Cystic Fibrosis Pulmonary Exacerbations Research Articles

The role of environmental pollution in the development of pulmonary exacerbations in cystic fibrosis: a narrative review.

Cystic fibrosis is the most common autosomal recessive disease in the Caucasian race. Its course is chronic and progressive, with pulmonary involvement being associated with greater morbidity and mortality. One of the factors most related to worse prognosis in these patients is respiratory exacerbations. Although limited, there is evidence demonstrating that increased exposure to environmental pollution, both acute and chronic, is associated with an increase in these exacerbations. It is crucial to fully understand this relationship in order to attempt to improve the respiratory health of these patients. That is why the available evidence is reviewed and measures are established to reduce exposure to pollutants.

Use of Lung Ultrasound in Cystic Fibrosis: Is It a Valuable Tool?

Cystic fibrosis (CF) is a multisystem disorder characterized by progressive respiratory deterioration, significantly impacting both quality of life and survival. Over the years, lung ultrasound (LUS) has emerged as a promising tool in pediatric respiratory due to its safety profile and ease at the bedside. In the era of highly effective CF modulator therapies and improved life expectancy, the use of non-ionizing radiation techniques could become an integral part of CF management, particularly in the pediatric population. The present review explores the potential role of LUS in CF management based on available data, analyzing all publications from January 2015 to January 2024, focusing on two key areas: LUS in CF pulmonary exacerbation and its utility in routine clinical management. Nonetheless, LUS exhibits a robust correlation with computed tomography (CT) scans and serves as an additional, user-friendly imaging modality in CF management, demonstrating high specificity and sensitivity in identification, especially in consolidations and atelectasis in the CF population. Due to its ability, LUS could be an instrument to monitor exacerbations with consolidations and to establish therapy duration and monitor atelectasis over time or their evolution after therapeutic bronchoalveolar lavage. On the basis of our analysis, sufficient data emerged showing a good correlation between LUS score and respiratory function tests. Good sensitivity and specificity of the methodology have been found in rare CF pulmonary complications such as effusion and pneumothorax. Regarding its use in follow-up management, the literature reports a moderate correlation between LUS scores and the type, extent, and CT severity score of bronchiectasis. A future validation of ultrasound scores specifically in CF patients could improve the use of LUS to identify pulmonary exacerbations and monitor disease progression. However, further research is needed to comprehensively establish the role of LUS in the CF population, particularly in elucidating its broader utility and long-term impact on patient care.

Biofilm Production and Its Implications in Pediatrics.

Biofilms, aggregates of bacteria enclosed in a self-produced matrix, have been implicated in various pediatric respiratory infections, including acute otitis media (AOM), otitis media with effusion (OME), adenoiditis, protracted bacterial bronchitis, and pulmonary exacerbations in cystic fibrosis. These infections are prevalent in children and often associated with biofilm-producing pathogens, leading to recurrent and chronic conditions. Biofilms reduce antibiotic efficacy, contributing to treatment failure and disease persistence. This narrative review discusses biofilm production by respiratory pathogens such as Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. It examines their mechanisms of biofilm formation, antibiotic resistance, and the challenges they present in clinical treatment. Various antibiofilm strategies have shown promise in vitro and in animal studies, including the use of N-acetylcysteine, enzymes like dispersin B, and agents disrupting quorum sensing and biofilm matrix components. However, their clinical application, particularly in children, remains limited. Traditional treatments for biofilm-associated diseases have not significantly evolved, even with biofilm detection. The transition from experimental findings to clinical practice is complex and requires robust clinical trials and standardized biofilm detection protocols. Addressing biofilms in pediatric respiratory infections is crucial for improving treatment outcomes and managing recurrent and chronic diseases effectively.

