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Numerous studies have examined the role of the microbiome and microbiome-based therapeutics in many childhood airway and lung diseases. In this narrative review, the authors first give a brief overview of the current methods used in microbiome research. The authors then review the literature linking the microbiome with (1) early-life acute respiratory infections due to respiratory syncytial virus, (2) childhood asthma onset, (3) cystic fibrosis, and (4) bronchopulmonary dysplasia, focusing on recent studies that have used culture-independent methods to characterize the respiratory or gut microbiome in the pediatric population., Competing Interests: Disclosure Dr E.T. Zemanick reports grants and personal consulting fees from the Cystic Fibrosis Foundation, Unites States and Vertex Pharmaceuticals, Unites States. Dr C. Rosas-Salazar reports grants from the NIH, Unites States/NHLBI, Unites States, NIH/OD, and NIH/NHLBI, as well as an ongoing consultant service from Amgen, Unites States and AstraZeneca, United Kingdom., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research. Here, we describe the current use of remote endpoints in CF clinical research, address key unanswered questions regarding their use and feasibility, and discuss the next steps to determine clinical trial readiness., Competing Interests: Declaration of competing interest Related to this work, MEJ reports employment by the Cystic Fibrosis Foundation (CFF). Unrelated to this work the authors report the following: DB reports consulting fees and stocks from Anagram Therapeutics Scientific Advisory Group and is a member of the Board of Directors for Anagram Therapeutics Scientific Advisory Group. CE reports honoraria for teaching presentations from Vertex and Chiesi. CHG reports grant funding from NIH NIDDK and NCRR, CFF, FDA Orphan Prod. Div. He received consulting fees from Enterprise Therapeutics and honoraria from Gilead and Vertex. He has received travel support from Vertex Pharmaceuticals and Enterprise Therapeutics. He participates on the DSMB for Novartis. He is a deputy editor for Annals of the ATS. He has stock in Air Therapeutics. GH reports grant funding from NIH NHLBI and CFF and support from CFCanada for travel. JEH reports grant funding from CFF and NIH, travel support from CF Canada, consulting fees from Vertex Pharmaceuticals and participation on an advisory board for Vertex Pharmaceuticals. DP reports grant funding from the CFF and consulting fees from Renexion Pharma. MSP reports grant funding from Dexcom Inc, CFF and Vertex Pharmaceuticals. She also reports consulting fees from Anagram Therapeutics and honoraria from Vertex Pharmaceuticals and TD Cowan. She is a member of the CFF DSMB and an associate editor for Endocrine Practice: Journal of the American Association of Clinical Endocrinologists. KAR reports grant funding from the CFF. MS reports grant funding from the CFF and Anagram Therapeutics. She has received consulting fees from Nestle International and Alcresta Therapeutics. She has received travel support from the CFF and serves on the CFF DSMB and reports a leadership role in the CFF. JS reports being a member of the CFF DSMB and advisory boards. ST reports honoraria from Vertex Pharmaceuticals. ETZ reports grant funding from CFF, NIH NHLBI, Vertex Pharmaceuticals. She has received consulting fees from CFF and Vertex Phamaceuticals and honoraria from the CFF and Asosciation for Diagnostic and Laboratory Medicine. She has received travel support from Vertex Pharmaceuticals, CFF and European Cystic Fibrosis Society. She has participated on advisory boards for CFF, CFF Therapeutics Development Network and Vertex Pharmaceuticals. MB, NL, KP and MR have no conflicts to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator., Methods: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies., Results: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %)., Conclusions: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Rationale: Despite the high prevalence and clear morbidity of cystic fibrosis (CF) pulmonary exacerbations (PEx), there have been no published clinical trials of outpatient exacerbation management. Objectives: To assess the feasibility of a pediatric clinical trial in which treatment of mild PEx is assigned randomly to immediate oral antibiotics or tailored therapy (increased airway clearance alone with oral antibiotics added only for prespecified criteria). The outcome on which sample size was based was the proportion of tailored therapy participants who avoided oral antibiotics during the 28 days after randomization. Methods: In this randomized, open-label, pilot feasibility study at 10 U.S. sites, children 6-18 years of age with CF were enrolled at their well baseline visits and followed through their first randomized PEx. Results: One hundred twenty-one participants were enrolled, of whom 94 (78%) reported symptoms of PEx at least once; of these, 81 (86%) had at least one exacerbation that met randomization criteria, of whom 63 (78%) were randomized. Feasibility goals were met, including enrollment, early detection of symptoms of PEx, and ability to randomize. Among the 33 participants assigned to tailored therapy, 10 (30%) received oral antibiotics, while 29 of 30 (97%) assigned to immediate antibiotics received oral antibiotics. The avoidance of oral antibiotics in 70% (95% confidence interval, 54-85%) was statistically significantly different from our null hypothesis that <10% of participants assigned to the tailored therapy arm would avoid antibiotics. Conclusions: Our pilot study demonstrates that conducting a randomized trial of oral antibiotic treatment strategies for mild PEx in children with CF is feasible and that assignment to a tailored therapy arm may reduce antibiotic exposure. Clinical trial registered with www.clinicaltrials.gov (NCT04608019).

