Chronic Pseudomonas Aeruginosa Research Articles

Normalization of Muc5b ameliorates airway mucus plugging during persistent Pseudomonas aeruginosa infection in the CFTR-/- rat.

In cystic fibrosis, the airway gel-forming mucin MUC5B accumulates in the airways, preventing clearance of pathogens like Pseudomonas aeruginosa (PA). The cystic fibrosis transmembrane conductance regulator (CFTR)-/- (KO) rat model exhibits a similar accumulation of Muc5b. Our lab has shown that increased Muc5b precipitates the development of chronic PA infection. We hypothesized that reducing Muc5b in the KO rat airway would prevent occlusive mucus plugs and development of persistent PA infection. Six-month-old KO rats received Muc5b or scramble siRNA via intratracheal instillation. Rats were then inoculated with 106 colony-forming units of mucoid P. aeruginosa isolate PAM57-15 and euthanized at 3- or 14-days post infection (dpi) to assess acute and persistent infection. At 14 dpi, Muc5b siRNA-treated KO rats had increased weight, decreased neutrophilic inflammation, and reduced mucus plugging in the small airways compared with scramble-treated KO and WT rats. These results indicate that pharmacological intervention of Muc5b reduces mucus plugging during persistent PA infection.NEW & NOTEWORTHY Although highly effective modulator therapies for cystic fibrosis (CF) have improved mucus-related outcomes of disease for people with CF, eradication of Pseudomonas aeruginosa (PA) infection has not been achieved in this population. In addition, current therapies for CF do not target mucin hypersecretion directly. Here, we show that a novel approach of normalizing airway Muc5b hypersecretion ameliorates infection-induced mucus plugging and neutrophilic inflammation during persistent PA infection in CFTR-/- rats.

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)

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.

Role of Inhalational Aztreonam Lysine in Lower Airway Infections in Cystic Fibrosis: An Updated Literature Review.

Cystic fibrosis (CF) is an inherited disorder most prevalent in the Caucasian population, characterized by a functional abnormality of the transmembrane conductance regulator protein that leads to a wide array of complications, including chronic lung infections. Pseudomonas aeruginosa (PA) is a frequently acquired microbe in CF patients and is associated with deterioration in pulmonary function and increased mortality. Inhaled anti-infective agents are an established curative therapy for CF airway infections, especially with chronic PA lung disease. Amongst them, aztreonam lysine for inhalation (AZLI) is an aerosolized monobactam antibiotic aztreonam, approved for use in CF patients nearly a decade ago. This literature review aims to explore studies based on the efficacy, safety, and tolerability of AZLI use in CF patients with pulmonary infections. We searched for all the relevant articles present in PubMed, Google Scholar, Cochrane Library, EMBASE, ClinicalTrials.gov, and Journal of Cystic Fibrosis for our data collection from 2000 to 2020. The use of AZLI has substantially improved lung function, respiratory symptoms, and remarkably reduced sputum PA density in CF patients, thereby improving the patient's overall quality of life. The adverse effects reported were compatible with CF lung disease. Hence, inhalational therapy with AZLI is highly efficacious and safe in the management of chronic airway infections. More clinical trials need to be conducted in the future to assess its long-term clinical benefits and adverse events as well as to explore the role of AZLI in the setting of acute lung infections.

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.

Prospectively predicting Pseudomonas aeruginosa infection/s using routine data from the UK cystic fibrosis register.

Rationale and aimsLung health of people with cystic fibrosis (PwCF) can be preserved by daily use of inhaled therapy. Adherence to inhaled therapy, therefore, provides an important process measure to understand the success of care and can be used as a quality indicator. Defining adherence is problematic, however, since the number of prescribed treatments varies considerably between PwCF. The problem is less pronounced among those with Pseudomonas aeruginosa (PA), for whom at least three daily doses of nebulized therapy should be prescribed and who thus constitute a more homogeneous group. The UK CF Registry provides routine data on PA status, but data are only available 12 months after collection. In this study, we aim to prospectively identify contemporary PA status from historic registry data.MethodUK CF Registry data from 2011 to 2015 for PwCF aged ≥16 was used to determine a pragmatic prediction rule for identifying contemporary PA status using historic registry data. Accuracy of three different prediction rules was assessed using the positive predictive value (PPV). The number and proportion of adults predicted to have PA infection were determined overall and per center for the selected prediction rule. Known characteristics linked to PA status were explored to ensure the robustness of the prediction rule.ResultsHaving CF Registry defined chronic PA status in the two previous years is the selected definition to predict a patient will have PA infection within the current year (population‐level PPV = 96%‐97%, centre level PPV = 85%‐100%). This approach provides a subset of data between 1852 and 1872 patients overall and a range of 8 to 279 patients per center.ConclusionHistoric registry data can be used to contemporaneously identify a subgroup of patients with chronic PA. Since this patient group has a narrower treatment schedule, this can facilitate a better benchmarking of adherence across centers.

