Search

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future., Competing Interests: Declaration of interests MS-H is supported by the UK National Institute for Health and Care Research (NIHR) Clinician Scientist Award (CS-2016-16-011; 2017–2023). MPS's laboratory is supported by the Calouste Gulbenkian Foundation, La Caixa Foundation (HR18-00502), Fundação para a Ciência e a Tecnologia (GlucoInfect, 5723/2014; FEDER029411, FEDER/29411/2017; Infectenergy, PTDC/MED-FSL/4681/2020; MalBil, 2022.02426.PTDC), the Oeiras–European Research Council Frontier Research Incentive Awards, SymbNET Research Grants (H2020-WIDESPREAD-2020-5-952537), and Congento (LISBOA-01-0145-FEDER-022170). MPS is an associate member of the Deutsche Forschungsgemeinschaft (DFG) Balance of the Microverse initiative (EXC 2051; 390713860). MB is principal investigator of the DFG Balance of the Microverse initiative (EXC 2051; 390713860). JCK is supported by the Medical Research Council (MR/V002503/1), a Wellcome Trust Investigator Award (204969/Z/16/Z), and Wellcome Trust grants (090532/Z/09/Z and 203141/Z/16/Z) to the Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, and the NIHR Oxford Biomedical Research Centre. JM reports grants from the Canadian Institutes of Health Research and has served as chair of data and safety monitoring boards for AM Pharma and Adrenomed. CWS reports grants from the US National Institutes of Health National Institute of General Medical Sciences, during the conduct of the study, and personal fees from Inotrem and Beckman Coulter, outside of the submitted work. IBM has received funding or consultancy fees from Abbvie, Amgen, Bristol Myers Squibb, Cabaletta, Causeway, Eli Lilly, Evelo, GSK, Janssen, Moonlake, Novartis, Pfizer, and UCB. TvdP has received grants from the EU's Horizon 2020 research and innovation funding programme (grant agreements: Flagellin Aerosol Therapy in Treatment of Drug-resistant Bacterial Pneumonia, 847786; ImmunoSEP, 847422). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

High quality health care research must involve patients and the public. This ensures research is important, relevant and acceptable to those it is designed to benefit. The world's first human challenge study with SARS-CoV-2 undertook detailed public involvement to inform study design despite the urgency to review and establish the study. The work was integral to the UK Research Ethics Committee review and approval of the study. Discussion with individuals from ethnic minorities within the UK population supported decision-making around the study exclusion criteria. Public review of study materials for consent processes led to the addition of new information, comparisons and visual aids to help volunteers consider the practicalities and risks involved in participating. A discussion exploring the acceptability of a human challenge study with SARS-CoV-2 taking place in the UK, given the current context of the pandemic, identified overall support for the study. Public concern for the wellbeing of trial participants, as a consequence of isolation, was identified. We outline our approach to public involvement and its impact on study design., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: PJMO reports grants from the EU Innovative Medicines Initiative (IMI) 2 Joint Undertaking during the submitted work; grants from UK Medical Research Council, EU-IMI, UK National Institute for Health Research, and UK Research and Innovation-Department for Business, Energy and Industrial Strategy; and personal fees from Pfizer, Nestle, Janssen, and Sequris, outside the submitted work. FL declares no competing interests.

