Introduction:It has previously been established that there is an increased incidence of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene amongst patients with non-cystic fibrosis bronchiectasis (NCFB). With the advent of new highly effective CFTR modulators, specifically elexacaftor-tezacaftor-ivacaftor (ETI), we asked whether NCFB patients with a single ETI amenable mutation who do not meet the criteria for a diagnosis of cystic fibrosis (CF) would benefit from this therapy. Methods:We assembled a retrospective cohort of patients (n=12) with a single CFTR mutation amenable to ETI treatment. Patients included in this cohort did not meet the diagnostic criteria for CF but presented with similar pulmonary symptoms and frequent exacerbations. Medical records were reviewed to determine the effects of ETI on clinical outcomes. Paired sample t-test for univariate analysis and multivariate linear mixed effect modeling for continuous and categorical variables were used to examine the impact of ETI therapy. Results:Improvements in pulmonary symptoms were observed in all 12 patients (100%), and 11 patients (91.6%) expressed improvement in quality of life. Mean % predicted forced expiratory volume in 1 s improved significantly from 69.3% to 75.0% (p=0.007). Mean reported pulmonary symptoms decreased to 2.17 (p=0.007) and mean reported pulmonary exacerbations decreased to 1.08 per year (p=0.0006). When controlling for sweat chloride and Poly T insertions, post-ETI improvement remained significant. Conclusion:Amongst patients presenting with NCFB and an amenable CFTR mutation, treatment with ETI improved lung function, symptoms and quality of life and led to a significant reduction in annual pulmonary exacerbations. Larger clinical studies are needed to further validate these findings.

Objective: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet® bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order cross-over trial (NCT #03258853). Research Design and Methods: Twenty participants with CFRD were assigned in random-order to 14-days each on the BP or their usual diabetes care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70–180 mg/dL (TIR) on days 3-14 of each arm, and key secondary outcomes included mean CGM glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL. Results: TIR was significantly higher in the BP arm compared to the UC arm (75±11 versus 62±22%, p=0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150±19 mg/dL versus 171±45 mg/dL, p=0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% versus 0.36%, p=1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs 0.4 median episodes per day, p=0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm. Conclusions: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared to their UC, suggesting this may be an important therapeutic option for this patient population.

The aerodigestive organs share a kindred embryologic origin that allows for a more complete explanation as to how the foregut can remain a barrier to normalcy in people with cystic fibrosis (pwCF). The structures of the aerodigestive tract include the nasopharynx, the oropharynx, the hypopharynx, the esophagus, the stomach, as well as the supraglottic, glottic, and subglottic tubular airways (including the trachea). Additional gastrointestinal (GI) luminal/alimentary organs of the foregut include the duodenum. Extraluminal foregut structures include the liver, the gall bladder, the biliary tree, and the pancreas. There are a variety of neurologic controls within these complicated anatomic compartments to separate the transit of food and liquid from air. These structures share the same origin from the primitive foregut/mesenchyme. The vagus nerve is a critical structure that unites respiratory and digestive functions. This article comments on the interconnected nature of cystic fibrosis and the GI tract. As it relates to the foregut, this has been typically treated as simple "reflux" as the cause of worsened lung function in pwCF. That terms like gastroesophageal reflux (GER), gastroesophageal reflux disease (GERD), heartburn, and regurgitation are used interchangeably to reflect pathology further complicates matters; we offer a more physiologically accurate term called "GI-related aspiration" or "GRASP." Broadly, this term reflects that aspiration of foregut contents from the duodenum through the stomach to the esophagus, into the pharynx and the respiratory tree in pwCF. As a barrier to normalcy in pwCF, GRASP is fundamentally two disease processes-GERD and gastroparesis-that likely contribute most to the deterioration of lung disease in pwCF. In the modulator era, successful GRASP management will be critical, particularly in those post-lung transplantation (LTx), only through successful management of both GERD and gastroparesis. Standardization of clinical management algorithms for GRASP in CF-related GRASP is a key clinical and research gap preventing normalcy in pwCF; what exists nearly exclusively addresses surgical evaluations or offers guidance for the management of GI symptoms alone (with unclear parameters for respiratory disease considerations). We begin first by describing the result of GRASP damage to the lung in various stages of lung disease. This is followed by a discussion of the mechanisms by which the digestive tract can injure the lungs. We summarize what we anticipate future research directions will be to reduce the impact of GRASP as a barrier to normalcy in pwCF.

