Understanding the role of the airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches.
To ...understand the association of the airway microbiome with neutrophilic and eosinophilic COPD at stability and during exacerbations.
An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 patients with COPD recruited at four UK sites of the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic COPD), COPDMAP (Chronic Obstructive Pulmonary Disease Medical Research Council/Association of the British Pharmaceutical Industry), and AERIS (Acute Exacerbation and Respiratory Infections in COPD) cohorts. The microbiome was analyzed using COPDMAP and AERIS as a discovery data set and BEAT-COPD as a validation data set.
The airway microbiome in neutrophilic COPD was heterogeneous, with two primary community types differentiated by the predominance of
. The
-predominant subgroup had elevated sputum IL-1β and TNFα (tumor necrosis factor α) and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to the greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic
and eosinophilic states that were otherwise mutually exclusive. Time-series analysis on the microbiome showed that the temporal trajectories of
and
were indicative of intrapatient switches from neutrophilic to eosinophilic inflammation, in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns among neutrophilic
-predominant, neutrophilic balanced microbiome, and eosinophilic subgroups.
The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are interchangeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.
Computed tomography (CT) is the modality of choice for imaging the thorax and lung structure. In chronic obstructive pulmonary disease (COPD), it used to recognise the key morphological features of ...emphysema, bronchial wall thickening and gas trapping. Despite this, its place in the investigation and management of COPD is yet to be determined, and it is not routinely recommended. However, lung CT already has important clinical applications where it can be used to diagnose concomitant pathology and determine which patients with severe emphysema are appropriate for lung volume reduction procedures. Furthermore, novel quantitative analysis techniques permit objective measurements of pulmonary and extrapulmonary manifestations of the disease. These techniques can give important insights into COPD, and help explore the heterogeneity and underlying mechanisms of the condition. In time, it is hoped that these techniques can be used in clinical trials to help develop disease-specific therapy and, ultimately, as a clinical tool in identifying patients who would benefit most from new and existing treatments. This review discusses the current clinical applications for CT imaging in COPD and quantification techniques, and its potential future role in stratifying disease for optimal outcome.
Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality despite current treatment strategies which focus on smoking cessation, pulmonary rehabilitation, and ...symptomatic relief. A focus of COPD care is to encourage self-management, particularly during COVID-19, where much face-to-face care has been reduced or ceased. Digital health solutions may offer affordable and scalable solutions to support COPD patient education and self-management, such solutions could improve clinical outcomes and expand service reach for limited additional cost. However, optimal ways to deliver digital medicine are still in development, and there are a number of important considerations for clinicians, commissioners, and patients to ensure successful implementation of digitally augmented care. In this narrative review, we discuss advantages, pitfalls, and future prospects of digital healthcare, which offer a variety of tools including self-management plans, education videos, inhaler training videos, feedback to patients and healthcare professionals (HCPs), exacerbation monitoring, and pulmonary rehabilitation. We discuss the key issues with sustaining patient and HCP engagement and limiting attrition of use, interoperability with devices, integration into healthcare systems, and ensuring inclusivity and accessibility. We explore the essential areas of research beyond determining safety and efficacy to understand the acceptability of digital healthcare solutions to patients, clinicians, and healthcare systems, and hence ways to improve this and sustain engagement. Finally, we explore the regulatory challenges to ensure quality and engagement and effective integration into current healthcare systems and care pathways, while maintaining patients’ autonomy and privacy. Understanding and addressing these issues and successful incorporation of an acceptable, simple, scalable, affordable, and future-proof digital solution into healthcare systems could help remodel global chronic disease management and fractured healthcare systems to provide best patient care and optimisation of healthcare resources to meet the global burden and unmet clinical need of COPD.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy ...and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19.
We did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed.
Between March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 95% CI 1·07-5·04; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 95% CI 1·03-4·69; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven 15% patients in the SNG001 group and five 10% in the placebo group). There were three deaths in the placebo group and none in the SNG001 group.
Patients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials.
Synairgen Research.
Respiratory viral infections in the elderly Watson, Alastair; Wilkinson, Tom M. A.
Therapeutic Advances in Respiratory Disease,
2021, Letnik:
15
Book Review, Journal Article
Recenzirano
Odprti dostop
With the global over 60-year-old population predicted to more than double over the next 35 years, caring for this aging population has become a major global healthcare challenge. In 2016 there were ...over 1 million deaths in >70 year olds due to lower respiratory tract infections; 13–31% of these have been reported to be caused by viruses. Since then, there has been a global COVID-19 pandemic, which has caused over 2.3 million deaths so far; increased age has been shown to be the biggest risk factor for morbidity and mortality. Thus, the burden of respiratory viral infections in the elderly is becoming an increasing unmet clinical need. Particular challenges are faced due to the interplay of a variety of factors including complex multimorbidities, decreased physiological reserve and an aging immune system. Moreover, their atypical presentation of symptoms may lead to delayed necessary care, prescription of additional drugs and prolonged hospital stay. This leads to morbidity and mortality and further nosocomial spread. Clinicians currently have limited access to sensitive detection methods. Furthermore, a lack of effective antiviral treatments means there is little incentive to diagnose and record specific non-COVID-19 viral infections. To meet this unmet clinical need, it is first essential to fully understand the burden of respiratory viruses in the elderly. Doing this through prospective screening research studies for all respiratory viruses will help guide preventative policies and clinical trials for emerging therapeutics. The implementation of multiplex point-of-care diagnostics as a mainstay in all healthcare settings will be essential to understand the burden of respiratory viruses, diagnose patients and monitor outbreaks. The further development of novel targeted vaccinations as well as anti-viral therapeutics and new ways to augment the aging immune system is now also essential.
