying myeloid cells. While there are many common themes between the various CDCs, each CDC also possesses specific features to optimally benefit the pathogen producing it. This review highlights host responses to CDC pathogenesis with a focus on macrophages. Due to their robust plasticity, macrophages play key roles in the outcome of bacterial infections. Understanding the unique features and differences within the common theme of CDCs bolsters new tools for research and therapy.

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Second cancer risk 40 years after cure for Hodgkin lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8039 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8039-8039

Author(s):

Michael Schaapveld ◽

Berthe M Aleman ◽

Anja M Eggermond ◽

Cecile P Janus ◽

Augustinus Krol ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Risk ◽

Hodgkin Lymphoma ◽

Hazard Ratio ◽

Treatment Modalities ◽

Second Cancer ◽

Radiation Fields ◽

Increased Risk ◽

The Impact

8039 Background: During the last decades Hodgkin Lymphoma (HL) treatment changed towards less toxic chemotherapy schemes and smaller radiation fields. The impact of these changes on second cancer (SC) risk is still unknown. Methods: We calculated standardized incidence ratios (SIR), comparing SC risk after HL treatment with expected risk, based on cancer incidence in the general population, and compared SC risk between treatment modalities, accounting for competing events, in a large Dutch cohort comprising 3,390 5-years HL survivors, aged 15-51 years at HL treatment and diagnosed between 1965-2000. Results: The median follow-up was 18.2 years; 23% of the patients was followed ≥25 years. During follow-up 734 SCs and 92 third cancers (TC) occurred. The SIR for any SC was 4.5 (95% confidence interval (95%CI) 4.1-4.9). SC risk was still elevated after 35 years of follow-up (SIR 3.9; 95%CI 2.5-5.8) and cumulative incidence (CI) reached 47.1% (95%CI 43.6-50.5) at 40 years follow-up. For TCs the SIR was 5.5 (95%CI 4.4-6.9); the 20-year CI was 22.3% (95%CI 17.8-27.2). Risks of NHL and leukemia strongly decreased in more recent treatment periods (P-trend <0.001). The CI of solid tumors (ST) between 5-19 years after HL treatment did not differ for patients treated between 1965-1979, 1980-1989 or 1990-2000 (P=0.21; 19-year CI 9.1%, 11.6% and 11.4%, respectively). Radiotherapy (RT) above the diaphragm increased risk of STs above the diaphragm (hazard ratio (HR) 2.4, P<0.001), while subdiaphragmatic RT was associated with a 1.7-fold increased HR of a subdiaphragmatic ST (P=0.001). An incomplete mantle field was associated with significantly lower breast cancer (BC) risk (hazard ratio (HR) 0.4, 95%CI 0.2-0.8). A cumulative procarbazine dose >4.2 g/m2 yielded a 1.3-fold increased HR (95%CI 1.0-1.7) for non-breast STs and a 2-fold (95%CI 1.2-3.1) increased HR for gastrointestinal STs, but was associated with a strongly decreased BC risk (HR 0.3, 95%CI 0.2-0.6). Conclusions: SC risk after HL has decreased with treatment changes over the last decades, due to strongly decreasing risk of leukemia and NHL. Smaller radiation fields and procarbazine doses >4.2 g/m2 are associated with lower breast cancer risk, while high procarbazine doses increase risk of gastrointestinal STs.

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Risk of depression following prostate cancer work-up: A nationwide study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5061 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5061-5061

Author(s):

Anne Sofie Friberg ◽

Klaus Brasso ◽

Elisabeth Wreford Andersen ◽

Signe Benzon Larsen ◽

John Thomas Helgstrand ◽

...

Keyword(s):

