EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

Sex differences in treatment patterns in cystic fibrosis pulmonary exacerbations.

BACKGROUND: Females with cystic fibrosis (CF) have been shown to have worse pulmonary exacerbation (PEx) related outcomes compared to males. However, it is unknown if sex differences in treatment patterns are contributing to these outcomes. Thus, we sought to explore sex differences in treatment patterns in the Standardized Treatment of Pulmonary Exacerbations (STOP) cohort. METHODS: Data for 220 participants from the STOP cohort were analyzed. Multivariable regression models were used to assess if female sex was associated with duration of treatment with IV antibiotics and inpatient length of stay. Secondary outcomes included antibiotic selection, adjunctive therapies, mean FEV1pp and CFRSD-CRISS respiratory symptom scores at the four study assessments. RESULTS: In our adjusted model, the average number of IV antibiotic treatment days was 13% higher in females compared to males (IRR 1.13, 95% CI=1.02,1.25; p=0.02). We found no sex differences in inpatient length of stay, number of IV antibiotics, antibiotic selection or initiation of adjunctive therapies. Overall, females had higher CFRSD-CRISS scores at the end of IV therapy indicating worse symptom severity (23.6 for females vs. 18.5 for males, p=0.03). CONCLUSIONS: Despite females having a longer treatment duration, our findings demonstrate that males and females are receiving similar treatments which suggest that the outcome disparities in females with CF may not be due to failure to provide the same level of care. Further research dedicated to sex differences in CF is necessary to understand why clinical outcomes differ between males and females.

Out-of-clinic measurement of sweat chloride using a wearable sensor during low-intensity exercise.

Wearable sensors have the potential to enable measurement of sweat chloride outside the clinic. Here we assess the feasibility of mild exercise as an alternative to pilocarpine iontophoresis for sweat generation. The results from this proof-of-concept study suggest that mild exercise could be a feasible approach to obtain reliable measurements of sweat chloride concentration within 20-30 min using a wearable sensor.

Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis.

BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history. METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period. RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ±â€¯13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ±â€¯21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up. CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.

Eradication of persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

BACKGROUND: The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in individuals with cystic fibrosis (CF) has increased significantly. While studies demonstrate that persistent MRSA infection in CF is associated with poor clinical outcomes, there are no randomized controlled studies informing management. METHODS: The Persistent MRSA Eradication Protocol was a double-blind, randomized, placebo-controlled study investigating a comprehensive 28-day treatment regimen with or without inhaled vancomycin for eradication of MRSA. Eligible participants had CF and documented persistent MRSA infection. All participants received oral antibiotics, topical decontamination, and environmental cleaning and were randomized to receive inhaled vancomycin or inhaled placebo. The primary outcome was the difference in MRSA eradication rates one month after completion of the treatment protocol. RESULTS: 29 participants were randomized. Four subjects in the inhaled vancomycin group required withdrawal from the study for bronchospasm before outcome data were collected and were excluded from analysis. There was no difference in the primary outcome: 2/10 (20%) of subjects in the intervention group and 3/15 (20%) in the placebo group had a MRSA negative sputum culture one month after treatment. There were no statistically significant differences in the rates of MRSA eradication at the end of treatment or three months after treatment completion. CONCLUSIONS: This study suggests that persistent MRSA infection is difficult to eradicate, even with multimodal antibiotics. The use of a single course of inhaled vancomycin may not lead to higher rates of MRSA eradication in individuals with CF and may be associated with bronchospasm. FUND: This trial was financially supported by the Cystic Fibrosis Foundation.

Cystic Fibrosis: Translating Molecular Mechanisms into Effective Therapies.