Background: Olfactory dysfunction (OD) is prevalent in people with cystic fibrosis (PwCF) and can negatively impact quality-of-life (QOL). This study evaluated perceptions of OD, investigated how OD impacts QOL, and assessed willingness to participate in OD research among the CF community., Methods: A 21-question survey was distributed through the CF Foundation's Community Voice program in 2023. The survey included questions on olfaction and interest in research. The Brief Questionnaire of Olfactory Disorders (BQOD), a validated person-reported outcome measure to assess QOL, was included., Results: Seventy-six responses were received. Overall, 91% (69/76) reported olfactory problems. Mean BQOD score was 5.0 (standard deviation=4.8), indicating olfactory QOL impairment was present. Ninety-five percent (72/76) reported research on OD is worthwhile and were willing to participate in research., Conclusion: Among PwCF, OD and olfactory-specific QOL impairments are prevalent. There is strong interest and willingness to participate in OD research among the CF community., Competing Interests: Declaration of Competing Interest JEM: none. CML: NIDCD grant related to this work. ETZ: In the last 36 months, she has received grants to her institution from the Cystic Fibrosis Foundation, National Institutes of Health, and Vertex Pharmaceuticals Incorporated; has received fees from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals Incorporated related to consultation, participation on advisory boards, and grant review committees. She served as chair of the CFF Therapeutics Development Network steering committee, reviewed grants for CF Canada, and received travel support from the European CF Society Clinical Trials Network for speaking at their annual meeting. JMW: In the last 36 months, he has received grants to her institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated; has received fees from Polarean LLC related to consultation on clinical and translational research. CHG: In the last 36 months, he has received grants from the National Institutes of Health, the Cystic Fibrosis Foundation, the Federal Drug Administration; has received fees from Enterprise Therapeutics for providing clinical trial design advice. He received honoraria from Gilead Sciences to serve as grant review committee chair and from Vertex Pharmaceuticals for speaking at the UK LEAD conference. He served as a DSMB Chair for a trial supported by Novartis and the European Commission. He serves as the Deputy Editor of the Annals of the American Thoracic Society. He has stock in Air Therapeutics. JLTC: In the last 36 months, she has received grants to her institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated, Eloxx, and 4DMT; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design, participation on advisory boards, and speaking engagements; and has served on advisory boards and/or provided clinical trial design consultation for Insmed, 4DMT, and AbbVie. She served on a DMC for AbbVie. She serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group, and as Co-Chair of the Heath Equity Team Science Awards study section. She also serves on the scientific advisory board for Emily's Entourage, and on the ATS Respiratory Health Awards Working Group and as Chair-Elect of the International Conference Committee. She is an Associate Editor for the Journal of Cystic Fibrosis and a member of the International Advisory Board for the Lancet Respiratory Medicine Journal. She serves on the Clinical Trials Review (CTLR) Study section for the National Institutes of Health/National Heart. Blood, Lung Institute. DMB: In the last 36 months, DMB has received grant support from CF Foundation related to this work as well as unrelated to this work. Unrelated to this work, DMB has received grant support from the International Society of Inflammation and Allergy of the Nose and the Sue Ann and John L. Weinberg Foundation, honoraria, and consulting fees on medicolegal cases and at Garner Health (equity)., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Tobramycin inhalation solution (TIS) and chronic azithromycin (AZ) have known clinical benefits for children with CF, likely due to antimicrobial and anti-inflammatory activity. The effects of chronic AZ in combination with TIS on the airway microbiome have not been extensively investigated. Oropharyngeal swab samples were collected in the OPTIMIZE multicenter, randomized, placebo-controlled trial examining the addition of AZ to TIS in 198 children with CF and early P. aeruginosa infection. Bacterial small subunit rRNA gene community profiles were determined. The effects of TIS and AZ were assessed on oropharyngeal microbial diversity and composition to uncover whether effects on the bacterial community may be a mechanism of action related to the observed changes in clinical outcomes., Results: Substantial changes in bacterial communities (total bacterial load, diversity and relative abundance of specific taxa) were observed by week 3 of TIS treatment for both the AZ and placebo groups. On average, these shifts were due to changes in non-traditional CF taxa that were not sustained at the later study visits (weeks 13 and 26). Bacterial community measures did not differ between the AZ and placebo groups., Conclusions: This study provides further evidence that the mechanism for AZ's effect on clinical outcomes is not due solely to action on airway microbial composition., (© 2023. The Author(s).)

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics., Competing Interests: Declaration of interests NM-H reports grants from the Cystic Fibrosis Foundation (CFF), the National Institutes of Health (NIH; P30 DK 089507 and UL1 TR002319), and the Food and Drug Administration (FDA); consulting fees from Enterprise Therapeutics; and data safety monitoring board (DSMB) membership for the NIH. JPC is an employee of CFF. RJ reports grants from CFF; consulting fees from Boehringer Ingelheim and Recode Therapeutics; honoraria from Vertex Pharmaceuticals; and travel support from CFF. SHD reports contracts from Calithera, CFF, NIH (P30 DK065988), Vertex Pharmaceuticals, 4D Molecular Therapeutics, and Chiesi USA; consulting fees from Polarean, 501 Ventures, Enterprise Therapeutics, and Boehringer Ingelheim; fees for participation on advisory boards for Innova Healthcare and Boehringer Ingleheim; travel fees from Enterprise Therapeutics and CFF; and participation on a board for Abbvie. IF reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, and Vertex Pharmaceuticals; honoraria from Vertex Pharmaceuticals; board participation for AbbVie, Boehringer Ingelheim, Kither Biotech, and Vertex Pharmaceuticals; and support to her institution from the European Cystic Fibrosis Society (ECFS). CHG reports grants and contracts from CFF, NIH (P30 DK 089507 and UL1 TR000423), and FDA; consulting fees from Enterprise Therapeutics; honoraria from Gilead Sciences and Vertex Pharmaceuticals; travel support from Vertex Pharmaceuticals and Enterprise Therapeutics; participation on the board for Novartis; stock options for Air Therapeutics; and leadership roles for the American Thoracic Society (ATS). DP reports grants from CFF (002805121), NIH, and Aclaris Pharmaceuticals; travel support from CFF; and board participation for Vertex Pharmaceuticals and Translate Bio. FR reports grants from Vertex Pharmaceuticals and consulting fees from Vertex Pharmaceuticals and Calithera. BSQ reports grants from CFF, Cystic Fibrosis Canada, Vertex Pharmaceuticals, and Gilead Sciences; honoraria from Vertex Pharmaceuticals; and travel support from CFF. ETZ reports grants from NIH, Vertex Pharmaceuticals, and CFF (002884121); consulting fees from CFF; travel support from CFF, Vertex Pharmaceuticals, and ECFS; and participation on boards for CFF and Vertex Pharmaceuticals. SCB reports grants from the National Health and Medical Research Council Australia (APP1102494), the Medical Research Futures Fund Australia, and CFF (BELL1480 and BELL19A0); and honoraria from Vertex Pharmaceuticals. JCD reports grants from the UK Cystic Fibrosis Trust (as part of their Clinical Trials Accelerator Platform), CFF, Cystic Fibrosis Ireland, the Engineering and Physical Sciences Research Council, and the National Institute for Health and Care Research; and honoraria from Vertex Pharmaceuticals, Boehringer Ingelheim, Eloxx, Algipharma, Abbvie, Arcturus, Enterprise Therapeutics, Recode, LifeArc, Genentech, and Tavanta. JCD serves as Deputy Editor for the Journal of Cystic Fibrosis. MWK reports grants from NIH (P01HL128192 and UL1TR002548) and CFF; consulting fees from AbbVie, AzurRx, Cystetic Medicines, EnBiotix, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Mylan, and PBM BC Holdings; board participation for AbbVie, CFF, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Sionna, and Vertex; and committee membership for CFF. MAM reports grants from the German Research Foundation (CRC 1449 project #431232613), the German Ministry for Education and Research (82DZL009B1), the German Innovation Fund, and Vertex Pharmaceuticals; consulting fees from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense, and Vertex Pharmaceuticals; honoraria from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals; and participation on boards for Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari, and Vertex Pharmaceuticals. EM reports grants from Vertex Pharmaceuticals; honoraria from Vertex Phamaceuticals; travel support from Menarini; and board participation for the Cystic Fibrosis Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. JHR reports grants from Cystic Fibrosis Canada, CFF, Vertex Phamaceuticals, the Canada Foundation for Innovation, and the Canadian Institutes of Health Research; consulting fees from Sanofi; and travel support from Vertex Pharmaceuticals. SMR reports grant funding from CFF (P30DK072482), NIH (UL1TR003096), Vertex Pharmaceuticals, Galapagos/Abbvie, Eloxx, Synspira, Translate Bio, Arcturus, Astra-Zenica, and Ionis; and consulting fees from Vertex Pharmaceuticals, Synspira (including stock options), Renovion (including stock options), Cystetic Medicines, and Arcturus. SMR's potential competing interests were resolved or ended in 2022 or earlier. JLT-C reports grants and contracts from CFF, Vertex Pharmaceutics, Eloxx, and 4DMT; consulting fees from Vertex Phamaceuticals, Insmed, and 4DMT; participation on a DSMB for Abbvie; and participation on advisory boards for CFF, ATS, Journal of Cystic Fibrosis, The Lancet Respiratory Medicine, and Emily's Entourage. GR-B reports grants and contracts from Vertex Pharmaceuticals and CFF. DGD reports grants from Chiesi Farmaceutici and CFF; consulting fees from Vertex and Insmed; honoraria from Chiesi and Gilead; travel support from ECFS and CFF; board participation for Momab and CSL Behring; and support from ECFS as director of the Clinical Trials Network. MJ, NRK, TL, KP, JMP, and LQ declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Peripherally inserted central catheters (PICCs) are used commonly to administer antibiotics to people with cystic fibrosis (CF), but their use can be complicated by venous thrombosis and catheter occlusion., Research Question: Which participant-, catheter-, and catheter management-level attributes are associated with increased risk of complications of PICCs among people with CF?, Study Design and Methods: This was a prospective observational study of adults and children with CF who received PICCs at 10 CF care centers in the United States. The primary end point was defined as occlusion of the catheter resulting in unplanned removal, symptomatic venous thrombosis in the extremity containing the catheter, or both. Three categories of composite secondary outcomes were identified: difficult line placement, local soft tissue or skin reactions, and catheter malfunction. Data specific to the participant, catheter placement, and catheter management were collected in a centralized database. Risk factors for primary and secondary outcomes were analyzed by multivariate logistic regression., Results: Between June 2018 and July 2021, 157 adults and 103 children older than 6 years with CF had 375 PICCs placed. Patients underwent 4,828 catheter-days of observation. Of the 375 PICCs, 334 (89%) were ≤ 4.5 F, 342 (91%) were single lumen, and 366 (98%) were placed using ultrasound guidance. The primary outcome occurred in 15 PICCs for an event rate of 3.11 per 1,000 catheter-days. No cases of catheter-related bloodstream infection occurred. Other secondary outcomes developed in 147 of 375 catheters (39%). Despite evidence of practice variation, no risk factors for the primary outcome and few risk factors for secondary outcomes were identified., Interpretation: This study affirmed the safety of contemporary approaches to inserting and using PICCs in people with CF. Given the low rate of complications in this study, observations may reflect a widespread shift to selecting smaller-diameter PICCs and using ultrasound to guide their placement., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Aspergillus fumigatus (Af) is a mold frequently detected in airway samples from people with cystic fibrosis (pwCF). Abnormal airway mucus may allow Af to germinate, resulting in airway infection or an allergic response. While Af is known to increase morbidity in pwCF, individual responses and the degree of impact on lung disease vary. Improved approaches to diagnosis, treatment, and prevention of Af, particularly the persistent Af infection, are needed. This update highlights our current understanding of Af pathophysiology in the CF airway, the effects of Af on pwCF, and areas of research needed to improve clinical outcomes.