Prostate Cancer ◽

Cumulative Incidence ◽

Treatment Modalities ◽

Income Quintile ◽

Increased Risk ◽

Diagnostic Work ◽

The Impact ◽

Work Up ◽

Diagnostic Work Up

5061 Background: Little is known about the psychological impact of undergoing evaluation for prostate cancer (PCa). We investigated the risk of developing a depression following PCa work-up with benign and malignant findings, respectively, compared with cancer-free men. Methods: A nationwide cohort of men who underwent prostate needle biopsies in Denmark from 1997–2011 was identified through the Danish Prostate Cancer Registry. Primary outcome was indication of moderate to severe depression defined as hospital contact for depression or first redemption of a prescribed antidepressant. For comparison, we selected a minimum of five age-matched cancer-free men per man who had undergone PCa specific diagnostic work-up. We excluded men with other cancer, major psychiatric disorder or use of antidepressants up to three years before study entry. Information on outcome and covariates (age, period, cohabitation status, income quintile and comorbidity) were retrieved from National Danish registries. We illustrated the risk of depression by cumulative incidence functions. Data were analyzed using Cox models adjusted for possible confounders. Results: We identified 54,766 men who underwent work-up including transrectal biopsies of the prostate, among these, 21,419 biopsy sets were benign and 33,347 men were diagnosed with PCa. We found an increasing cumulative incidence of depression in all groups. However, men diagnosed with PCa had a significantly higher risk throughout up to 18 years of follow-up. The adjusted hazard ratio (HR) of depression in men diagnosed with PCa was increased throughout follow-up with the highest risk in the two years following diagnosis (HR 2.77, 95% CI 2.66–2.87). After undergoing biopsies, men with benign results had an increased risk of depression (HR 1.22, 95% CI 1.14–1.31) in the first two years compared with cancer-free men; hereafter, we found no difference. Conclusions: We found an increased risk of depression in men following diagnostic work-up for PCa compared with a matched background population. In men diagnosed with PCa, the risk remained increased throughout the study period. Future studies are needed to further analyze the impact of stage and treatment modalities.

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Impact of Prophylaxis with Aerosolized Amphotericin-B Deoxycholate (d-AmB) on Respiratory Tract Invasive Fungal Infections (IFIs) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).

Blood ◽

10.1182/blood.v110.11.4986.4986 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4986-4986

Author(s):

Enrico Morello ◽

Irene M. Cavattoni ◽

Pietro Fabris ◽

Silvia Coin ◽

Barbara Amato ◽

...

Keyword(s):

Respiratory Tract ◽

Bacterial Infections ◽

Fungal Infections ◽

Unrelated Donor ◽

X Rays ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Number Of Patients ◽

Increased Risk ◽

The Impact

Abstract Background and aims IFIs still pose major challenges in HSCT, and effective prophylaxis remains a matter of debate. The aim of this retrospective study was to evaluate the impact of aerosolized d-AmB on respiratory tract IFIs in a homogeneous cohort of allogeneic HSCT patients, transplanted at our institution. Patients and methods Since 1999, 81 consecutive patients were transplanted from matched related (N=61) or unrelated donor (MUD). Analysis was performed on 74 evaluable patients, in order to monitor the prevalence of respiratory tract IFIs within 40 days after HSCT, according to current guidelines (possible, probable, proven IFIs). Conventional antifungal prophylaxis was based on the association of fluconazole (400 mg/d), plus aerosolized d-AmB (15 mg bid) in 54 out of 74 cases (73%). All the patients were screened before transplant and monitored thereafter with CT or x-rays (paranasal sinuses, thorax), surveillance swabs and galactomannan antigenemia. Chi square test was performed to evaluate correlations between variables. Results Aerosolised d-AmB was administered to 70 patients for a median time of 15 days (range 1–45). Prolonged administration was not associated with increased severe bacterial infections, nor severe adverse events were observed; only a patient developed moderate bronchial spasm. In 13 pts, aerosolized d-AmB was delivered for less than 7 days, due to worsened clinical conditions, or poor compliance. In this group, proven IFIs were diagnosed in 2 patients (1 mucormycosis and 1 fusariosis), possible aspergillosis in one and probable aspergillosis in another one. A shortened administration (<7 days) of aerosolized d-AmB was associated with an increased risk of IFIs (p=0,002). Overall, 95% of patients did not experience IFIs and nobody died due to IFIs. Nine patients had a pre-transplant nasal swab positive for Aspergillus spp., and 8 of them received Aerosolized d-AmB; subsequent surveillance swabs proved negative. On the other hand, the only patient with positive swab who was not able to receive aerosolized d-AmB due to bronchial spasm developed a possible aspergillosis. Discussion Despite the low number of patients, prolonged aerosolized d-AmB seems to play a role in preventing respiratory tract IFIs, but a randomised controlled trial is recommended to verify the impact of this prophylaxis in the setting of allogeneic HSCT.

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Factor V Leiden Mutation Increases the Risk of Venous Thromboembolism in Cancer Patients – Results From the Vienna Cancer and Thrombosis Study (CATS).