Background Most respiratory microbiome studies have focused on amplicon rather than metagenomics sequencing due to high host DNA content. We evaluated efficacy of five host DNA depletion methods on previously frozen human bronchoalveolar lavage (BAL), nasal swabs, and sputum prior to metagenomic sequencing. Results Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum and BAL samples had 94.1%, 99.2%, and 99.7% host-reads. The effect of host depletion differed by sample type. Most treatment methods increased microbial reads, species richness and predicted functional richness; the increase in species and predicted functional richness was mediated by higher effective sequencing depth. For BAL and nasal samples, most methods did not change Morisita-Horn dissimilarity suggesting limited bias introduced by host depletion. Conclusions Metagenomics sequencing without host depletion will underestimate microbial diversity of most respiratory samples due to shallow effective sequencing depth and is not recommended. Optimal host depletion methods vary by sample type.

IntroductionsCystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Onset is often insidious, so screening for early detection of glycemic abnormalities is important. Continuous glucose monitoring (CGM) has been validated in people with CF and has been shown to detect early glycemic variability otherwise missed on 2-hour oral glucose tolerance testing (OGTT). We previously reported that CGM measures of hyperglycemia and glycemic variability are superior to hemoglobin A1c (HbA1c) in distinguishing those with and without CFRD. However, little is known about the long-term predictive value of CGM measures of glycemia for both the development of CFRD and their effect on key clinical outcomes such as weight maintenance and pulmonary function. In addition, there have been no studies investigating advanced glycation endproducts (AGE) assessed by skin autofluorescence in people with CF.MethodsIn this prospective observational study, CGM and HbA1c were measured at 2 to 3 time points 3 months apart in 77 adults with CF. Participants who did not have CFRD at the time of enrollment underwent OGTT at the baseline visit, and all participants had AGE readings at baseline. Follow up data including anthropometric measures, pulmonary function and CFRD status were collected by review of medical records 1- and 2-years after the baseline visits. We applied multivariable linear regression models correlating glycemic measures to change in key clinical outcomes (weight, BMI, FEV1) accounting for age, gender and elexacaftor/tezacaftor/ivacaftor (ETI) use. We also conducted logistic regression analyses comparing baseline glycemic data to development of CFRD during the 2-year follow up period.ResultsOf the 77 participants, 25 had pre-existing CFRD at the time of enrollment, and six participants were diagnosed with CFRD by the OGTT performed at the baseline visit. When adjusting for age, gender, and ETI use, multiple CGM measures correlated with weight and BMI decline after one year but not after two years. CGM and HbA1c at baseline did not predict decline in FEV1 (p>0.05 for all). In the 46 participants without a diagnosis of CFRD at baseline, two participants were diagnosed with CFRD over the following two years, but CGM measures at baseline did not predict progression to CFRD. Baseline AGE values were higher in individuals with CFRD and correlated with multiple measures of dysglycemia (HbA1c, AG, SD, CV, TIR, % time >140, >180, >250) as well as weight. AGE values also correlated with FEV1 decline at year 1 and weight decline at year 1 and year 2ConclusionsSeveral key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD (n=2) during the follow up period and the initiation of ETI by many participants, affecting their trajectory in weight and pulmonary function. These results provide additional data supporting the potential role for CGM in identifying clinically significant dysglycemia in CF. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD and to understand the implications of AGE measures in this patient population.

BackgroundThe benefits of Elexecaftor-Tezacaftor-Ivacaftor (ETI) therapy on the health and wellbeing of people with CF (pwCF) are well documented. Since approval, however, a growing number of potential side effects have emerged in reports from clinical practice. With current understanding of ETI tolerability limited to data from clinical trials, the prevalence of side effects and their impact on care decision making remains poorly categorized.MethodsA 10-question survey was developed and distributed to patients 18 years or older who were treated at the Massachusetts General Hospital CF centers. Reports of side effects were measured across 12 distinct categories, and dose adjustments and discontinuation due to side effects were collected. If a patient reported no side effects, they did not have to complete the entire survey.ResultsAmong 92 respondents initiated on ETI, 51 respondents (55.4%) reported potential side effects and 41 (44.5%) respondents reported no adverse events. The most commonly reported side effects were mental health, changes in appearance, and gastrointestinal complaints, which were reported by 22.8%, 30.4%, and 21.7% of patients, respectively. Eighteen (19.6%) respondents modified their dosing in response to side effects, and six discontinued treatment permanently (6.52%) due to persistent side effects.ConclusionsResponses demonstrated marked heterogeneity, with most respondents reporting at least one side effect following initiation. Dose modification was commonly utilized to mitigate adverse effects, however few respondents had to discontinue treatment. These findings demonstrate the importance of monitoring for potential drug-related side effects of ETI in clinical settings.