The reviews of this paper are available via the supplemental material section.
Highlights•An investigational NTHi vaccine was tested for the first time in adults with COPD. •The vaccine had acceptable safety and reactogenicity. •Vaccine-elicited antibody concentrations were ...higher than baseline 1 year post-dose 2.
Alterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD.
To ...characterise longitudinal changes in the lung microbiome in the AERIS study (Acute Exacerbation and Respiratory InfectionS in COPD) and their relationship with associated COPD outcomes.
We surveyed 584 sputum samples from 101 patients with COPD to analyse the lung microbiome at both stable and exacerbation time points over 1 year using high-throughput sequencing of the 16S ribosomal RNA gene. We incorporated additional lung microbiology, blood markers and in-depth clinical assessments to classify COPD phenotypes.
The stability of the lung microbiome over time was more likely to be decreased in exacerbations and within individuals with higher exacerbation frequencies. Analysis of exacerbation phenotypes using a Markov chain model revealed that bacterial and eosinophilic exacerbations were more likely to be repeated in subsequent exacerbations within a subject, whereas viral exacerbations were not more likely to be repeated. We also confirmed the association of bacterial genera, including
and
, with disease severity, exacerbation events and bronchiectasis.
Subtypes of COPD have distinct bacterial compositions and stabilities over time. Some exacerbation subtypes have non-random probabilities of repeating those subtypes in the future. This study provides insights pertaining to the identification of bacterial targets in the lung and biomarkers to classify COPD subtypes and to determine appropriate treatments for the patient.
Results, NCT01360398.
The aetiology of acute exacerbations of COPD (AECOPD) is incompletely understood. Understanding the relationship between chronic bacterial airway infection and viral exposure may explain the ...incidence and seasonality of these events.
In this prospective, observational cohort study (NCT01360398), patients with COPD aged 40-85 years underwent sputum sampling monthly and at exacerbation for detection of bacteria and viruses. Results are presented for subjects in the full cohort, followed for 1 year. Interactions between exacerbation occurrence and pathogens were investigated by generalised estimating equation and stratified conditional logistic regression analyses.
The mean exacerbation rate per patient-year was 3.04 (95% CI 2.63 to 3.50). At AECOPD, the most common bacterial species were non-typeable
(NTHi) and
, and the most common virus was rhinovirus. Logistic regression analyses (culture bacterial detection) showed significant OR for AECOPD occurrence when
was detected regardless of season (5.09 (95% CI 2.76 to 9.41)). When NTHi was detected, the increased risk of exacerbation was greater in high season (October-March, OR 3.04 (1.80 to 5.13)) than low season (OR 1.22 (0.68 to 2.22)). Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than stable state (8.6%). A significant interaction was detected between NTHi and rhinovirus presence and AECOPD risk (OR 5.18 (1.92 to 13.99); p=0.031).
AECOPD aetiology varies with season. Rises in incidence in winter may be driven by increased pathogen presence as well as an interaction between NTHi airway infection and effects of viral infection.
Results, NCT01360398.
Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity might be key to ...controlling infection, but the responses of NTHi-specific T-cell populations are not well understood. Mucosal-associated invariant T (MAIT) cells are a recently discovered, innate-like subset of T cells with cytotoxic function, the role of which in lung immunity is unclear.
The aim of this study was to determine the mechanisms behind conventional T-cell and MAIT cell cytotoxic responses to NTHi.
Human ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using flow cytometry.
We found significant upregulation of the cytotoxic markers CD107a and granzyme B in lung CD4+, CD8+, and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time-dependent antigen presentation and a novel mechanism through which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor.
Overall, our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T-cell responses. Understanding these mechanisms might lead to new therapeutic opportunities to modulate the antibacterial response and improve clinical outcome.
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Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) predicts response to treatment, especially corticosteroids. We studied the nature of eosinophilic inflammation in COPD ...prospectively to examine the stability of this phenotype and its dynamics across exacerbations, and its associations with clinical phenotype, exacerbations and infection.127 patients aged 40-85 years with moderate to very severe COPD underwent repeated blood and sputum sampling at stable visits and within 72 h of exacerbation for 1 year.Blood eosinophils ≥2% was prevalent at baseline, and predicted both predominantly raised stable-state eosinophils across the year (area under the curve 0.841, 95% CI 0.755-0.928) and increased risk of eosinophilic inflammation at exacerbation (OR 9.16; p<0.001). Eosinophils ≥2% at exacerbation and eosinophil predominance at stable visits were associated with a lower risk of bacterial presence at exacerbation (OR 0.49; p=0.049 and OR 0.25; p=0.065, respectively). Bacterial infection at exacerbation was highly seasonal (winter
summer OR 4.74; p=0.011) in predominantly eosinophilic patients.Eosinophilic inflammation is a common and stable phenotype in COPD. Blood eosinophil counts in the stable state can predict the nature of inflammation at future exacerbations, which when combined with an understanding of seasonal variation provides the basis for the development of new treatment paradigms for this important condition.
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