Cystic Fibrosis Pulmonary Exacerbations Research Articles

A randomized 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 (PExs) 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 second (ppFEV1) in CF PExs not responding to antibiotic therapy. This was a randomized, double-blind, placebo-controlled trial in pwCF treated with intravenous (IV) antibiotics for a PEx. At Day 7, those who had not returned to >90% baseline ppFEV1 were randomized to adjuvant prednisone 1 mg·kg-1 twice daily (max 60 mg/day) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline ppFEV1 at Day 14 of IV antibiotic therapy. 173 subjects were enrolled, with 76 randomized. 50% of subjects in the prednisone group recovered baseline FEV1 on Day 14 compared to 39% of subjects in the placebo group for a difference of 11% (95% CI -11, 34%, p=0.34). The mean (sd) change in ppFEV1 from Day 7 to Day 14 was 6.8% predicted (8.8) in the prednisone group and 4.6% (6.9) 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 (HR 0.83, 95% CI 0.45, 1.53; p=0.54). This study failed to detect a difference in ppFEV1 recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of IV antibiotic therapy for PExs.

STOP Using Corticosteroids in Cystic Fibrosis Pulmonary Exacerbations.

STOP Using Corticosteroids in Cystic Fibrosis 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)

590 Changing face of pediatric pulmonary exacerbations in cystic fibrosis

590 Changing face of pediatric pulmonary exacerbations in cystic fibrosis

104 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

104 Effect of acute systemic corticosteroids on clinical outcomes in cystic fibrosis pulmonary exacerbations

143 High-dose vitamin D treatment of cystic fibrosis pulmonary exacerbations modulates the correlation profile of plasma immune mediators

143 High-dose vitamin D treatment of cystic fibrosis pulmonary exacerbations modulates the correlation profile of plasma immune mediators

Breath of fresh insight: unraveling the evolution of our understanding of cystic fibrosis pulmonary exacerbations.

Pulmonary exacerbations are critical events with significant negative impacts in persons with cystic fibrosis, but their diagnosis and management are highly variable. Highly effective modulator therapies have greatly improved health and reduced exacerbation events, but have also reshaped how they present. This review discusses the complexities of the diagnosis and management of pulmonary exacerbations as well as the emerging work and evidence in this area. The shifting epidemiology and our understanding of risk factors for pulmonary exacerbations are discussed. As symptoms may be more subtle in the modulator context, novel technologies including studies of remote monitoring are presented. The continued relevance of pulmonary exacerbations, the heterogeneity in their management, as well as current and forthcoming clinical trials to optimize treatment approaches are detailed. In spite of the dramatic reductions in pulmonary exacerbations, airway infections persist, a proportion of persons with cystic fibrosis either on or off modulator therapies continue to experience exacerbation events, and long-term data is lacking. Innovative approaches and studies will be crucial to enable standardized and generalizable strategies to improve outcomes in persons with cystic fibrosis.

Factors associated with lung function response with oral antibiotic treatment of pulmonary exacerbations in cystic fibrosis

Pulmonary exacerbations treated with oral antibiotics (oPEx) have a significant effect on lung function decline in people with cystic fibrosis (CF). However, factors associated with lung function response with oPExs are not well defined.We performed a retrospective cohort study of pediatric and adult patients with CF followed in the Toronto CF Database. Lung function response was measured both as the change in forced expiratory volume in 1 second (FEV1) from Day 0 of antibiotic therapy to end of treatment as well as from baseline to end of treatment. Drop from baseline to Day 0 FEV1 was strongly associated with lung function response (p<0.001). Greater FEV1 improvements were associated with longer antibiotic treatment durations. Older, female patients had less improvements in FEV1 at end of treatment compared to younger, male patients.

Ceftolozane/tazobactam heteroresistance in cystic fibrosis-related Pseudomonas aeruginosa infections.

Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations. This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single P. aeruginosa colony. Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130). Ceftolozane/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.