Chronic Pseudomonas Aeruginosa Infection Research Articles

A novel in vitro model to study prolonged Pseudomonas aeruginosa infection in the cystic fibrosis bronchial epithelium.

Pseudomonas aeruginosa (PA) is known to chronically infect airways of people with cystic fibrosis (CF) by early adulthood. PA infections can lead to increased airway inflammation and lung tissue damage, ultimately contributing to decreased lung function and quality of life. Existing models of PA infection in vitro commonly utilize 1-6-hour time courses. However, these relatively early time points may not encompass downstream airway cell signaling in response to the chronic PA infections observed in people with cystic fibrosis. To fill this gap in knowledge, the aim of this study was to establish an in vitro model that allows for PA infection of CF bronchial epithelial cells, cultured at the air liquid interface, for 24 hours. Our model shows with an inoculum of 2 x 102 CFUs of PA for 24 hours pro-inflammatory markers such as interleukin 6 and interleukin 8 are upregulated with little decrease in CF bronchial epithelial cell survival or monolayer confluency. Additionally, immunoblotting for phosphorylated phospholipase C gamma, a well-known downstream protein of fibroblast growth factor receptor signaling, showed significantly elevated levels after 24 hours with PA infection that were not seen at earlier timepoints. Finally, inhibition of phospholipase C shows significant downregulation of interleukin 8. Our data suggest that this newly developed in vitro "prolonged PA infection model" recapitulates the elevated inflammatory markers observed in CF, without compromising cell survival. This extended period of PA growth on CF bronchial epithelial cells will have impact on further studies of cell signaling and microbiological studies that were not possible in previous models using shorter PA exposures.

P277 A survey of UK cystic fibrosis centres regarding stopping anti-Pseudomonas aeruginosa (PA) nebulised therapy in children who become free from Pa infection

Chronic Pseudomonas aeruginosa (PA) infection in children with cystic fibrosis (CF) has a detrimental effect on morbidity and mortality. There is clear and well referenced guidance on the diagnostic criteria for chronic PA infection and how to treat it. However, the nebulised treatment is burdensome and the guidelines do not advise how to manage children who stop isolating PA and specifically, if the treatment should be discontinued. This is particularly important in the era of highly effective CFTR modulator therapy as monitoring lower airways is more difficult in children not productive of sputum.

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

AtbFinder Diagnostic Test System Improves Optimal Selection of Antibiotic Therapy in Persons with Cystic Fibrosis

Cystic fibrosis (CF) is characterized by mutations of CFTR that lead to increased viscous secretions, bacterial colonization, and recurrent infections. Chronic Pseudomonas aeruginosa infection in persons with CF is associated with progressive and accelerated lung function decline despite aggressive antibiotic treatment. We report the management of respiratory infections in persons with CF with antibiotic therapy that was based on the recommendations of AtbFinder, a novel, rapid, culture-based diagnostic test system that employs a novel paradigm of antibiotic selection. AtbFinder mimics bacterial interactions with antibiotics at concentrations that can be achieved in affected tissues or organs and models conditions of interbacterial interactions within polymicrobial biofilms. This open-label, single-arm, investigator-initiated clinical study was designed to identify the efficacy of antibiotics selected using AtbFinder in persons with CF. Microbiological and clinical parameters were assessed following the change of antibiotic therapy to antibiotics selected with AtbFinder between January 2016 and December 2018 and retrospectively compared with clinical data collected between January 2013 and December 2015. We enrolled 35 persons with CF (33 with chronic P. aeruginosa colonization). Antibiotics selected using AtbFinder resulted in clearance of P. aeruginosa in 81.8% of subsequent cultures, decreased pulmonary exacerbations from 1.21 per patient per annum to 0, and an increase in predicted percent predicted forced expiratory volume in 1 s up to 28.4% from baseline. The number of systemic antibiotic courses used in patients after switching to the AtbFinder-selected therapy was reduced from 355 to 178. These findings describe the superiority of antibiotic regimens selected with AtbFinder compared with routine antimicrobial susceptibility testing.

Albumin-coated pH-responsive dimeric prodrug-based nano-assemblies with high biofilm eradication capacity.