Objective: To assess the feasibility of enrolling people with CF (pwCF) taking the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) in clinical trials of a new modulator., Methods: PwCF receiving ETI at CHEC-SC study (NCT03350828) enrollment were surveyed for interest in 2-week to 6-month placebo- (PC) and active-comparator (AC) modulator studies. Those taking inhaled antimicrobials (inhABX) were surveyed for interest in PC inhABX studies., Results: Of 1791 respondents, 75% [95% CI 73, 77] would enroll in a 2-week PC modulator study versus 51% [49, 54] for a 6-month study; 82% [81, 84] and 63% [61, 65] would enroll in 2-week and 6 month AC studies; 77% [74, 80] of 551 taking inhABX would enroll in a 2-week PC inhABX study versus 59% [55, 63] for a 6-month study. Previous clinical trial experience increased willingness., Conclusions: Study designs will affect feasibility of future clinical trials of new modulators and inhABX in people receiving ETI., Competing Interests: Declaration of Competing Interest The authors have no competing or conflicting interests to report., (Copyright © 2023. Published by Elsevier B.V.)

Background: Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables., Methods: Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis., Results: 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year., Conclusions: Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life., Competing Interests: Declaration of Competing Interest Dr. Harris reports grants from the Cystic Fibrosis Foundation during the conduct of the study Dr. Wagner has nothing to disclose Dr. Robertson has nothing to disclose Dr. Lingard has nothing to disclose Dr. Borowitz has nothing to disclose Dr. Leung reports other from Merck, grants and other from Gilead, grants from Abbvie, grants from CF Foundation, outside the submitted work Dr. Heltshe has nothing to disclose Dr. Ramsey has nothing to disclose Dr. Zemanick reports grants from Cystic Fibrosis Foundation, NIH/NCATS, NIH/NHLBI, Savara and Calithera Biosciences during the conduct of the study, grants and fees from Vertex Pharmaceuticals, Cystic Fibrosis Foundation outside the submitted work, (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Cystic fibrosis is a life-limiting, autosomal recessive genetic disorder resulting in multi-organ disease due to CF transmembrane conductance regulator ( CFTR ) protein dysfunction. CF treatment previously focused on mitigation of disease signs and symptoms. The recent introduction of highly effective CFTR modulators, for which ~90% of people with CF are CFTR variant-eligible, has resulted in substantial health improvements., Areas Covered: In this review, we will describe the clinical trials leading to approval of the highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor (ETI), with a focus on the safety and efficacy of this treatment in children aged 6-11 years., Expert Opinion: The use of ETI in variant-eligible children aged 6-11 is associated with marked clinical improvements with a favorable safety profile. We anticipate that introduction of ETI in early childhood may result in the prevention of pulmonary, gastrointestinal, and endocrine complications from CF, consequently leading to previously unimaginable gains in the quality and quantity of life. However, there is an urgent need to develop effective treatments for the remaining 10% of people with CF who are not eligible or unable to tolerate ETI treatment, and to increase access of ETI to more pwCF across the world.

Persons with cystic fibrosis (PwCF) suffer from pulmonary exacerbations (PEx) related in part to lung infection. While higher microbial diversity is associated with higher lung function, the data on the impact of short-term antibiotics on changes in microbial diversity is conflicting. Further, Prevotella secretes beta-lactamases, which may influence recovery of lung function. We hypothesize that sub-therapeutic and broad spectrum antibiotic exposure leads to decreasing microbial diversity. Our secondary aim was to evaluate the concerted association of beta-lactam pharmacokinetics (PK), antibiotic spectrum, microbial diversity, and antibiotic resistance on lung function recovery using a pathway analysis. This was a retrospective observational study of persons with CF treated with IV antibiotics for PEx between 2016 and 2020 at Children's National Hospital; respiratory samples and clinical information were collected at hospital admission for PEx (E), end of antibiotic treatment (T), and follow-up (F). Metagenomic sequencing was performed; PathoScope 2.0 and AmrPlusPlus were used for taxonomic assignment of sequences to bacteria and antibiotic resistance genes (ARGs). M/W Pharm was used for PK modeling. Comparison of categorical and continuous variables and pathway analysis were performed in STATA. Twenty-two PwCF experienced 43 PEx. The study cohort had a mean age of 14.6 years. Only 12/43 beta-lactam courses had therapeutic PK, and 18/43 were broad spectrum. A larger decrease in richness between E and T was seen in the therapeutic PK group (sufficient - 20.1 vs. insufficient - 1.59, p = 0.025) and those receiving broad spectrum antibiotics (broad - 14.5 vs. narrow - 2.8, p = 0.030). We did not detect differences in the increase in percent predicted forced expiratory volume in one second (ppFEV1) at end of treatment compared to PEx based on beta-lactam PK (sufficient 13.6% vs. insufficient 15.1%) or antibiotic spectrum (broad 11.5% vs. narrow 16.6%). While both therapeutic beta-lactam PK and broad-spectrum antibiotics decreased richness between PEx and the end of treatment, we did not detect longstanding changes in alpha diversity or an association with superior recovery of lung function compared with subtherapeutic PK and narrow spectrum antimicrobials., (© 2023. The Author(s).)

