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New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD). There is now considerable evidence that infection plays a major role in the pathogenesis and clinical course of COPD. A vicious circle of infection and inflammation is thought to lead to exacerbations of the disease. New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD). Considerable evidence suggests that a vicious circle of infection and inflammation leads to exacerbations of the disease. Historical Perspective In the 1950s and 1960s, according to a theory known as the British hypothesis, repeated airway infection and hypersecretion of mucus were thought to be the causes of chronic obstructive pulmonary disease (COPD). Subsequently, exposure to tobacco smoke was identified as the predominant cause. Researchers were still unable to relate the frequency of exacerbations — acute increases in the respiratory symptoms of COPD that require medical intervention — and hypersecretion of mucus to the progression of airflow obstruction. 1 Instead, the frequency of bacterial isolation from sputum was found to be similar in stable COPD and during exacerbations. On . . .

Background. Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have fundamental impairment of phagocytosis for nontypeable Haemophilus influenzae (NTHI). However, relative selectivity of dysfunctional phagocytosis among diverse respiratory pathogens: NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP), and nonbacterial particles, as well as the contribution of impaired phagocytosis to severity of COPD, has not been explored. Methods. Alveolar macrophages, obtained from nonsmokers (n = 20), COPD ex-smokers (n = 32), and COPD active smokers (n = 64), were incubated with labeled NTHI, MC, SP, and fluorescent microspheres. Phagocytosis was measured as intracellular percentages of each. Results. Alveolar macrophages of COPD ex-smokers and active smokers had impaired complement-independent phagocytosis of NTHI (P =.003) and MC (P = .0007) but not SP or microspheres. Nonetheless, complement-mediated phagocytosis was enhanced within each group only for SP. Defective phagocytosis was significantly greater for NTHI than for MC among COPD active smokers (P<. 0001) and ex-smokers (P =.028). Moreover, severity of COPD (FEV₁% predicted) correlated with impaired AM phagocytosis for NTHI (P = .0016) and MC (P = .01). Conclusions. These studies delineate pathogen-and host-specific differences in defective alveolar macrophages phagocytosis of respiratory bacteria in COPD, further elucidating the immunologie basis for bacterial persistence in COPD and provide the first demonstration of association of impaired phagocytosis to severity of disease.

The fourth leading cause of death in the US, Chronic Obstructive Pulmonary Disease (COPD) is punctuated by frequent viral and bacterial infections causing severe acute exacerbations (AECOPD) and increased mortality. In previous work we have shown that altered immune cell signaling may confer increased and persistent susceptibility to infection. Here we continue this investigation by conducting broad-spectrum proteomic profiling of circulating white blood cells to assemble an empirical protein-protein interaction network associated with frequency of infectious exacerbation. In a novel extension of conventional cross-sectional data analyses, we translate these undirected protein-protein interactions into candidate regulatory relationships with both direction and mode of action. The latter are inferred by formulating and solving a constraint satisfaction problem (SAT) whereby predicted dynamic behaviors of any valid regulatory network must support the expected persistent nature of low and high vulnerability phenotypes. Solving this SAT problem produced a set of competing candidate protein regulatory network architectures and signalling rules that unanimously highlighted several novel candidate pathway elements involved in oxidative stress response. Analysis of the overall dynamics supported by these networks, again supported the hypothesis that progression beyond an immune tipping point may confer persistent susceptibility to infection and that this may constitute a stable phenotype or regulatory trap in COPD characterized by a reactive oxygen cascade.

