73 results on '"KEREM, E."'
Search Results
2. The new face of cystic fibrosis in the era of population genetic carrier screening.
- Author
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Dotan M, Blau H, Singer A, Stafler P, Prais D, Cohen-Cymberknoh M, Reiter J, Efrati O, Dagan A, Bentur L, Gur M, Livnat G, Yaacoby-Bianu K, Aviram M, Golan Tripto I, Bar-On O, Matar R, Hagit S, Malcov M, Altarescu G, Segev H, Feldman B, Kerem E, and Mei-Zahav M
- Subjects
- Humans, Retrospective Studies, Female, Israel epidemiology, Male, Infant, Newborn, Infant, Genetic Testing methods, Genetic Testing statistics & numerical data, Child, Registries, Pregnancy, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Preimplantation Diagnosis statistics & numerical data, Preimplantation Diagnosis methods, Cystic Fibrosis genetics, Cystic Fibrosis diagnosis, Cystic Fibrosis epidemiology, Genetic Carrier Screening methods
- Abstract
Background: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features., Methods: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected., Results: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p= 0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04)., Conclusions: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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3. Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.
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Cohen-Cymberknoh M, Ariel Dabby M, Gindi Reiss B, Melo Tanner J, Pérez G, Lechtzin N, Polverino E, Perez Miranda J, Gramegna A, Aliberti S, Levine H, Mussaffi H, Blau H, Prais D, Mei-Zahav M, Shteinberg M, Livnat G, Gur M, Bentur L, Downey DG, Dagan A, Golan-Tripto I, Aviram M, Mondejar-Lopez P, Picard E, Schwarz C, Jakubec P, Kazmerski TM, Amsalem H, Hochner Celnikier D, Kerem E, and Reiter J
- Subjects
- Humans, Female, Pregnancy, Adult, Retrospective Studies, Young Adult, Infant, Newborn, Adolescent, Parity, Middle Aged, Pregnancy Complications epidemiology, Disease Progression, Premature Birth epidemiology, Pregnancy, Multiple, Severity of Illness Index, Risk Factors, Cystic Fibrosis complications, Pregnancy Outcome
- Abstract
Background: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown., Methods: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy., Results: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV
1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications., Conclusions: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies., Competing Interests: Declaration of competing interest MCC received honoraria for lectures from Vertex. EP received a grant from Grifols; consulting fees from Moderna, Pfizer, Insmed and Chiesi; honoraria for lectures from Moderna, Pfizer, Vertex, GSK, TEVA, Chiesi and Insmed; payment for expert testimony from Chiesi; and support for attending meetings from Moderna, Pfizer, Vertex, GSK and Insmed. AG received consuting fees (personal) from Vertex, Menarini and Zambon; honoraria for lectures (personal) from Insmed and Vertex; support for attending meetings from Neupharma and Zambon; and payment (personal) for participation on a Data Safety Monitoring (DSM) Board or Advisory Board from Vertex. She is also an Associate Editor for Respiratory Research, Managment board member at IRENE NTM network and ERS chair Adult CF group-assembly 10. DP received consulting fees from Vertex. MMZ received support from the ECFS to attend the European CF meeting 2023. MS received grants from GSK and Trudell pharma; consulting fees (personal) from AstraZeneca, Boehringer Ingelheim, Dexel, Kamada, Synchrony medical, Trumed and Zambon; honoraria for lectures (personal) from AstraZeneca, Boehringer Ingelheim, Kamada and Sanofi; support for attending meetings from Boehringer Ingelheim, AstraZeneca and Kamada; payment (personal) for participating on DSM Board or Advisory Board from Bonus Biotherapeutics, Boehringer Ingelheim and AstraZeneca; and received oPEP devices for clinical trial from Trudell Medical International. She is also an Associate Editor at AJRCCM; Management board member at the Israeli Pulmonology society, Israeli society for Tuberculosis and mycobacterial diseases; and Editorial board member: Chest ERJ taskforce-bronchiectasis guidelines. DGD received grants from Chiesi; consulting fees from Vertex, Proteostasis and Insmed; honoraria for lectures from Chiesi and Gilead. He is also the current Director of the European CF Society Clinical Trials Network. PML received grant (institution) and payment for testimony (personal) from Vertex; consulting fees and honoraria for lectures (personal) from Vertex and Chiesi; support for attending meetings (personal) from Chiesi, Pari and AstraZeneca; and participation on a DSM Board or Advisory Board for Vertex and AstraZeneca. PJ received consulting fees from Centrum hydraulického výzkumu spol. s.r.o.; honoraria for lectures from MSD and Vertex; support for attending meetings, and participation on a DSM Board or Advisory Board from Chiesi: and leadership or fiduciary role in Vertex. TMK received a grant from the Cystic Fibrosis Foundation and the National Institutes of Health; consulting fees from the Cystic Fibrosis Foundation; and honoraria for lectures from the Johns Hopkins Institute. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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4. ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.