Introduction: Pulmonary exacerbations (PEx) in persons with cystic fibrosis (CF) are primarily related to acute or chronic inflammation associated with bacterial lung infections, which may be caused by several bacteria that activate similar bacterial genes and produce similar by-products. The goal of our study was to perform a stratified functional analysis of bacterial genes at three distinct time points in the treatment of a PEx in order to determine the role that specific airway microbiome community members may play within each clinical state (i.e., PEx, end of antibiotic treatment, and follow-up). Our secondary goal was to compare the change between clinical states with the metabolic activity of specific airway microbiome community members., Methods: This was a prospective observational study of persons with CF treated with intravenous antibiotics for PEx between 2016 and 2020 at Children's National Hospital. Demographic and clinical information as well as respiratory samples were collected at hospital admission for PEx, end of antibiotic treatment, and follow-up. Metagenomic sequencing was performed; MetaPhlAn3 and HUMANn3 were used to assign sequences to bacterial species and bacterial metabolic genes, respectively., Results: Twenty-two persons with CF, with a mean age of 14.5 (range 7-23) years, experienced 45 PEx during the study period. Two-hundred twenty-one bacterial species were identified in the respiratory samples from the study cohort. Ten bacterial species had differential gene abundance across changes in the clinical state including Staphylococcus aureus , Streptococcus salivarius , and Veillonella atypica (all padj < 0.01 and log2FoldChange > |2|). These corresponded to a differential abundance of bacterial genes, with S. aureus accounting for 81% of the genes more abundant in PEx and S. salivarius accounting for 83% of the genes more abundant in follow-up, all compared to the end of treatment. Lastly, 8,653 metabolic pathways were identified across samples, with again S. aureus and S. salivarius contributing to the differential abundance of pathways (106 in PEx vs. 66 in follow-up, respectively). V. atypica was associated with a single metabolic pathway (UDP- N -acetyl-D-glucosamine biosynthesis) increased in follow-up compared to PEx., Discussion: Taken together, these data suggest that the metabolic potential of bacterial species can provide more insight into changes across clinical states than the relative abundance of the bacteria alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shumyatsky, Burrell, Chaney, Sami, Koumbourlis, Freishtat, Crandall, Zemanick and Hahn.)

Background: Cystic fibrosis (CF) is characterized by recurrent pulmonary exacerbations (PEx) and lung function decline. PEx are frequently treated with antibiotics. However, little is known about the effects of antibiotics on the airway microbiome of persons with CF over time. The purpose of this study was to evaluate changes in the microbiome and lung function in persons with CF over 1 year following an initial study pulmonary exacerbation (iPEx)., Methods: Twenty children aged ≤18 years with CF were enrolled in the study, which occurred prior to the routine administration of highly effective modulator therapy. Respiratory samples and spirometry were obtained at a minimum of quarterly visits and up to 1 year after an iPEx. Metagenomic sequencing was performed, and bacterial taxa were assigned using MetaPhlAn 2.0. Paired t test, analysis of variance, and generalized least squares regression were used to compare outcome variables., Results: The mean age of study participants at the time of the iPEx was 10.6 years. There were 3 ± 1.6 PEx treated with antibiotics per person during the study period. Bacterial richness was similar at 1 year compared to iPEx (40.3 vs 39.3, P  = .852), whereas the mean Shannon diversity index was significantly higher at 1 year (2.84 vs 1.62, P  < .001). The number of PEx treated with antibiotics was not associated with changes in microbial diversity but was associated with changes in lung function., Conclusions: In our 1-year prospective study, we found that microbial diversity increased despite decreases in lung function associated with repeated PEx events requiring antibiotic therapy., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Cystic fibrosis and other chronic lung disease clinical trials often use time to first pulmonary exacerbation (PEx) or total PEx count as endpoints. The use of these outcomes may fail to capture patterns or timing of multiple exacerbations and how covariates influence the risk of future exacerbations. Analysis of gap times between PEx provides a useful framework to understand risks of subsequent events, particularly to assess if there is a temporary increase in a hazard of a subsequent PEx following the occurrence of a PEx. This may be useful for estimating the amount of time needed to follow patients after a PEx and predicting which patients are more likely to have multiple PEx. We propose a smoothed hazard for gap times to account for elevated hazards after exacerbations. A simulation study was conducted to explore model performance and was able to appropriately estimate parameters in all situations with an underlying change point with independent or correlated recurrent events. Models with different change-point structures and trends are compared using Early Pseudomonas Infection Control (EPIC) observational study data, using a quasi-likelihood modification of the Akaike information criterion; a model with a change-point provided a better fit than a model without one. The analysis suggests that the change point may be 1.8 years (SE 0.09) after the end of a PEx. Models including covariates in the hazard function revealed that having one or two copies of the Δ $\Delta$ F508 mutation, female sex, and higher numbers of previous PEx were significantly associated with increased risk of another PEx., (© 2022 Wiley-VCH GmbH.)

