Search

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are available to the majority of people with CF in the United States (US); little is known about pregnancy outcomes with modulator use. This retrospective study aims to determine the impact of CFTR modulators on maternal outcomes., Research Question: Does pregnancy differentially impact outcomes in females with CF with and without CFTR modulators?, Study Design and Methods: We collected data on pregnancies from 2010-2021 from 11 US adult CF centers. We conducted multivariable longitudinal regression analysis to assess whether changes in percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), and Pseudomonas aeruginosa prevalence differed from before, during, and after pregnancy by CFTR modulator use, while adjusting for confounders. We also describe infant outcomes based on maternal modulator use., Results: Among 307 pregnancies, mean age at conception was 28.5 years (range: 17-42), pre-pregnancy ppFEV1 was 74.2 and BMI was 22.3 kg/m 2 . One hundred and fourteen pregnancies (37.1%) had CFTR modulator exposure during pregnancy (77 with highly effective modulator therapy [HEMT] and 37 with other modulators). The adjusted mean change in ppFEV1 from pre- to during pregnancy was -2.36 (95%CI: -3.56, -1.16) in the unexposed group and +2.60(95%CI: 0.23, 4.97) in the HEMT group, with no significant change from during to one-year post-pregnancy. There was an overall decline in ppFEV1 from pre- to post-pregnancy in the no modulator group (-2.56; 95%CI:-3.62, -1.49) that was not observed in the HEMT group (1.10; 95%CI: -1.13, 3.34). PEx decreased from pre- to post-pregnancy in the HEMT group and BMI increased from pre- to during pregnancy in all groups but without a significant change post-pregnancy. Missing infant outcome data precluded firm conclusions., Interpretation: We observed superior pregnancy and post-pregnancy pulmonary outcomes in individuals who used HEMT, including a preservation of ppFEV1, compared with those unexposed to HEMT., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients., Methods: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert., Results: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis)., Conclusion: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients., (© 2024 Wiley Periodicals LLC.)

Insulin secretion within 30 minutes of nutrient ingestion is reduced in people with cystic fibrosis (PwCF) and pancreatic insufficiency and declines with worsening glucose tolerance. The glucose potentiated arginine (GPA) test is validated for quantifying β-cell secretory capacity as an estimate of functional β-cell mass but requires technical expertise and is burdensome. This study sought to compare insulin secretion during mixed-meal tolerance testing (MMTT) to GPA-derived parameters in PwCF., Methods: Secondary data analysis of CF-focused prospective studies was performed in PwCF categorized as 1) pancreatic insufficient [PI-CF] or 2) pancreatic sufficient [PS-CF] and in 3) non-CF controls. MMTT: insulin secretory rates (ISR) were derived by parametric deconvolution using 2-compartment model of C-peptide kinetics, and incremental area under the curve (AUC) was calculated for 30, 60 and 180-minutes. GPA: acute insulin (AIR) and C-peptide responses (ACR) were calculated as average post-arginine insulin or C-peptide response minus pre-arginine insulin or C-peptide under fasting (AIR arg and ACR arg ), ~230 mg/dL (AIR pot and ACR pot ), and ~340 mg/dL (AIR max and ACR max ) hyperglycemic clamp conditions. Relationships of MMTT to GPA parameters were derived using Pearson's correlation coefficient. Predicted values were generated for MMTT ISR and compared to GPA parameters using Bland Altman analysis to assess degree of concordance., Results: 85 PwCF (45 female; 75 PI-CF and 10 PS-CF) median (range) age 23 (6-56) years with BMI 23 (13-34) kg/m 2 , HbA 1c 5.5 (3.8-10.2)%, and FEV1%-predicted 88 (26-125) and 4 non-CF controls of similar age and BMI were included. ISR AUC 30min positively correlated with AIR arg ( r =0.55), AIR pot ( r =0.62), and AIR max ( r =0.46) and with ACR arg ( r =0.59), ACR pot ( r =0.60), and ACR max ( r =0.51) (all P <0.001). ISR AUC 30min strongly predicted AIR arg (concordance=0.86), AIR pot (concordance=0.89), and AIR max (concordance=0.76) at lower mean GPA values, but underestimated AIR arg , AIR pot , and AIR max at higher GPA-defined β-cell secretory capacity. Between test agreement was unaltered by adjustment for study group, OGTT glucose category, and BMI., Conclusion: Early-phase insulin secretion during MMTT can accurately predict GPA-derived measures of β-cell function and secretory capacity when functional β-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify β-cell function and secretory capacity., 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 © 2024 Sheikh, Stefanovski, Kilberg, Hadjiliadis, Rubenstein, Rickels and Kelly.)