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De Wachter E, De Boeck K, Sermet-Gaudelus I, Simmonds NJ, Munck A, Naehrlich L, Barben J, Boyd C, Veen SJ, Carr SB, Fajac I, Farrell PM, Girodon E, Gonska T, Grody WW, Jain M, Jung A, Kerem E, Raraigh KS, van Koningsbruggen-Rietschel S, Waller MD, Southern KW, and Castellani C
- Subjects
- Humans, Genetic Counseling, Genetic Testing methods, Infant, Newborn, Cystic Fibrosis therapy, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Standard of Care
- Abstract
After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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5. Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.
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Sadras I, Kerem E, Livnat G, Sarouk I, Breuer O, Reiter J, Gileles-Hillel A, Inbar O, Cohen M, Gamliel A, Stanleigh N, Gunawardena T, Bartlett C, Gonska T, Moraes T, Eckford PDW, Bear CE, Ratjen F, Kerem B, Wilschanski M, Shteinberg M, and Cohen-Cymberknoh M
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- Humans, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Mutation, Benzodioxoles therapeutic use, Aminophenols therapeutic use, Chloride Channel Agonists therapeutic use, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics
- Abstract
Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA., Methods: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment., Results: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m
2 , and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity., Conclusions: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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6. Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children.
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Orenti A, Pranke I, Faucon C, Varilh J, Hatton A, Golec A, Dehillotte C, Durieu I, Reix P, Burgel PR, Grenet D, Tasset C, Gachelin E, Perisson C, Lepissier A, Dreano E, Tondelier D, Chevalier B, Weiss L, Kiefer S, Laurans M, Chiron R, Lemonnier L, Marguet C, Jung A, Edelman A, Kerem BS, Girodon E, Taulan-Cadars M, Hinzpeter A, Kerem E, Naehrlich L, and Sermet-Gaudelus I
- Subjects
- Adolescent, Humans, Child, Codon, Nonsense, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Forced Expiratory Volume, RNA, Messenger, Mutation, Cystic Fibrosis genetics, Cystic Fibrosis metabolism
- Abstract
Rationale: Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del+/+)., Methods: Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC (n = 657) were compared with F508del+/+ (n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF., Main Results: As compared to F508del+/+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV
1 ) from 7 years (-1.33 for F508del +/+, -1.59 for F508del/PTC; -1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del +/+, -1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del +/+, -1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del+/+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level., Conclusions: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)- Published
- 2023
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7. Impact of gut microbiota on liver transplantation.
