Jon Hazeldine

University of Birmingham · Institute of Inflammation and Ageing

Background Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of...

An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and...

Introduction Alcohol-related liver disease (ARLD) accounts for over one third of all deaths from liver conditions, and mortality from alcohol-related liver disease has increased nearly five-fold over the last 30 years. Severe alcohol-related hepatitis almost always occurs in patients with a background of chronic liver disease with extensive fibrosi...

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected contr...

Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological ageing may play a role, we performed an epigenetic, transcriptomic and phenot...

Background: Electronic (e-)cigarette use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease (COPD). Neutrophils are central to the pathogenesis of COPD, with changes in phenotype and function implicated in tissue damage. Objective: This study aime...

Introduction The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods In a prospec...

Associated with the development of hospital-acquired infections, major traumatic injury results in an immediate and persistent state of systemic immunosuppression, yet the underlying mechanisms are poorly understood. Detected in the circulation in the minutes, days and weeks following injury, damage associated molecular patterns (DAMPs) are a heter...

Background: Tissue factor (TF) is essential for hemostasis. TF-expressing extracellular vesicles (TF+ EVs) are released in pathological conditions, such as trauma and cancer, and are linked to thrombosis. Detection of TF+ EV antigenically in plasma is challenging due to their low concentration but may be of clinical utility. Objectives: We hypth...

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after d...

Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between Mar...

Objective Trauma-induced steroid changes have been studied post-hospital admission, resulting in a lack of understanding of the speed and extent of the immediate endocrine response to injury. The Golden Hour Study was designed to capture the ultra-acute response to traumatic injury. Design An observational cohort study including adult male trauma...

Two opposing clinical syndromes characterise the immune and inflammatory response to major trauma. Defined by immune activation and raised circulating levels of pro-inflammatory cytokines, a systemic inflammatory response syndrome (SIRS) is accompanied by a counteracting compensatory anti-inflammatory response syndrome (CARS), which is characterise...

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In...

Background Traumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury. Method...

Background Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods In...

Background The global COVID-19 pandemic has significantly evolved since first identified in November 2019. Viral antigenic shift has seen the emergence of several new strains leading to spikes in infection. Transmissibility has increased with each emerging strain, corresponding with a decrease in overall mortality. We have previously demonstrated d...

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objecti...

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the...

Background Major thermal injury induces a complex pathophysiological state characterized by burn shock and hypercatabolism. Steroids are used to modulate these post-injury responses. However, the effects of steroids on acute post-burn outcomes remain unclear. Methods In this study of 52 thermally injured adult patients (median total burn surface a...

Recent advances in emergency medicine and the co-ordinated delivery of trauma care mean more critically-injured patients now reach the hospital alive and survive life-saving operations. Indeed, between 2008 and 2017, the odds of surviving a major traumatic injury in the UK increased by nineteen percent. However, the improved survival rates of sever...

Cellular senescence is a state of stable cell cycle arrest triggered by internal and external stressors. A major hallmark of senescent cells is the senescent associated secretory phenotype (SASP), an inflammatory secretome consisting of cytokines, chemokines, growth factors and proteases. When transient in nature, senescent cells are beneficial, ai...

Rational Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based predominantly on transcriptomics or single functional assays. Cell functions are interwoven pathways, and so understanding the effect of COVID-19 across the spectrum of neutrophil function may identify t...

Introduction: Burn-induced changes in the phenotype and function of neutrophils, cells which provide front-line protection against rapidly dividing bacterial infections, are emerging as potential biomarkers for the early prediction of sepsis. In a longitudinal study of adult burns patients, we recently demonstrated that a combined measurement of n...

Background Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue a...

Introduction The improvements in short-term outcome after severe trauma achieved through early resuscitation and acute care can be offset over the following weeks by an acute systemic inflammatory response with immuneparesis leading to infection, multiorgan dysfunction/multiorgan failure (MOF) and death. Serum levels of the androgen precursor dehyd...

Rational: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based predominantly on transcriptomics or single functional assays. Cell functions are interwoven pathways, and so understanding the effect of COVID-19 across the spectrum of neutrophil function may identify...

Whilst the majority of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, experience mild to moderate symptoms, approximately 20% develop severe respiratory complications that may progress to acute respiratory distress syndrome, pulmonary failure and death. To date, single cel...

Background Traumatic injury is associated with increased concentrations of cell-free DNA (cfDNA) in the circulation, which contribute to post-injury complications. The endonuclease deoxyribonuclease 1 (DNase-1) is responsible for removing 90% of circulating cfDNA. Recently, DNase activity was reported to be significantly reduced following major non...

Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) p...

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes,...

The immune response to major trauma has been analysed mainly within post-hospital admission settings where the inflammatory response is already underway and the early drivers of clinical outcome cannot be readily determined. Thus, there is a need to better understand the immediate immune response to injury and how this might influence important pat...