Extracellular vesicles in sputum of children with cystic fibrosis pulmonary exacerbations

Extracellular vesicles in sputum of children with cystic fibrosis pulmonary exacerbations

Dual inhaled antibiotics for treatment of pulmonary exacerbations in cystic fibrosis – A real life pilot study

Dual inhaled antibiotics for treatment of pulmonary exacerbations in cystic fibrosis – A real life pilot study

P091 Dual inhaled antibiotics for treatment of pulmonary exacerbations in cystic fibrosis – a real life pilot study

P091 Dual inhaled antibiotics for treatment of pulmonary exacerbations in cystic fibrosis – a real life pilot study

Clinical Outcomes Following SARS-CoV-2 Infection in Pediatric Cystic Fibrosis Patients.

Background Cystic fibrosis (CF) is a genetic disorder of the cystic fibrosis transmembrane conductance regulator chloride channel that leads to impaired mucus clearance in the airways, which leads to deteriorations in lung function and chronic respiratory infection. These effects of CF contribute to the hypothesis that patients with CF may be at increased risk of complications when they catch coronavirus disease 2019 (COVID-19), which swept the world in a global pandemic starting in 2019. Overall, however, the role of CF in COVID-19 has not been well studied, particularly in pediatric patients. Methods In this retrospective review, pediatric patients with CF who contracted COVID-19 (3/1/2020-3/1/2023) (N=69) were compared to two equally sized control cohorts of patients with only CF or COVID-19 matched based on demographics and clinical baselines. Occurrences of adverse outcomes (emergency room visits, hospitalizations, CF pulmonary exacerbations, etc.) were assessed for each subject. The mean percentage of predicted forced expiratory volume in 1 second (FEV1%pred) was also assessed for CF patients. Fisher's exact test assesseddifferences between the proportions of subjects who experienced each outcome. Independent two-variable t-testing assessed mean FEV1%pred differences. Analysis was conducted using IBMSPSSStatistics for Windows, Version 29 (Released 2023; IBM Corp., Armonk, New York, United States)with a significance α=0.05. Ad hoc power analysis was conducted using G*Powerv3.1. Results Overall, CF/COVID subjects fared similarly to control groups without either CF or COVID-19 history, including among subgroups stratified based on baseline respiratory function,P. aeruginosacolonization status, and COVID-19 vaccination status. One notable finding was that CF/COVID subjects experienced significantly fewer pulmonary exacerbations compared to CF-only subjects (p=0.004). Conclusion In conclusion, pediatric CF patients performed similarly to their peers without CF with regardto COVID-19and generally did not demonstrate significant deteriorations in pulmonary function following infection. Lower incidence of pulmonary exacerbations in CF/COVID subjects could be explained by stringent monitoring by parents, quarantine, or close pulmonology follow-up. These findings will provide guidance on management and care for pediatric CF patients with COVID-19.

A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Effect of vitamin D supplementation on cystic fibrosis pulmonary exacerbations: A pilot randomized crossover clinical trial

Effect of vitamin D supplementation on cystic fibrosis pulmonary exacerbations: A pilot randomized crossover clinical trial

Lung clearance index short-term variability in cystic fibrosis: a pre-post pulmonary exacerbation study

BackgroundMultiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF after intravenous (IV) antibiotic therapy.MethodsA single-center study was conducted at CF Unit of Bambino Gesù Children’s Hospital among hospitalized > 3 years patients for pulmonary exacerbations and treated with antibiotic IV treatment for 14 days. MBW and spirometry were evaluated within 72 h of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated.ResultsFifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average reduction of -6,99%; 37/57 patients denoted an improvement, 20/57 are stable or worsened in LCI2.5 values and 4/57 (7.02%) had a significant deterioration (> 15%) at end of treatment. On the contrary a significative elevation of FEV1 and FVC were found, respectively of + 7,30% and of + 5,46%. A positive good correlection among LCI 2.5 and Scond (rho = + 0,615, p = 0.000) and LCI 2.5 and Sacin (rho = + 0,649, p = 0.000) and a negative strong correlation between FEV1 and LCI 2.5 were found in post treatment period. A similar modification of LCI 2.5 and FEV1 was noticed in both adult and pediatric population.ConclusionsLCI may have a role in the routine clinical care of both adult and pediatric CF patients as a good tool to assess response to IV antibiotic end-therapy in the same way as FEV1.