Pseudomonas aeruginosa (PA) biofilms cause many persistent chronic infections in humans, especially in cystic fibrosis (CF) patients. The biofilms form a strong barrier which may inhibit antimicrobial agents from penetrating the biofilms and killing PA bacteria that reside deep within the biofilms. Concomitant therapies based on tobramycin (TOB) and azithromycin (AZM) have demonstrated beneficial effects in CF patients with chronic PA infections. However, the co-delivery of TOB and AZM has rarely been reported. In this study, we constructed a self-assembled pH-sensitive nano-assembly (DPNA) based on a dimeric prodrug (AZM-Cit-TOB) by simply inserting citraconic amide bonds between AZM and TOB. Moreover, the cationic surface of DPNA was further modified with anionic albumin (HSA) via electrostatic interactions to form an electrostatic complex (termed HSA@DPNA) for better biocompatibility. Upon arrival at the infected tissues, the citraconic amide bonds would be cleaved at acidic pH, resulting in the release of TOB and AZM for bacteria killing and biofilm eradication. As expected, HSA@DPNA showed comparable antibacterial abilities against the P. aeruginosa strain PAO1 in both planktonic and biofilm modes of growth compared to the TOB/AZM mixture in vitro. Moreover, HSA@DPNA exhibited excellent therapeutic efficacy on mice with PAO1-induced lung infection compared to the TOB/AZM mixture, and no detectable toxicity to mammalian cells/animals was observed during the therapeutic process. In summary, our study provides a promising method for the co-delivery of AZM and TOB in concomitant therapies against PAO1-related infection.

Prevalence, trends and outcomes of long-term inhaled antibiotic treatment in people with cystic fibrosis without chronic Pseudomonas aeruginosa infection – A European cystic fibrosis patient registry data analysis

BackgroundLong-term treatment with inhaled antibiotics is recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (PA). However, pwCF without chronic PA infection are also commonly treated with inhaled antibiotics. Using data from the European Cystic Fibrosis Patient Registry (ECFSPR) we aimed to determine the prevalence and factors associated with inhaled antibiotic treatment in pwCF without chronic PA infection, and long-term outcomes with inhaled antibiotics use. MethodsThe ECFSPR was searched for pwCF 6 years of age and older who were not chronically infected with PA at baseline. Factors associated with inhaled antibiotic use were first assessed through a logistic regression. From this model a propensity score was computed for each individual, providing the likelihood of being treated with inhaled antibiotics. Long-term outcomes with and without inhaled antibiotics were assessed separately for propensity scores tertiles. Results7210 pwCF without chronic PA infection at baseline were included, with 2722 (37.75%) receiving long-term treatment with inhaled antibiotics. Treatment with inhaled antibiotics was more prevalent with severe genotype, diabetes, pancreatic insufficiency, and past infection with chronic PA (OR 3.8, 95% CI, 2.88–5.04). Treatment with inhaled antibiotics was not associated with a reduced risk for acquisition of PA or other resistant pathogens, or with improved lung function decline, mortality, or transplantation. ConclusionsMany pwCF without chronic PA infection are receiving long-term treatment with inhaled antibiotics despite lack of support from clinical trials or practice guidelines. We did not observe improve outcomes with inhaled antibiotics. Our findings suggest controlled studies evaluating specific inhaled antibiotic regimens targeting specific pathogens or indications be performed to determine their effect.

Issues on the treatment of lower respiratory tract infection caused by Pseudomonas aeruginosa

The tendency to form biofilm and drug resistance accounts for the difficulty in the treatment of lower respiratory tract infections caused by Pseudomonas aeruginosa (PA). The treatment goals and strategies are different between acute and chronic PA infections. Optimization of antimicrobial drug selection and its rational use based on antimicrobial activity and pharmacokinetic properties is crucial in improving outcomes. Besides, non-antimicrobial treatments such as airway clearance and anti-biofilm treatment also play an important role in the management of PA infections.

Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study

BackgroundSince nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels.MethodsWe have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017–September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis.ResultsOsteoporosis (T-score ≤ − 2.5) and osteopenia (T-score − 1 to − 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50–59-, 60–69-, and 70–79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07–1.18), female sex (aOR = 36.3; 95% CI = 7.57–174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14–1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07–41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis.ConclusionsMiddle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

The Pseudomonas aeruginosa Secreted Protein PA3611 Promotes Bronchial Epithelial Cell Epithelial-Mesenchymal Transition via Integrin αvβ6-Mediated TGF-β1-Induced p38/NF-κB Pathway Activation.