Abstract Severe injuries are the major cause of death in those aged under 40, mainly due to road traffic collisions. Endocrine, metabolic and immune pathways respond to limit the tissue damage sustained and initiate wound healing, repair and regeneration mechanisms. However, depending on age and sex, the response to injury and patient prognosis dif...

Background: Circulating cell-free DNA (cfDNA) is not found in healthy subjects, but is readily detected after thermal injury and may contribute to the risk of multiple organ failure. The hypothesis was that a postburn reduction in DNase protein/enzyme activity could contribute to the increase in cfDNA following thermal injury. Methods: Patients...

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicle which rapidly and preferentially bound to blood monocytes compared t...

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, bu...

Major traumatic injury induces significant remodeling of the circulating neutrophil pool and loss of bactericidal function. Although a well-described phenomenon, research to date has only analyzed blood samples acquired post-hospital admission, and the mechanisms that initiate compromised neutrophil function post-injury are therefore poorly underst...

Exercising in a state of reduced muscle glycogen content (“compete‐high, train‐low”) enhances metabolic adaptation in skeletal muscle. However, despite the increasing popularity of such regimes, how this training strategy affects post‐exercise immune disturbances and an athlete's susceptibility to acute upper respiratory tract infections (URTIs) is...

Background Renal disease is a major global public health issue. Renal interstitial fibrosis is the characteristic histopathological finding in all progressive renal disease. Caveolin-1 is the essential structural protein for lipid rafts called caveolae that are ubiquitously distributed among fibroblasts, endothelial and epithelial cells. Caveolin-1...

BACKGROUND: Preclinical studies report that higher plasma viscosity improves microcirculatory flow after haemorrhagic shock and resuscitation, but no clinical study has tested this hypothesis. OBJECTIVE: We investigated the relationship between plasma viscosity and sublingual microcirculatory flow in patients during resuscitation for traumatic hae...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Background Cell free deoxyribonucleic acid (cfDNA) has been proposed as a biomarker of secondary complications following trauma. Raised thrombomodulin and syndecan-1 levels have been used to indicate endotheliopathy, and are associated with inflammation, coagulopathy, and mortality. The current study aimed to analyse the association between cfDNA a...

Database of the study's raw data. (XLSX)

Physiological ageing is associated with significant re-modelling of the immune system. Termed immunesenescence, age-related changes have been described in the composition, phenotype and function of both the innate and adaptive arms of the immune system. As the first line of defence against invading pathogens, age-associated alterations in innate im...

Background: Trauma patients are vulnerable to coagulopathy and inflammatory dysfunction associated with endotheliopathy of trauma (EoT). In vitro evidence has suggested that tranexamic acid (TXA) may ameliorate endotheliopathy. We aimed to investigate how soon after injury EoT occurs, its association with multiple organ dysfunction syndrome (MODS),...

Background Extracellular vesicles (EV) released into the circulation after traumatic injury may influence complications. We thus evaluated the numbers of EV in plasma over 28 days after trauma and evaluated their pro-coagulant and inflammatory effects. Methods and findings 37 patients suffering trauma with an injury severity score >15 were studied...

The frequency distribution of EV diameter derived by NTA in plasma from controls and patients at different times after injury. Data are for controls, GHS 1 hour (T0), Day 1 (pooled GHS and SIRS), Day 3 (pooled GHS and SIRS) and subsequent days (SIRS only). Data are median values. (TIF)

Data for all studies. NTA, FC and leukocyte adhesion data tabulated for controls and patients. (PDF)

Background: Endothelial cell damage and glycocalyx shedding following trauma can increase the risk of inflammation, coagulopathy, vascular permeability and death. Bedside sublingual video-microscopy may detect worse flow and perfusion associated with this endotheliopathy. We compared markers of endotheliopathy with physical flow dynamics following...

Background Almost all studies that have investigated the immune response to trauma have analysed blood samples acquired post-hospital admission. Thus, we know little of the immune status of patients in the immediate postinjury phase and how this might influence patient outcomes. The objective of this study was therefore to comprehensively assess th...

Database of the study’s raw data. (XLSX)

Serum concentrations of monocyte chemoattractant protein-1 (MCP-1) post-trauma. The number of patient and healthy control (HC) samples analysed is indicated below each time point. The horizontal line for HC data depicts the median value. (TIF)

Flow diagram showing immune and inflammatory analysis of blood samples obtained within 1 hour of traumatic injury from patients who subsequently did or did not develop MODS. Insufficient sample volume and equipment breakdown accounts for the differences in patient numbers between each parameter analysed. LOS, length of stay; MODS, multiple organ dy...

Demographics of healthy controls (HCs). (DOCX)

Study protocol. (DOC)

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. (DOC)

Rationale: Dysregulated neutrophil functions are described with age and sepsis. Statins are associated with improved infection survival in some observational studies but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. Objective: To assess neutrophil migratory accuracy with age during re...