Understanding the causes and factors related to readmission for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) within a nationwide database including all payers and ages can provide valuable input for the development of generalizable readmission reduction strategies. To determine the rates, causes, and predictors for early (3-, 7-, and 30-d) readmission in patients hospitalized with AECOPD in the United States using the Nationwide Readmission Database after the initiation of the Hospital Readmissions Reduction Program, but before its expansion to COPD. We conducted an analysis of the Nationwide Readmission Database from 2013 to 2014. Index admissions and readmissions for an AECOPD were defined consistent with Hospital Readmissions Reduction Program guidelines. We investigated the percentage of 30-day readmissions occurring each day after discharge and the most common readmission diagnoses at different time periods after hospitalization. The relationship between predictors (categorized as patient, clinical, and hospital factors) and early readmission were evaluated using a hierarchical two-level logistic model. To examine covariate effects on early-day readmission, predictors for 3-, 7-, and 30-day readmissions were modeled separately. There were 202,300 30-day readmissions after 1,055,830 index AECOPD admissions, a rate of 19.2%. The highest readmission rates (4.2-5.5%) were within the first 72 hours of discharge, and 58% of readmissions were within the first 15 days. Respiratory-based diseases were the most common reasons for readmission (52.4%), and COPD was the most common diagnosis (28.4%). Readmission diagnoses were similar at different time periods after discharge. Early readmission was associated with patient (Medicaid payer status, lower household income, and higher comorbidity burden) and clinical factors (longer length of stay and discharge to a skilled nursing facility). Predictors did not vary substantially by time of readmission after discharge within the 30-day window. Thirty-day readmissions after an AECOPD remain a major healthcare burden, and are characterized by a similar spectrum of readmission diagnoses. Predictors associated with readmission include both patient and clinical factors. Development of a COPD-specific risk stratification algorithm based on these factors may be necessary to better predict patients with AECOPD at high risk of early readmission.

Coronavirus disease 2019 (COVID-19), caused by the highly contagious novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a worldwide pandemic and currently represents a major public health issue. COVID-19 has highlighted the need for clear and accurate guidance on the use of aerosol-generating procedures, such as nebulization, for the treatment of patients with respiratory diseases with or without COVID-19. Despite the lack of evidence, there is heightened concern about the potential risk of transmission of SARS-CoV-2 in the form of aerosolized respiratory droplets during the nebulized treatment of patients with COVID-19. Consequently, the use of metered-dose inhalers (MDIs) has risen considerably as an alternative to nebulized therapy, which has led to inadequate supplies of MDIs in some parts of the United States. In this article, we review and discuss the role of nebulization in patients with SARS-CoV-2 and the treatment of noninfected patients with chronic respiratory diseases. The following two important questions are addressed: (1) should nebulized therapy be used in hospital or home settings by patients infected with SARS-CoV-2; and (2) should nebulized therapy be continued in patients already using it for chronic respiratory disease management in hospital or home settings? The reviews of this paper are available via the supplemental material section.

Infectious agents are a major cause of acute exacerbations of chronic bronchitis (AECB) and COPD. Several respiratory viruses are associated with 30% of exacerbations, with or without a superimposed bacterial infection. Atypical bacteria, mostly Chlamydia pneumoniae, have been implicated in < 10% of AECB. The role of bacterial pathogens when isolated from the respiratory tract during AECB has become better defined by application of several newer investigative techniques. Bacterial pathogens can be isolated in significant concentrations from distal airways in 50% of AECB. Specific immune responses to surface exposed antigens of the infecting pathogen have been shown to develop after an exacerbation. Emerging evidence from molecular epidemiology and measurement of airway inflammation further support the role of bacteria in AECB. When properly defined, 80% of AECB are likely to be infectious in origin.

Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by worsening respiratory symptoms, which are almost always accompanied by an increase in airway inflammation.1-3 The majority of these exacerbations are caused by microbial infection.4 By current estimates, about 50% of exacerbations are caused by bacteria, either alone or in combination with viruses.4 Before 1970, multiple attempts were made to test the hypothesis that prophylactic antibiotics can reduce the frequency of COPD exacerbations. Unfortunately, the trials were small, with differing methods and antibiotic choices. Most used antibiotics that would likely not be effective today, given changes in antibiotic susceptibilities of bacterial pathogens. A systematic review of these trials did show a small reduction in the frequency of exacerbations (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.84-0.99).5 However, because the effect was modest and because of methodologic limitations and concerns about antibiotic resistance, these results cannot be applied in the present-day care of patients with COPD. It is probable that immunomodulatory effects are responsible for at least a part of the actions of macrolides in COPD. In vitro cell culture and animal models have shown that macrolides possess potent anti-inflammatory and immunomodulatory properties (Box 2).11,12 Relative to alveolar macrophages from healthy controls, those from patients with COPD have decreased ability to phagocytose apoptotic cells (efferocytosis)14 and pathogenic bacteria.15 Azithromycin reverses this deficit in efferocytosis14 and improves the ability of macrophages from patients with COPD to phagocytose bacteria. 16 Furthermore, macrolides were successful in preventing exacerbations and improving lung function in cystic fibrosis17,18 and improving survival in diffuse panbronchiolitis.19 In these two airway diseases, the major pathogen is P. aeruginosa, against which macrolides are decidedly ineffective in conventional antimicrobial terms. In addition, two trials of erythromycin prophylaxis in COPD used doses lower than required for antimicrobial effects, but the drug was nevertheless beneficial.20,21 However, measurements of pro-inflammatory cytokines in patients with COPD enrolled in macrolide treatment trials have yielded conflicting results. Therefore, there is still no clear evidence that the benefits of macrolides in COPD are related to these immunomodulatory effects. In patients with COPD, intermittent use of macrolides to treat exacerbations has been associated with isolation of macrolide-resistant strains of S. pneumoniae from sputum.31 [Albert] and colleagues26 observed an increase in the incidence of macrolide-resistant nasopharyngeal bacteria among patients receiving azithromycin. In that study, nasopharyngeal swabs were used to evaluate respiratory colonization, and swabs were obtained for about 85% of patients. The rates of colonization by Staphylococcus aureus, H. influenzae, M. catarrhalis and S. pneumoniae did not differ between the groups at the start of the study. By the end of the study period, significantly fewer patients in the azithromycin group had colonization with the same pathogens. However, among patients in the azithromycin group with occurrence of colonization during the study period, the chance of azithromycin resistance in the pathogens isolated was significantly higher (p < 0.001). In other words, when patients on long-term azithromycin acquired new nasopharyngeal bacteria, those bacterial strains were more likely to be resistant to azithromycin.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

COPD patients have high pulmonary and systemic oxidative stress that correlates with severity of disease. Sulforaphane has been shown to induce expression of antioxidant genes via activation of a transcription factor, nuclear factor erythroid-2 related factor 2 (Nrf2). This parallel, placebo-controlled, phase 2, randomized trial was conducted at three US academic medical centers. Patients who met GOLD criteria for COPD and were able to tolerate bronchoscopies were randomly assigned (1:1:1) to receive placebo, 25 μmoles, or 150 μmoles sulforaphane daily by mouth for four weeks. The primary outcomes were changes in Nrf2 target gene expression (NQ01, HO1, AKR1C1 and AKR1C3) in alveolar macrophages and bronchial epithelial cells. Secondary outcomes included measures of oxidative stress and airway inflammation, and pulmonary function tests. Between July 2011 and May 2013, 89 patients were enrolled and randomized. Sulforaphane was absorbed in the patients as evident from their plasma metabolite levels. Changes in Nrf2 target gene expression relative to baseline ranged from 0.79 to 1.45 and there was no consistent pattern among the three groups; the changes were not statistically significantly different from baseline. Changes in measures of inflammation and pulmonary function tests were not different among the groups. Sulforaphane was well tolerated at both dose levels. Sulforaphane administered for four weeks at doses of 25 μmoles and 150 μmoles to patients with COPD did not stimulate the expression of Nrf2 target genes or have an effect on levels of other anti-oxidants or markers of inflammation. Clinicaltrials.gov: NCT01335971.

Background Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1β. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic , moderate-to-very severe COPD. Methods This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study. Subjects aged 45–75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks. The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation). Secondary endpoints were severe AECOPD rate and St George’s Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation). Results Of subjects randomised to placebo ( n  = 164) and MEDI8968 ( n  = 160), 79.3% and 75.0%, respectively, completed the study. There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores. Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome. The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar. The most common TEAE was worsening of COPD. Conclusions In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life. Trial registration ClinicalTrials.gov, NCT01448850 , date of registration: 06 October 2011.