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.

In Vitro Newly Isolated Environmental Phage Activity against Biofilms Preformed by Pseudomonas aeruginosa from Patients with Cystic Fibrosis.

As disease worsens in patients with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) colonizes the lungs, causing pulmonary failure and mortality. Progressively, PA forms typical biofilms, and antibiotic treatments determine multidrug-resistant (MDR) PA strains. To advance new therapies against MDR PA, research has reappraised bacteriophages (phages), viruses naturally infecting bacteria. Because few in vitro studies have tested phages on CF PA biofilms, general reliability remains unclear. This study aimed to test in vitro newly isolated environmental phage activity against PA isolates from patients with CF at Bambino Gesù Children’s Hospital (OBG), Rome, Italy. After testing in vitro phage activities, we combined phages with amikacin, meropenem, and tobramycin against CF PA pre-formed biofilms. We also investigated new emerging morphotypes and bacterial regrowth. We obtained 22 newly isolated phages from various environments, including OBG. In about 94% of 32 CF PA isolates tested, these phages showed in vitro PA lysis. Despite poor efficacy against chronic CF PA, five selected-lytic-phages (Φ4_ZP1, Φ9_ZP2, Φ14_OBG, Φ17_OBG, and Φ19_OBG) showed wide host activity. The Φ4_ZP1-meropenem and Φ14_OBG-tobramycin combinations significantly reduced CF PA biofilms (p < 0.001). To advance potential combined phage-antibiotic therapy, we envisage further in vitro test combinations with newly isolated phages, including those from hospital environments, against CF PA biofilms from early and chronic infections.

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.

Diagnostic value of sputum cultures in children under 2 years of age with chronic suppurative lung diseases.

Acquiring sputum cultures from infants is considered challenging. We describe their yield in infants with cystic fibrosis (CF) and other chronic suppurative lung diseases (CSLDs). Retrospective medical record review over a 4-year period, for infants aged 0-2 years with ≥2 airway bacterial cultures acquired by deep suction or induced sputum ≥4 weeks apart. Data included demographics, culture results, and clinical status. A total of 98 infants (16 CF) were evaluated and 534 sputum cultures acquired, 201 in CF and 333 in CSLD. There were 12 (2-23), median (range) cultures/CF infant, and 3 (2-21)/CSLD infant. Age at first culture was 3.8 (1-19.5) months for CF and 10.4 (0.5-22) months for CSLD; p = .016. In total, 360 cultures (67%) were positive for any bacteria, with 170/234 (73%) positive during exacerbations, compared with 190/300 (63%) during routine visits; p = .05. More infants with CF than CSLD had cultures positive for Staphylococcus aureus (SA; 75% vs. 34%; p = .004) throughout the period. Pseudomonas aeruginosa (PA) was common in both CF and CSLD (56% and 44%, respectively; p = .42) and increased over time for CF but was high throughout for CSLD. The number of hospital days before PA acquisition was 6 (10.2) for CF and 28.8 (38.7) for CSLD (p = .003). No CF but 6/82 (7%) CSLD infants had chronic PA (p = .56). Sputum cultures showed that infection, in particular PA, is common in CF and CSLD whereas SA is more common in CF. Prospective studies are warranted to elucidate the role of active surveillance in guiding antibiotic therapy.

Exacerbations and Pseudomonas aeruginosa colonization are associated with altered lung structure and function in primary ciliary dyskinesia

BackgroundRecurrent bacterial infections of the respiratory tract are one of the major clinical features of the primary ciliary dyskinesia (PCD), a rare genetic disease due to malfunctioning of motile cilia. Chronic infections and persistent inflammation of the respiratory system result in progressive lung disease.Aim of the study was to highlight the main factors associated with clinical, functional and anatomical deterioration in PCD patients.MethodsWe retrospectively analyzed data from 58 patients with PCD, 37 adults and 21 children. The demographic and clinical data, forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), sputum microbiology and imaging results (chest CT scores-modified Bhalla) were recorded. Patients were stratified according to the number of exacerbations (< 2/year vs ≥ 2/year) and chronic Pseudomonas aeruginosa (PA) colonization. The possible correlations between lung function and chest CT scores were assessed; we also evaluated the correlation between these parameters and the severity scores for bronchiectasis (BSI, FACED and e-FACED).ResultsChest CT scores showed a significant correlation with FEV1 (p = 0.0002), age (p < 0.0001), BMI (p = 0.0002) and number of lung lobes involved (p < 0.0001). PA colonization had an overall prevalence of 32.6%: no significant difference in FEV1 between PA colonized and non-colonized patients was found (p = 0.70), while chest CT score was significantly worse in chronic PA colonized patients (p = 0.009). Patients with a high number of exacerbation (≥ 2/year) were older (p = 0.01), had lower FEV1 (p = 0.03), greater number of lobes involved (p < 0.001) and worse CT score than patients with low number of exacerbations (p = 0.001); they also had higher prevalence of PA chronic bronchial infection (33.3% versus 13.6%, p = 0.10). Multivariable linear regression analyses adjusted for gender, age and BMI showed positive associations between PA colonization and number of exacerbations with severity of disease (number of lobes involved, CT score, BSI, FACED, and e-FACED).ConclusionsIn our PCD population the number of exacerbations (≥ 2/year) and PA colonization were the two most relevant factors associated with severity of disease.