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to dysfunction of the CFTR protein. CFTR dysfunction leads to disease in the respiratory and gastrointestinal systems. Disorders of the cardiovascular system in individuals with CF are usually attributed to secondary effects from progressive lung disease. However, CFTR has been localized to vascular endothelium and smooth muscle, suggesting that CFTR dysfunction may directly impact cardiovascular function. As treatments for CF improve and life-expectancy increases, the risk of vascular disease may increase in prevalence related to primary and secondary CFTR dysfunction, chronic systemic inflammation, nutritional health and hyperglycemia in individuals with CF related diabetes. Here we review the available literature on CF and the cardiovascular system, examining the secondary effects and evidence for direct CFTR dysfunction in the heart, aorta, pulmonary vessels, and vasculature, as well as future directions and treatment options., Competing Interests: Declaration of Competing Interest Dr. Taylor–Cousar reports grants and personal fees from Gilead, grants from N30, grants and personal fees from Vertex, grants and personal fees from Proteostasis, grants from Bayer, personal fees from Novartis, personal fees from Genentech, personal fees from Protalix, personal fees from Santhera, personal fees from 4DMT, personal fees from Polarean Imaging, personal fees from Insmed, personal fees from Abbvie, grants and personal fees from Celtaxys outside the submitted work; and Service on the CF TDN Clinical Research Executive Committee, Clinical Research Advisory Board, and as Chair of the Women's Health Research Working Group as well as service as the Chair of the ATS Clinical Problems Assembly Program Committee. Dr. Zemanick reports personal fees from Cystic Fibrosis Foundation, site clinical trial support from Vertex Pharmaceuticals and Savara Pharmaceuticals Inc., and material agreements and consulting contracts with Calithera Biosciences and Concert Pharmaceuticals outside the scope of the submitted work., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Individuals with cystic fibrosis (CF) and fungal airway infection may present with fungal bronchitis, allergic bronchopulmonary aspergillosis (ABPA) or may appear unaffected despite fungal detection. We sought to characterize people with CF with frequent detection of fungi from airway samples and determine clinical outcomes., Methods: This retrospective study included individuals with CF with ≥4 lower airway cultures over a 2-year baseline period and ≥2 years of follow-up. We defined two groups: ≤1 positive fungus culture (rare) or ≥2 positive cultures during baseline (frequent). Clinical characteristics and outcomes were determined., Results: Between 2004 and 2016, 294 individuals met inclusion with 62% classified as rare and 38% as frequent fungi during baseline. Median follow-up was 6 years (range: 2-9 years). Aspergillus fumigatus was the most common fungal species detected. Individuals with frequent fungi were older (13.7 vs. 11.7 years, p = .02) and more likely to have Stenotrophomonas maltophilia (35% vs. 17%, p < .001) at baseline, but did not differ in lung function or ABPA diagnosis. During follow-up, those with frequent fungi were more likely to have chronic Pseudomonas aeruginosa and S. maltophilia. Individuals with ABPA and frequent fungi had the highest rates of co-infection and co-morbidities, and a trend towards more rapid lung function decline., Discussion: Fungal infection in CF was associated with frequent P. aeruginosa and S. maltophilia co-infection even in those without ABPA. Individuals with frequent fungi and ABPA had worse outcomes, highlighting the potential contribution of fungi to CF pulmonary disease., (© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies. Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (<18 years) microbiota in acute and chronic respiratory conditions, with >10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses. Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus . Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively. Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis., Competing Interests: MPi reports personal fees from Mérieux Université, grants from Abacus Diagnostica, outside the submitted work. AM reports grants and personal fees from Janssen, personal fees from Merck, personal fees from Sanofi-Pasteur, personal fees from Roche, outside the submitted work. EZ reports grants and personal fees from Cystic Fibrosis Foundation, outside the submitted work. OS is an employee of Nestlé Research – Societé des Produits Nestlé S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Broderick, Waite, Marsh, Camargo, Cardenas, Chang, Cookson, Cuthbertson, Dai, Everard, Gervaix, Harris, Hasegawa, Hoffman, Hong, Josset, Kelly, Kim, Kong, Li, Mansbach, Mejias, O’Toole, Paalanen, Pérez-Losada, Pettigrew, Pichon, Ramilo, Ruokolainen, Sakwinska, Seed, van der Gast, Wagner, Yi, Zemanick, Zheng, Pillarisetti and Taylor.)

Background: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design., Methods: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride., Results: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement., Conclusions: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators., Competing Interests: Declaration of Competing Interest ETZ, NMH, DRV, SMR, MWK: grants or consulting CFF; DRV consults for aMoon, Arrevus, Eloxx, Enbiotix, Felix, Ionis, Matinas, Merck, Polyphor, Respirion, Savara; SMR consults for Vertex; MWK consults for Anthera, AzurRx, Celtaxsys, Chiesi, Ionis, Kala, Laurent, Merck, Paranta, pH Pharma, Santhera, Vertex; JPC, KOD and MS: none., (Copyright © 2021. Published by Elsevier B.V.)

Background: The role of anaerobic organisms in the cystic fibrosis (CF) lung microbiome is unclear. Our objectives were to investigate the effect of broad (BS) versus narrow (NS) spectrum antianaerobic antibiotic activity on lung microbiome diversity and pulmonary function, hypothesizing that BS antibiotics would cause greater change in microbiome diversity without a significant improvement in lung function., Methods: Pulmonary function tests and respiratory samples were collected prospectively in persons with CF before and after treatment for pulmonary exacerbations. Treatment antibiotics were classified as BS or NS. Gene sequencing data from 16S rRNA were used for diversity analysis and bacterial genera classification. We compared the effects of BS versus NS on diversity indices, lung function and anaerobic/aerobic ratios. Statistical significance was determined by multilevel mixed-effects generalized linear models and mixed-effects regression models., Results: Twenty patients, 6-20 years of age, experienced 30 exacerbations. BS therapy had a greater effect on beta diversity than NS therapy when comparing time points before antibiotics to after and at recovery. After antibiotics, the NS therapy group had a greater return toward baseline forced expiratory volume at 1 second and forced expiratory flow 25%-75% values than the BS group. The ratio of anaerobic/aerobic organisms showed a predominance of anaerobes in the NS group with aerobes dominating in the BS group., Conclusions: BS antianaerobic therapy had a greater and possibly longer lasting effect on the lung microbiome of persons with CF, without achieving the recovery of pulmonary function seen with the NS therapy. Specific antibiotic therapies may affect disease progression by changing the airway microbiome., Competing Interests: A.H. and the data in this study were funded by the National Heart, Lung and Blood Institute award number K12HL119994; partially supported by the National Center for Advancing Translational Sciences, award number UL1TR000075. A.H. is also supported by a Harry Shwachman Award through the Cystic Fibrosis Foundation. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cystic fibrosis (CF) is a chronic lung disease characterized by acute pulmonary exacerbations (PExs) that are frequently treated with antibiotics. The impact of antibiotics on airway microbial diversity remains a critical knowledge gap. We sought to define the association between beta-lactam pharmacokinetic (PK) and pharmacodynamic target attainment on richness and alpha diversity. Twenty-seven children <18 years of age with CF participated in the prospective study. Airway samples were collected at hospital admission for PEx, end of antibiotic treatment (Tr), and >1 month in follow-up (FU). Metagenomic sequencing was performed to determine richness, alpha diversity, and the presence of antibiotic resistance genes. Free plasma beta-lactam levels were measured, and PK modeling was performed to determine time above the minimum inhibitory concentration ( f T>MIC). 52% of study subjects had sufficient f T>MIC for optimal bacterial killing. There were no significant differences in demographics or PEx characteristics, except for F508del homozygosity. No significant differences were noted in richness or alpha diversity at individual time points, and both groups experienced a decrease in richness and alpha diversity at Tr compared with PEx. However, alpha diversity remained decreased at FU compared with PEx in those with sufficient f T>MIC but increased in those with insufficient f T>MIC (Shannon -0.222 vs +0.452, p=0.031, and inverse Simpson -1.376 vs +1.388, p=0.032). Fluoroquinolone resistance was also more frequently detected in those with insufficient f T>MIC (log2 fold change (log2FC) 2.29, p=0.025). These findings suggest sufficient beta-lactam f T>MIC is associated with suppressed recovery of alpha diversity following the antibiotic exposure period., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Collection of respiratory cultures for airway microbiology surveillance is an essential component of routine clinical care in cystic fibrosis (CF). The COVID-19 global pandemic has necessitated increased use of telehealth, but one limitation of telehealth is the inability to collect respiratory specimens. We initiated a protocol for at-home collection of oropharyngeal (OP) swabs from children with CF., Methods: Home respiratory specimen collection was offered during telehealth encounters. Home OP swab kits were sent to participating families via mail with instructions for collection and return. Specimens were returned by overnight shipping or dropped off at a hospital lab for processing and culture. We evaluated demographic data and compared culture results from the home-collected specimen to the most recent specimen collected in clinic. We also tracked the frequency of newly identified Pseudomonas aeruginosa., Results: Home OP swab kits were sent to families of 33 children with CF (range 1.5-19 years). OP swab kits were successfully returned from 19 children (range 1.5-19 years). One or more CF pathogens grew from 79% of the specimens. For four individuals, the home collected specimen demonstrated the new growth of P. aeruginosa., Conclusions: Home collection of OP swabs for bacterial culture is feasible in children with CF across a range of ages. Most home-collected specimens demonstrated growth of one or more CF pathogens and results were similar to recent in-clinic specimens, suggesting acceptable sample collection technique. Anti-pseudomonal therapy was initiated for four children based on the growth of P. aeruginosa from the home respiratory specimen., (© 2021 Wiley Periodicals LLC.)