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Sucu S, Basarir KE, Mihaylov P, Balik E, Lee JTC, Fridell JA, Emamaullee JA, and Ekser B
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- Animals, Humans, Liver, Immunosuppressive Agents, Liver Transplantation, Gastrointestinal Microbiome, Liver Diseases surgery
- Abstract
The gut microbiota has been gaining attention due to its interactions with the human body and its role in pathophysiological processes. One of the main interactions is the "gut-liver axis," in which disruption of the gut mucosal barrier seen in portal hypertension and liver disease can influence liver allograft function over time. For example, in patients who are undergoing liver transplantation, preexisting dysbiosis, perioperative antibiotic use, surgical stress, and immunosuppressive use have each been associated with alterations in gut microbiota, potentially impacting overall morbidity and mortality. In this review, studies exploring gut microbiota changes in patients undergoing liver transplantation are reviewed, including both human and experimental animal studies. Common themes include an increase in Enterobacteriaceae and Enterococcaceae species and a decrease in Faecalibacterium prausnitzii and Bacteriodes, while a decrease in the overall diversity of gut microbiota after liver transplantation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Burcin Ekser, MD, PhD reports administrative support was provided by Indiana University School of Medicine. Burcin Ekser reports a relationship with American Society of Transplant Surgeons that includes: speaking and lecture fees., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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8. Acute pancreatitis in pancreatic-insufficient cystic fibrosis patients treated with CFTR modulators.
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Sadras I, Cohen-Cymberknoh M, Kerem E, Koplewitz BZ, Simanovsky N, Wilschanski M, Birimberg-Schwartz L, and Breuer O
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- Humans, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator therapeutic use, Quality of Life, Acute Disease, Aminophenols therapeutic use, Benzodioxoles therapeutic use, Mutation, Cystic Fibrosis complications, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Pancreatitis chemically induced, Pancreatitis diagnosis, Pancreatitis drug therapy
- Abstract
Cystic fibrosis transmembrane conductance regulator modulator therapy is associated with substantial clinical benefit and improved quality of life in patients with cystic fibrosis (CF). While their effect on lung function has been clearly reported, we are still in the process of unraveling the full impact they have on the pancreas. We present two cases of pancreatic-insufficient CF patients who presented with acute pancreatitis shortly after commencing elexacaftor/tezacaftor/ivacaftor modulator therapy. Both patients were treated with ivacaftor for 5 years prior to elexacaftor/tezacaftor/ivacaftor initiation, but had no previous episodes of acute pancreatitis. We suggest that highly effective modulator combination therapy may restore additional pancreatic acinar activity, resulting in the development of acute pancreatitis in the interim until ductal flow is improved. This report adds to the growing evidence for possible restoration of pancreatic function in patients receiving modulator therapy, and highlights that treatment with elexacaftor/tezacaftor/ivacaftor may be associated with acute pancreatitis until ductal flow is restored, even in pancreatic-insufficient CF patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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9. The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF).
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Cohen-Cymberknoh M, Dimand I, Tanny T, Blau H, Mussaffi H, Kadosh D, Gartner S, Bentur L, Nir V, Gur M, Reiter J, Kerem E, and Berger I
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- Child, Humans, Adolescent, Young Adult, Adult, Middle Aged, Aged, Quality of Life, Patient Acuity, Lung, Chronic Disease, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Cystic Fibrosis epidemiology, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity epidemiology, Attention Deficit Disorder with Hyperactivity etiology
- Abstract
Background: The hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data., Methods: Based on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7-68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV
1 )%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers., Results: A positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters., Conclusion: There is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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10. Disease severity of people with cystic fibrosis carrying residual function mutations: Data from the ECFS Patient Registry.
