Acute Respiratory Exacerbations Research Articles

Self-report underestimates the frequency of the acute respiratory exacerbations of COPD but is associated with BAL neutrophilia and lymphocytosis: an observational study

RationaleResearch studies typically quantify acute respiratory exacerbation episodes (AECOPD) among people with chronic obstructive pulmonary disease (COPD) based on self-report elicited by survey questionnaire. However, AECOPD quantification by self-report could be inaccurate, potentially rendering it an imprecise tool for identification of those with exacerbation tendency.ObjectiveDetermine the agreement between self-reported and health records-documented quantification of AECOPD and their association with airway inflammation.MethodsWe administered a questionnaire to elicit the incidence and severity of respiratory exacerbations in the three years preceding the survey among current or former heavy smokers with or without diagnosis of COPD. We then examined electronic health records (EHR) of those with COPD and those without (tobacco-exposed persons with preserved spirometry or TEPS) to determine whether the documentation of the three-year incidence of moderate to very severe respiratory exacerbations was consistent with self-report using Kappa Interrater statistic. A subgroup of participants also underwent bronchoalveolar lavage (BAL) to quantify their airway inflammatory cells. We further used multivariable regressions analysis to estimate the association between respiratory exacerbations and BAL inflammatory cell composition with adjustment for covariates including age, sex, height, weight, smoking status (current versus former) and burden (pack-years).ResultsOverall, a total of 511 participants completed the questionnaire, from whom 487 had EHR available for review. Among the 222 participants with COPD (70 ± 7 years-old; 96% male; 70 ± 38 pack-years smoking; 42% current smoking), 57 (26%) reported having any moderate to very severe AECOPD (m/s-AECOPD) while 66 (30%) had EHR documentation of m/s-AECOPD. However, 42% of those with EHR-identified m/s-AECOPD had none by self-report, and 33% of those who reported m/s-AECOPD had none by EHR, suggesting only moderate agreement (Cohen’s Kappa = 0.47 ± 0.07; P < 0.001). Nevertheless, self-reported and EHR-identified m/s-AECOPD events were both associated with higher BAL neutrophils (ß ± SEM: 3.0 ± 1.1 and 1.3 ± 0.5 per 10% neutrophil increase; P ≤ 0.018) and lymphocytes (0.9 ± 0.4 and 0.7 ± 0.3 per 10% lymphocyte increase; P ≤ 0.041). Exacerbation by either measure combined was associated with a larger estimated effect (3.7 ± 1.2 and 1.0 ± 0.5 per 10% increase in neutrophils and lymphocytes, respectively) but was not statistically significantly different compared to the self-report only approach. Among the 184 TEPS participants, there were fewer moderate to very severe respiratory exacerbations by self-report (n = 15 or 8%) or EHR-documentation (n = 9 or 5%), but a similar level of agreement as those with COPD was observed (Cohen’s Kappa = 0.38 ± 0.07; P < 0.001).DiscussionWhile there is modest agreement between self-reported and EHR-identified m/s-AECOPD, events are missed by relying on either method alone. However, m/s-AECOPD quantified by self-report or health records is associated with BAL neutrophilia and lymphocytosis.

ACPM Position Statement: Air Pollution and Environmental Justice

The American Lung Association's “State of the Air” 2023 report reveals almost 36% of Americans live with unhealthy levels of air pollution. Studies link air pollution with acute respiratory symptoms and exacerbation of respiratory and cardiovascular diseases. Differential air pollution exposures between white and non-white communities are significant components of environmental injustices. Even during the COVID-19 lockdown, when the United States experienced significant decreases in polluting activities, these differences persisted. The American College of Preventive Medicine's Science and Translation Committee conducted a nonsystematic literature review to explore initiatives addressing air pollution as a key component of environmental justice, the state of the science regarding health impacts, and evidence supporting mitigations to reduce those impacts. We recommend advocacy for cleaner energy sources and increasing green space; and increasing research, surveillance, and education and training on linkages between air pollutants and health. We recommend preventive medicine physicians raise awareness about increased risks of cardiovascular disease, cancer, asthma, and reduced lung function with air pollution exposure. Preventive medicine physicians may also educate patients and other practitioners about exposures, and how “conventional” disease prevention strategies may have unintended consequences; and influence healthcare leaders to improve efficiency and reduce emissions. We also recommend physicians utilize social determinants of health (SDOH) Z-Codes to capture environmental factors. Private payers should incorporate pollution exposure data into SDOH risk-adjustments for Medicare Advantage programs. Medicaid agencies should develop provider recommendations for pediatric populations, and states should finance in-home interventions for asthma.