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del -minimal function or F508del - F508del genotypes. Methods: In this 24-week open-label phase 3 study, children ( N  = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV 1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index 2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z -score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).

Fungi are frequently recovered from lower airway samples from people with cystic fibrosis (CF), yet the role of fungi in the progression of lung disease is debated. Recent studies suggest worsening clinical outcomes associated with airway fungal detection, although most studies to date are retrospective or observational. The presence of fungi can elicit a T helper cell type 2 (Th-2) mediated inflammatory reaction known as allergic bronchopulmonary aspergillosis (ABPA), particularly in those with a genetic atopic predisposition. In this review, we discuss the epidemiology of fungal infections in people with CF, risk factors associated with development of fungal infections, and microbiologic approaches for isolation and identification of fungi. We review the spectrum of fungal disease presentations, clinical outcomes after isolation of fungi from airway samples, and the importance of considering airway co-infections. Finally, we discuss the association between fungi and airway inflammation highlighting gaps in knowledge and future research questions that may further elucidate the role of fungus in lung disease progression.

Background: Acid blockade is commonly prescribed in patients with cystic fibrosis (CF). Growing concerns, however, exist about its possible role in the pathophysiology of pulmonary infections. We aimed to investigate if acid blockade alters esophageal and respiratory microbiota leading to dysbiosis and inflammation., Methods: We performed a cross sectional study of children with CF who were either prescribed acid blockade or not. Samples from the gastrointestinal and respiratory tracts were obtained and microbiome analyzed. Mixed effect models were used to compare outcomes between cohorts and across sampling sites. A random subject intercept was included to account for the multiple sampling sites per individual., Results: A cohort of 25 individuals, 44% girls with median age of 13.8 years [IQR 11.2--14.8] were enrolled. Alpha diversity, total bacterial load, and beta diversity were similar across anatomic compartments, across the upper gastrointestinal tract, and in respiratory samples. Similar alpha diversity, total bacterial load, and beta diversity results were also observed when comparing individuals on versus those off acid blockade. IL-8 was elevated in the distal versus proximal esophagus in the whole cohort (P < 0.01). IL-8 concentrations were similar in the distal esophagus in patients on and off acid blockade, but significantly greater in the proximal esophagus of subjects on treatment (P < 0.01)., Conclusions: On the basis of these data, acid blockade use does not appear to influence the microbiome of the aerodigestive tract in children with cystic fibrosis suggesting a complex interplay between these medications and the bacterial composition of the esophagus and lung., Competing Interests: Conflict of interest statement: G.F. is the Chief Medical Officer-EnteroTrack, the company that produces the esophageal string test. The other authors have no other conflicts of interest to report., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Competing Interests: The authors have no conflicts of interest to disclose.

Background: Pulmonary and critical care medicine (PCCM) fellowship requires a high degree of medical knowledge and procedural competency. Gaps in fellowship readiness can result in significant trainee anxiety related to starting fellowship training., Objective: To improve fellowship readiness and alleviate anxiety for PCCM-bound trainees by improving confidence in procedural skills and cognitive domains., Methods: Medical educators within the American Thoracic Society developed a national resident boot camp (RBC) to provide an immersive, experiential training program for physicians entering PCCM fellowships. The RBC curriculum is a 2-day course designed to build procedural skills, medical knowledge, and clinical confidence through high-fidelity simulation and active learning methodology. Separate programs for adult and pediatric providers run concurrently to provide unique training objectives targeted to their learners' needs. Trainee assessments include multiple-choice pre- and post-RBC knowledge tests and confidence assessments, which are scored on a four-point Likert scale, for specific PCCM-related procedural and cognitive skills. Learners also evaluate course material and educator effectiveness, which guide modifications of future RBC programs and provide feedback for individual educators, respectively., Results: The American Thoracic Society RBC was implemented in 2014 and has grown annually to include 132 trainees and more than 100 faculty members. Mean knowledge test scores for participants in the 2019 RBC adult program increased from 55% (±14% SD) on the pretest to 72% (±11% SD; P  < 0.001) after RBC completion. Similarly, mean pretest scores for pediatric course attendees increased from 54% (±13% SD) to 62% (±19% SD; P  = 0.17). Specific content domains that improved by 10% or more between pre- and posttests included airway management, bronchoscopy, pulmonary function testing, and code management for adult course participants, and airway management, pulmonary function testing, and extracorporeal membrane oxygenation for pediatric course participants. Trainee confidence also significantly improved across all procedural and cognitive domains for adult trainees and in 10 of 11 domains for pediatric course attendees. Course content for the 2019 RBC was overwhelmingly rated as "on target" for the level of learner, with <4% of respondents indicating any specific session was "much too basic" or "much too advanced.", Conclusion: RBC participation improved PCCM-bound trainee knowledge, procedural familiarity, and confidence. Refinement of the RBC curriculum over the past 7 years has been guided by educator and course evaluations, with the ongoing goal of meeting the evolving educational needs of rising PCCM trainees., (Copyright © 2021 by the American Thoracic Society.)

Introduction: Oral antibiotics are frequently prescribed for outpatient pulmonary exacerbations (PEx) in children with cystic fibrosis (CF). This study aimed to characterize oral antibiotic use for PEx and treatment outcomes at two large US CF centers., Methods: Retrospective, descriptive study of oral antibiotic prescribing practices among children with CF ages 6-17 years over 1 year. The care setting for antibiotic initiation (clinic or phone encounter) was determined and outcomes were compared., Results: A total of 763 oral antibiotic courses were prescribed to 312 patients aged 6-17 years (77% of 403 eligible patients) with a median of two courses per year (range: 1-10). Fifty-eight percent of prescriptions were provided over the phone. Penicillin was the most commonly prescribed antibiotic class (36% of prescriptions) but differences in antibiotic class prescriptions were noted between the two centers. Hospitalizations occurred within 3 months following 19% of oral antibiotic courses. Forced expiratory volume in 1 s (FEV 1 ) recovered to within 90% of prior baseline within 6 months in 87% of encounters; the mean (SD) % recovery was 99.6% (12.1%) of baseline. Outcomes did not differ between phone and clinic prescriptions., Conclusions: Phone prescriptions, commonly excluded in studies of PEx, made up more than half of all oral antibiotic courses. Heterogeneity in prescribing patterns was observed between the two centers. Most patients had improvement in FEV 1 returning to near their prior baseline, but hospitalizations occurred in one-fifth following oral antibiotic treatment. Efforts to optimize PEx treatment must consider care that occurs over the phone; this is particularly important as the use of telemedicine increases., (© 2020 Wiley Periodicals LLC.)

