Search

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

With advances in medical care, patients with cystic fibrosis are more commonly living into adulthood, yet there are limited data describing the need for GI surgery and its outcomes in adult cystic fibrosis patients.We aim to use a national administrative database to evaluate trends in abdominal GI surgery and associated postoperative outcomes among adult cystic fibrosis patients.This was a national retrospective cohort study.A national all-payor administrative database from 2000 to 2014 was used.Patients included adults (age ≥18 years) with cystic fibrosis undergoing abdominal GI surgery.The primary outcome was trend over time in number of surgical admissions. Secondary outcomes included morbidity and mortality by procedure type.We identified 3075 admissions for abdominal surgery, of which 28% were elective. Major GI surgical procedures increased over the study period ( p0.01), whereas appendectomy and cholecystectomy did not demonstrate a clear trend ( p = 0.90). The most common procedure performed was cholecystectomy ( n = 1280; 42%). The most common major surgery was segmental colectomy ( n = 535; 18%). Obstruction was the most common surgical indication ( n = 780; 26%). For major surgery, in-hospital mortality was 6%, morbidity was 37%, and mean length of stay was 15.9 days (SE 1.2).The study is limited by a lack of granular physiological and clinical data within the administrative data source.Major surgical admissions for adult patients with cystic fibrosis are increasing, with the majority being nonelective. Major surgery is associated with significant morbidity, mortality, and prolonged length of hospital stay. These findings may inform perioperative risk for adult patients with cystic fibrosis in need of GI surgery. See Video Abstract at http://links.lww.com/DCR/B850 .ANTECEDENTES:Con los avances en la medicina, los pacientes con fibrosis quística viven más comúnmente hasta la edad adulta, pero hay datos escasos que describan la necesidad de cirugía gastrointestinal y sus resultados en pacientes adultos con fibrosis quística.OBJETIVO:Nuestro objetivo es utilizar una base de datos administrativa nacional para evaluar las tendencias en la cirugía gastrointestinal abdominal y los resultados posoperatorios asociados entre los pacientes adultos con fibrosis quística.DISEÑO:Estudio de cohorte retrospectivo nacional.AJUSTE:Base de datos administrativa nacional de todas las instituciones pagadoras desde 2000 a 2014.PACIENTES:Todos los pacientes adultos (edad18) con fibrosis quística sometidos a cirugía gastrointestinal abdominal.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la tendencia a lo largo del tiempo en el número de ingresos quirúrgicos. Los resultados secundarios incluyeron morbilidad y mortalidad por tipo de procedimiento.RESULTADOS:Identificamos 3.075 ingresos por cirugía abdominal de los cuales el 28% fueron electivos. Los procedimientos quirúrgicos gastrointestinales mayores aumentaron durante el período de estudio (p0,01) mientras que la apendicectomía y la colecistectomía no demostraron una tendencia clara (p = 0,90). El procedimiento realizado con mayor frecuencia fue la colecistectomía (n = 1.280; 42%). La cirugía mayor más común fue la colectomía segmentaria (n = 535; 18%). La obstrucción fue la indicación quirúrgica más común (n = 780; 26%). Para la cirugía mayor, la mortalidad hospitalaria fue del 6%, la morbilidad del 37% y la estadía media de 15,9 días (EE 1,2).LIMITACIONES:El estudio está limitado por la falta de datos clínicos y fisiológicos granulares dentro de la fuente de datos administrativos.CONCLUSIONES:Los ingresos quirúrgicos mayores de pacientes adultos con fibrosis quística están aumentando y la mayoría no son electivos. La cirugía mayor se asocia con una morbilidad y mortalidad significativas y una estancia hospitalaria prolongada. Estos hallazgos pueden informar el riesgo perioperatorio para pacientes adultos con fibrosis quística que necesitan cirugía gastrointestinal. Consulte Video Resumen en http://links.lww.com/DCR/B850 . (Traducción-Dr. Felipe Bellolio ).