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.

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.

Osteogenic Sarcoma in an Adolescent With Cystic Fibrosis: Successful Treatment Despite Significant Obstacles

Introduction: We describe the case of a 16-year old male with cystic fiborosis (CF) who presented with an osteosarcoma of his right distal tibia.Case Report: Treatment consisted of neoadjuvant chemotherapy of cisplatin, doxorubicin and high dose methotrexate followed by distal tibial resection and free fibula flap reconstruction and consolidation chemotherapy. Treatment was complicated by a pulmonary exacerbation, where Pseudomonas aeruginosa (PsA) and Staphylococcus aureus were grown on sputum culture which was treated with a 2-week course of intravenous piptazobactam and tobramycin. Mycobacterium intracellulare and Mycobacterium abscessus were also cultured following commencement of chemotherapy and successfully treated with a 6-month course of oral azithromycin, ethambutol, and moxifloxacin along with a 1-month course of inhaled amikacin. Pulmonary function improved during his treatment from baseline FEV1 of 3.8 l (93.9%) to 4.15 l (102.3% predicted) whilst nutritional status remained stable.Discussion: The combination of CF and osteosarcoma is rare with only one previous case reported (1). Our case is instructive as the patient faced the challenge of chronic PsA and the first reported culturing and successful treatment of non-tuberculous mycobacterium (NTM) during chemotherapy. Fatal outcomes have been reported previously for CF patients during immunosuppression (2). In concordance with our findings, a recent report noted an improvement in respiratory function in a child treated for leukemia (3). The anti-inflammatory nature of some chemotherapy agents could be responsible for the observed clinical improvement in CF with low dose methotrexate having been shown to increase FEV1 in adolescents with advanced CF (4). Whilst doxorubicin could improve pulmonary outcomes through increased total cellular CFTR protein expression and CFTR associated chloride secretion (5). It is hypothesized that the improved pulmonary function in patients with CF who require chemotherapy could be due to increased production of Multi-Drug Resistance Proteins (MDR) and Multi-Drug Resistant Associated Proteins (MRP) that may complement the depleted CFTR protein (6).Concluding Remarks: We report the well-tolerated management of osteosarcoma in a patient with CF including the first reported identification and eradication of NTM during chemotherapy. The observed positive pulmonary outcome following chemotherapy highlights several potential cellular mechanisms that deserve to be explored.

Lentivirus-mediated overexpression of suppressor of cytokine signaling-3 reduces neutrophilic airway inflammation by suppressing T-helper 17 responses in mice with chronic Pseudomonasaeruginosa lung infections.

The aim of the present study was to explore the effect of overexpressed suppressor of cytokine signaling‑3 (SOCS3) on T-helper (Th)17 cell responses and neutrophilic airway inflammation in mice with chronic Pseudomonasaeruginosa (PA) infections. SOCS3 expression was enhanced via the administration of tail vein injections of therapeutic lentivirus in mice with chronic PA lung infections. SOCS3 expression in the blood and lung tissue was assessed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. Total and differential cell numbers and myeloperoxidase levels in the bronchoalveolar lavage (BAL) fluid were assessed, as well as the number of bacterial colonies in the lungs. Histological analysis of lung tissue was performed using hematoxylin and eosin staining and phosphorylated‑signal transducer and activator of transcription‑3 (p‑STAT3) expression was measured by western blot analysis and immunohistochemistry. The expression of STAT3 mRNA and retinoid‑related orphan receptor (ROR)γt were measured by RT‑qPCR. The percentage of interleukin (IL)‑17+ cells among cluster of differentiation (CD)4+ cells was calculated using flow cytometry and levels of IL‑17A and IL‑6 were assessed by ELISA. The expression of SOCS3 was significantly increased in CD4+ Tcells following lentivirus injection and the inflammation of neutrophilic airways was notably ameliorated. Enhanced SOCS3 expression was associated with a significant decrease in the expression of p‑STAT3 and RORγt in CD4+ Tcells. Additionally, the percentage of IL‑17+ cells among CD4+ Tcells and the IL‑17 contents in the BAL fluid were significantly decreased. Lentivirus‑mediated overexpression of SOCS3 was revealed to ameliorate neutrophilic airway inflammation by inhibiting pulmonary Th17 responses in mice with chronic PA lung infections.