Background: The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes., Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107)., Findings: We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9-6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40-59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity., Interpretation: We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care., Funding: UK Research and Innovation and National Institute for Health Research., Competing Interests: Declaration of interests JDC reports grants and personal fees from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, and Insmed, personal fees from Chiesi, Zambon, Janssen, and Grifols, and grants from Gilead Sciences, outside the submitted work. TC reports grants from Guy's and St Thomas' Charity, fees from workshops, and fees from writing self-help books on fatigue, outside the submitted work. NE received a donation of SARS-CoV-2 lateral flow antigen test kits from Mologic, in relation to an unrelated COVID-19 project. Neither NE nor his institution have received any financial compensation and he has no financial relationship of any kind with Mologic. RAE reports grants from GlaxoSmithKline during the conduct of the study; and grants from the National Institute for Health Research (NIHR) and personal fees from GlaxoSmithKline, AstraZeneca, and Chiesi, outside the submitted work. AH reports personal fees from Vertex Pharmaceuticals, Mylan Healthcare, and the Cystic Fibrosis Foundation, and grants from JP Moulton Trust and NIHR, outside the submitted work. LGH reports receiving sponsorship for attending international scientific meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Napp Pharmaceuticals, personal fees from Novartis, Hoffman la Roche/Genentech, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance, and Circassia, and grants from Medimmune, Novartis UK, Roche/Genentech, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, Aerocrine, and Vitalograph, outside the submitted work. NH reports that his research group has received unrestricted grants (managed by Guy's & St Thomas' Foundation Trust) from Philips and Resmed. Philips are contributing to the development of the MYOTRACE technology. SH reports personal fees and fees to institution for advisory boards and consultancy from Novo Nordisk, Eli Lilly, Zealand Pharma, and Sanofi Aventis, outside the submitted work. JJ reports personal fees from Boehringer Ingelheim, Roche, GlaxoSmithKline, and NHSX, outside the submitted work. RGJ reports personal fees and research funding from Biogen, personal fees from Galapagos, Heptares, Boehringer Ingelheim, Pliant, Roche/InterMune, MedImmune, PharmAkea, Bristol Myers Squibb, Chiesi, Roche/Promedior, Veracyte, and GlaxoSmithKline research funding from Galecto, collaborative award from RedX and Nordic Biosciences, and was an advisory board member for NuMedii, outside the submitted work. RGJ is supported by an NIHR Professorship (RP-2017-08-ST2-014) and is a trustee for Action for Pulmonary Fibrosis. GM reports grants from AstraZeneca, outside the submitted work. PJMO reports grants from the Medical Research Council (MRC), the EU, and NIHR, and personal fees from Pfizer, Nestle, and Janssen, outside the submitted work. PP reports a grant from NIHR, outside the submitted work. MRo reports a senior clinical fellowship as part of research training and a 1-year post working in Pharma Development Neurosciences with Roche Pharmaceuticals, outside the submitted work. ADS reports grants and personal fees from AstraZeneca, Bayer, Boehringer, Chiesi, Forest Laboratories, GlaxoSmithKline, Grifols, Insmed, MedImmune, Novartis, Pfizer, and 30T, outside the submitted work. MGS reports grants from NIHR, MRC, and the Health Protection Research Unit in Emerging & Zoonotic Infections, University of Liverpool, during the conduct of the study; and reports being a minority owner and chair of the infectious disease scientific advisory board for Integrum Scientific, outside the submitted work. AShe reports being a Member of the Scottish Government's Chief Medical Officer's COVID-19 Advisory Group. MT reports personal fees from Merck Sharp & Dohme and GlaxoSmithKline, and grants and personal fees from Bayer and Actelion, during the conduct of the study. LVW reports grants from GlaxoSmithKline and Orion, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use., Methods: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16-49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma., Findings: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p<0·0001), and patients aged 50 years and older with chronic pulmonary disease (with or without asthma) were significantly less likely than those without a respiratory condition to receive critical care (adjusted OR 0·66 [0·60-0·72] for those without asthma and 0·74 [0·62-0·87] for those with asthma; p<0·0001 for both). In patients aged 16-49 years, only those with severe asthma had a significant increase in mortality compared to those with no asthma (adjusted hazard ratio [HR] 1·17 [95% CI 0·73-1·86] for those on no asthma therapy, 0·99 [0·61-1·58] for those on SABAs only, 0·94 [0·62-1·43] for those on inhaled corticosteroids only, 1·02 [0·67-1·54] for those on inhaled corticosteroids plus LABAs, and 1·96 [1·25-3·08] for those with severe asthma). Among patients aged 50 years and older, those with chronic pulmonary disease had a significantly increased mortality risk, regardless of inhaled corticosteroid use, compared to patients without an underlying respiratory condition (adjusted HR 1·16 [95% CI 1·12-1·22] for those not on inhaled corticosteroids, and 1·10 [1·04-1·16] for those on inhaled corticosteroids; p<0·0001). Patients aged 50 years and older with severe asthma also had an increased mortality risk compared to those not on asthma therapy (adjusted HR 1·24 [95% CI 1·04-1·49]). In patients aged 50 years and older, inhaled corticosteroid use within 2 weeks of hospital admission was associated with decreased mortality in those with asthma, compared to those without an underlying respiratory condition (adjusted HR 0·86 [95% CI 0·80-0·92])., Interpretation: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease., Funding: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions., Methods: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London)., Findings: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model., Interpretation: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19., Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Influenza viruses are highly transmissible, both within and between host species. The severity of the disease they cause is highly variable, from the mild and inapparent through to the devastating and fatal. The unpredictability of epidemic and pandemic outbreaks is accompanied but the predictability of seasonal disease in wide areas of the Globe, providing an inexorable toll on human health and survival. Although there have been great improvements in understanding influenza viruses and the disease that they cause, our knowledge of the effects they have on the host and the ways that the host immune system responds continues to develop. This review highlights the importance of the mucosa in defence against infection and in understanding the pathogenesis of disease. Although vaccines have been available for many decades, they remain suboptimal in needing constant redesign and in only providing short-term protection. There are real prospects for improvement in treatment and prevention of influenza soon, based on deeper knowledge of how the virus transmits, replicates and triggers immune defences at the mucosal surface.

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.

Respiratory syncytial virus (RSV) causes intense pulmonary inflammatory responses in some infected infants. The surface attachment protein 'G' of RSV has membrane-bound and secreted forms and shows homology to the CX3C chemokine fractalkine. Using recombinant techniques, we generated replication-competent recombinant clonal RSV expressing normal G proteins ('rRSV') or only the membrane-bound form of G ('Gmem rRSV'). Both recombinants grew well in HEp-2 cells, but after primary intranasal infection in mice, pulmonary Gmem rRSV replication was reduced tenfold compared to parental or rRSV; moreover, CCL2 and CCL5 production was greatly reduced and no apparent disease or pulmonary cellular infiltration was observed. However, Gmem rRSV-infected mice developed good antibody responses and were fully protected against subsequent intranasal challenge with parental virus. Even in mice sensitized to G by cutaneous infection with recombinant vaccinia expressing G, intranasal challenge with Gmem rRSV caused insignificant disease. We conclude that secreted G is a key viral product assisting virus replication in vivo, enhancing CCL2 and CCL5 production and promoting illness. Engineered RSV mutants lacking the ability to secrete G are thus promising vaccine candidates.