In clinical environments, many serious antibiotic-resistant infections are caused by biofilm-forming species. This presents issues when attempting to determine antimicrobial dosing as traditional antibiotic susceptibility tests (ASTs) are typically designed around planktonic bacteria and thus offer information that is not relevant to the biofilm phenotype present in the patient. Even the popular Calgary biofilm device may provide inaccurate minimum biofilm inhibitory concentrations (MBICs) and can be time- and material-intensive. In this work, we present a method utilizing oxygen-sensitive nanosensor technology to monitor the oxygen consumption dynamics of living biofilms as they are exposed to antibiotics. We incorporated our nanosensors into biofilms grown from P. aeruginosa strains of varying sensitivity to traditional classes of antibiotics. Through measuring nanosensor response under antibiotic administration we determined the concentrations able to cease biofilm metabolism. This method provides information on the MBIC as well as kinetic response information in a manner that requires fewer materials and is more reflective of biofilm behavior than a traditional AST.

Background: Culture-independent next generation sequencing has identified diverse microbial communities within the cystic fibrosis (CF) airway. The study objective was to test for differences in the upper airway microbiome of children with CF and healthy controls and age-related differences in children with CF., Methods: Oropharyngeal swabs and clinical data were obtained from 25 children with CF and 50 healthy controls aged ≤6 years. Bacterial DNA was amplified and sequenced for the V4 region of 16S rRNA marker-gene. Alpha diversity was measured using operational taxonomic units (OTUs), Shannon diversity, and the inverse Simpson's index. Beta diversity was measured using Morisita-Horn and Bray-Curtis and Jaccard distances. General linear models were used for comparison of alpha diversity measures between groups to account for differences in demographics and exposures. Mixed effects general linear models were used for longitudinal comparisons 1) between children with CF of different ages and 2) between children with CF receiving CF transmembrane conductance regulator (CFTR) modulators, children with CF not receiving CFTR modulators, and healthy controls to adjust for repeated measures per subject., Results: Children with CF were more likely to have received antibiotics in the prior year than healthy controls (92% vs 24%, p < 0.001). Controlling age, race, ethnicity, length of breastfeeding, and having siblings, children with CF had a lower richness than healthy controls: OTUs 62.1 vs 83, p = 0.022; and trended toward lower diversity: Shannon 2.09 vs 2.35, p = 0.057; inverse Simpson 5.7 vs 6.92, p = 0.118. Staphylococcus , three Rothia OTUs, and two Streptococcus OTUs were more abundant in CF children versus healthy controls (all p < 0.05). Bray-Curtis and Jaccard distances, which reflect overall microbial community composition, were also significantly different (both p = 0.001). In longitudinally collected samples from children with CF, Morisita-Horn trended toward more similarity in those aged 0-2 years compared to those aged 3-6 years (p = 0.070). In children >2 years of age, there was a significant trend in increasing alpha diversity measures between children with CF not receiving CFTR modulators, children with CF receiving CFTR modulators, and healthy controls: OTUs 63.7 vs 74.7 vs 97.6, p < 0.001; Shannon 2.11 vs 2.34 vs 2.56, p < 0.001; inverse Simpson 5.78 vs 7.23 vs 7.96, p < 0.001., Conclusions: Children with CF have lower bacterial diversity and different composition of organisms compared with healthy controls. This appears to start in early childhood, is possibly related to the use of antibiotics, and may be partially corrected with the use of CFTR modulators., (© 2020 The Author(s).)

Background: Pseudomonas aeruginosa accounts for ~80% of cystic fibrosis (CF) airway infection. It shows a remarkable correlation with presence of autoantibody to bactericidal/permeability-increasing protein (BPI), which is not understood. In this study, we sought to better understand the characteristics of systemic and mucosal autoimmunity and their relation to humoral immunity to P. aeruginosa., Methods: Antibody titers and isotypes to BPI and P. aeruginosa were characterized in sera and bronchoalveolar lavage (BAL) of adult and pediatric CF patients (n = 131), by ELISA and/or immunoblot., Results: Serum BPI autoantibodies were common (~43%) in adult while rare (≪5%) in pediatric (≤18 yrs) CF patients. Serum BPI IgG autoantibodies were of high avidity and strongly correlated with anti-P. aeruginosa IgG responses. A parallel relationship was observed with IgA, but not IgG, responses in adult and pediatric CF patient in the BAL. Thus, BAL IgA anti-BPI antibodies were independent of age and correlated with the presence of BPI cleavage in BAL., Conclusions: IgG and IgA autoreactivity to BPI in CF patients was demonstrated in serum and BAL, respectively, and correlated with the isotype of the antibody response to P. aeruginosa. The co-occurrence of anti-BPI and anti-P. aeruginosa IgA in the BAL, but not serum, of pediatric CF patients suggests that BPI tolerance is broken in the P. aeruginosa-infected airway and that serologic IgG autoantibodies are later induced, potentially through a separate pathway. The relationship between P. aeruginosa, BPI cleavage, and IgA autoantibodies in the BAL suggests a role for cryptic epitope generation in the breaking of tolerance., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Rationale: Modulation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with CF and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation. Objectives: To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment. Methods: The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV 1 ) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction ( n  = 14) or by spontaneous expectoration ( n  = 17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined. Results: The cohort that spontaneously expectorated sputum had a lower FEV 1 , a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. Although the overall cohort experienced significant improvements in FEV 1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients. Conclusions: In this multicenter cohort, 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and antiinflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

This review summarizes the discussion of a session held during the 2018 North American Cystic Fibrosis (CF) Conference titled "Challenging Cases in Nontuberculous Mycobacterial (NTM) Management." In this session, a multidisciplinary panel of NTM experts discussed clinical challenges related to the management of NTM infection in people with CF in which decision-making falls outside of the Cystic Fibrosis Foundation/European Cystic Fibrosis Society NTM guidelines. Topics discussed included managing newly acquired NTM infection, selecting and monitoring treatment regimens, determining treatment endpoints, and caring for patients after NTM treatment., (© 2019 Wiley Periodicals, Inc.)

Background: Pulmonary exacerbations (PEx) are important contributors to morbidity and mortality in cystic fibrosis (CF). Understanding risk factors for PEx is critical to improve treatment; pulmonary exacerbations also serve as an important outcome in CF clinical trials. Current risk estimates generally only evaluate time to the first PEx. Methods accounting for multiple exacerbations during the observation period could provide more power to detect significant risk factors., Methods: The Early Pseudomonas Infection Control (EPIC) Observational Study enrolled participants between 2004 and 2006 who were ≤ 12 years of age and negative for Pseudomonas aeruginosa. First and multiple event analyses were used to investigate risk factors for pulmonary exacerbations., Results: We evaluated a total of 5129 PEx from 1734 CF patients in the EPIC study. Multiple event analysis identified 2 more factors associated with occurrence of PEx compared to first event analysis. After adjusting for multiple factors, the following were associated with higher occurrence of PExs: female gender, older age at enrollment, household cigarette smoke exposure, increased cough at the most recent encounter, having used antibiotics since the previous encounter, a positive culture for any CF organism at the most recent encounter, and having had a PEx in the last 30 days., Conclusions: Multiple event analyses use all PEx events and may identify more risk factors for PEx than analysis of time to first PEx. We have provided an example of how to apply this type of analysis and how to interpret estimates in the context of the EPIC study., (Published by Elsevier B.V.)

