Chronic Pa Research Articles

Eosinophilic Bronchiectasis: Prevalence, Severity, and Associated Features-A Cohort Study.

Background: Bronchiectasis (BE) has been traditionally associated with neutrophilic inflammation, but eosinophilic bronchiectasis (EB) has recently emerged. Data about prevalence, clinical features, and disease severity are lacking. This study aimed to assess the EB prevalence, compare EB with non-EB, evaluate the Type-2 (T2) high endotype in BE (T2-high EB) versus non-T2-high EB, and identify EB predictors. Methods: We conducted a prospective study involving 153 BE patients. The data collected included clinical, radiological, and microbiological findings. BE severity was assessed using the bronchiectasis severity index (BSI), FACED and E-FACED scores, and the bronchiectasis etiology and comorbidity index (BACI). EB was defined as a blood eosinophil count (BEC) ≥ 300 cells/μL, and T2-high EB as BEC ≥ 300 cells/μL with fractional exhaled nitric oxide (FeNO) ≥ 25 ppb. Results: Prevalence was 27% for EB and 20% for T2-high EB. EB patients exhibited poorer lung function and more severe radiologic features, with significantly higher severity scores [BSI, FACED, E-FACED, BACI (p < 0.05)], and a higher median exacerbation rate [4 (2-5) in EB vs. 2 (1-4) in non-EB, p = 0.0002], compared with non-EB patients. T2-high EB patients showed higher severity scores [BSI, FACED, E-FACED (p < 0.05)], as well as worse lung function parameters [FEV1%, FVC%, FEF 25-75% (p < 0.05)] compared with non-T2-high EB patients. In our study, patients with EB exhibited notably worsened lung function and higher BE severity scores compared with their non-EB counterparts, with exacerbations playing a major role in these differences. We found statistically significant positive correlations between BEC and disease severity scores, such as BSI, FACED, and mMRC, as well as an inverse relationship with pulmonary function. The likelihood of EB being present was significantly higher in association with mMRC ≥ 1 (OR = 2.53; 95% CI, 1.26-5.64), exacerbations/year ≥ 1 (OR = 1.27; 95% CI, 1.0-1.63), and chronic PA colonization (OR = 3.9; 95% CI, 1.08-15.8). Conclusions: EB is a distinct endotype. Dyspnea, exacerbations, and PA colonization may be predictive of EB, emphasizing the importance of early detection for improved outcomes. BEC could serve as a useful biomarker of disease severity to consider when diagnosing EB.

Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding.

Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by Pa and acts as a structural element in Pa biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.

Azithromycin regulates bacterial virulence and immune response in a murine model of ceftazidime-treated Pseudomonas aeruginosa acute pneumonia.

Pseudomonas aeruginosa (PA) remains one of the leading causes of nosocomial acute pneumonia. The array of virulence factors expressed by PA and the intense immune response associated with PA pneumonia play a major role in the severity of these infections. New therapeutic approaches are needed to overcome the high resistance of PA to antibiotics and to reduce the direct damage to host tissues. Through its immunomodulatory and anti-virulence effects, azithromycin (AZM) has demonstrated clinical benefits in patients with chronic PA respiratory infections. However, there is relatively little evidence in PA acute pneumonia. We investigated the effects of AZM, as an adjunctive therapy combined with ceftazidime (CAZ), in a murine model of PA acute pneumonia. We observed that the combined therapy (i) reduces the weight loss of mice 24 h post-infection (hpi), (ii) decreases neutrophil influx into the lungs at 6 and 24 hpi, while this effect is absent in a LPS-induced pneumonia or when PA is pretreated with antibiotics and mice do not receive any antibiotics, and that (iii) AZM, alone or with CAZ, modulates the expression of PA quorum sensing regulators and virulence factors (LasI, LasA, PqsE, PhzM, ExoS). Our findings support beneficial effects of AZM with CAZ on PA acute pneumonia by both bacterial virulence and immune response modulations. Further investigations are needed to clarify the exact underlying mechanisms responsible for the reduction of the neutrophils influx and to better discriminate between direct immunomodulatory properties of AZM, and indirect effects on neutrophilia resulting from bacterial virulence modulation.

