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Annals of Translational Medicine Jan 2023Bronchiectasis exacerbations are significant events in the natural course of the disease and determine long-term clinical outcomes. This review aims to discuss the... (Review)
Review
BACKGROUND AND OBJECTIVE
Bronchiectasis exacerbations are significant events in the natural course of the disease and determine long-term clinical outcomes. This review aims to discuss the definition, causes, risk factors, management and prevention of bronchiectasis exacerbations.
METHODS
The PubMed database was searched for relevant articles published in English between January 1990 and March 2022 using keywords "bronchiectasis" and "exacerbation".
KEY CONTENT AND FINDINGS
Causes of bronchiectasis exacerbation are multifactorial; it can be associated with bacterial and viral pathogens, host inflammatory responses, and external environmental effects. In addition, recent advances in bronchiectasis research highlight the phenotype of patients who are more prone to exacerbations, including those with chronic infection, worse symptoms, greater lung inflammation and comorbid airway diseases. Once bronchiectasis exacerbations occur, antibiotics are the mainstay treatment. Preventing exacerbations is of paramount importance because frequent exacerbations are linked to a detrimental disease course and higher mortality. To prevent frequent exacerbations, clinicians should attempt to understand the risk factors for exacerbation that are amenable to therapeutic intervention: so called "treatable traits". Treatments are personalised but include improving mucociliary clearance by physiotherapy and mucoactive therapy, reducing airway infection by inhaled antibiotics, and inflammation by long-term macrolide or in specific subpopulations, inhaled corticosteroids (ICS). Novel approaches to prevent exacerbations including direct anti-inflammatory therapies are in development for bronchiectasis.
CONCLUSIONS
Future research is needed to better manage and prevent exacerbations in patients with bronchiectasis, although recent studies have characterised frequent exacerbator phenotype and enhanced our understanding of various aspects of exacerbations.
PubMed: 36760239
DOI: 10.21037/atm-22-3437 -
Redox Biology Feb 2023The increasing abundance of fine particulate matter (PM2.5) in the environment has increased susceptibility to acute exacerbation of COPD (AECOPD). During PM2.5...
The increasing abundance of fine particulate matter (PM2.5) in the environment has increased susceptibility to acute exacerbation of COPD (AECOPD). During PM2.5 exposure, excessive reactive oxygen species (ROS) production triggers a redox imbalance, which contributes to damage to organelles and disruption of homeostasis. At present, there are limited data on whether NOX4/Nrf2 redox imbalance increases susceptibility to acute exacerbation of COPD (AECOPD), and the underlying mechanism is unclear. Therefore, the current study was aimed to evaluate the role of NOX4/Nrf2 redox balance on AECOPD induced by PM2.5-CS-exposure. Here, we report that PM2.5 exacerbates cytotoxicity by enhancing NOX4/Nrf2 redox imbalance-mediated mitophagy. First, exposure to a low-dose of PM2.5 (200 μg/ml) significantly exacerbated oxidative stress and mitochondrial damage by increasing the ROS overproduction, enhancing the excessive NOX4/Nrf2 redox imbalance, decreasing the mitochondrial membrane potential (MMP), and enhancing the mitochondrial fragmentation that were caused by a low-dose of CSE (2.5%). Second, coexposure to PM2.5 and CSE (PM2.5-CSE) induced excessive mitophagy. Third, PM2.5 exacerbated CS-induced COPD, as shown by excessive inflammatory cell infiltration, inflammatory cytokine production and mucus hypersecretion, goblet cell hyperplasia, NOX4/Nrf2 redox imbalance, and mitophagy, these effects triggered excessive ROS production and mitochondrial damage in mice. Mechanistically, PM2.5-CS-induced excessive levels of mitophagy by triggering redox imbalance, leading to greater cytotoxicity and AECOPD; however, reestablishing the NOX4/Nrf2 redox balance via NOX4 blockade or mitochondria-specific ROS inhibitor treatment alleviated this cytotoxicity and ameliorated AECOPD. PM2.5 may exacerbate NOX4/Nrf2 redox imbalance and subsequently enhance mitophagy by increasing the ROS and mito-ROS levels, thereby increasing susceptibility to AECOPD.
Topics: Mice; Animals; Reactive Oxygen Species; NF-E2-Related Factor 2; Mitophagy; Pulmonary Disease, Chronic Obstructive; Particulate Matter; Oxidation-Reduction; NADPH Oxidase 4
PubMed: 36608590
DOI: 10.1016/j.redox.2022.102587 -
Hepatology (Baltimore, Md.) May 2023Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen...