Utility of non-invasive mechanical ventilation in critically ill patients with exacerbated COPD. Systematic review

Background: Non-invasive mechanical ventilation is a useful ventilatory support method for patients with acute respiratory failure or exacerbation of chronic obstructive pulmonary disease mediated by different mechanisms. It helps to reduce airflow resistance and facilitates lung expansion, reducing respiratory muscle fatigue. This allows the patient to breathe more efficiently. By providing positive pressure into the airways, it helps to open the collapsed alveoli and lower airways improving gas exchange. As a consequence oxygenation enhances. Additionally, by increasing air flow, it helps to eliminate carbon dioxide accumulated in the lungs. It reduces respiratory stress by relieving the feeling of shortness of breath as well as excessive respiratory work, reducing anxiety and stress associated with respiratory distress. Importantly, the decision to use non-invasive ventilation as an alternative to endotracheal intubation should be based on a careful evaluation of the patient and continuous monitoring of their response to the treatment. Not all patients are suitable candidates for non-invasive ventilation and in some cases endotracheal intubation may be necessary to ensure adequate ventilation. Material and methods: A systematic review was carried out. Results: 6 articles that met the criteria were reviewed, the number of patients included was 552. 23% (127 patients) were hospitalized in the general ward and 77% (425 patients) in the Intensive Care Unit, of the total patients. 83.51% received treatment with non-invasive ventilation, 11.77% oxygen therapy and 4.71% endotracheal intubation upon admission. 5.61% of the total patients required endotracheal intubation during the course of their hospitalization. Conclusion: In selected patients, Non-invasive ventilation reduces the rate of endotracheal intubation, infectious complications, hospital stay and relapsed. When appropriately used from its implementation until its withdrawal once the respiratory failure is solved, it has a beneficial impact on the patient as well as the economic burden by reducing healhcare cost.

Erdosteine in children and adults with bronchiectasis (BETTER trial): study protocol for a multicentre, double-blind, randomised controlled trial

IntroductionBronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to...

Clinical characterization and outcomes of impulse oscillometry-defined bronchodilator response: an ECOPD cohort-based study

BackgroundThe clinical significance of the impulse oscillometry-defined small airway bronchodilator response (IOS-BDR) is not well-known. Accordingly, this study investigated the clinical characteristics of IOS-BDR and explored the association between lung function decline, acute respiratory exacerbations, and IOS-BDR.MethodsParticipants were recruited from an Early Chronic Obstructive Pulmonary Disease (ECOPD) cohort subset and were followed up for two years with visits at baseline, 12 months, and 24 months. Chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio < 0.70. IOS-BDR was defined as meeting any one of the following criteria: an absolute change in respiratory system resistance at 5 Hz ≤ − 0.137 kPa/L/s, an absolute change in respiratory system reactance at 5 Hz ≥ 0.055 kPa/L/s, or an absolute change in reactance area ≤ − 0.390 kPa/L. The association between IOS-BDR and a decline in lung function was explored with linear mixed-effects model. The association between IOS-BDR and the risk of acute respiratory exacerbations at the two-year follow-up was analyzed with the logistic regression model.ResultsThis study involved 466 participants (92 participants with IOS-BDR and 374 participants without IOS-BDR). Participants with IOS-BDR had higher COPD assessment test and modified Medical Research Council dyspnea scale scores, more severe emphysema, air trapping, and rapid decline in FVC than those without IOS-BDR over 2-year follow-up. IOS-BDR was not associated with the risk of acute respiratory exacerbations at the 2-year follow-up.ConclusionsThe participants with IOS-BDR had more respiratory symptoms, radiographic structural changes, and had an increase in decline in lung function than those without IOS-BDR.Trial registrationChinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

892. Epidemiology, clinical features, and outcomes of Rhinovirus/Enterovirus in older adults hospitalized with acute respiratory infections and those with CHF and COPD exacerbations