Physical activity in leisure time and motivation among citizens with chronic disease in in Denmark

Abstract Background Physical activity (PA) has a preventive effect on chronic disease, but PA also promotes health among citizens with chronic disease. However, the presence of chronic disease may be a barrier for PA engagement. The aim of this study was to examine the difference between citizens with various chronic diseases and all citizens in The Capital Region of Denmark in terms of the proportion who reports low PA levels in their leisure time, wants to be more physically active, and has been advised to exercise by their doctor. Methods Information from national registers on hospital diagnoses and medical treatment was used to identify citizens with chronic diseases. Data from “The Danish Capital Region Health Survey” among citizens (≥16 years) in The Capital Region in 2021 (N = 56,245, response rate=54.9%) were used to obtain information about citizens’ movement behaviour in leisure time, their motivation to become more physically active and whether they have been advised by their doctor to exercise. Results for several diseases will be presented but heart disease is used as example in this abstract. Results Preliminary results show that the proportion in 2021 who has reported low PA levels in their leisure time is almost twice as high among citizens with heart disease (35%) compared with all citizens in The Capital Region (18%). Less citizens with heart disease (62%) are motivated to become more physically active compared with all citizens in The Capital Region (73%). The proportion who has been advised to exercise by their doctor is not significantly different among citizens with heart disease (31%) and all citizens in The Capital Region (28%). Conclusions Among citizens with heart disease low PA levels in leisure time are more prevalent, they are less motivated to become more physically active and, despite their chronic illness, they receive advice from their doctor to the same extent. For citizens with chronic disease, it is important to engage in PA. Key messages • Among citizens with chronic diseases low PA levels in leisure time are more prevalent and they are less motivated to become physically active compared with all citizens in The Capital region in DK. • Despite their illness, they receive advice from their doctor about exercising to the same extent as all citizens in The Capital Region of Denmark.

P228 In vitro evolution of levofloxacin resistance in lineages of clinical Pseudomonas aeruginosa isolates cultured at different stages of infection from people with cystic fibrosis

In people with cystic fibrosis (pwCF), Pseudomonas aeruginosa (Pa) respiratory infection can be classified as initial, intermittent and chronic, depending on persistence of Pa in consecutive respiratory samples. Inhaled antibiotics such as nebulised levofloxacin (LVX) are used to treat chronic Pa infection. This study determined if Pa isolates from different infection stages differed in ability to adapt in vitro to LVX.

Association of Pseudomonas aeruginosa infection stage with lung function trajectory in children with cystic fibrosis

BackgroundPseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) is characterized in stages: never (prior to first positive culture) to incident (first positive culture) to chronic. The association of Pa infection stage with lung function trajectory is poorly understood and the impact of age on this association has not been examined. We hypothesized that FEV1 decline would be slowest prior to Pa infection, intermediate after incident infection and greatest after chronic Pa infection. MethodsParticipants in a large US prospective cohort study diagnosed with CF prior to age 3 contributed data through the U.S. CF Patient Registry. Cubic spline linear mixed effects models were used to evaluate the longitudinal association of Pa stage (never, incident, chronic using 4 different definitions) with FEV1 adjusted for relevant covariates. Models contained interaction terms between age and Pa stage. Results1,264 subjects born 1992–2006 provided a median 9.5 (IQR 0.25 to 15.75) years of follow up through 2017. 89% developed incident Pa; 39–58% developed chronic Pa depending on the definition. Compared to never Pa, incident Pa infection was associated with greater annual FEV1 decline and chronic Pa infection with the greatest FEV1 decline. The most rapid FEV1 decline and strongest association with Pa infection stage was seen in early adolescence (ages 12–15). ConclusionsAnnual FEV1 decline worsens significantly with each Pa infection stage in children with CF. Our findings suggest that measures to prevent chronic infection, particularly during the high-risk period of early adolescence, could mitigate FEV1 decline and improve survival.

Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis.

The severity and progression of lung disease are highly variable across individuals with cystic fibrosis (CF) and are imperfectly predicted by mutations in the human gene CFTR, lung microbiome variation or other clinical factors. The opportunistic pathogen Pseudomonas aeruginosa (Pa) dominates airway infections in most CF adults. Here we hypothesized that within-host genetic variation of Pa populations would be associated with lung disease severity. To quantify Pa genetic variation within CF sputum samples, we used deep amplicon sequencing (AmpliSeq) of 209 Pa genes previously associated with pathogenesis or adaptation to the CF lung. We trained machine learning models using Pa single nucleotide variants (SNVs), microbiome diversity data and clinical factors to classify lung disease severity at the time of sputum sampling, and to predict lung function decline after 5 years in a cohort of 54 adult CF patients with chronic Pa infection. Models using Pa SNVs alone classified lung disease severity with good sensitivity and specificity (area under the receiver operating characteristic curve: AUROC=0.87). Models were less predictive of lung function decline after 5 years (AUROC=0.74) but still significantly better than random. The addition of clinical data, but not sputum microbiome diversity data, yielded only modest improvements in classifying baseline lung function (AUROC=0.92) and predicting lung function decline (AUROC=0.79), suggesting that Pa AmpliSeq data account for most of the predictive value. Our work provides a proof of principle that Pa genetic variation in sputum tracks lung disease severity, moderately predicts lung function decline and could serve as a disease biomarker among CF patients with chronic Pa infections.