BACKGROUND AND AIMS
Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear.
APPROACH AND RESULTS
By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen-derived CD11b + cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis.
CONCLUSIONS
CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.
Topics: Mice; Animals; Spleen; Macrophages; Liver; Liver Cirrhosis; Monocytes; Mice, Inbred C57BL
PubMed: 36098707
DOI: 10.1002/hep.32782 -
International Journal of Oral Science Sep 2021Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a...
Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.
Topics: Animals; Colitis, Ulcerative; Mice; Mice, Inbred C57BL; Porphyromonas gingivalis; Protein-Arginine Deiminases; Virulence Factors
PubMed: 34593756
DOI: 10.1038/s41368-021-00136-2 -
The Journal of Allergy and Clinical... 2014The role of infection in asthma is varied in that it may exacerbate established asthma or contribute to the initial development of the clinical onset of asthma. Mounting... (Review)
Review
The role of infection in asthma is varied in that it may exacerbate established asthma or contribute to the initial development of the clinical onset of asthma. Mounting evidence implicates both roles with particular viral pathogens, namely human rhinovirus and respiratory syncytial virus, among the most likely culprits in asthma inception. Once asthma is present, infection, particularly viral infection, is a common precipitant of asthma exacerbations. Bacterial infections and colonization also have been associated with exacerbation and recurrent wheeze, an effect that may be independent or a cofactor with viruses. Atypical bacterial infections such as Mycoplasma pneumoniae and Chlamydia pneumoniae and fungi in the case of allergic bronchopulmonary aspergillosis, also play a potential role in inducing and exacerbating this disease. In addition, certain individuals may have a genetic predisposition toward viral-induced wheezing and the development of asthma. This article will discuss host and environmental factors, common pathogens, clinical characteristic, and genetic influences associated with infection-related asthma.
Topics: Animals; Asthma; Bacterial Infections; Comorbidity; Genetic Markers; Genetic Predisposition to Disease; Humans; Lung; Phenotype; Prognosis; Respiratory Tract Infections; Risk Factors; Virus Diseases
PubMed: 25439354
DOI: 10.1016/j.jaip.2014.09.011 -
Archivos de Bronconeumologia Jan 2022The Spanish COPD Guidelines (GesEPOC) were first published in 2012, and since then have undergone a series of updates incorporating new evidence on the diagnosis and...
The Spanish COPD Guidelines (GesEPOC) were first published in 2012, and since then have undergone a series of updates incorporating new evidence on the diagnosis and treatment of COPD. GesEPOC was drawn up in partnership with scientific societies involved in the treatment of COPD and the Spanish Patients' Forum. Their recommendations are based on an evaluation of the evidence using GRADE methodology, and a narrative description of the evidence in areas in which GRADE cannot be applied. In this article, we summarize the recommendations on the pharmacological treatment of stable COPD based on 9 PICO questions. COPD treatment is a 4-step process: 1) diagnosis, 2) determination of the risk level, 3) initial and subsequent inhaled therapy, and 4) identification and management of treatable traits. For the selection of inhaled therapy, high-risk patients are divided into 3 phenotypes: non-exacerbator, eosinophilic exacerbator, and non-eosinophilic exacerbator. Some treatable traits are general and should be investigated in all patients, such as smoking or inhalation technique, while others affect severe patients in particular, such as chronic hypoxemia and chronic bronchial infection. COPD treatment is based on long-acting bronchodilators with single agents or in combination, depending on the patient's risk level. Eosinophilic exacerbators must receive inhaled corticosteroids, while non-eosinophilic exacerbators require a more detailed evaluation to choose the best therapeutic option. The new GesEPOC also includes recommendations on the withdrawal of inhaled corticosteroids and on indications for alpha-1 antitrypsin treatment. GesEPOC offers a more individualized approach to COPD treatment tailored according to the clinical characteristics of patients and their level of complexity.
PubMed: 33840553
DOI: 10.1016/j.arbres.2021.03.005 -
International Journal of Chronic... 2022Studies have shown that chronic obstructive pulmonary disease (COPD) exacerbation events are related to future events; however, previous literature typically reports...
BACKGROUND
Studies have shown that chronic obstructive pulmonary disease (COPD) exacerbation events are related to future events; however, previous literature typically reports frequent vs infrequent exacerbations per patient-year and no studies have investigated increasing number of severe exacerbations in relation to COPD outcomes.
OBJECTIVE
To investigate the association between baseline frequency and severity of exacerbations and subsequent mortality and exacerbation risk in a COPD cohort.