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Mei Zahav M, Orenti A, Jung A, Hatziagorou E, Olesen HV, and Kerem E
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- Humans, Young Adult, Adult, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator therapeutic use, Quality of Life, Mutation, Patient Acuity, Registries, Cystic Fibrosis diagnosis, Cystic Fibrosis epidemiology, Cystic Fibrosis genetics
- Abstract
Rational: People with cystic fibrosis carrying residual function (RF) mutations are considered to have a mild disease course. This may influence caregivers and patients on how intensive the treatments should be., Objectives: Characterize disease severity of patients carrying RF mutations, using the European CF Society Patient Registry (ECFSPR) data., Methods: Demographic, clinical characteristics, lung function and death probability of patients carrying at least one RF mutation were analyzed and compared to patients homozygous to minimal function mutations (MF)., Main Results: Of the 44,594 eligible patients (median age 19.5 years, IQR 10-29.8), 6,636 (14.6%) carried RF mutations, and 37,958 (85.1%) MF mutations. Patients carrying RF mutations were older, diagnosed at a later age, had lower sweat chloride at diagnosis and better FEV1pp at each age group. However, their FEV1pp declined with age and rates of chronic Pseudomonas aeruginosa increased with age. A significant number of patients with RF had FEV1pp similar to patients with MF at each age group. 4.5% of RF patients were treated with oxygen and 2.61% had a lung transplant. With increasing age, 26.6% of RF patients were treated with pancreatic enzymes associated with a more severe lung disease. RF patients had shortened life spans, with mortality starting around the age of 20 years., Conclusions: Patients carrying an RF mutations experience a decline of pulmonary function with age, leading to life-shortening. Standard of care therapies and augmenting CFTR function may improve their survival and quality of life., Competing Interests: Declaration of Competing Interest This research did not receive funding from any agency in the public, commercial, or not-for-profit sectors. Authors have no conflict of interest., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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11. Clinical outcomes associated with Achromobacter species infection in people with cystic fibrosis.
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Kerem E, Orenti A, Zolin A, Annicchiarico L, and Drevinek P
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- Humans, Young Adult, Adult, Lung, Pseudomonas aeruginosa, Cystic Fibrosis complications, Cystic Fibrosis epidemiology, Cystic Fibrosis microbiology, Achromobacter genetics, Gram-Negative Bacterial Infections diagnosis, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections epidemiology, Respiratory Tract Infections microbiology
- Abstract
Background: Achromobacter species are emerging pathogens isolated from respiratory samples of Patients with cystic fibrosis (pwCF) causing growing concerns in the CF community. The epidemiology and the clinical impact of Achromobacter in CF is unclear since data are restricted to small case control studies or selected populations., Aim: To characterize the effect of Achromobacter respiratory infection on CF lung disease., Methods: European CF Society Patient Registry data was analysed for association between Achromobacter infection and demographic/clinical characteristics and outcomes of pwCF., Results: Of eligible 38,795 patients, Achromobacter infection was reported in 2,093 (prevalence (95% CI) of 5.40% (5.17 - 5.62). The prevalence varied significantly between the countries and increased with age peaking at the age 20-30. Achromobacter infection was more prevalent in pwCF carrying class minimal function mutations, having worse nutrition or lower pulmonary function, and more patients inhaled antibiotics against P. aeruginosa. Patient infected with Achromobacter had similar pulmonary function and BMI to patients infected with P. aeruginosa at all age groups. Being infected with both bacteria was associated with significantly lower pulmonary function and BMI at all age groups., Conclusions: Achromobacter infection was associated with disease severity similar to infection with P. aeruginosa. Being infected with both bacteria is associated with even more severe disease. This suggests to study if eradication will improve the outcome of pwCF., (Copyright © 2022. Published by Elsevier B.V.)
- Published
- 2023
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12. Antisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutation.