Abstract Background While Rhinovirus/Enterovirus (RV/EV) infections are common, the clinical characteristics of infections in hospitalized adults are not fully understood. Methods Adults ≥ 50 years of age hospitalized for Acute Respiratory Infections (ARI) or exacerbations of CHF or COPD in two hospitals in Atlanta, GA during the 2018-2019 and 2019-2020 respiratory seasons were offered enrollment. Following informed consent, participants were tested via BioFire® FilmArray® respiratory panels of nasopharyngeal and oropharyngeal swabs (combined), and standard-of-care molecular testing results were also recorded. Subjects were considered positive for RV/EV if any method of testing resulted positive. Baseline characteristics and clinical features were gathered via subject interviews and medical record abstractions. Variables were compared between subjects with RV/EV and two control groups: those negative for all pathogens and those negative for only RV/EV. Participants with RV/EV who had co-infections were excluded from the analysis. Descriptive statistics were performed using SAS v9.4. Results Of 1429 enrolled participants, 123 (8.6%) were positive for RV/EV, of whom 111 had RV/EV alone. When compared to those negative for all tested pathogens (n=1034), participants with RV/EV more commonly had underlying COPD (45.0% vs. 35.5%, P=0.047) and less commonly had CHF (36.0% vs. 48.3%, P=0.014) or experienced acute myocardial dysfunction (29.7% vs. 41.2%, P=0.019). Participants with RV/EV also more commonly experienced fever (39.6% vs. 27.7%, P=0.008), cough (90.1% vs. 69.0%, P&amp;lt; 0.001), sore throat (54.1% vs. 39.5%, P=0.003), chest pain (48.6% vs. 37.8%, P=0.026), and dyspnea/respiratory distress (25.2% vs. 13.1%, P&amp;lt; 0.001) than those negative for all pathogens. Differences between RV/EV positive and negative groups were similar to the all pathogen negative group, with the exception of no significant differences in acute myocardial dysfunction, fever, and COPD in the RV/EV negative group. Conclusion Among older adults hospitalized with ARIs, CHF, and/or COPD exacerbations, RV/EV was associated with symptoms of both upper and lower respiratory tract infection and was more frequent identified among those with COPD. Disclosures Elizabeth Begier, M.D., M.P.H., Pfizer: EB is an employee of Pfizer, the sponsor of this study|Pfizer: Stocks/Bonds Robin Hubler, MS, Pfizer, Inc.: Employee|Pfizer, Inc.: Stocks/Bonds Qing Liu, M.S., Pfizer Inc.: Stocks/Bonds Bradford D. Gessner, M.D., M.P.H., Pfizer: I am an employee of Pfizer|Pfizer: Stocks/Bonds Benjamin Lopman, PhD, Epidemiological Research and Methods, LLC: Advisor/Consultant|Hillevax, Inc: Advisor/Consultant Satoshi Kamidani, MD, CDC: Grant/Research Support|Emergent BioSolutions: Grant/Research Support|NIH: Grant/Research Support|Pfizer Inc: Grant/Research Support Nadine Rouphael, MD, Icon, EMMES, Sanofi, Seqirus, Moderna: Advisor/Consultant Evan J. Anderson, MD, GSK: Advisor/Consultant|GSK: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kentucky Bioprocessing, Inc.: Safety Monitoring Board|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Currently an employee|Moderna: Stocks/Bonds|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Safety Monitoring Board|WCG/ACI Clinical: Data Adjudication Board Christina A. Rostad, MD, BioFire Inc.: Grant/Research Support|GlaxoSmithKline Biologicals: Grant/Research Support|Janssen: Grant/Research Support|MedImmune LLC: Grant/Research Support|Meissa Vaccines, Inc.: RSV vaccine technology|Merck &amp; Co., Inc.: Grant/Research Support|Micron Technology, Inc.: Grant/Research Support|Moderna, Inc.: Grant/Research Support|Novavax: Grant/Research Support|PaxVax: Grant/Research Support|Pfizer, Inc.: Grant/Research Support|Regeneron: Grant/Research Support|Sanofi Pasteur: Grant/Research Support

Oral corticosteroid use and sarcopenia-related traits in older people with chronic airway disease: a population-based study.