BACKGROUND: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. METHODS: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. RESULTS: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV(1) improvement was significantly (p

Summary Background and objective Presbyphonia is an age-related voice disorder characterized by vocal fold atrophy and incomplete glottal closure during phonation. The extent to which the effects of presbyphonia may be compounded by age-related declines in the respiratory system and further impact communication and quality of life remains unknown. Therefore, the objective of this study was to determine how variations in respiratory function impacts voice measures in a sample of participants with presbyphonia. Methods In this pilot study, 21 participants with presbyphonia underwent respiratory assessments (spirometry and respiratory muscle strength testing) and voice assessments (videostroboscopy, acoustic analysis, auditory-perceptual ratings, aerodynamic assessment, and self-assessments). Factor and cluster analyses were conducted to extract voice and respiratory constructs and to identify groups of participants with similar profiles. Correlations and regression analyses were conducted to better describe the relationships between voice and respiratory function. Results Respiratory function was found to impact voice via two main pathways: through its physiological effect on voice and through its impact on general health and impairment. A lower respiratory function was associated with a lower vocal fold pliability and regularity of vibration and with an elevated aerodynamic resistance accompanied by laryngeal hyperfunction. Standardized measures of respiratory function were associated with perceived voice-related handicap. Respiratory function did not associate with voice quality, which was mostly influenced by the severity of vocal fold atrophy. Conclusion Poor respiratory health exacerbates the burden of vocal fold atrophy and, therefore, implementation of respiratory screening prior to starting voice therapy may significantly affect the treatment plan and consequently the outcomes of voice therapy in this patient population.

Patients with cystic fibrosis (CF) and pancreatic insufficiency are at risk for suboptimal fat absorption, inability to maintain weight, poor growth, and increased gastrointestinal (GI) symptoms due to malabsorption. Enteral nutrition (EN) is used to supplement caloric intake and requires pancreatic enzyme replacement for effective digestion. We evaluated the relationship between long-term use of an in-line digestive enzyme cartridge with EN and changes in anthropometric measures and GI symptoms in patients with CF.This is a single-center, retrospective case review of patients with CF using a digestive enzyme cartridge with EN. Data were collected from the patient medical records and included weight, height, body mass index, EN regimen, and reported GI symptoms.Thirteen pediatric and five adult patients with a mean age of 12.6 years used a digestive enzyme cartridge with EN for a period of 3-27 months. Most patients (n = 14) had been using oral digestive enzymes with EN before using the digestive enzyme cartridge, whereas four started from the onset of EN. The indications to convert from oral enzymes to the digestive enzyme cartridge included poor growth (72.2%) and poor tolerance of EN (69.2%). There was a reduction in reported GI symptoms after initiating use of the digestive enzyme cartridge. After 12 months of digestive cartridge use, there were improvements in anthropometrics.This real-world experience with prolonged use of a digestive enzyme cartridge with EN demonstrated improved clinical outcomes and a reduction in GI symptoms in patients with CF.

Background People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. Methods People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. Results 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. Conclusions People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

The South Carolina cystic fibrosis (CF) newborn screening (NBS) program changed in 2019 to include CFTR genotyping for babies with top 4% immunoreactive trypsinogen, which improves sensitivity and timeliness, but increases carrier detection. Carrier identification has genetic implications for the family and parents of NBS+ babies have increased emotional distress. Genetic counseling (GC) may increase parent understanding and reduce anxiety yet is not uniformly offered at CF centers. We report our early results after implementing GC for NBS+ families at the time of sweat chloride testing (SCT). Sixteen mothers participated in an online survey about their experience. The child’s pediatrician notified 10 (62.5%) of the NBS+ result. Parents felt they were notified in a timely manner (68.8%), by someone knowledgeable about NBS (62.5%), SCT (62.5%), CF (43.8%), and genetics (43.8%) and who cared about them (81.3%). Parents felt worried (81.3%), confused (81.3%), empowered (25%) and other (sad, shocked, scared, overwhelmed, devastated, defeated). Most (87.5%) sought additional information before SCT. Sadness and anxiety increased transiently with NBS+ result; bondedness with the baby was not affected. Nine mothers received GC with suggestion of reduced distress. Knowledge was high among both cohorts. GC was rated very helpful, informative, comforting, and minimally distracting. Data from this single-center study suggest benefit of GC and that families would value earlier contact with an expert.