Purpose of Review: This review provides an update on definitions of chronicity of infection, approaches to airway sampling to detect infection, strategies for Pseudomonas aeruginosa eradication, impact of cystic fibrosis transmembrane regulator protein (CFTR) modulators and future challenges for clinical trials., Recent Findings: Rates of P. aeruginosa have decreased over the past two decades with establishment of effective eradication protocols. Definitions of chronic P. aeruginosa infection have required adaptation for healthier populations. Although molecular (PCR) approaches to early P. aeruginosa detection are sensitive, to date, earlier diagnosis has not impacted on clinical outcomes. Despite eradication regimens, some people with early P. aeruginosa fail to clear their infection. Most people also experience a recurrence and eventual transition to chronic infection. Several recent studies sought to address this gap. CFTR modulators (predominantly ivacaftor) demonstrated reduced P. aeruginosa density, although infection may persist or recur demonstrating the need for continued antiinfective therapies in the modulator era., Summary: Future studies of approaches to P. aeruginosa eradication will be complex due to expanded availability and ongoing competitive clinical trials of CFTR modulators. Studies to address optimal eradication therapy, particularly in adults, will be required, though adequate recruitment to power these studies may prove challenging.

Bacterial biofilms can form persistent infections on wounds and implanted medical devices and are associated with many chronic diseases, such as cystic fibrosis. These infections are medically difficult to treat, as biofilms are more resistant to antibiotic attack than their planktonic counterparts. An understanding of the spatial and temporal variation in the metabolism of biofilms is a critical component toward improved biofilm treatments. To this end, we developed oxygen-sensitive luminescent nanosensors to measure three-dimensional (3D) oxygen gradients, an application of which is demonstrated here with Pseudomonas aeruginosa biofilms. The method was applied here and improves on traditional one-dimensional (1D) methods of measuring oxygen profiles by investigating the spatial and temporal variation of oxygen concentration when biofilms are challenged with antibiotic attack. We observed an increased oxygenation of biofilms that was consistent with cell death from comparisons with antibiotic kill curves for PAO1. Due to the spatial and temporal nature of our approach, we also identified spatial and temporal inhomogeneities in the biofilm metabolism that are consistent with previous observations. Clinical strains of P. aeruginosa subjected to similar interrogation showed variations in resistance to colistin and tobramycin, which are two antibiotics commonly used to treat P. aeruginosa infections in cystic fibrosis patients. IMPORTANCE Biofilm infections are more difficult to treat than planktonic infections for a variety of reasons, such as decreased antibiotic penetration. Their complex structure makes biofilms challenging to study without disruption. To address this limitation, we developed and demonstrated oxygen-sensitive luminescent nanosensors that can be incorporated into biofilms for studying oxygen penetration, distribution, and antibiotic efficacy-demonstrated here with our sensors monitoring antibiotic impacts on metabolism in biofilms formed from clinical isolates. The significance of our research is in demonstrating not only a nondisruptive method for imaging and measuring oxygen in biofilms but also that this nanoparticle-based sensing platform can be modified to measure many different ions and small molecule analytes., (Copyright © 2019 American Society for Microbiology.)

Purpose: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. The aim is to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations., Experimental Design: BALF is collected clinically from 50 patients with CF and nine disease controls, processed, and stored per protocol. BALF supernatants are analyzed for 1129 proteins by aptamer approach (SOMAscan proteomics platform). Proteins are compared across groups and used for pathway analysis. Endotypes are identified within the CF group., Results: CF BALF has increased concentrations of neutrophil elastase, myeloperoxidase, and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens., Conclusions and Clinical Relevance: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In persons with cystic fibrosis (CF), decreased airway microbial diversity is associated with lower lung function. Conflicting data exist on the impact of short-term antibiotics for treatment of acute pulmonary exacerbations. However, whether differences in antibiotic exposure impacts airway microbiome changes has not been studied. We hypothesized that subtherapeutic beta-lactam antibiotic exposure, determined by the pharmacokinetics and pharmacodynamics (PK/PD) after intravenous (IV) antibiotic administration, would be associated with different patterns of changes in CF airway microbial diversity. Eligible children were enrolled when well; study assessments were performed around the time of pulmonary exacerbation. Plasma drug concentrations and bacterial minimum inhibitory concentrations (MICs) were used to determine therapeutic versus subtherapeutic beta-lactam antibiotic exposure. Respiratory samples were collected from children, and extracted bacterial DNA was amplified for the V4 region of the 16S rRNA gene. Twenty children experienced 31 APEs during the study; 45% (n = 14) of antibiotic courses were deemed therapeutic. Those in the therapeutic group had more significant decreases in alpha diversity at end of treatment and post-recovery compared to baseline than those in the subtherapeutic group. Therapeutic and subtherapeutic beta-lactam use is associated with different patterns of changes in CF airway microbial diversity following antibiotic administration.

Background: Pulmonary exacerbations (PEx) in children with cystic fibrosis (CF) are frequently treated in the outpatient setting with oral antibiotics. However, little is known about the characteristics of PEx managed on an outpatient basis and the effectiveness of oral antibiotic therapy. We sought to prospectively evaluate clinical and laboratory changes associated with oral antibiotic treatment for PEx., Methods: Children with CF between 8 and 18 years of age prescribed two weeks of oral antibiotics for a PEx were eligible to enroll. The study consisted of a visit within 48 h of starting antibiotics and a second visit within one week of antibiotic completion. Twenty-eight participants were evaluated by exacerbation score, quality of life measurements, lung function, sputum microbiology and inflammation., Results: Oral antibiotic treatment was associated with a significant improvement in exacerbation score and quality of life measured by the CF Questionnaire-Revised (CFQ-R) respiratory domain. Following treatment, forced expiratory volume in 1 s (FEV 1 ) % predicted increased [median (range)] 9% (-8%, 31%), and 22 (81%) subjects returned to 90% or higher of baseline FEV 1 . Bacterial density of the primary organism identified on sputum culture decreased significantly with a median (range) decrease of 0.8 log 10 cfu/mL (-8 log 10 , 2 log 10, p = 0.03). Sputum neutrophil elastase [-37 μg/mL (-464, 272), p = 0.02] and IL-1β [-2.8 × 10 3 μg/mL (-6.9 × 10 4 , 3.3 × 10 4 ), p = 0.03] decreased significantly following treatment in this cohort., Conclusions: Treatment of PEx with oral antibiotics was associated with measurable improvements in patient reported outcomes, lung function, bacterial density and sputum inflammatory markers., (Published by Elsevier B.V.)