Sarcopenia is characterised by two major phenotypic components: low handgrip strength (HGS) and appendicular skeletal muscle index (ASMI). Oral corticosteroid (OCS) use is an important medication for acute respiratory exacerbations in patients with COPD and asthma. However, the association of OCS and sarcopenia components in older people is largely unexplored. The aim of this study was to examine the association between OCS use and HGS or ASMI in the general population and explore interactions with chronic airway diseases. From the population-based Rotterdam Study, 5054 participants (age 69.0±8.8 years; 56% females) were included in the cross-sectional analysis and 1324 in the longitudinal analysis. Associations between OCS and muscle strength and mass were analysed using linear regression models adjusted for age, sex, fat %, height, kidney function, smoking and comorbidities. At baseline, ever-OCS users had lower handgrip strength (β= -0.48, 95% CI -0.84- -0.12) than never-OCS users, with cumulative frequency (≥10 OCS prescriptions)-dependent effects (β= -1.25, 95% CI -2.16- -0.33). COPD ever-OCS users, but not asthma, had lower handgrip strength (β= -0.98, 95% CI -1.91- -0.06) and lower lean mass (β= -0.14, 95% CI -0.27- -0.01) than never-OCS users. After 5.6 years of follow-up in those free of sarcopenia traits at baseline, COPD ever-OCS users developed lower handgrip strength (β= -1.64, 95% CI -2.87- -0.40) with frequency (β= -3.64, 95% CI -6.57- -0.72) and duration (β= -1.51, 95% CI -2.87- -0.15) association compared to never-OCS users. OCS use is associated with a decline in handgrip strength in people with COPD in a cumulative frequency and duration-dependent manner. Routine muscle examination may be necessary for patients with COPD.

Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety

BackgroundFibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients.MethodsWe...

Application of BI-V for contact children and adolescents from focies of multidrug-resistant tuberculous infection: evaluation of effectiveness

Objective — to study the need of using the natural immunomodulator ВІ-V for contact children and adolescents from focies of multidrug-resistant tuberculous infection (MDR-TBI) for a non-specific immunoprevention of tuberculosis (TB). Materials and methods. A retrospective analysis of the medical records of 120 contacts (75 children and 45 adolescents) from focies of MDR-TBI and 102 adult with TB, who became the source of infection was carried out. Microbiological examination in adults included the detection of Mycobacterium tuberculosis (MBT) in sputum by smear microscopy, sowing of material on Levenstein—Jensen medium, typing of isolated MBT on BACTEC MGIT 960, determination of the drug susceptibility test (DST) of MBT to antimycobacterial drugs (AMBDs) of first- and second-line, as well as molecular genetic researched of sputum, in particular by the method of GeneXpert MTB/RIF and linear probe analysis. In the contact children from focies of MDR-TBI the determination of the population and subpopulation composition of blood lymphocytes was carried out among 25 children before and among 22 children after immuno­preven­tion. Results and discussion. Most contact children and adolescents (61.7 %) from focies of MDR-TBI had concomitant diseases. The prophylactic administration of the BI-V immunomodulator reduced the frequency of acute respiratory viral infections and exacerbations of non-specific bronchopulmonary diseases by 2.0 times, the development of an active process from the latent tuberculous infection by 2.6 times, the frequency of transformation of latent tuberculosis infection into an active process by 2.6 times, improved appetite, memory, learning outcomes and increased physical activity. The latent tuberculous infection based on the Mantoux test results was found in 82.5 % (99) children. The quantiferon test confirmed the presence of a latent form of tuberculosis in 104 (86.7 %) contacts, the rest of the test results were negative. In children who received ВІ-V, latent tuberculous infection turned into an active process 2.8 times less often than in infected children who did not take this immunomodulator. The existing deviations into the regulatory system and the cellular response system disappeared after the autumn-spring course of ВІ-V. Conclusions. Immunomodulator ВІ-V is an effective preventive means for bronchopulmonary diseases, including MDR-TB among contact children and adolescents from focies of MDR-TBI.

Sputum bacterial load and bacterial composition correlate with lung function and are altered by long-term azithromycin treatment in children with HIV-associated chronic lung disease

BackgroundLong-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown.MethodAfrican children with HCLD (defined as forced expiratory volume in 1 s z-score (FEV1z) less than − 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (6 months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rRNA gene qPCR and V4 region amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression.ResultsIn total, 347 participants (median age: 15.3 years, interquartile range [12.7–17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rRNA copies/µl in log10, mean difference and 95% confidence interval [CI] of AZM vs placebo − 0.54 [− 0.71; − 0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p < 0.05, ANCOM ω = 32) and Moraxella (1% vs. 1.9%, p < 0.05, ANCOM ω = 47). This reduction was sustained at 72 weeks relative to baseline. Lung function (FEV1z) was negatively associated with bacterial load (coefficient, [CI]: − 0.09 [− 0.16; − 0.02]) and positively associated with Shannon diversity (0.19 [0.12; 0.27]). The relative abundance of Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (− 6.1, [1.2], q < 0.001) were positively and negatively associated with FEV1z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002).ConclusionsAZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD.7vbprNKyGgPWNKm5AZ24DEVideo

Impact of remote vital sign monitoring on health outcomes in acute respiratory infection and exacerbation of chronic respiratory conditions: systematic review and meta-analysis.