The mortality caused by sepsis is high following thermal injury. Diagnosis is difficult due to the ongoing systemic inflammatory response. Previous studies suggest that cellular parameters may show promise as diagnostic markers of sepsis. The aim of this study was to evaluate the effect of thermal injury on novel haematological parameters and to st...

Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clini...

Objective Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading...

Exercising in a state of reduced muscle glycogen content (“compete-high, train-low”) enhances metabolic adaptation in skeletal muscle. However, despite the increasing popularity of such regimes, how this training strategy affects post-exercise immune disturbances and an athlete’s susceptibility to acute upper respiratory tract infections (URTIs) is...

Traumatic brain injury (TBI) is the leading cause of death and disability under the age of 45 years in Western countries. Despite many studies, no reliable biomarkers have been found to assess TBI severity and predict recovery. MicroRNA (miRNA) profiling has become widely used to identify biomarkers and therapeutic targets. The expression of 754 mi...

AIM 1. To determine baseline levels of serum 25-hydroxyvitamin D (25-OHD) in UK trauma patients 2. To define the natural history of 25-OHD in trauma patients during the immediate, early and late phases following injury 3. To determine whether there is a significant difference in serum 25-OHD levels between patients with TBI and those without at all...

As secondary complications remain a significant cause of morbidity and mortality amongst hospitalised trauma patients, the need to develop novel approaches by which to identify patients at risk of adverse outcome is becoming increasingly important. Centred on the idea that patients who experience “poor” outcome post trauma elicit a response to inju...

Non-alcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis, and is regarded as the hepatic manifestation of the metabolic syndrome (MetS). Glucocorticoids (GCs) can promote steatosis by stimulating lipolysis within adipose tissue, FFA delivery to liver and h...

Objective: The aim of this study was to measure neutrophil function longitudinally following burn injury and to examine the relationship between neutrophil dysfunction and sepsis. Background: Sepsis prevalence and its associated mortality is high following burn injury, and sepsis diagnosis is complicated by the ongoing inflammatory response. Pre...

Nosocomial infections are a common occurrence in patients following traumatic brain injury (TBI) and are associated with an increased risk of mortality, longer length of hospital stay, and poor neurological outcome. Systemic immune suppression arising as a direct result of injury to the central nervous system (CNS) is considered to be primarily res...

Compared to younger patients, traumatic injury in older patients is associated with increased mortality and a range of adverse outcomes such as higher rates of infectious episodes, longer length of hospital stay and poor functional outcome at follow up. Data emerging from human and murine-based studies suggest age-related changes in immune function...

Traumatic injury results in a systemic inflammatory response syndrome (SIRS), a phenomenon characterised by the release of pro-inflammatory cytokines into the circulation and immune cell activation. Released from necrotic cells as a result of tissue damage, damage associated molecular patterns (DAMPs) are thought to initiate the SIRS response by ac...

A well-established feature of physiological ageing is altered immune function, a phenomenon termed immunesenescence. Thought to be responsible in part for the increased incidence and severity of infection reported by older adults, as well as the age-related decline in vaccine efficacy and autoimmunity, immunesenescence affects both the innate and a...

Neutrophil extracellular traps (NETs) are a recently discovered addition to the defensive armamentarium of neutrophils, assisting in the immune response against rapidly dividing bacteria. Although older adults are more susceptible to such infections, no study has examined whether aging in humans influences NET formation. We report that TNF-α-primed...

Forming the first line of defence against virally-infected and malignant cells, natural killer (NK) cells are critical effector cells of the innate immune system. With age, significant impairments have been reported in the two main mechanisms by which NK cells confer host protection: direct cytotoxicity and the secretion of immunoregulatory cytokin...

Purpose of review: Neutrophils are a key component of innate immunity. At sites of infection, they unleash cytotoxic molecules allowing them to kill invading pathogens. However, these molecules can also be deleterious to the host tissue. Therefore, neutrophils undergo apoptosis and are removed from the site of infection following elimination of th...

Physiological aging is accompanied by a marked reduction in natural killer (NK) cell cytotoxicity (NKCC) at the single cell level, but the underlying mechanisms are unknown. To address this issue, we isolated NK cells from healthy young (≤ 35 years) and old (≤ 60 years) subjects and examined the effect of age on events fundamental to the process of...

Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently,...

Background Age is associated with a decline in immunity, including neutrophil function. This may partially explain the worsening clinical outcomes seen following pneumonia in the elderly. Statins may improve outcomes from pneumonia although it is unknown whether they influence neutrophil function at conventional therapeutic concentrations. This is...

Dehydroepiandrosterone (DHEA) is a C19 steroid of adrenal origin. Notably, its secretion declines with age, a phenomenon referred to as the "adrenopause". For many years, the physiological significance of DHEA remained elusive. However, many studies have now shown that DHEA has significant immune modulatory function, exhibiting both immune stimulat...