Blood ◽

10.1182/blood.v120.21.2253.2253 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2253-2253

Author(s):

Ingrid Pabinger ◽

Cihan Ay ◽

Daniela Dunkler ◽

Johannes Thaler ◽

Eva-Maria Reitter ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Factor V Leiden ◽

Treatment Modalities ◽

Individual Risk ◽

Factor V ◽

Newly Diagnosed ◽

Factor V Leiden Mutation ◽

Increased Risk ◽

The Impact

Abstract Abstract 2253 Background: Patients with cancer are at an increased risk of venous thromboembolism (VTE). The risk varies markedly in different patient populations and improvement of the prediction of VTE would be of advantage for tailoring thrombosis prophylaxis. Factor V Leiden is the most common genetic risk factor for VTE and the impact of factor V Leiden on cancer-associated thrombosis is not yet fully elucidated. Objective: To study the impact of factor V Leiden on the risk of VTE in cancer patients. Patients and Methods: Nine-hundred-eighty-two patients with newly diagnosed cancer (n=745) or progression of disease after complete or partial remission (n=237) were included in the cancer and thrombosis study (CATS), a prospective observational single centre cohort study at the Medical University Vienna. Patients were followed for a maximum period of 2 years. Blood samples were collected at inclusion and factor V Leiden was determined by genotyping. The main outcome measure was symptomatic or lethal objectively confirmed VTE. All VTE events were adjudicated independently. Results: Of the 982 patients (median age 62 years, interquartile range (IQR) 52–68, 537 men, 445 women) factor V-Leiden was found in 72 (7.3%), 70 had a heterozygous and two a homozygous genotype. Ten of 72 (14%) patients with factor V-Leiden developed VTE, whereas this was the case in 69 of 910 (7.6%) patients without factor V-Leiden. Interestingly, both patients with homozygous factor V Leiden developed VTE. In multivariable analysis that included age, sex, different tumour types, newly diagnosed versus recurrence of disease and the treatment modalities (chemotherapy, radiotherapy and surgery) the hazard ratio (HR) for factor V Leiden was 2.04 (95% confidence interval (CI) 1.04–3.97)). In patients with newly diagnosed tumours the HR for factor V Leiden was 3.7 (95% CI 1.2–12.2) after 30 days. In Kaplan Meier analysis the probability for development of VTE after 6 months was 5.7% in those without and 13% in those with factor V Leiden, after one year the corresponding rates were 7.3% and 15%. Conclusions: Factor V Leiden is a genetically determined and thus disease-independent parameter, which is associated with VTE in cancer patients, especially shortly after cancer diagnosis, and could therefore be used for individual risk assignment. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Burden of Increased Body Mass Index from Childhood on Adult Dyslipidemia: The i3C Consortium Study

Journal of Clinical Medicine ◽

10.3390/jcm8101725 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1725 ◽

Cited By ~ 1

Author(s):

Yinkun Yan ◽

Lydia A. Bazzano ◽

Markus Juonala ◽

Olli T. Raitakari ◽

Jorma S. A. Viikari ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Early Life ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Lipid Lowering ◽

Lipid Levels ◽

Increased Risk ◽

The Impact

Background: Data are limited regarding the association of cumulative burden and trajectory of body mass index (BMI) from early life with adult lipid disorders. Methods: The study cohort consisted of 5195 adults who had BMI repeatedly measured 4 to 21 times from childhood and had blood lipid measurements of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and information on lipid-lowering medications in the last adult survey. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI. Results: Participants with dyslipidemia, high LDL-C, low HDL-C and high TG had consistently and significantly higher BMI levels from childhood to adulthood compared to those with normal lipid levels. After adjusting for age, race, sex, and cohort, increased risk of adult dyslipidemia was significantly associated with higher values of childhood BMI, adulthood BMI, total AUC and incremental AUC, with odds ratio (95% confidence interval) = 1.22 (1.15–1.29), 1.85 (1.74–1.97), 1.61 (1.52–1.71), and 1.59 (1.50–1.69), respectively, and p < 0.001 for all. The association patterns were similar in most race–sex subgroups. Conclusions: Adults with dyslipidemia versus normal lipid levels have consistently higher levels and distinct life-course trajectories of BMI, suggesting that the impact of excessive body weight on dyslipidemia originates in early life.

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