Our aim was to investigate the effectiveness of virtual wards on health outcomes in patients with acute respiratory infection. We searched four electronic databases from January 2000 to March 2021 for randomised controlled trials (RCTs). We included studies in people with acute respiratory illness or an acute exacerbation of a chronic respiratory illness, where a patient or carer measured vital signs (oximetry, blood pressure, pulse) for initial diagnosis and/or asynchronous monitoring, in a person living in private housing or a care home. We performed random-effects meta-analysis for mortality. We reviewed 5834 abstracts and 107 full texts. Nine RCTs were judged to be relevant for inclusion, in which sample sizes ranged from 37 to 389 (total n=1627) and mean ages ranged between 61 and 77 years. Five were judged to be at low risk of bias. Five RCTs had fewer hospital admissions in the intervention (monitoring) group, out of which two studies reported a significant difference. Two studies reported more admissions in the intervention group, with one reporting a significant difference. We were unable to perform a meta-analysis on healthcare utilisation and hospitalisation data due to lack of outcome definition in the primary studies and variable outcome measurements. We judged two studies to be at low risk of bias. The pooled summary risk ratio for mortality was 0.90 (95% CI 0.55-1.48). The limited literature for remote monitoring of vital signs in acute respiratory illness provides weak evidence that these interventions have a variable impact on hospitalisations and healthcare utilisation, and may reduce mortality.

Divergent dynamics of inflammatory mediators and multiplex PCRs during airway infection in cystic fibrosis patients and healthy controls: Serial upper airway sampling by nasal lavage.

In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls. Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1β/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed. Altogether, 49 CF patients and 38 healthy controls (HCs) completed the study, and 214 NLF samples were analyzed. Of the 49 CF patients, 20 were at least intermittently colonized with P. aeruginosa and received azithromycin and/or inhaled antibiotics as standard therapy. At baseline, IL-6 and IL-8 tended to be elevated in CF compared to controls. During infection, inflammatory mediators increased in both cohorts, reaching significance only for IL-6 in controls (p=0.047). Inflammatory responses tended to be higher in controls [1.6-fold (NE) to 4.4-fold (MMP-9)], while in CF, mediators increased only moderately [1.2-1.5-fold (IL-6/IL-8/NE/TIMP-1/MMP-9)]. Patients receiving inhalative antibiotics or azithromycin (n=20 and n=15, respectively) revealed lower levels of IL-1β/IL-6/IL-8 and NE during exacerbation compared to CF patients not receiving those antibiotics. In addition, CF patients receiving azithromycin showed MMP-9 levels significantly lower than CF patients not receiving azithromycin at stable phase and exacerbation. Altogether, rhinoviruses were the most frequently detected virus, detected at least once in n=24 (49.0%) of the 49 included pwCF and in n=26 (68.4%) of the 38 healthy controls over the 13-month duration of the study. Remarkably, during exacerbation, rhinovirus detection rates were significantly higher in the HC group compared to those in CF patients (65.8% vs. 22.4%; p<0.0001). Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system.

Intracellular replication of Inquilinus limosus in bronchial epithelial cells

Inquilinus limosus is an emerging multi-resistant opportunistic pathogen documented mainly in cystic fibrosis patients. Infection with I. limosus is accompanied by either an acute respiratory exacerbation or a progressive loss of pulmonary function. This study examined the interaction of Inquilinus limosus with the bronquial human epithelial cell line 16HBE14o−. Almost 100% of the bacteria that attached to the bronquial cells were found internalized and located in acidic LAMP2 positive compartments. According to confocal studies combined with antibiotic protection assays, I. limosus is able to survive and eventually replicate in these compartments. I. limosus was found nontoxic to cells and did not induce neither IL-6 nor IL-8 cytokine production, a characteristic that may help the bacteria to evade host immune response. Overall, this study indicates that I. limosus displays pathogenic properties based on its ability to survive intracellularly in epithelial cells eventually leading to antibiotic failure and chronic infection.