METHODS
Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics data were used to identify patients registered at general practices in the UK, who had a diagnosis of COPD, were over the age of 40 years, were smokers or ex-smokers and had data recorded from 2004 onwards. Frequency and severity of exacerbations in the baseline year were identified as moderate exacerbations (general practice events) and severe exacerbations (hospitalised events). Patients were categorised as having: none, 1 moderate only, 2 moderate only, 3+ moderate only, 1 severe (and any moderate), 2 severe (and any moderate), and 3+ severe (and any moderate exacerbations). Poisson regression was used to investigate the association between baseline exacerbation frequency/severity and exacerbation events and mortality over follow-up.
RESULTS
Overall, 340,515 COPD patients were included. Patients had higher rates of future exacerbations with increasing frequency and severity of baseline exacerbations compared to no baseline exacerbations. Adjusted incidence rate ratios (IRR) for patients with 1, 2, and 3+ moderate exacerbations compared to 0 exacerbations were 1.70 (95% CI 1.66-1.74), 2.31 (95% CI 2.24-2.37), and 3.52 (95% CI 3.43-3.62), respectively. Patients with increased frequency of baseline exacerbations were more likely to die from all-cause, COPD-related, and cardiovascular-related mortality in a graduated fashion.
CONCLUSION
Increasing number and severity of exacerbations were associated with increasing risk of subsequent exacerbations, all-cause mortality and COPD-related mortality. Even a single moderate event increases the risk of future events, illustrating that every exacerbation counts.
Topics: Adult; Delivery of Health Care; Disease Progression; Humans; Incidence; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; United Kingdom
PubMed: 35264849
DOI: 10.2147/COPD.S346591 -
Tuberculosis and Respiratory Diseases Jul 2023Bronchiectasis, which is characterized by irreversibly damaged and dilated bronchi, causes significant symptoms, poor quality of life, and increased economic burden and...
Bronchiectasis, which is characterized by irreversibly damaged and dilated bronchi, causes significant symptoms, poor quality of life, and increased economic burden and mortality rates. Despite its increasing prevalence and clinical significance, bronchiectasis was previously regarded as an orphan disease, and ideal treatment of this disease has been poorly understood. The European Respiratory Society and British Thoracic Society have recently published guidelines to assist physicians in the clinical field. Guidelines and reports suggest comprehensive management that includes both non-pharmacological and pharmacological treatment. Physiotherapy and pulmonary rehabilitation are two of the most important non-pharmacologic therapies in bronchiectasis patients; long-term inhaled antibiotics and macrolide therapy have gained significant evidence in reducing exacerbation risk in frequent exacerbators. In this review, we summarize recent updates on bronchiectasis treatment to prevent exacerbation and manage clinical deterioration.
PubMed: 37165624
DOI: 10.4046/trd.2023.0010 -
American Journal of Respiratory and... Aug 2018There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations. (Randomized Controlled Trial)
Randomized Controlled Trial
Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial.
RATIONALE
There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations.
OBJECTIVES
To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD).
METHODS
This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 μg once daily) or continuation of triple therapy (tiotropium [18 μg] once daily plus combination of salmeterol/fluticasone propionate [50/500 μg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV. Moderate or severe exacerbations were predefined secondary endpoints.
MEASUREMENTS AND MAIN RESULTS
A total of 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV of -26 ml (95% confidence interval, -53 to 1 ml) with confidence limits exceeding the noninferiority margin of -50 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with ≥300 blood eosinophils/μl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups.
CONCLUSIONS
In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/μl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Bronchodilator Agents; Double-Blind Method; Female; Fluticasone-Salmeterol Drug Combination; Glucocorticoids; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Treatment Outcome
PubMed: 29779416
DOI: 10.1164/rccm.201803-0405OC -
American Journal of Respiratory and... Sep 2022The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of... (Randomized Controlled Trial)
Randomized Controlled Trial
The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2 and T2 at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2 (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2 (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2 and 76.4% (230) T2. The T2 group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2 events were indistinguishable from T2 exacerbations in terms of lung function (mean fall in T2 FEV 200 [400] ml vs. T2 200 [300] ml; = 0.93) and symptom increase (ACQ5: T2, 1.4 [0.8] vs. T2, 1.3 [0.8]; = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2 exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Asthma exacerbations demonstrating a T2 phenotype were physiologically and symptomatically similar to T2 exacerbations. T2 asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).
Topics: Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Biomarkers; Disease Progression; Female; Humans; Male; Phenotype; Risk Factors
PubMed: 35549845
DOI: 10.1164/rccm.202201-0129OC