Background Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an uncommon mycobacterial infection characterized by worsening lung function and increased health care resource utilization; however, the overall risk for hospitalization among patients with NTM-PD remains unclear. Research Question What is the hospitalization risk among older adults with NTM-PD? Study Design and Methods A retrospective, nested, case-control study was conducted by using the Medicare claims database. Cases were defined as patients with ≥ 2 NTM-PD claims ≥ 30 days apart between January 1, 2007, and December 31, 2015. The study included individuals aged ≥ 65 years with ≥ 12 months of continuous enrollment in both Parts A and B before the first NTM-PD diagnosis. Cases were matched 1:2 to Medicare beneficiaries without NTM-PD (control subjects) according to age and sex. Hospitalizations following the first NTM-PD claim were compared between case and control subjects by using univariate and multivariate analyses. Results A total of 35,444 case subjects and 65,467 matched control subjects (mean age, 76.6 years; 70% female; ≥ 87% White) were identified. Baseline comorbidities, particularly pulmonary comorbidities, were more common in case subjects than in control subjects (81.1% vs 17.7% for COPD; 44.6% vs 0.6% for bronchiectasis). All-cause hospitalization was observed in 65.7% of case subjects and 44.9% of control subjects. Unadjusted annual hospitalization rates were significantly (P < .05) greater among case subjects than control subjects. Case subjects also had a significantly shorter time to hospitalization than control subjects. The increased burden due to hospitalization was reflected in multivariate analysis adjusting for baseline comorbidities. All-cause hospitalization in patients with NTM-PD relative to control subjects was 1.2 times more likely (relative risk, 1.23; 95% CI, 1.21-1.25; P < .0001) with a 46% greater hazard (hazard ratio, 1.46; 95% CI, 1.43-1.50; P < .0001). Interpretation Patients with NTM-PD were significantly more likely to be hospitalized, had greater annualized hospitalization rates, and had shorter time to hospitalization than age- and sex-matched control subjects without NTM-PD. These findings highlight the significantly increased burden of hospitalizations among patients with NTM-PD., Graphical Abstract

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Background : Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults. Methods : This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV1) 40–90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 averaged over the 26-week treatment period. Results : Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively. Conclusions : In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353.

1Cystic fibrosis (CF) is an autosomal recessive genetic condition with multisystemic disease manifestations, the most prominent of which occur in the respiratory system. Despite significant developments in disease understanding and therapeutics, each contributing to improved lung function and survival in patients with CF, several pulmonary complications, including pneumothorax, massive hemoptysis, and respiratory failure, continue to occur. In this review, we briefly describe each of these complications and their management and discuss how they impact the care and disease trajectory of individuals in whom they occur. Finally, we discuss the evolving role that palliative care and CF transmembrane conductance regular modulator therapies play in the natural disease course and care of patients with CF.

Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Study Design and Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic Pseudomonas aeruginosa ( Pa) is the most prevalent infective organism and is difficult to eradicate owing to its adaptation to the CF lung microenvironment. Long-term suppressive treatment with inhaled antimicrobials is the standard care for reducing exacerbation frequency, improving quality of life and increasing measures of lung function. Levofloxacin (a fluoroquinolone antimicrobial) has been approved as an inhaled solution in Europe and Canada, for the treatment of adults with CF with chronic P. aeruginosa pulmonary infections. Here, we review the clinical principles relating to the use of inhaled antimicrobials and inhaled levofloxacin for the management of P. aeruginosa infections in patients with CF.