Long-term Azithromycin in Children With Bronchiectasis Unrelated to Cystic Fibrosis: Treatment Effects Over Time

Following evidence from randomized controlled trials, patients with bronchiectasis unrelated to cystic fibrosis receive long-term azithromycin to reduce acute respiratory exacerbations. However, the period when azithromycin is effective and which patients are likely to most benefit remain unknown. (i) What is the period after its commencement when azithromycin is most effective? and (ii) Which factors may modify azithromycin effects? A secondary analysis was conducted of our previous randomized controlled trial involving 89 indigenous children with bronchiectasis unrelated to cystic fibrosis. Semi-parametric Poisson regression identified the azithromycin efficacy period. Multivariable Poisson regression identified factors that modify azithromycin effect. Azithromycin was associated with fewer exacerbations per child-week during weeks 4 through 96, with the most effective period observed between weeks 17 and 62. Eleven factors were associated with different azithromycin effects; four were significant at the P< .05 level. Compared with their counterparts, higher reduction in exacerbations was observed in children with nasopharyngeal carriage of bacterial pathogens (incidence rate ratio [IRR]= 0.81 [95%CI, 0.57-1.14] vs0.29 [0.20-0.44]; P< .001); New Zealand children (IRR= 0.73 [0.51-1.03] vs0.39 [0.28-0.55]; P= .012); and those with higher weight-for-height z scores (interaction IRR= 0.82 [0.67-0.99]; P= .044). Compared with their counterparts, lower reduction was observed in those born preterm (IRR= 0.41 [0.30-0.55] vs0.74 [0.49-1.10]; P= .012). Regular azithromycin is best used for at least 17weeks and up to 62weeks, as these periods provide maximum benefit for indigenous children with bronchiectasis unrelated to cystic fibrosis. Several factors modified azithromycin benefits; however, these traits need confirmation in larger studies before being adopted into clinical practice. Australian New Zealand Clinical Trials Registry; ACTRN12610000383066.

Exercise versus airway clearance techniques for people with cystic fibrosis.

Exercise versus airway clearance techniques for people with cystic fibrosis.

Adherence to additional medication for management of HIV-associated comorbidities among older children and adolescents taking antiretroviral therapy.

BackgroundManagement of co-morbidities among persons living with HIV is an emerging priority, which may require additional medication over and above life-long antiretroviral therapy (ART). We explored factors associated with adherence to the trial drug among children and adolescents with perinatally acquired HIV taking antiretroviral therapy (ART) in the Bronchopulmonary Function in Response to Azithromycin Treatment for Chronic Lung Disease in HIV-Infected Children (BREATHE) trial.MethodsThe BREATHE trial recruited 6–19 year olds with perinatally acquired HIV and co-morbid chronic lung disease as measured by FEV1. This two-site trial was individually randomised (1:1), double-blind and placebo-controlled. Participants received a once-weekly weight-based dose of 1–5 tablets of azithromycin (AZM: 250mg) or placebo, taken orally. We used pharmacy dispensing records and count of returned pills to measure adherence to study medication. Logistic regression was used to explore factors associated with adherence coverage. Poisson regression with Lexis expansion for time was used to explore whether adherence modified the effect of azithromycin on the incidence of acute respiratory exacerbation, a secondary outcome of the trial. Trial registration: ClinicalTrials.gov NCT02426112.ResultsThe 347 participants (median age 15.3, 51% male) consumed 14,622 doses of study medication over 16,220 person-weeks under study. Adherence was higher for those randomised to AZM (73.4%) than placebo (68.4%) and declined over the 48 weeks of the study (Score test for trend <0.02). Those with unsuppressed HIV viral load at baseline had 2.08 (95% CI: 1.19, 3.63) times the odds of non-adherence than those with viral suppression. Differences were also observed between trial sites.ConclusionThe majority of children and adolescents tolerated the addition of a once-weekly dose of medication to their pill burden. Barriers in adhering to treatment for co-morbid conditions are likely common to barriers in adhering to ART. Control of co-morbidities will therefore present additional challenges in HIV care.

Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial

IntroductionPrimary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving...