Cystic fibrosis is a genetic disease that affects approximately 75,000 individuals around the world. Long regarded as a lethal and life-limiting disease, with the most severe manifestations expressed in the progressive decline of lung function, treatment advances focusing on airway clearance and management of chronic lung infection have resulted in improved outcomes for individuals with cystic fibrosis. These advances have been realized in conjunction with an improved understanding of the genetic basis of this disease, dating back to the discovery of the cystic fibrosis gene in 1989. The identification of the cystic fibrosis gene and the advancement of our understanding of the resultant cystic fibrosis transmembrane conductance regulator protein have led to the development of a new class of cystic fibrosis therapies designed to directly impact the function of this protein. These therapeutic developments have progressed, targeting the various mutations that can cause cystic fibrosis. These new medications, known as cystic fibrosis transmembrane conductance regulator modulators, have changed the landscape of cystic fibrosis care and cystic fibrosis research. Their demonstrated effect in patients with specific cystic fibrosis mutations has ignited the hope that such therapies will soon be available to more individuals with this disease, moving the cystic fibrosis community significantly closer to the ultimate goal of curing this disease.

Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis.

BACKGROUND: Aspergillus species are increasingly detected in the respiratory tracts of individuals with cystic fibrosis (CF), and chronic Aspergillus fumigatus is associated with more frequent hospitalizations for pulmonary exacerbations. However, patient and clinical factors that may contribute to the acquisition of persistent Aspergillus infection have yet to be identified. The objective of this study was to identify risk factors for development of Aspergillus respiratory isolation in CF. METHODS: A retrospective cohort study of participants in the CF Foundation Patient Registry between 2006 and 2012 was conducted. Generalized estimating equation models were used to evaluate the association between the development of persistent Aspergillus respiratory isolation and individual level demographic and clinical characteristics. RESULTS: Among 16,095 individuals with CF followed from 2006 to 2012, 1541 (9.6%) subjects developed persistent Aspergillus isolation. White race (Odds Ratio [OR] 1.74, 95% confidence interval 1.23, 2.48, p<0.001) and pancreatic insufficiency (OR 1.50, 95% CI 1.09, 2.06, p<0.001) were found to be risk factors for persistent Aspergillus isolation. Chronic therapies, including inhaled antibiotics (OR 1.33; 95% CI 1.21, 1.46), macrolides (OR 1.23, 95% CI 1.14, 1.32, p<0.001), and inhaled corticosteroids (OR 1.13, 95% CI 1.04, 1.20, p<0.001) were also independently associated with an increased risk for persistent Aspergillus isolation. CONCLUSIONS: We identified macrolides and inhaled antibiotics, which individually have been shown to improve CF outcomes, and inhaled corticosteroids as risk factors for developing persistent Aspergillus isolation. Further work is needed to determine whether these associations are causal or due to confounding by other factors.

Frequency of small-colony variants and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus in cystic fibrosis patients.

BACKGROUND: Small-colony variants (SCVs) are a distinct phenotype of Staphylococcus aureus, known for their role in chronic, difficult to treat infections, including cystic fibrosis (CF) lung disease. The goal of this study was to characterize SCV MRSA infection in an adult and pediatric CF population and to identify antibiotic susceptibility patterns unique to SCV MRSA. METHODS: We recovered methicillin-resistant S. aureus (MRSA) from respiratory culture samples from CF patients at the Johns Hopkins Hospital during a 6month study period. RESULTS: Of 1161 samples, 200 isolates (17%) were identified as MRSA, and 37 isolates from 28 patients were identified as SCV MRSA. A higher proportion of MRSA was found among SCV isolates (37/66, 56%) compared to normal colony variant (NCV) isolates (163/417, 39%), p=0.02. All SCV MRSA isolates from individual patients were susceptible to vancomycin and ceftaroline, but they demonstrated higher rates of antibiotic resistance to trimethoprim/sulfamethoxazole, moxifloxacin, and erythromycin, compared to NCV MRSA isolates. Additionally, individuals with SCV MRSA had lower lung function, higher rates of persistent MRSA infection, and higher rates of previous antibiotic use, compared to individuals with NCV MRSA. CONCLUSIONS: A significant proportion of MRSA isolates recovered from patients with CF have the SCV morphology. Compared to individuals with NCV MRSA, those with SCV MRSA have higher rates of persistent MRSA infection and lower lung function. SCV MRSA isolates were more resistant than NCV, but they are highly susceptible to vancomycin, linezolid and ceftaroline.

Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important pathogen in cystic fibrosis (CF). Over 25% of individuals in the United States with CF are found to have MRSA in respiratory culture specimens, and persistent MRSA infection has been associated with more rapid decline in lung function and increased mortality. The objective of this study was to investigate clinical and demographic characteristics that are associated with the development of persistent MRSA infection in a CF population. METHODS: This was a retrospective cohort study of individuals followed from 2002 to 2012 in the Cystic Fibrosis Foundation Patient Registry. A time-to-event analysis for the development of persistent MRSA infection was performed, and multivariable Cox proportional hazards models were constructed to identify risk factors for infection. RESULTS: The study cohort included 19,434 individuals, of which 5844 would develop persistent MRSA infection. In the adjusted model, pancreatic insufficiency (HR: 1.49; 95% CI: 1.29-1.72), CF related diabetes (HR: 1.13; 95% CI: 1.05-1.20), co-infection with P. aeruginosa (HR: 1.21; 95% CI: 1.13-1.28), and number of hospitalizations/year (HR: 1.09; 95% CI: 1.06-1.12) were all associated with increased risk, whereas higher socio-economic status (HR: 0.87; 95% CI: 0.82-0.93) was associated with a lower risk. Receiving care at a CF center with increased MRSA prevalence was associated with increased risk of MRSA infection: highest quartile (HR: 2.33; 95% CI: 2.13-2.56). CONCLUSIONS: No easily modifiable risk factors for persistent MRSA were identified in this study. However, several risk factors for patients at higher risk for persistent MRSA infection were identified, for example centers with a high baseline MRSA prevalence, and may be useful in designing center-specific MRSA infection prevention and control strategies and/or eradication protocols. Additional studies are needed in order to evaluate if attention to these risk factors can improve clinical outcomes.

An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor.

RATIONALE: In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation. OBJECTIVE: As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF. RESULTS: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor. Patients were followed from 1 year before drug initiation to up to 11 months postinitiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial. Of 116 individuals identified who started lumacaftor/ivacaftor treatment, 46 (39.7%) reported adverse effects related to lumacaftor/ivacaftor, with the vast majority (82.2%) being pulmonary adverse effects, and 20 (17.2%) discontinued lumacaftor/ivacaftor because of adverse effects. The mean change in FEV1% predicted was 0.11% (range: -39% to +20%; P = 0.9). Nineteen individuals had an FEV1% predicted of 40% or less before treatment, and there was a higher percentage of patients in this subgroup who reported adverse effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female sex was associated with a higher odds of drug discontinuation (adjusted odds ratio, 3.12, 95% confidence interval, 1.04-9.38). CONCLUSIONS: This study highlights the prevalence of adverse effects in a CF population newly exposed to lumacaftor/ivacaftor and demonstrates a relatively high rate of drug intolerance.

Eradication strategy for persistent methicillin-resistant Staphylococcus aureus infection in individuals with cystic fibrosis--the PMEP trial: study protocol for a randomized controlled trial.

BACKGROUND: The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) respiratory infection in cystic fibrosis (CF) has increased dramatically over the last decade, and is now affecting approximately 25% of patients. Epidemiologic evidence suggests that persistent infection with MRSA results in an increased rate of decline in FEV1 and shortened survival. Currently, there are no conclusive studies demonstrating an effective and safe treatment protocol for persistent MRSA respiratory infection in CF. METHODS/DESIGN: The primary objective of this study is to evaluate the safety and efficacy of a 28-day course of vancomycin for inhalation in combination with oral antibiotics in eliminating MRSA from the respiratory tract of individuals with CF and persistent MRSA infection. This is a two-center, randomized, double-blind, comparator-controlled, parallel-group study with 1:1 assignment to either vancomycin for inhalation (250 mg twice a day) or taste-matched placebo for 28 days in individuals with cystic fibrosis. In addition, both groups will receive oral rifampin, a second oral antibiotic - trimethoprim/sulfamethoxazole (TMP/SMX) or doxycycline, protocol determined - mupirocin intranasal cream, and chlorhexidine body washes. Forty patients with persistent respiratory tract MRSA infection will be enrolled: 20 will be randomized to vancomycin for inhalation and 20 to a taste-matched placebo. The primary outcome will be the presence of MRSA in sputum respiratory tract cultures 1 month after the conclusion of treatment. Secondary outcomes include the efficacy of the intervention on: FEV1% predicted, patient reported outcomes, pulmonary exacerbations, and MRSA colony-forming units found in respiratory tract sample culture. DISCUSSION: Results of this study will provide guidance to clinicians regarding the safety and effectiveness of a targeted eradication strategy for persistent MRSA infection in CF. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT01594827, received 05/07/2012) and is funded by the Cystic Fibrosis Foundation (Grants: PMEP10K1 and PMEP11K1).

Update on key emerging challenges in cystic fibrosis.

Cystic fibrosis (CF) is a multisystem disease causing severe chronic sinopulmonary disease and loss of pancreatic exocrine function, which affects approximately 70,000 individuals worldwide. New therapeutic developments over the last few decades have resulted in a significant increase in survival, with the median predicted survival now reaching the late thirties and more and more CF patients living well into adulthood. However, with this advent of new therapies and the associated increase in survival, new challenges in CF care have also emerged. Two of these challenges, i.e. chronic methicillin-resistant Staphylococcus aureus lung infection and patient adherence to very complicated and time-consuming therapeutic regimens, are reviewed in detail here. In addition, the ultimate challenge of treating the underlying cause of CF by correcting the dysfunction of the CF transmembrane conductance regulator chloride channel is reviewed, as agents to correct channel function will likely significantly alter CF clinical outcomes and treatment approaches in the next decade.

Differential responsiveness among "high risk" pediatric brain tumors in a pilot study of dose-intensive induction chemotherapy.

BACKGROUND: These factors have been predictive for progressive disease on therapy (PDOT) among pediatric brain tumors: >1.5 cm(2) unresectable tumor, glioblastoma, supratentorial primitive neuroectodermal tumor, and metastatic medulloblastoma (MBL). This pilot study sought to correlate cytoreductive response with progression free survival. PROCEDURES: Four courses of cisplatinum, cyclophosphamide, etoposide, and vincristine preceded hyperfractionated radiotherapy (RT). Maintenance chemotherapy consisted of eight cycles of carboplatin, etoposide, and vincristine. Biopsy specimens were immunohistochemically studied for labeling index, hypoxia, and multidrug resistance proteins. RESULTS: Twenty newly diagnosed patients [nine primitive neuroectodermal tumors/MBL, one choroid plexus carcinoma, eight malignant gliomas, and two anaplastic ependymomas] were treated. Ten patients, who required neuraxis irradiation, constituted the "PNET" group. These demonstrated five complete and one partial response (PR), with an estimated median progression free survival of 44 months and median survival in excess of 53 months. Patients treated with involved field irradiation were designated the "Glioma" group. Induction chemotherapy produced partial and minor responses (MRs) among 5/10. Their estimated median progression free survival was 6.9 months (P = 0.035 relative to the PNET) with a median survival of 10.7 months (P = 0.04). Age, labeling index, the presence of hypoxia, and Pgp/MDR1 expression failed to discriminate between the two groups. CONCLUSIONS: This induction regimen produced a cytoreductive response in 6/10 and achieved a significant improvement in progression free survival among 7/10 in the PNET group. Unfortunately, responses among Glioma patients did not translate into durable control. Expression of the biologic factors was similar between both groups and did not correlate with diagnosis or response.

Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group.

PURPOSE: This Children's Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Pneumocystis carinii pneumonia in a girl with a midbrain glioma.

A 7-year-old girl with a midbrain glioma contracted Pneumocystis carinii pneumonia (PCP) in the absence of cytotoxic or corticosteroid therapy. Gliomas are known to cause immunosuppression, and PCP prophylaxis should be considered for patients with these tumors.