Pseudomonas aeruginosa (PA) is an important pathogen that has been proven to colonize and cause infection in the respiratory tract of patients with structural lung diseases and to lead to bronchial fibrosis. The development of pulmonary fibrosis is a complication of PA colonization of the airway, resulting from repeated infection, damage and repair of the epithelium. Bronchial epithelial cell epithelial-mesenchymal transition (EMT) plays a vital role in bronchial fibrosis. To date, research on bronchial epithelial cell EMT caused by PA-secreted virulence factors has not been reported. Here, we found that PA3611 protein stimulation induced bronchial epithelial cell EMT with mesenchymal cell marker upregulation and epithelial cell marker downregulation. Moreover, integrin αvβ6 expression and TGF-β1 secretion were markedly increased, and p38 MAPK phosphorylation and NF-κB p65 subunit phosphorylation were markedly enhanced. Further research revealed that PA3611 promoted EMT via integrin αvβ6-mediated TGF-β1-induced p38/NF-κB pathway activation. The function of PA3611 was also verified in PA-infected rats, and the results showed that ΔPA3611 reduced lung inflammation and EMT. Overall, our results revealed that PA3611 promoted EMT via integrin αvβ6-mediated TGF-β1-induced p38/NF-κB pathway activation, suggesting that PA3611 acts as a crucial virulence factor in bronchial epithelial cell EMT and is a potential target for the clinical treatment of bronchial EMT and fibrosis caused by chronic PA infection.

Acidic Microenvironment Determines Antibiotic Susceptibility and Biofilm Formation of Pseudomonas aeruginosa

Pseudomonas aeruginosa is the most prevalent bacterial species that contribute to cystic fibrosis (CF) respiratory failure. The impaired function of CF transmembrane conductance regulator leads to abnormal epithelial Cl–/HCO3– transport and acidification of airway surface liquid. However, it remains unclear why the CF lung is most commonly infected by Pseudomonas aeruginosa versus other pathogens. We carried out studies to investigate if lower pH helps Pseudomonas aeruginosa adapt and thrive in the CF-like acidic lung environment. Our results revealed that Pseudomonas aeruginosa generally forms more biofilm, induces antibiotic resistance faster in acidic conditions, and can be reversed by returning the acidic environment to physiologically neutral conditions. Pseudomonas aeruginosa appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic Pseudomonas aeruginosa infection and colonization.

Exploring factors associated with acquisition and chronicity of infection in bronchiectasis: A population-based study

IntroductionChronic infection is associated with adverse outcomes among people with bronchiectasis. However, it is not known which factors are associated with a bacterial infection, and with persistence of an infection after the first episode. We aimed to determine factors associated with a new infection and with chronicity of Pseudomonas aeruginosa (PA) and H. influenzae (HI), the most common organisms in bronchiectasis infection. MethodsUsing an Israeli population database, we identified individuals diagnosed with bronchiectasis. Cox proportional hazard models were used to assess risk factors for first isolation and Logistic regression for chronicity of infection after a first isolation of PA and HI. ResultsWe included 1305 people with a median of 5 respiratory samples per individual. PA was initially isolated in 297 people, of whom 97 (33%) developed chronic PA infection. HI was newly identified in 169 people, of whom 39 (23%) developed chronic infection (p = 0.029). Factors associated with increased risk of a new infection with PA were COPD (HR 1.87 [1.52–2.28], previous isolation of HI (HR 1.38 [1.07–1.78]), and alcohol abuse (HR 2.22 [1.13–4.3]). Younger age was associated with increased risk of HI infection, while COPD was associated with a lower risk of HI infection. Prescription of an anti- PA antibiotic was associated with chronic PA after a new infection (OR = 1.8 [1.09–2.9], p = 0.02). A landmark analysis showed that survival was worse in people with chronic PA infection vs. single or intermittent infection (Log rank: p = 0.034) ConclusionsYounger age and presence of PCD are associated with a new isolation of HI. A new infection with PA is associated with previous HI infection, PCD, COPD, and alcohol abuse. Unexpectedly, treatment with appropriate anti-PA antimicrobials was not associated with a reduced risk of chronicity.

Risk factors for respiratory Aspergillus fumigatus in German Cystic Fibrosis patients and impact on lung function

Airway inflammation and chronic lung infections in cystic fibrosis (CF) patients are mostly caused by bacteria, e.g. Pseudomonas aeruginosa (PA). The role of fungi in the CF lung is still not well elucidated, but evidence for a harmful and complex role is getting stronger. The most common filamentous fungus in CF is Aspergillus fumigatus (AF). Age and continuous antibiotic treatment have been discussed as risk factors for AF colonisation but did not differentiate between transient and persistent AF colonisation. Also, the impact of co-colonisation of PA and AF on lung function is still under investigation. Data from patients with CF registered in the German Cystic Fibrosis Registry database in 2016 and 2017 were retrospectively analysed, involving descriptive and multivariate analysis to assess risk factors for transient or persistent AF colonisation. Age represented an independent risk factor for persistent AF colonisation. Prevalence was low in children less than ten years, highest in the middle age and getting lower in higher age (≥ 50 years). Continuous antibiotic lung treatment was significantly associated with AF prevalence in all age groups. CF patients with chronic PA infection had a lower lung function (FEV1%predicted), which was not influenced by an additional AF colonisation. AF colonisation without chronic PA infection, however, was significantly associated with a lower function, too. Older age up to 49 years and continuous antibiotic use were found to be the main risk factors for AF permanent colonisation. AF might be associated with decrease of lung function if not disguised by chronic PA infection.

Clinically Relevant Epithelial Lining Fluid Concentrations of Meropenem with Ciprofloxacin Provide Synergistic Killing and Resistance Suppression of Hypermutable Pseudomonas aeruginosa in a Dynamic Biofilm Model.

Treatment of exacerbations of chronic Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation, and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic in vitro CDC biofilm reactor (CBR). Two hypermutable P. aeruginosa strains, PAOΔmutS (MIC of ciprofloxacin [MICciprofloxacin], 0.25 mg/liter; MICmeropenem, 2 mg/liter) and CW44 (MICciprofloxacin, 0.5 mg/liter; MICmeropenem, 4 mg/liter), were investigated for 120 h. Concentration-time profiles achievable in epithelial lining fluid (ELF) following FDA-approved doses were simulated in the CBR. Treatments were ciprofloxacin at 0.4 g every 8 h as 1-h infusions (80% ELF penetration), meropenem at 6 g/day as a continuous infusion (CI) (30% and 60% ELF penetration), and their combinations. Counts of total and less-susceptible planktonic and biofilm bacteria and MICs were determined. Antibiotic concentrations were quantified by an ultrahigh-performance liquid chromatography photodiode array (UHPLC-PDA) assay. For both strains, all monotherapies failed, with substantial regrowth and resistance of planktonic (≥8 log10 CFU/ml) and biofilm (>8 log10 CFU/cm2) bacteria at 120 h (MICciprofloxacin, up to 8 mg/liter; MICmeropenem, up to 64 mg/liter). Both combination treatments demonstrated synergistic bacterial killing of planktonic and biofilm bacteria of both strains from ∼48 h onwards and suppressed regrowth to ≤4 log10 CFU/ml and ≤6 log10 CFU/cm2 at 120 h. Overall, both combination treatments suppressed the amplification of resistance of planktonic bacteria for both strains and of biofilm bacteria for CW44. The combination with meropenem at 60% ELF penetration also suppressed the amplification of resistance of biofilm bacteria for PAOΔmutS Thus, combination treatment demonstrated synergistic bacterial killing and resistance suppression against difficult-to-treat hypermutable P. aeruginosa strains.

Nebulized Azithromycin Versus Oral Azithromycin as Anti-Inflammatory Therapy in Children with Cystic Fibrosis: A Prospective Randomized Open-Label Trial

Background: Oral azithromycin is recommended as anti-inflammatory therapy for patients with cystic fibrosis (CF) 6 years of age and older to improve lung function and reduce exacerbations. Objectives: We evaluated the short-term efficacy and safety of nebulized azithromycin as anti-inflammatory therapy in children with CF chronically infected with Pseudomonas aeruginosa. Methods: In a randomized prospective study, children aged 8 - 18 years with clinically stable CF and FEV1 25% - 75% predicted with no recent use of oral, intravenous or inhaled antipseudomonal antibiotics and azithromycin were randomized to receive either nebulized azithromycin (70 mg daily) or oral azithromycin 3 times per week for 28 days. Primary endpoint was changes in pulmonary function (FEV1). Secondary outcomes included changes in Pseudomonas aeruginosa (PA) colonization characteristics (count, phenotype), quality of life and weight. Results: A total of 280 patients were screened, of whom 60 were found eligible. Forty five patients (25 in the nebulized group) and 20 in the oral group) completed the study. After 28 days of treatment, nebulized azithromycin was significantly associated with improvements in FEV1 % predicted, quality of life measure and weight. Also PA count was significantly decreased. Importantly, improvements of FEV1 % predicted, quality of life, weight and the decline in PA count were statistically significantly greater with nebulized azithromycin compared with oral azithromycin. No significant difference was observed in PA phenotype in either treatment arms. Conclusions: Nebulized azithromycin is associated with a significant improvement in lung function, PA count, quality of life and weight in clinically stable CF children with chronic PA infection. The improvements observed were greater compared with oral azithromycin. Nebulized azithromycin could be suggested as a new therapeutic strategy for this life-limiting disease. Further clinical trials with novel nebulizer formulation of azithromycin and large number of participants are needed to further assess the efficacy, safety and sustained effect of this new therapeutic approach in children with CF.

Synergistic Meropenem-Tobramycin Combination Dosage Regimens against Clinical Hypermutable Pseudomonas aeruginosa at Simulated Epithelial Lining Fluid Concentrations in a Dynamic Biofilm Model.

Exacerbations of chronic Pseudomonas aeruginosa infections are a major treatment challenge in cystic fibrosis due to biofilm formation and hypermutation. We aimed to evaluate different dosage regimens of meropenem and tobramycin as monotherapies and in combination against hypermutable carbapenem-resistant P. aeruginosa A hypermutable P. aeruginosa isolate (meropenem and tobramycin MICs, 8 mg/liter) was investigated in the dynamic CDC biofilm reactor over 120 h. Regimens were meropenem as the standard (2 g every 8 h, 30% epithelial lining fluid [ELF] penetration) and as a continuous infusion (CI; 6 g/day, 30% and 60% ELF penetration) and tobramycin at 10 mg/kg of body weight every 24 h (50% ELF penetration). The time courses of totally susceptible and less-susceptible bacteria and MICs were determined, and antibiotic concentrations were quantified by liquid chromatography-tandem mass spectrometry. All monotherapies failed, with the substantial regrowth of planktonic (>6 log10 CFU/ml) and biofilm (≥6 log10 CFU/cm2) bacteria occurring. Except for the meropenem CI (60% ELF penetration), all monotherapies amplified less-susceptible planktonic and biofilm bacteria by 120 h. The meropenem standard regimen with tobramycin caused initial killing followed by considerable regrowth with resistance (meropenem MIC, 64 mg/liter; tobramycin MIC, 32 mg/liter) for planktonic and biofilm bacteria. The combination containing the meropenem CI at both levels of ELF penetration synergistically suppressed the regrowth of total planktonic bacteria and the resistance of planktonic and biofilm bacteria. The combination with the meropenem CI at 60% ELF penetration, in addition, synergistically suppressed the regrowth of total biofilm bacteria. Standard regimens of meropenem and tobramycin were ineffective against planktonic and biofilm bacteria. The combination with meropenem CI exhibited enhanced bacterial killing and resistance suppression of carbapenem-resistant hypermutable P. aeruginosa.

A real world evaluation of the long-term efficacy of strategies to prevent chronic Pseudomonas aeruginosa pulmonary infection in children with cystic fibrosis

BackgroundChildren with cystic fibrosis (CF) are susceptible to chronic Pseudomonas aeruginosa (PA) infection. Early eradication of PA has proven short-term efficacy. No studies have evaluated the long- term impact of early eradication for CF patients, particularly those diagnosed by newborn screening (NBS). Our objective was to quantify the long-term impact of early PA eradication on the risk of chronic PA infection in children (0–18 years old) with CF prior to and following the introduction of a province-wide NBS program. MethodsThis 20-year retrospective cohort study compared 94 patients eligible for treatment with inhaled tobramycin at first PA isolation (“recent cohort”) with 27 historical controls (“historical cohort”). ResultsA smaller proportion of patients in the recent cohort developed chronic PA (24% versus 78%; P<0.001); the adjusted risk of chronic infection was 2.90 (95%CI 1.47, 5.76; P=0.002) in the historical vs recent cohort. However, NBS was not independently associated with the risk of chronic PA infection after its introduction. ConclusionsEarly eradication of PA, irrespective of early diagnosis, is associated with reduced risk of chronic PA. However, concomitant improvements in medical care since the introduction of early eradication protocols may have contributed to these long-term observed benefits.

Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease

BackgroundIn bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients.MethodsThis cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George’s Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography.ResultsThe study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively).ConclusionsMACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

Anti-Pseudomonas aeruginosa IgG antibodies and chronic airway infection in bronchiectasis

BackgroundIdentification of chronic Pseudomonas aeruginosa (PA) infection is important in the management of bronchiectasis, but requires repeated sputum sampling. We hypothesized that serum anti-PA IgG antibodies could diagnose chronic PA infection at a single visit. MethodsClinically stable bronchiectasis patients were studied prospectively. Chronic PA infection was defined as 2 or more positive sputum samples at least 3 months apart and/or failure to clear PA following eradication treatment. Baseline serum anti-PA IgG was determined by a validated ELISA kit. ResultsA total of 408 patients were included. Sixty of them (14.7%) had chronic PA infection and had higher anti-PA IgG levels (median 6.2 vs. 1.3 units, p < 0.001). Antibody levels showed direct significant correlations with exacerbation frequency, the bronchiectasis severity index and sputum inflammatory markers. Fifty-seven patients with chronic PA infection had a positive test, giving 95% sensitivity, 74.4% specificity and AUROC of 0.87. During follow-up, 38 patients had a new PA isolation. Eradication at 12 months was achieved in 89.5% of subjects with a negative antibody test and 15.8% of patients with a positive test. ConclusionsAnti-PA IgG test is highly accurate to detect chronic PA infection in bronchiectasis patients. In addition, it may be a marker of disease severity and treatment response.

IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection

BackgroundInterleukin (IL)-22 is a critical mediator of mucosal immunity and tissue regeneration, protecting against a number of respiratory pathogens. Whether IL-22 confers protection against chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is unknown. MethodsExplanted CF lungs were examined for IL-22 production and immune-localization. A murine model of persistent pulmonary PA infection was used to examine production of IL-22 following infective challenge. The role of IL-22 was examined using IL-22 knockout (KO) animals. ResultsIL-22 is produced within the adult CF lung and localizes to the airway epithelium. IL-22 is produced by murine pulmonary lymph node cells following lung infection. The absence of IL-22 resulted in no significant difference in acute mortality, bacterial burden, chronic infection rates, histological changes or neutrophilic inflammation in the chronic PA infection model. However, IL-22 KO animals lost less weight following infection. ConclusionIL-22 is produced in the CF lung and in response to PA infection yet is dispensable in protection against chronic pulmonary P. aeruginosa infection in a murine model. However, we identified a novel role for the cytokine in promoting infection-related weight-loss, a significant prognostic factor in the CF population.

Efficacy and long-term outcomes of palivizumab prophylaxis to prevent respiratory syncytial virus infection in infants with cystic fibrosis in Northern Ireland.

RSV causes considerable morbidity and mortality in children. In cystic fibrosis (CF) viral infections are associated with worsening respiratory symptoms and bacterial colonization. Palivizumab is effective in reducing RSV hospitalization in high risk patient groups. Evidence regarding its effectiveness and safety in CF is inconclusive. CF screening in N. Ireland enabled timely palivizumab prophylaxis, becoming routine in 2002. To determine the effect of palivizumab on RSV-related hospitalization and compare lung function and bacterial colonization at age 6 years for those born pre- and post-introduction of palivizumab prophylaxis. A retrospective audit was conducted for all patients diagnosed with CF during the period from 1997 to 2007 inclusive. RSV-related hospitalization, time to Pseudomonas aeruginosa (PA) 1st isolate, lung function and growth parameters were recorded. Comparisons were made for outcomes pre- and post-introduction of routine palivizumab administration in 2002. A cost evaluation was also performed. Ninety-two children were included; 47 pre- and 45 post-palivizumab introduction. The overall RSV-positive hospitalization rate was 13%. The relative risk of RSV infection in palivizumab non-recipients versus recipients was 4.78 (95%CI: 1.1-20.7), P = 0.027. Notably, PA 1st isolate was significantly earlier in the palivizumab recipient cohort versus non-recipient cohort (median 57 vs. 96 months, P < 0.025) with a relative risk of 2.5. Chronic PA infection at 6 years remained low in both groups, with similar lung function and growth parameters. Total costs were calculated at £96,127 ($151,880) for the non-recipient cohort versus £137,954 ($217,967) for the recipient cohort. Palivizumab was effective in reducing RSV-related hospitalization infection in CF patients. Surprisingly, we found a significantly earlier time to 1st isolate of PA in palivizumab recipients which we could not explain by altered or improved diagnostic tests.