Bronchiectasis - Exercise as Therapy (BREATH): rationale and study protocol for a multi-center randomized controlled trial

BackgroundGlobally, bronchiectasis (BE) unrelated to cystic fibrosis (CF) is recognized as a major cause of respiratory morbidity, mortality, and healthcare utilization. Children with BE regularly experience exacerbations of their condition resulting in frequent hospitalizations and decreased health-related quality of life (HR-QoL). Guidelines for the treatment and management of BE call for regular exercise as a means of improving aerobic fitness and HR-QoL. Moreover, research in adults with BE has shown that exercise can reduce the frequency of exacerbations, a potent predictor of future lung function decline and respiratory morbidity. Yet, to date, the health benefits resulting from therapeutic exercise have not been investigated in children with BE. The BREATH, Bronchiectasis - Exercise as Therapy, trial will test the efficacy of a novel 8-week, play-based therapeutic exercise program to reduce the frequency of acute exacerbations over 12 months in children with BE (aged ≥ 4 and < 13 years). Secondary aims are to determine the cost-effectiveness of the intervention and assess the program’s impact on aerobic fitness, fundamental movement skill (FMS) proficiency, habitual physical activity, HR-QoL, and lung function.MethodsThis multi-center, observer-blinded, parallel-group (1:1 allocation), randomized controlled trial (RCT) will be conducted at three sites. One hundred and seventy-four children ≥ 4 and < 13 years of age with BE will be randomized to a developmentally appropriate, play-based therapeutic exercise program (eight, 60-min weekly sessions, supplemented by a home-based program) or usual care. After completing the baseline assessments, the number of exacerbations and secondary outcomes will be assessed immediately post-intervention, after 6 months of follow-up, and after 12 months of follow-up. Monthly, parental contact and medical review will document acute respiratory exacerbations and parameters for cost-effectiveness outcomes.DiscussionThe BREATH trial is the first fully powered RCT to test the effects of a therapeutic exercise on exacerbation frequency, fitness, movement competence, and HR-QoL in children with bronchiectasis. By implementing a developmentally appropriate, play-based exercise program tailored to the individual needs of children with bronchiectasis, the results have the potential for a major paradigm shift in the way in which therapeutic exercise is prescribed and implemented in children with chronic respiratory conditions. The exercise program can be readily translated. It does not require expensive equipment and can be delivered in a variety of settings, including the participant’s home. The program has strong potential for translation to other pediatric patient groups with similar needs for exercise therapy, including those with obesity, childhood cancers, and neurological conditions such as cerebral palsy.Trial registrationAustralian and New Zealand Clinical Trials Register (ANZCTR) ACTRN12619001008112

Chronotropic index during 6-minute walk and acute respiratory events in COPDGene

BackgroundLower heart rate (HR) increases during exercise and slower HR recovery (HRR) after exercise are markers of worse autonomic function that may be associated with risk of acute respiratory events (ARE). MethodsData from 6-min walk testing (6MWT) in COPDGene were used to calculate the chronotropic index (CI) [(HR immediately post 6MWT – resting HR)/((220 – age) – resting HR)] and HRR at 1 min after 6MWT completion. We used zero-inflated negative binomial regression to test associations of CI and HRR with rates of any ARE (requiring steroids and/or antibiotics) and severe ARE (requiring emergency department visit or hospitalization), among all participants and in spirometry subgroups (normal, chronic obstructive pulmonary disease [COPD], and preserved ratio with impaired spirometry). ResultsAmong 4,484 participants, mean follow-up time was 4.1 years, and 1,966 had COPD. Among all participants, CI-6MWT was not associated with rate of any ARE [adjusted incidence rate ratio (aIRR) 0.98 (0.95–1.01)], but higher CI-6MWT was associated with lower rate of severe ARE [0.95 (0.92–0.99)]. Higher HRR was associated with a lower rate of both any ARE [0.97 (0.95–0.99)] and severe ARE [0.95 (0.92–0.98)]. Results were similar in the COPD spirometry subgroup. ConclusionHeart rate measures derived from 6MWT tests may have utility in predicting risk of acute respiratory events and COPD exacerbations.

Cardiac involvement in cystic fibrosis evaluated using cardiopulmonary magnetic resonance

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m2 vs. control 50 ± 8 g/m2; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7–29.8]% vs. control 24.8 [22.9–26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = − 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity.