Limited access to testing early in the outbreak, false negative results for nasopharyngeal swabs in early stages of disease, and presentation with gastrointestinal symptoms may have led to some ...patients with COVID-19 being misclassified and placed in non-COVID-19 areas with different infection prevention control processes.3 Enteric features, and the ability of SARS-CoV-2 to persist on surfaces, raise the possibility of faecal-oral transmission in care settings under severe pressure, although the role of this transmission route is uncertain.5 As SARS-CoV-2 is likely to persist as an endemic or seasonal virus in coming years, it is critical to use the lessons learned so far in the pandemic to minimise the burden of hospital-acquired infections, and to consider new approaches to reduce the burden further. Unlike at the beginning of the pandemic, there are opportunities to pre-empt hospital-acquired infections and break chains of transmission through regular patient, resident, and staff testing including point-of-care diagnostics, as recently introduced for NHS staff, coupled with robust hospital infection prevention and control policies that include staff vaccination, environmental disinfection, and appropriate isolation, all supported by sentinel monitoring systems. PJMO reports personal fees for consultancy from Janssen and from the European Respiratory Society; grants from the MRC and Wellcome; funding from the EU and the European Federation of Pharmaceutical Industries and Associations for the respiratory syncytial virus consortium in Europe; and funding from the NIHR, the MRC, and GSK to the EMINENT Network.
Even in nonpandemic times, respiratory viruses account for a vast global burden of disease. They remain a major cause of illness and death and they pose a perpetual threat of breaking out into ...epidemics and pandemics. Many of these respiratory viruses infect repeatedly and appear to induce only narrow transient immunity, but the situation varies from one virus to another. In the absence of effective specific treatments, understanding the role of immunity in protection, disease, and resolution is of paramount importance. These problems have been brought into sharp focus by the coronavirus disease 2019 (COVID-19) pandemic. Here, we summarise what is now known about adaptive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and draw comparisons with immunity to other respiratory viruses, focusing on the longevity of protective responses.
Neutralising antibody from long-lived plasma cells, supported by memory B and T cells, can provide lifelong protection against severe disease caused by many respiratory viruses. However, antigenic viral variation can undermine such immunity.Viral immunomodulation of memory responses may contribute to reinfections by certain respiratory viruses, though reinfections of healthy adults with homologous viruses are uncommon and usually mild in severity.Robust systemic antibody, B and T cell responses are mounted upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in almost all individuals, and these facets of immune memory are sustained for over 8 months postinfection.Mucosal immunity, provided mainly by IgA and tissue-resident T cells, is associated with rapid and potent protection against respiratory infection. However, the durability of these responses has not been established.Studies of systemic antibody and cellular responses suggest that protection against severe disease caused by nonvariant SARS-CoV-2 may be long-lasting in most individuals.
Long COVID: clues about causes Liew, Felicity; Efstathiou, Claudia; Openshaw, Peter J M
The European respiratory journal,
05/2023, Letnik:
61, Številka:
5
Journal Article
Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed ...compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of
in both Zaire Ebolavirus (EBOV) and COVID-19 patient cohorts. We also show unique characteristics absent in Respiratory Syncytial Virus or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risk off-target effects.
AbstractObjectiveTo characterise the clinical features of patients admitted to hospital with coronavirus disease 2019 (covid-19) in the United Kingdom during the growth phase of the first wave of ...this outbreak who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study, and to explore risk factors associated with mortality in hospital.DesignProspective observational cohort study with rapid data gathering and near real time analysis.Setting208 acute care hospitals in England, Wales, and Scotland between 6 February and 19 April 2020. A case report form developed by ISARIC and WHO was used to collect clinical data. A minimal follow-up time of two weeks (to 3 May 2020) allowed most patients to complete their hospital admission.Participants20 133 hospital inpatients with covid-19.Main outcome measuresAdmission to critical care (high dependency unit or intensive care unit) and mortality in hospital.ResultsThe median age of patients admitted to hospital with covid-19, or with a diagnosis of covid-19 made in hospital, was 73 years (interquartile range 58-82, range 0-104). More men were admitted than women (men 60%, n=12 068; women 40%, n=8065). The median duration of symptoms before admission was 4 days (interquartile range 1-8). The commonest comorbidities were chronic cardiac disease (31%, 5469/17 702), uncomplicated diabetes (21%, 3650/17 599), non-asthmatic chronic pulmonary disease (18%, 3128/17 634), and chronic kidney disease (16%, 2830/17 506); 23% (4161/18 525) had no reported major comorbidity. Overall, 41% (8199/20 133) of patients were discharged alive, 26% (5165/20 133) died, and 34% (6769/20 133) continued to receive care at the reporting date. 17% (3001/18 183) required admission to high dependency or intensive care units; of these, 28% (826/3001) were discharged alive, 32% (958/3001) died, and 41% (1217/3001) continued to receive care at the reporting date. Of those receiving mechanical ventilation, 17% (276/1658) were discharged alive, 37% (618/1658) died, and 46% (764/1658) remained in hospital. Increasing age, male sex, and comorbidities including chronic cardiac disease, non-asthmatic chronic pulmonary disease, chronic kidney disease, liver disease and obesity were associated with higher mortality in hospital.ConclusionsISARIC WHO CCP-UK is a large prospective cohort study of patients in hospital with covid-19. The study continues to enrol at the time of this report. In study participants, mortality was high, independent risk factors were increasing age, male sex, and chronic comorbidity, including obesity. This study has shown the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks.Study registrationISRCTN66726260.
Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting ...viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1(-/-)) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/-) mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1(-/-) mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production.
The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.
Immunity to RSV in Early-Life Lambert, Laura; Sagfors, Agnes M; Openshaw, Peter J M ...
Frontiers in immunology,
09/2014, Letnik:
5
Journal Article
Recenzirano
Odprti dostop
Respiratory Syncytial Virus (RSV) is the commonest cause of severe respiratory infection in infants, leading to over 3 million hospitalizations and around 66,000 deaths worldwide each year. RSV ...bronchiolitis predominantly strikes apparently healthy infants, with age as the principal risk factor for severe disease. The differences in the immune response to RSV in the very young are likely to be key to determining the clinical outcome of this common infection. Remarkable age-related differences in innate cytokine responses follow recognition of RSV by numerous pattern recognition receptors, and the importance of this early response is supported by polymorphisms in many early innate genes, which associate with bronchiolitis. In the absence of strong, Th1 polarizing signals, infants develop T cell responses that can be biased away from protective Th1 and cytotoxic T cell immunity toward dysregulated, Th2 and Th17 polarization. This may contribute not only to the initial inflammation in bronchiolitis, but also to the long-term increased risk of developing wheeze and asthma later in life. An early-life vaccine for RSV will need to overcome the difficulties of generating a protective response in infants, and the proven risks associated with generating an inappropriate response. Infantile T follicular helper and B cell responses are immature, but maternal antibodies can afford some protection. Thus, maternal vaccination is a promising alternative approach. However, even in adults adaptive immunity following natural infection is poorly protective, allowing re-infection even with the same strain of RSV. This gives us few clues as to how effective vaccination could be achieved. Challenges remain in understanding how respiratory immunity matures with age, and the external factors influencing its development. Determining why some infants develop bronchiolitis should lead to new therapies to lessen the clinical impact of RSV and aid the rational design of protective vaccines.
Bronchiolitis Smyth, Rosalind L; Openshaw, Peter JM
The Lancet (British edition),
07/2006, Letnik:
368, Številka:
9532
Journal Article
Recenzirano
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.
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