Frail2Fit study protocol: a feasibility and acceptability study of a virtual multimodal intervention delivered by volunteers to improve functional outcomes in older adults with frailty after discharge from hospital

IntroductionPhysical activity (PA) and replete nutritional status are key to maintaining independence and improving frailty status among frail older adults. In response to the COVID-19 pandemic, healthcare has increasingly turned...

Filamentous bacteriophage delays healing of Pseudomonas-infected wounds

SummaryChronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa pathogenesis. Rather, Pf impedes keratinocyte migration, which is essential for wound healing, through direct inhibition of CXCL1 signaling. In support of these findings, a prospective cohort study of 36 human patients with chronic Pa wound infections reveals that wounds infected with Pf-positive strains of Pa are more likely to progress in size compared with wounds infected with Pf-negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian cells. These findings suggest Pf may have potential as a biomarker and therapeutic target in chronic wounds.

The effect of TGF-β1 polymorphisms on pulmonary disease progression in patients with cystic fibrosis

BackgroundTransforming Growth Factor-β1 (TGF-β1) is a genetic modifier in patients with cystic fibrosis (CF). Several single nucleotide polymorphisms (SNPs) of TGF-β1 are associated with neutrophilic inflammation, lung fibrosis and loss of pulmonary function.AimThe aim of this study was to assess the relationship between genetic TGF-β1 polymorphisms and pulmonary disease progression in CF patients. Furthermore, the effect of TGF-β1 polymorphisms on inflammatory cytokines in sputum was investigated.Methods56 CF-patients and 62 controls were genotyped for three relevant SNPs in their TGF-β1 sequence using the SNaPshot® technique. Individual “slopes” in forced expiratory volume in 1 s (FEV1) for all patients were calculated by using documented lung function values of the previous five years. The status of Pseudomonas aeruginosa (Pa) infection was determined. Sputum concentrations of the protease elastase, the serine protease inhibitor elafin and the cytokines IL-1β, IL-8, IL-6, TNF-α were measured after a standardized sputum induction and processing.ResultsThe homozygous TT genotype at codon 10 was associated with a lower rate of chronic Pa infection (p < 0.05). The heterozygous GC genotype at codon 25 was associated with lower lung function decline (p < 0.05). Patients with homozygous TT genotype at the promotor SNP showed higher levels of TNF-α (p < 0,05). Higher levels of TGF-β1 in plasma were associated with a more rapid FEV1 decline over five years (p < 0.05).ConclusionsOur results suggest that polymorphisms in the TGF-β1 gene have an effect on lung function decline, Pa infection as well as levels of inflammatory cytokines. Genotyping these polymorphisms could potentially be used to identify CF patients with higher risk of disease progression. TGF-β1 inhibition could potentially be developed as a new therapeutic option to modulate CF lung disease.

Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis

Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years (“Green 3/4”) resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency.

Pseudomonas aeruginosa in Bronchiectasis.

Pseudomonas aeruginosa (PA) in patients with bronchiectasis (BE) is associated with a poor outcome and quality of life, and its presence is considered a marker of disease severity. This opportunistic pathogen is known for its ability to produce biofilms on biotic or abiotic surfaces and to survive environmental stress exerted by antimicrobials, inflammation, and nutrient or oxygen depletion. The presence of PA biofilms has been linked to chronic respiratory infection in cystic fibrosis but not in BE. There is considerable inconsistency in the reported infection/eradication rates of PA and chronic PA. In addition, inadequate antimicrobial treatment may potentiate the progression from intermittent to chronic infection and also the emergence of antibiotic resistance. A better comprehension of the pathophysiology of PA infections and its implications for BE is urgently needed. This can drive improvements in diagnostic accuracy, can move us toward a new consensus definition of chronic infection, can better define the follow-up of patients at risk of PA, and can achieve more successful eradication rates. In addition, the new technological advances regarding molecular diagnostics, -omics, and biomarkers require us to reconsider our traditional concepts.

Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study

BackgroundPseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection. MethodsPatients on the UK CF Registry in 2016 were grouped into: absent (Pa-), intermittent (Pai) or chronic Pa (Pac), each with Asp positive (Asp+) or negative (Asp-). Primary outcome was best percentage predicted FEV1 (ppFEV1) that year. Secondary outcomes were intravenous (IV) antibiotic courses, growth (height, weight, BMI) and additional disease complications. Associations between outcomes and infection-status were assessed using regression models adjusting for significant confounders (age, sex, Phe508del homozygosity and CF-related diabetes (CFRD)). Results9,270 patients were included (median age 19 [IQR 9-30] years, 54% male, 50% Phe508del/F508del). 4,142 patients (45%) isolated Pa, 1,460 (16%) Asp. Pa-/Asp+ subjects had an adjusted ppFEV1 that was 5.9% lower than Pa-/Asp- (p < 0.0001). In patients with Pai or Pac, there was no additional impact of Asp on ppFEV1. However, there was a higher probability that Pac/Asp+ patients had required IV antibiotics than Pac/Asp- group (OR 1.23 [1.03-1.48]). Low BMI, ABPA, CF-liver disease and CFRD were all more frequent with Asp alone than Pa-/Asp-, though not more common in Pac/Asp+ than Pac/Asp-. ConclusionsCo-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

Could Azithromycin Be Part of Pseudomonas aeruginosa Acute Pneumonia Treatment?

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including Pseudomonas aeruginosa (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted in vitro, these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. In vitro and in vivo studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.

Measurement of the Gene Expression and Polymorphisms of c-myc and p53 Genes in HBV Infected Patients

This study explained the c-myc and p53 gene expression and polymorphisms in chronic (40), cirrhosis (30) and Hepatocellular Carcinoma, (HCC) (30) patients related to Hepatitis B Virus (HBV) infection and healthy control (50) in Egypt. Where, c-myc (intron 8) and p53 (codon 72) gene expression and polymorphisms were determined using qRT-PCR and PCR-RFLP techniques. The results showed that c-myc gene expression (2-ddct) was significantly increased in chronic (1.38), cirrhosis (1.47) and HCC (5.59) compared to the control group (1.00), while p53 gene expression (2-ddct) was significantly decreased compared to the control group (0.82, 0.65, 0.33 and 1.00, respectively). In HCC group, c-myc genotype (CC) was predominant (90%) more than cirrhosis, chronic and control (73.33, 22.5 and 6%, respectively), GG genotype was predominant in control (70%) more than chronic, cirrhosis and HCC groups (67.5, 6.66 and 6.66%, respectively) and GC genotype was high in control (24%) more than cirrhosis, chronic and HCC groups (20, 10 and 3.33%, respectively). p53 PP (88%) genotype was predominant in control more than chronic, cirrhosis and HCC groups (30, 30 and 6.66%, respectively), AA genotype was predominant in HCC group (73.33%) more than chronic, cirrhosis and control (50, 10 and 4%, respectively) and genotype PA was predominant in cirrhosis (60%) more than chronic, HCC and control (20, 20 and 8%, respectively). These results suggest clearly that both c-myc and p53 gene expression and polymorphisms influence clinical outcome and progression of HBV infection and then considered an accurate genetic biomarker to determine and predict the progression of HBV infection.

A comparison of the CFHH criteria against the Leeds criteria in determining the Pseudomonas aeruginosa status among adults with cystic fibrosis

BackgroundPseudomonas aeruginosa (PA) status influences management decisions in cystic fibrosis (CF) but diagnostic approaches vary. We evaluated the ability of the CFHealthHub (CFHH) criteria, which consist of two major and four minor statements, in diagnosing chronic PA infection among adults with CF. MethodsIn this retrospective cross-sectional analysis, we compared the CFHH criteria against the Leeds criteria. Data were collected between 1st January and 31st December 2016 from all adults with CF receiving care at Sheffield, excluding those with lung transplantation (n = 7) or on ivacaftor (n = 13). The CFHH criteria PA status were cross-tabulated against the Leeds criteria, and clinical outcomes between chronic PA vs non chronic PA for both criteria were compared. ResultsThis analysis included 186 adults with CF (90 females, median age 27 years, median baseline FEV1 78.5%). The CFHH criteria diagnosed more cases of chronic PA (116/186, 62.4% vs 79/186, 42.5%), and 37/107 cases of non-chronic PA according to the Leeds criteria were deemed chronic PA by the CFHH criteria. The magnitude of difference in %FEV1 decline between chronic PA vs non chronic PA was slightly greater for the CFHH criteria (−0.6%, 95% CI –1.8 to 0.6%) compared to the Leeds criteria (−0.2%, 95% CI –1.3 to 1.0%). ConclusionsThe CFHH criteria detected more chronic PA cases yet still retained similar levels of discrimination for health outcomes in comparison to the Leeds criteria. These findings provide preliminary evidence for the validity of the CFHH criteria among adults with CF.