Diminished airway host innate response in people with cystic fibrosis who experience frequent pulmonary exacerbations.

Pulmonary exacerbations are clinically impactful events that accelerate cystic fibrosis (CF) lung disease progression. The pathophysiological mechanisms underlying an increased frequency of pulmonary exacerbations have not been explored. To compare host immune response during intravenous antibiotic treatment of pulmonary exacerbations in people with CF who have a history of frequent versus infrequent exacerbations. Adults with CF were recruited at onset of antibiotic treatment of a pulmonary exacerbation and were categorised as infrequent or frequent exacerbators based on their pulmonary exacerbation frequency in the previous 12 months. Clinical parameters, sputum bacterial load and sputum inflammatory markers were measured on day 0, day 5 and at the end of treatment. Shotgun proteomic analysis was performed on sputum using liquid chromatography-mass spectrometry. Many sputum proteins were differentially enriched between infrequent and frequent exacerbators (day 0 n=23 and day 5 n=31). The majority of these proteins had a higher abundance in infrequent exacerbators and were secreted innate host defence proteins with antimicrobial, antiprotease and immunomodulatory functions. Several differentially enriched proteins were validated using ELISA and Western blot including secretory leukocyte protease inhibitor (SLPI), lipocalin-1 and cystatin SA. Sputum from frequent exacerbators demonstrated potent ability to cleave exogenous recombinant SLPI in a neutrophil elastase dependent manner. Frequent exacerbators had increased sputum inflammatory markers (interleukin (IL)-1β and IL-8) and total bacterial load compared to infrequent exacerbators. A diminished innate host protein defence may play a role in the pathophysiological mechanisms of frequent CF pulmonary exacerbations. Frequent exacerbators may benefit from therapies targeting this dysregulated host immune response.

Adjunctive Systemic Corticosteroids for Pulmonary Exacerbations of Cystic Fibrosis.

Rationale: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization, and diminished survival in people with cystic fibrosis (PWCF) and are characterized by excess inflammation. Corticosteroids are potent, widely available antiinflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials in PWCF are limited. Objectives: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. Methods: We performed a secondary analysis of Standardized Treatment of Pulmonary Exacerbations 2 (STOP2), a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score matching for covariates including age, sex, baseline forced expiratory volume in 1 second (FEV1), genotype, and randomization arm. The primary outcome measure was the change in percentage predicted FEV1 (ppFEV1). Symptoms, time to next PEx, and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. Results: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Cotreatment with corticosteroids was independent of treatment arm allocation and did not result in greater mean ppFEV1 response, longer median time to next PEx, or more substantial symptomatic improvement compared with propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs-but not the number of corticosteroid-related or PEx-related SAEs-was higher among patients receiving corticosteroids. Conclusions: Empiric, physician-directed treatment with systemic corticosteroids, although common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Improved recognition of lung function decline as signal of cystic fibrosis pulmonary exacerbation: a Cystic Fibrosis Learning Network Innovation Laboratory quality improvement initiative

IntroductionCystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk...

Safety of non-cuffed tunneled central venous catheters in adults with cystic fibrosis

BackgroundPeripherally inserted central catheters (PICCs) are the most common route of intravenous (I.V.) access for treatment of cystic fibrosis (CF) pulmonary exacerbations, but repeated PICC placement can result in upper extremity peripheral venous stenosis. Once peripheral stenosis develops, a non-cuffed tunneled central venous catheter (NcTCVC) is an alternative route for IV access. While these are regularly used at some CF centers, the safety and complication rate compared to PICCs in adults with CF has not been reported. This study aims to describe the safety of NcTCVCs in adults with CF. MethodsA retrospective cohort study was performed at a CF Foundation accredited institution including adults with CF who received NcTCVCs in interventional radiology from 7/19/2007 to 3/09/2020. Complications analyzed included catheter related deep venous thrombosis (DVT), central line associated blood stream infection (CLABSI), and catheter related central venous stenosis. Complications were considered attributable if they occurred while the catheter was in place or within 30 days of catheter removal. ResultsDuring the study duration, 386 NcTCVCs were placed in 60 unique patients (55 % female) with a mean of 6.4 catheters per patient. Majority of NcTCVCs placed were 4 French (61.4 %). Average duration of indwelling NcTCVC was 16.2 days. No patients demonstrated catheter attributable symptomatic DVT. The incidence of DVT, CLABSI, and central venous stenosis was 0 (0 %), 4 (1 %), and 1 (0.3 %), respectively. ConclusionsMany adults with CF have required insertion of numerous PICCs for the treatment of recurrent pulmonary exacerbations. In those adults that develop PICC-associated peripheral vein stenosis precluding PICC placement, these results indicate NcTCVCs are a safe alternative.