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, 99.2%, and 99.7% host reads, respectively. Host depletion effects varied by sample type, generally increasing microbial reads, species and functional richness; this was mediated by higher effective sequencing depth. Rarefaction curves showed species richness saturation at 0.5-2 million microbial reads. Most methods did not change Morisita-Horn dissimilarity for BAL and nasal samples although the proportion of gram-negative bacteria decreased for sputum from pwCF. Freezing did not affect the viability of Staphylococcus aureus but reduced the viability of Pseudomonas aeruginosa and Enterobacter spp.; this was mitigated by adding a cryoprotectant. QIAamp-based host depletion minimally impacted gram-negative viability even in non-cryoprotected frozen isolates. While some host depletion methods may shift microbial composition, metagenomics sequencing without host depletion severely underestimates microbial diversity of respiratory samples due to shallow effective sequencing depth and is not recommended.

Objective: The study objective was to assess the safety and efficacy of a preemptive direct-acting antiviral therapy in lung transplants from hepatitis C virus donors to uninfected recipients. Methods: This study is a prospective, open-label, nonrandomized, pilot trial. Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Recipients of nucleic acid test positive lungs were compared with recipients of lungs from nucleic acid test negative donors. Primary end points were Kaplan-Meier survival and sustained virologic response. Secondary outcomes included primary graft dysfunction, rejection, and infection. Results: Fifty-nine lung transplantations were included: 16 nucleic acid test positive and 43 nucleic acid test negative. Twelve nucleic acid test positive recipients (75%) developed hepatitis C virus viremia. Median time to clearance was 7 days. All nucleic acid test positive patients had undetectable hepatitis C virus RNA by week 3, and all alive patients (n = 15) remained negative during follow-up with 100% sustained virologic response at 12 months. One nucleic acid test positive patient died of primary graft dysfunction and multiorgan failure. Three of 43 nucleic acid test negative patients (7%) had hepatitis C virus antibody positive donors. None of them developed hepatitis C virus viremia. One-year survival was 94% for nucleic acid test positive recipients and 91% for nucleic acid test negative recipients. There was no difference in primary graft dysfunction, rejection, or infection. One-year survival for nucleic acid test positive recipients was similar to a historical cohort of the Scientific Registry of Transplant Recipients (89%). Conclusions: Recipients of hepatitis C virus nucleic acid test positive lungs have similar survival as recipients of nucleic acid test negative lungs. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission.

Abstract Background Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. To elucidate the kinetics and variant cross-protection of vaccine-induced antibodies in this population, we conducted a prospective longitudinal study in heart and lung transplant recipients receiving the SARS-CoV-2 messenger RNA (mRNA) 3-dose vaccination series. Methods We measured longitudinal serum antibody and neutralization responses against the ancestral and major variants of SARS-CoV-2 in SARS-CoV-2-uninfected lung (n = 18) and heart (n = 17) transplant recipients, non–lung-transplanted patients with cystic fibrosis (n = 7), and healthy controls (n = 12) before, during, and after the primary mRNA vaccination series. Results Among healthy controls, strong anti-spike responses arose immediately following vaccination and displayed cross-neutralization against all variants. In contrast, among transplant recipients, after the first 2 vaccine doses, increases in antibody concentrations occurred gradually, and cross-neutralization was completely absent against the Omicron B.1.1.529 variant. However, most (73%) of the transplant recipients had a significant response to the third vaccine dose, reaching levels comparable to those of healthy controls, with improved but attenuated neutralization of immune evasive variants, particularly Beta, Gamma, and Omicron. Responses in non–lung-transplanted patients with cystic fibrosis paralleled those in healthy controls. Conclusions In this prospective, longitudinal analysis of variant-specific antibody responses, lung and heart transplant recipients display delayed and defective responses to the first 2 SARS-CoV-2 vaccine doses but significantly augmented responses to a third dose. Gaps in antibody-mediated immunity among transplant recipients are compounded by decreased neutralization against Omicron variants, leaving many patients with substantially weakened immunity against currently circulating variants.

The airway microbiome in persons with cystic fibrosis (pwCF) is correlated with lung function and disease severity. Supplemental oxygen use is common in more advanced CF, yet its role in perturbing airway microbial communities is unknown.