Context: Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF)., Objective: This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls)., Methods: Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing., Results: Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics., Conclusion: ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Following availability of the highly effective cystic fibrosis (CF) transmembrane conductance regulator modulator, elexacaftor/tezacaftor/ivacaftor, there was a near doubling of pregnancies reported in the United States (US) in people with CF. We sought to determine health impacts of planned (PP) versus unplanned pregnancies (UP)., Methods: We collected retrospective pregnancy data from January 2010-December 2020 from 11 US CF centers. After adjusting for potential confounding effects, we conducted multivariable, multilevel longitudinal regression analysis using mixed effect modeling to assess whether changes in percent predicted forced expiratory volume in one second (ppFEV 1 ), body mass index (BMI), and pulmonary exacerbations (PEx) 1-year-pre- to 1-year-post-pregnancy were associated with pregnancy planning., Results: Our analysis included 163 people with 226 pregnancies; the cohort had a mean age at conception of 29.6 years, mean pre-pregnancy ppFEV 1 of 75.4 and BMI of 22.5 kg/m 2 . PpFEV 1 declined in both PP (adjusted decline of -2.5 (95% CI: -3.8, -1.2)) and UP (adjusted decline of -3.0 (95% CI: -4.6, -1.4)) groups, they did not differ from each other (p = 0.625). We observed a difference in change in the annual number of PEx pre- to post-pregnancy (PP: 0.8 (0.7, 1.1); UP: 1.3 (1.0, 1.7); interaction effect p = 0.029). In a subset of people with available infant data, infants resulting from UP had more preterm births, lower APGAR scores, and more intensive care unit stays., Conclusions: Following UP, there is an increased trajectory for PEx and potentially for infant complications compared to PP. Clinicians should consider increased surveillance in the setting of UP., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that would cause bias to the content of this manuscript. GP – no conflicts; JTC, ML, AW, NW, TK, AU, MA, AR, LB, JG, DH, SM, PF, RJ – CF Foundation institutional research funding for work related to this manuscript; Additional conflicts of interest unrelated to the content of this manuscript may be included in the attached ICMJE disclosures., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Rationale: The clinical significance of Aspergillus fumigatus ( Af ) detection in the absence of allergic bronchopulmonary aspergillosis in cystic fibrosis (CF) airways remains unclear. Yet, some clinicians initiate antifungal therapy for Af -positive respiratory cultures out of concern for infection in people with CF. Objectives: To determine the association between the presence of Af and respiratory outcomes in individuals with CF. Methods: We conducted a prospective longitudinal cohort study of 206 adults and adolescents (age 14 yr and older) with CF and collected sputum for selective fungus culture. We assessed clinical outcome measurements, including patient-reported outcomes (measured by the Cystic Fibrosis Questionnaire-Revised), spirometry, and number of pulmonary exacerbations (PEx) for a 1-year period. We used mixed-effects linear models to determine the association between positive Af culture results, defined as Af detection in sputum culture at the study visit, with both respiratory domain score and forced expiratory volume in 1 second (FEV 1 ) percent predicted, adjusted for confounders. Mixed-effects Poisson regression models were employed to examine the association between positive Af culture results and PEx events. We explored the association between Af history, defined as Af detection at baseline or within 2 years of enrollment, and respiratory outcomes. Results: Af prevalence was 10.3% (95% confidence interval [CI], 6.8, 15.7) at baseline. Forty-eight (23.3%; 95% CI, 17.7, 29.7) participants had at least one Af -positive culture result during the study period. Positive Af culture result was not associated with lower respiratory domain score. However, Af history was associated with a 6.48-point lower respiratory domain score, reflective of worse respiratory quality of life (95% CI, -11.96, -0.99; P  = 0.02). Positive Af culture result was associated with a 2.54% lower FEV 1 percent predicted (95% CI, -4.64, -0.44; P  = 0.02) and a 1.71-fold increase in severe PEx incidence (95% CI, 1.05, 2.76; P  = 0.03). Conclusions: Positive Af culture result was not associated with lower patient-reported, respiratory-related quality of life. Yet, positive Af culture result was associated with both lower FEV 1 percent predicted and increased frequency of severe PEx warranting intravenous antibiotics in adolescents and adults with CF. Future studies are required to better understand the direct role of Af in lung disease progression in CF.

Background: The respiratory tract fungal microbiome in cystic fibrosis (CF) has been understudied despite increasing recognition of fungal pathogens in CF lung disease. We sought to better understand the fungal communities in adults with CF, and to define relationships between fungal profiles and clinical characteristics., Methods: We enrolled 66 adults with CF and collected expectorated sputum, spirometry, Cystic Fibrosis Questionnaire-revised, and clinical data. Fungi were molecularly profiled by sequencing of the internal transcribed spacer (ITS) region. Total fungal abundance was measured by quantitative PCR. Relative abundance and qPCR-corrected abundances were determined. Selective fungus culture identified cultivable fungi. Alpha diversity and beta diversity were measured and relationships with clinical parameters were interrogated., Results: Median age was 29 years and median FEV 1 percent predicted 58%. Members of the Candida genus were the most frequent dominant taxa in CF sputum. Apiotrichum, Trichosporon, Saccharomyces cerevisiae, and Scedosporium were present in high relative abundance in few samples; whereas, Aspergillus species were detected at low levels. Higher FEV 1 % predicted and CFTR modulator use were associated with greater alpha-diversity. Chronic azithromycin use was associated with lower alpha-diversity. Patients with acute pulmonary had distinct fungal community composition compared to clinically stable subjects. Differing yeast species were mainly responsible for the community differences., Conclusion: The respiratory tract fungal microbiome in adults with CF is associated with lung function, pulmonary exacerbation status, macrolide use, and CFTR modulator use. Future work to better understand fungal diversity in the CF airway and its impact on lung health is necessary., 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 © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

To prevent or mitigate chronic illness burden, people with cystic fibrosis (pwCF) and their family caregivers need primary (generalist-level) palliative care from the time of diagnosis forward. We used qualitative methods to explore their preferences about a screening-and-triage model (" Improving Life with CF ") developed to standardize this care. We purposively sampled and interviewed 14 pwCF and caregivers from 5 Improving Life with CF study sites. Thematic analysis was guided by a priori codes using the National Consensus Project's Guidelines for Quality Palliative Care. Participants included 7 adults and 2 adolescents with CF (3 with advanced disease), 4 parents, 1 partner (7 women; 5 people of color). Few were familiar with palliative care. Illness burden was described in multiple domains, including physical (e.g., dyspnea, pain), psychological (e.g., anxiety), and social (e.g., family well-being; impact on work/school). Most preferred survey-based screening with care coordination by the CF team. Preferences for screening approaches varied. PwCF and caregivers experience illness burden and are receptive to a CF-team delivered primary palliative care screening-and-triage model with flexible processes., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJB receives research support from the Cystic Fibrosis Foundation in addition to the submitted work, and a grant from a federal source (AHRQ 1R03HS026970-01A1), outside the submitted work. LD receives research support from the Cystic Fibrosis Foundation [GEORGI19QI0]. RP receives research support from NIH grants. JW reports grants from the Cystic Fibrosis Foundation (CFF); consultation fees from the Data Safety Monitoring Board of CFF, irrelevant to the submitted work. PW reports grants support from Cystic Fibrosis Foundation (CFF); consultation fees from Cystic Fibrosis Foundation (CFF); grant support from Vertex Pharmaceuticals, irrelevant to the submitted work. BMO reports grants from Cystic Fibrosis Foundation; consulting and travel reimbursement from CFF. RWL reports grants from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals; consulting fees and serving on advisory boards for Vertex Pharmaceuticals, outside of the submitted work. DF reports grants from the Cystic Fibrosis Foundation (CFF), Dutch Cystic Fibrosis Foundation, and Vertex Pharmaceuticals, and travel reimbursement from the CFF. MB receives research support from the Cystic Fibrosis Foundation [GEORGI19QI0]. DH reports grants from the Cystic Fibrosis Foundation (CFF), NIH; consulting fees from ADAM Medical review; personnel fees from global CF conference, Metropolitan Jewish Health System and Astra Zeneca advisory board. AMG reports personal fees and travel reimbursement from Cystic Fibrosis Australia; grants, personal fees, and travel reimbursement from Cystic Fibrosis Foundation; grants from the Dutch Cystic Fibrosis Foundation; travel reimbursement from the European Cystic Fibrosis Society; personal fees from Johns Hopkins University/DKBmed; personal fees from Saudi Pediatric Pulmonology Association; grants and personal fees from Vertex Pharmaceuticals. The authors (SD, JP, CK, RA, LY, MM, MS, FF, SP, MH, NC) do not have any personal, professional, or financial conflicts of interest to disclose for this work. The authors did not work with or were otherwise influenced by any external sponsors for this work., (© The Author(s) 2023.)

Background: As survival and health improve in people with cystic fibrosis (CF), more women with CF (wwCF) are considering their sexual and reproductive health (SRH). This study compared SRH experiences, behaviors, and care utilization of wwCF to the general population and defined CF-impacted considerations and care preferences., Methods: We surveyed wwCF aged ≥25 years regarding SRH and compared results to the US National Survey of Family Growth (NSFG;n = 4357) and friend controls(n = 123). We used descriptive statistics and chi-squared/Fisher's exact testing and linear regression for comparisons., Results: A total of 460 wwCF (mean age 36.1 years) completed the survey. WwCF were less likely to report current contraceptive use (43%vs76% NSFG, p<0.001;60% friends, p = 0.005). Nearly 25% of wwCF reported worsened CF symptoms during their menstrual cycles, 50% experienced urinary incontinence, and 80% vulvovaginal candidiasis. WwCF were significantly less likely to be parents (46%vs62% friends, p = 0.015) and to have experienced pregnancy (37%vs78% NSFG, p<0.001;58% friends, p = 0.002). More wwCF required medical assistance to conceive (29%vs12% NSFG, p<0.001 and 5% friends, p<0.001). Eighty-four percent of wwCF view their CF doctor as their main physician and 41% report no primary care provider (vs19% friends; p<0.001). WwCF report suboptimal rates of contraceptive and preconception counseling/care and are less likely to have received HPV vaccination (42%vs55%friends, p = 0.02). Despite desiring SRH conversations with their CF team, <50% report discussing SRH topics., Conclusion: WwCF have significantly different SRH experiences than non-CF peers. They report suboptimal SRH care compared to their preferences highlighting an urgent need to encourage SRH counseling/care in the CF model., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose related to this work. This study was funded by the Cystic Fibrosis Foundation (KAZMER18A0).|, (Copyright © 2022. Published by Elsevier B.V.)

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis., (© 2022 by the American Diabetes Association.)

BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).

It is unknown whether some donor specific antibodies (DSA) can be crossed at the time of lung transplant without desensitization or augmented induction immunosuppression. This study assessed whether crossing low-level pre-transplant DSA (defined as mean fluorescence intensity [MFI] 1000-6000) without augmented immunosuppression is associated with worse retransplant-free or chronic lung allograft dysfunction (CLAD)-free survival. Of the 458 included recipients, low-level pre-transplant DSA was crossed in 39 (8.6%) patients. The median follow-up time was 2.2 years. There were 15 (38.5%) patients with Class I DSA and 24 (61.5%) with Class II DSA. There was no difference in adjusted overall retransplant-free survival between recipients where pre-transplant DSA was and was not crossed (HR: .98 [95% CI = .49-1.99], P = .96). There was also no difference in CLAD-free survival (HR: .71 [95% CI = .38-1.33], P = .28). There was no difference in Grade 3 PGD at 72 h (OR: 1.13 [95% CI = .52-2.48], P = .75) or definite or probable AMR (HR: 2.22 [95% CI = .64-7.61], P = .21). Lung transplantation in the presence of low-level DSA without planned augmented immunosuppression is not associated with worse overall or CLAD-free survival among recipients with intermediate-term follow-up., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)