Development of Chronic Pseudomonas aeruginosa-Positive Respiratory Cultures in Children with Tracheostomy.

Up to 90% of children develop Pseudomonas aeruginosa (Pa)-positive respiratory cultures after tracheotomy. To identify the factors associated with chronic Pa-positive respiratory cultures in the first 2years after tracheotomy. We conducted a retrospective cohort study of 210 children ≤ 18years old who underwent tracheotomy at a single freestanding children's hospital that had two or more years of respiratory cultures post-tracheotomy available for analysis. We conducted multivariable logistic regression to test the association between demographic and clinical factors to our primary outcome of chronic Pa infection, defined as > 75% of respiratory cultures positive for Pa in the first 2years after tracheotomy. Of the primarily male (61%), Hispanic (68%), and publicly insured (88%) cohort, 18% (n = 37) developed chronic Pa-positive respiratory cultures in the first 2years. On multivariable logistic regression, pre-tracheotomy Pa-positive respiratory culture (aOR 11.3; 95% CI 4-1.5) and discharge on beta agonist (aOR 6.3; 95% CI 1.1-36.8) were independently associated with chronic Pa-positive respiratory cultures, while discharge on chronic mechanical ventilation was associated with decreased odds (aOR 0.3; 95% CI 0.1-0.7). On sensitivity analysis examining those without a pre-tracheotomy Pa-positive respiratory culture, discharge on MV continued to be associated with decreased odds of chronic Pa (aOR 0.1; 95% CI 0.02-0.4) and three other variables (male gender, chronic lung disease, and discharge on inhaled corticosteroids) were associated with increased odds of chronic Pa. Because pre-tracheotomy Pa growth on respiratory culture is associated with post-tracheotomy chronic Pa-positive respiratory cultures, future research should examine pre-tracheotomy Pa eradication or suppression protocols.

P4684Differential right ventricular adaptation patterns to chronic pressure overload

Abstract Background Right ventricular (RV) dysfunction is the most important prognostic factor in chronic pulmonary hypertension (PH), but its underlying mechanisms are unknown. Clinical observation and prior experimental work suggest that RV pressure overload is not the only cause since the degree of RV adaptation varies with similar RV end-systolic pressures. Purpose Our aim was to characterize serial RV adaptation by cardiac magnetic resonance (CMR) in 3 different experimental large-animal models of increased afterload: a model of chronic postcapillary PH, a model of PH secondary to systemic-to-pulmonary shunt and a model of mechanical RV pressure overload (generated by pulmonary artery [PA] banding). Methods Four-week old piglets underwent pulmonary vein banding surgery to generate the chronic postcapillary PH model (n=20), aorto-pulmonary shunt (n=6), PA banding (n=7) or sham operation (n=7). They were followed up monthly with CMR and right heart catheterization (RHC). All procedures followed the “Principles of laboratory animal care”. Comparison of continuous variables among groups was performed with Mann-Whitney U test. Results Animals with either postcapillary PH or PH secondary to aorto-pulmonary shunt presented significant RV dilatation, hypertrophy and dysfunction that was maintained during follow-up (median RV end-systolic volume [RVESV]=32.6 ml/m2 for postcapillary PH and 32.6 ml/m2 for shunt vs. 16.1 ml/m2 in sham controls; median RV ejection fraction [RVEF]=61.5% for postcapillary PH and 60.5% for shunt vs. 69.6% in sham controls at the end of follow-up). Animals with PA banding also presented with significant RV dilatation and hypertrophy at the first month follow-up, but unlike all other groups, they developed reverse RV remodeling from the second month onwards and maintained normal RV volumes and RVEF values until the end of follow-up despite having severe RV hypertrophy (RV mass 22.6 g/m2 in PA banding vs. 16.1 g/m2 in controls at the 4th month follow-up; Figure). CMR parameters (median values). Conclusion In PH there is a maladaptive RV hypertrophy that is not present in a model of progressive RV pressure overload without alterations of the pulmonary circulation. Increased RV pressure overload alone does not fully explain PH-associated RV dysfunction. Further research is needed to clarify the underlying mechanisms of adaptive and maladaptive hypertrophy in PH. Acknowledgement/Funding The CNIC is supported by the Ministerio de Ciencia, Innovaciόn y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence

Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1)

In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate.We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection.In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7–28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis.As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-β (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.