Integrating airway microbiome and blood proteomics data to identify multi-omic networks associated with response to pulmonary infection

Host response to airway infections can vary widely. Cystic fibrosis (CF) pulmonary exacerbations provide an opportunity to better understand the interplay between respiratory microbes and the host. This study aimed to investigate the observed heterogeneity in airway infection recovery by analyzing microbiome and host response (i.e., blood proteome) data collected during the onset of 33 pulmonary infection events. We used sparse multiple canonical correlation network (SmCCNet) analysis to integrate these two types of -omics data along with a clinical measure of recovery. Four microbe–protein SmCCNet subnetworks at infection onset were identified that strongly correlate with recovery. Our findings support existing knowledge regarding CF airway infections. Additionally, we discovered novel microbe–protein subnetworks that are associated with recovery and merit further investigation.

2229. Impact of Elexacaftor/tezacaftor/ivacaftor on Utilization of Antibiotics at a Single Pediatric Cystic Fibrosis Center

Abstract Background Intravenous (IV) and oral (PO) antibiotics (ABX) are standard treatments for pulmonary exacerbations (PEx) in people with cystic fibrosis (pwCF). Frequent ABX use may lead to adverse events and ABX resistance. Cystic fibrosis transmembrane conductance regulator modulator treatments have significantly reduced PEx in qualifying pwCF, but impact on ABX use is unknown. The approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019 makes these treatments accessible to the majority of pwCF. The primary objective was to examine utilization of ABX pre-and post-ETI in pwCF managed at Children’s Mercy Kansas City’s (CMKC) CF center. Methods A retrospective analysis of PO and IV ABX for CF PEx was performed at CMKC. The pre-ETI treatment period was defined as 1/1/2017-12/31/2019 and post-ETI treatment period as 1/1/2020-12/31/2022. A paired analysis including pwCF managed by CMKC during both periods was used to compare ABX courses pre- and post-ETI. Results A total of 293 pwCF and 110 pwCF received PO and IV ABX during the study period, respectively. Of these, 224 pwCF managed by CMKC during both periods were included. IV ABX were received by 25 pwCF in both periods whereas 138 pwCF did not receive IV ABX in either period. There were 43 pwCF who received IV ABX only in the pre-ETI period compared to 18 pwCF who received IV ABX only in the post-ETI period (p=0.0021) resulting in a discordance of 27.2%. PO ABX were prescribed for 119 pwCF in both periods whereas 35 pwCF did not have PO ABX prescribed in either period. There were 52 pwCF who received PO ABXs in the pre-ETI period only compared to 18 pwCF who received PO ABX in the post-ETI period only (p=0.0001) resulting in a discordance of 31.3%. The number of patients receiving ABX directed against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus significantly decreased between periods. The median duration of ABX did not significantly change for IV (9.2 days vs. 8.9 days, p=0.958) or PO (14 days vs. 14 days, p=0.384) ABX during both periods. Conclusion CMKC pwCF experienced a dramatic decline in prescribing both PO and IV ABX following approval of ETI. Future investigations are necessary to determine this trend nationwide and ascertain the overall impact from decreased ABX exposure in pwCF. Disclosures All Authors: No reported disclosures

Factors influencing treatment response of pulmonary exacerbation in children with cystic fibrosis.