There is an increasing prevalence of nontuberculous mycobacteria pulmonary disease (NTM-PD) in the US. Treatment of NTM-PD typically requires multiple medications, which can be associated with unpleasant morbidity and eradication of infection is difficult. Therefore, there is a critical need for novel effective and well-tolerated therapies. Recent in vitro data and case reports have suggested that nitric oxide, inhaled as a gas (gNO), has antimicrobial activity against NTM. We sought to investigate the effect of gNO in patients with NTM-PD in an open-label proof of concept trial.Eligible participants had NTM-PD with persistently positive respiratory cultures for NTM even if on antibiotic treatment. Participants were treated with gNO for 50 min three times daily, five days per week, for three weeks (total of 15 treatment days).Ten participants, of whom nine were on long-term NTM antibiotic therapy, were enrolled. All participants completed the regimen without interruption or discontinuation. Small increases in methemoglobin were noted during treatment, and all resolved to baseline within 2 h. Four participants (40%) met the primary outcome measure of negative sputum cultures after three weeks of therapy. Following treatment discontinuation, three of these participants were again culture positive during the 3-month post-treatment monitoring period, although with measures suggesting low bacterial burden.Patients tolerated a 3-week regimen of gNO without safety concerns, and despite highly refractory disease four individuals completed the study with negative cultures, although three were again positive in subsequent months. These data support further investigation of gNO as a potential therapy for NTM-PD.

Aminoglycosides are commonly used to treat infections in CF patients and are highly ototoxic. The incidence of tobramycin-induced hearing loss, tinnitus, vertigo or dizziness (ototoxicity) varies widely from 0 to 56% secondary to variation in patient enrollment, dosing, audiometry, and ototoxic criteria. The aim of this study is to determine the incidence of ototoxicity after one course of once-daily IV tobramycin in CF patients. Adult CF patients with acute pulmonary exacerbations were enrolled on IV tobramycin (10 mg/kg/d, ≥10 days). Pure-tone audiometry was performed for standard and extended high frequencies in the sensitive range for ototoxicity (SRO). American-Speech-Language-Hearing-Association cochleotoxicity criteria were applied. Distortion product otoacoustic emissions (DPOAE) and the words-in-noise-test (WINT) were assessed. Tinnitus Functional Index (TFI) and Vertigo Symptoms Scale (VSS) were used. Eighteen CF patients, mean age 31.1 (18–59), were enrolled. The incidence of cochleotoxic change from baseline at 2 and 4 weeks post-treatment was 89% and 93%. For DPOAE, a measure of outer hair-cell function, the incidence of ≥5 dB decrease was 82% and 80%. For WINT, a measure of word recognition, the incidence of ≥10% decrease was 17% and 40%. For TFI, the incidence of ≥10pt increase was 12% and 8%, and for VSS, the incidence of ≥6pt increase was 0% and 8%. One course of IV tobramycin was sufficient to cause hearing loss and other ototoxic symptoms four weeks after treatment ended. Audiometric measures were more sensitive to ototoxic change than TFI & VSS. Age and duration of tobramycin treatment were not obvious factors for predicting ototoxicity.

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop.

Purpose of review This review will discuss the challenges of defining a pulmonary exacerbations in cystic fibrosis and the key pathogens, which contribute. It will discuss the treatment options currently available and the importance of preventing pulmonary exacerbations. Recent findings The basis for treatment of pulmonary exacerbations remains unchanged over the past 15 years and whilst there have been trials exploring alternative antibiotics, there has been little change. However, there are ongoing studies that are expected to establish a platform for identifying best practices. Chronic cystic fibrosis therapies have been shown to reduce pulmonary exacerbations. In the era of new CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies, the number of pulmonary exacerbations are expected to be even fewer. However, it is unclear whether the other chronic therapies can be discontinued without losing their benefits in reducing exacerbations. Summary Although there is no universal definition of a pulmonary exacerbation in cystic fibrosis, proposed definitions have many similarities. We have outlined the current recommendations for treatment of pulmonary exacerbations, including the duration and location of treatments. We have also summarized the key therapies used for prevention of pulmonary exacerbations in cystic fibrosis.

Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks.Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A.TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV

BACKGROUND: The purpose of these analyses was to determine whether overall costs were reduced in cystic fibrosis (CF) patients experiencing pulmonary exacerbation (PEx) who received shorter versus longer durations of treatment. METHODS: Among people with CF experiencing PEx, we calculated 30-day inpatient, outpatient, emergency room, and medication costs and summed these to derive total costs in 2020 USD. Using the Kaplan-Meier sample average (KMSA) method, we calculated adjusted costs and differences in costs within two pairs of randomized groups: early robust responders (ERR) randomized to receive treatment for 10 days (ERR-10 days) or 14 days (ERR-14 days), and non-early robust responders (NERR) randomized to receive treatment for 14 days (NERR-14 days) or 21 days (NERR-21 days). RESULTS: Patients in the shorter treatment duration groups had shorter lengths of stay per hospitalization (mean ± standard deviation (SD) for ERR-10 days: 7.9 ± 3.0 days per hospitalization compared to 10.1 ± 4.2 days in ERR-14 days; for NERR-14 days: 8.7 ± 4.9 days per hospitalization compared to 9.6 ± 6.5 days in NERR-21 days). We found statistically significantly lower adjusted mean costs (95% confidence interval) among those who were randomized to receive shorter treatment durations (ERR-10 days: $60,800 ($59,150 – $62,430) vs $74,420 ($72,610 – $76,450) in ERR-14 days; NERR-14 days: $66,690 ($65,960–$67,400) versus $74,830 ($73,980–$75,650) in NERR-21 days). CONCLUSIONS: Tied with earlier evidence that shorter treatment duration was not associated with worse clinical outcomes, our analyses indicate that treating with shorter antimicrobial durations can reduce costs without diminishing clinical outcomes.

We report elexacaftor-tezacaftor-ivacaftor (ETI) treatment of a F508del carrier who was pregnant with a F508del homozygous fetus. At 23-weeks gestation meconium ileus (MI) was evident on ultrasound including dilated, hyperechoic bowel, which persisted on subsequent imaging. Through shared decision-making, the mother began ETI at 32 weeks with intent to treat fetal MI. The ultrasound findings persisted at treatment day 13, but bowel dilation had resolved by imaging on treatment day 27. A female infant was delivered vaginally at 36 weeks with no complications. The mother continued ETI while breastfeeding. Stool elastase at age 2 weeks was 240 mcg/g. Sweat chloride measurement was 64 and 62 mEq/L. Maternal and infant liver function testing have been normal. Maternal ETI treatment likely led to resolution of the MI and there is evidence supporting continued infant benefit through breastmilk. Logistical and ethical considerations regarding treatment of a carrier mother for infant benefit are discussed.

Background Mycobacterial time to positivity (TTP) in liquid culture media has predictive value for longer term outcomes in pulmonary tuberculosis, but has not been thoroughly studied in nontuberculous mycobacterial pulmonary disease. This study sought to evaluate for association between TTP and sputum culture conversion to negative in pulmonary disease caused by Mycobacterium avium complex (MAC). Methods Data from the CONVERT trial (NCT02344004) that evaluated efficacy of guideline-based-therapy with or without amikacin liposome inhalation suspension in adults with refractory MAC-PD (Mycobacterium avium complex pulmonary disease) were analyzed. We evaluated TTP measures for sputum obtained prior to study treatment initiation and at monthly visits, assessing reproducibility of measures as well as association of TTP with culture conversion on treatment. Results Data from 71 participants with at least one screening visit TTP value were analyzed. For participants who provided more than one sputum sample at a given visit, there was moderate between-sample reliability, with median intraclass correlation coefficient 0.62 (IQR 0.50, 0.70). Median TTP at screening was longer in those participants who subsequently achieved vs. did not achieve culture conversion (10.5 [IQR 9.4] days vs. 4.2 [IQR 2.8] days, p = 0.0002). Individuals with culture conversion by study treatment month 6 were more likely to have a screening TTP > 5 days compared to those who did not achieve culture conversion (OR 15.4, 95% CI 1.9, 716.7, p = 0.0037) and had increasing TTPs over time. Conclusions TTP prior to and on treatment is associated with microbiological treatment response in patients with MAC-PD.

Introduction : Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822. Methods : Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression. Results : Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to –11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was –26 [–29, –23]. Odds of –26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041). Conclusions : CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.