Purpose Inhaled tobramycin (iTOBI) is used in bilateral lung transplant recipients (LTRs) to prevent PsA colonization. Pharmacokinetic studies show that iTOBI is not systemically absorbed, making it an alternative to intravenous formulations. Case reports exist of LTRs on iTOBI developing renal failure with detectable tobramycin troughs (DTTs). The purpose of this review is to describe the incidence of DTT in LTRs receiving iTOBI immediately post-transplant. Methods This single-center, retrospective review included patients in their index lung transplant admission who received iTOBI with a DTT (≥ 0.5 mg/L). All LTRs received iTOBI 300 mg q12hr prophylaxis for at least one month with levels drawn for cause when concerned for accumulation. Primary outcome was the number of LTRs with DTTs. Secondary outcomes included duration of therapy and incidence of SCr increase ≥ 0.3 mg/dL within 48 hours (AKI). Descriptive statistics were used to analyze baseline characteristics and outcomes. Results We reviewed 211 LTRs from January 2014 to August 2021. Twenty patients (9.5%) met inclusion criteria with 32 DTTs and 4 were excluded due to undetectable troughs. Median time to initial DTT was 10 (2-34) days of therapy. AKI occurred within a week prior to 84% of DTT, with a median of 3 days to elevated trough. Median time to DTT clearance (undetectable level or resumption of therapy) was 2 days. Therapy was discontinued in 10% of patients due to concern for nephrotoxicity (Table 1). Conclusion iTOBI therapy may cause systemic drug levels in the early post-transplant phase. Given known association of systemic tobramycin with nephrotoxicity, particularly in the presence of nephrotoxic medications, iTOBI trough surveillance may be prudent to guide therapy. Rapid DTT clearance may render repeat levels unnecessary. Larger studies are needed to assess the renal risk, timing of iTOBI accumulation in LTRs and thresholds for serum monitoring.

The rise of antimicrobial resistant (AMR) bacteria is a global public health threat. AMR Achromobacter bacteria pose a challenging clinical problem, particularly for those with cystic fibrosis (CF) who are predisposed to chronic bacterial lung infections. Lytic bacteriophages (phages) offer a potential alternative to treat AMR infections, with the possible benefit that phage selection for resistance in target bacteria might coincide with reduced pathogenicity. The result is a genetic "trade-off," such as increased sensitivity to chemical antibiotics, and/or decreased virulence of surviving bacteria that are phage resistant. Here, we show that two newly discovered lytic phages against Achromobacter were associated with stabilization of respiratory status when deployed to treat a chronic pulmonary infection in a CF patient using inhaled (nebulized) phage therapy. The two phages demonstrate traits that could be generally useful in their development as therapeutics, especially the possibility that the phages can select for clinically useful trade-offs if bacteria evolve phage resistance following therapy. We discuss the limitations of the current study and suggest further work that should explore whether the phages could be generally useful in targeting pulmonary or other Achromobacter infections in CF patients.

Purpose Lung transplant patients are at risk of fungal infections post-transplant and require anti-fungal prophylaxis (AFP). However, utilization and duration of these agents can be limited by adverse effects. The purpose of this evaluation was to assess the tolerability and duration of AFP post-lung transplant at a large academic medical center. Methods This single-center retrospective review included lung transplant patients transplanted from August 2017 to August 2018 who received at least 7 days of AFP and were followed for three years. Patients received a combination of an azole anti-fungal agent, inhaled amphotericin B lipid complex (iABLC), and nystatin suspension immediately post-transplant. Pre-transplant colonization rates, prior fungal infections, transplant indication and baseline characteristics were collected. The primary outcome was tolerability of AFP. Secondary outcomes assessed were adherence and duration of AFP. Results Forty patients were included and one patient was excluded from the azole analysis due to a history of liver hyperplasia precluding therapy (Table 1). Patients remained on an azole, iABLC, and nystatin therapy a median of 13.9, 36.6, and 32 months post-transplant, respectively. The most common reason for AFP discontinuation was provider decision to end prophylaxis coverage (Table 2). Seven (19.4%) patients in the azole group, one (4.8%) patient in the iABLC group, and one (4.3%) patient in the nystatin group discontinued therapy due to intolerable side effects and adverse reactions. Patient reported adherence rates were highest in the azole group (87.2%), followed by iABLC (67.5%) and lowest with nystatin (45%). Conclusion Despite an extended duration of broad AFP, most patients tolerated therapy without limiting adverse effects. Oral AFP of shorter duration yielded the highest patient reported adherence.