Pulmonary exacerbations in cystic fibrosis (CF) significantly impact morbidity and mortality. This study aimed to assess treatment response rates and identify contributing factors towards treatment response. In this single-center, retrospective, longitudinal study spanning four years, we analyzed all pulmonary exacerbation admissions. We compared lung function at baseline, admission, end of treatment, and 6-week follow-up. Treatment response was defined as ≥95% recovery of baseline FEV<inf>1</inf>%. There were 78 children who required a total of 184 admissions. The mean duration of treatment was 14.9±2.9 days. FEV<inf>1</inf>% returned to 95% of baseline in 59% following treatment. The magnitude of the decline in lung function on admission in children who did not respond to treatment was 21.7±15.2% while the decline in children who responded to treatment was 8.3±9.4%, P<0.001. Children who experienced a decline in FEV<inf>1</inf>% greater than 40% exhibited an 80% reduced likelihood of returning to their baseline values (OR -0.8, 95% CI -0.988; -0.612). Similarly, those with FEV<inf>1</inf>% reductions in the ranges of 30-39% (OR -0.63, 95% CI -0.821; -0.439), 20-29% (OR -0.52, 95% CI -0.657; -0.383), and 10-19% (OR -0.239, 95% CI -0.33; -0.148) showed progressively lower odds of returning to baseline. Fourty-eight children required readmission within 7.7±5.4 months, children who responded to treatment had a longer time taken to readmission (8.9±6.4 months) versus children who did not respond to treatment (6.4±3.5 months), (OR: -0.20, 95% CI -0.355; -0.048). A greater decline in lung function on admission and readmission within 6 months of the initial admission predicts non-response to treatment. This highlights the importance of re-evaluating follow-up strategies following discharge.

Frequent microbiological surveillance during inpatient cystic fibrosis pulmonary exacerbations has limited clinical value

BackgroundNo evidence exists to guide the frequency of obtaining bacterial respiratory cultures during inpatient treatment of pediatric cystic fibrosis (CF) pulmonary exacerbations (PEx). At our institution, admission and weekly respiratory cultures are routinely collected to guide antimicrobial selection. This study evaluates the extent that this practice informs clinical management and the healthcare-related costs associated with routinely repeating cultures. MethodsAll children with CF with at least one hospital admission for IV antibiotics from January 2015 to December 2019 were included. Data collected included patient demographics, culture results, and antibiotic history. Respiratory cultures were numbered from the last clinic culture (`Culture 1′), culture on admission (`Culture 2′), and so on (`Cultures 3–6′). Outcomes assessed were microbiological results, frequency and timing of antibiotic change, and total microbiological laboratory costs. ResultsSeventy-eight children with 224 admissions and 695 bacterial cultures were analyzed. Repeated microbiology sampling revealed 118 new bacterial species in 82 admissions. Culture 2 was most likely to identify a new bacterial species (91/115, 79.1 %) and most likely to be followed by a change in antibiotic (33/37; 89.2 %). The total cost of all cultures was $18,264.79. Eliminating Cultures 3–6 from routine practice could represent a 51 % cost-savings ($9,362.89), without significant impact on identification of new clinically relevant isolates. ConclusionOngoing bacterial surveillance during a CF PEx beyond admission culture provides minimal information, rarely impacts clinical management, and can increase healthcare costs. An optimized approach would be to routinely obtain admission cultures and to obtain further cultures only if clinically indicated.

360 Iron deficiency is associated with shorter time to next pulmonary exacerbation in cystic fibrosis

360 Iron deficiency is associated with shorter time to next pulmonary exacerbation in cystic fibrosis

709 Randomized, double-blind, placebo-controlled trial of oral prednisone as adjunctive treatment in pulmonary exacerbations in cystic fibrosis (PIPE Study)

709 Randomized, double-blind, placebo-controlled trial of oral prednisone as adjunctive treatment in pulmonary exacerbations in cystic fibrosis (PIPE Study)