Cystic fibrosis (CF) lung disease is characterized by the development of progressive bronchiectasis and impaired lung function with severe airflow obstruction. CF patients suffer from shortened life expectancy, primarily driven by respiratory failure. The mechanism by which CF lung disease develops is the result of an interplay of multiple intrinsic and extrinsic factors including genotype, abnormalities in mucus composition and movement, chronic inflammation, and chronic airway infection. Although all CF patients are at increased risk for pulmonary complications including hemoptysis, pneumothorax, pulmonary hypertension, and chronic hypoxic and hypercapnic respiratory failure, the risk of developing these complications increases with progression of lung disease. The focus of this article is to summarize the pathophysiology, epidemiology, and management of these key pulmonary complications.

Background We explored the time-dependent impact of pulmonary exacerbations (PEx) on health-related quality of life (HRQoL) using Cystic Fibrosis Questionnaire–Revised (CFQ-R) data from 2 large cystic fibrosis (CF) trials. Methods This exploratory post-hoc analysis evaluated the impact of PEx on CFQ-R domains of functioning in 80 patients with CF (homozygous for F508del-CFTR), aged ≥14 years randomized to placebo in the TRAFFIC and TRANSPORT trials who experienced 1 PEx. Results Scores on the CFQ-R were significantly lower within 1 week of PEx start in 8 out of 12 domains (Respiratory Symptoms, Physical Functioning, Emotional Functioning, Health Perceptions, Role Functioning, Social Functioning, Eating, and Vitality). Patients whose PEx was treated with hospitalization or intravenous antibiotics had greater reductions in some domains of HRQoL compared with those treated with oral antibiotics. In the immediate weeks post-PEx, improvement was seen on Emotional Functioning, Respiratory Symptoms, and Health Perceptions, while further decline was seen for Eating, Physical Functioning, Role Functioning, Vitality, and Weight. For some measures (Physical Functioning, Vitality), full recovery to pre-PEx levels took several weeks. Conclusions Pulmonary exacerbations have significant effects on multiple domains of HRQoL, and recovery across multiple domains post-PEx can take several weeks. These findings provide insight into the impact of PEx on patient HRQoL and recovery post-PEx. Clinical trial registration: ClinicalTrials.gov identifiers, NCT01807923 and NCT01807949

Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward.

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic

Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a 300% increase in overweight status, and400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was$20,000, having at least one allele with a class IV or V mutation, a ppFEV

BACKGROUND Asymptomatic colonization by nontuberculous mycobacteria (NTM) found in sputum isolates are commonly encountered and clinicians lack a biomarker for prognosticating the risk of transition asymptomatic colonization to active clinical disease. Chest computed tomography (CT) imaging is commonly obtained in this patient population and may serve a role for this purpose. METHODS We conducted a single-center, cross-sectional study of patients followed in the NTM clinic at our center between August 2019 and August 2020. All patients had a history of NTM isolated from their airways and were cohorted as either nontuberculous mycobacteria-pulmonary disease (NTM-PD) if they met ATS/IDSA guidelines for treatment or as nontuberculous mycobacteria-colonized (NTM-C) if they did not meet ATS/IDSA criteria for NTM treatment. Patients with a chest CT were included in the analysis and CT scans were assessed for features including bronchiectasis, nodules, and cavities. Bronchiectasis severity was calculated using the modified Reiff scoring system. Univariate analyses were conducted to compare patients with NTM-C and NTM-PD. RESULTS Eighty-four patients were included in the analysis and 27 were classified as NTM-C and 57 as NTM-PD. NTM-PD patients had a greater median number of lung lobes affected by bronchiectatic airways (6 [1] NTM-PD vs. 5 [3] NTM-C P=0.005) and a greater frequency of cystic bronchiectasis (17.5% NTM-PD vs. 0% NTM-PD, P=0.016). Bronchiectasis severity was higher for NTM-PD patients (7 [9] NTM-PD vs. 5 [1.5] NTM-C, P

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Introduction: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. Methods: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. Results: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17–129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12–13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. Conclusions: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.