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Oren YS, Avizur-Barchad O, Ozeri-Galai E, Elgrabli R, Schirelman MR, Blinder T, Stampfer CD, Ordan M, Laselva O, Cohen-Cymberknoh M, Kerem E, Bear CE, and Kerem B
- Subjects
- Codon, Nonsense, Humans, Mutation, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense metabolism, Oligonucleotides, Antisense pharmacology, RNA Splicing genetics, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism
- Abstract
Background: Antisense oligonucleotide- based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, to eliminate the W1282X nonsense mutation and avoid RNA degradation induced by the nonsense mediated mRNA decay mechanism, allowing production of partially active CFTR proteins lacking exon 23., Methods: ∼80 ASOs were screened in 16HBEge W1282X cells. ASO candidates showing significant exon skipping were assessed for their W1282X allele selectivity and the increase of CFTR protein maturation and function. The effect of a highly potent ASO candidates was further analyzed in well differentiated primary human nasal epithelial cells, derived from a W1282X homozygous patient., Results: ASO screening led to identification of several ASOs that significantly decrease the level of CFTR transcripts including exon 23. These ASOs resulted in significant levels of mature CFTR protein and together with modulators restore the channel function following free uptake into these cells. Importantly, a highly potent lead ASOs, efficiently delivered by free uptake, was able to increase the level of transcripts lacking exon 23 and restore the CFTR function in cells from a W1282X homozygote patient., Conclusion: The highly efficient exon 23 skipping induced by free uptake of the lead ASO and the resulting levels of mature CFTR protein exhibiting channel function in the presence of modulators, demonstrate the ASO therapeutic potential benefit for CF patients carrying the W1282X mutation with the objective to advance the lead candidate SPL23-2 to proof-of-concept clinical study., Competing Interests: Declaration of competing interest Batsheva Kerem has equity in SpliSense and is paid for consultancy. All other authors have no financial conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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13. Ethical Dilemma: Elexacaftor-Tezacaftor-Ivacaftor or Lung Transplantation in Cystic Fibrosis and End-Stage Lung Disease?
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Breuer O, Shoseyov D, Koretz S, Alyan N, Reiter J, Cohen-Cymberknoh M, Wexler I, and Kerem E
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- Aminophenols therapeutic use, Benzodioxoles, Child, Chloride Channel Agonists therapeutic use, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Drug Combinations, Humans, Indoles, Lung, Mutation, Pyrazoles, Pyridines, Pyrrolidines, Quinolones, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Lung Transplantation
- Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of this disease. We present an ethical dilemma involving an 11-year-old child with CF and end-stage lung disease. Shortly after starting treatment with elexacaftor-tezacaftor-ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other are limited. A survey of CF center team members was conducted for the purpose of this article. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared with other team members, are more likely to provide a specific recommendation vs presenting the information to the family and letting them decide (OR, 4.0; 95% CI, 1.2-12.8; P = .021). A shared decision-making model, stressing our moral obligation as physicians to respect autonomy by appreciating family values, while offering to participate in the decision-making process and ensuring nonmaleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. The current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making, which is focused on respecting autonomy, is our preferred approach in these situations., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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14. The Use of Infant Pulmonary Function Tests in the Diagnosis of Neuroendocrine Cell Hyperplasia of Infancy.
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Breuer O, Cohen-Cymberknoh M, Picard E, Bentur L, Bar-Yoseph R, Shoseyov D, Tsabari R, Kerem E, and Hevroni A
- Subjects
- Case-Control Studies, Female, Functional Residual Capacity, Humans, Hyperplasia diagnosis, Hyperplasia physiopathology, Hypoxia physiopathology, Infant, Infant, Premature, Lung Diseases pathology, Lung Diseases physiopathology, Male, Plethysmography, Residual Volume, Respiratory Sounds physiopathology, Sensitivity and Specificity, Spirometry methods, Tachypnea physiopathology, Total Lung Capacity, Lung Diseases diagnosis, Neuroendocrine Cells pathology, Respiratory Function Tests methods
- Abstract
Background: Infant pulmonary function tests (iPFTs) in subjects with neuroendocrine cell hyperplasia of infancy (NEHI) have demonstrated substantial expiratory airflow obstruction and air trapping., Research Question: Can indices from iPFTs be used in the diagnosis of NEHI?, Study Design and Methods: This is an observational case-control study evaluating iPFT results from a registry of patients assessed at the Hadassah Hebrew University Medical Center between 2008 and 2018. iPFTs results in infants with NEHI were compared to two disease control infant groups (infants evaluated for recurrent wheezing and infants evaluated due to prematurity) and a spirometry control group of infants with normal expiratory airflow, using the Kruskal-Wallis test. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy of iPFT indices., Results: We evaluated iPFT data in 481 infants (15, NEHI; 292, wheezing; 128, premature; and 46, spirometry control group). Infants with NEHI had significantly increased trapped air volumes (median functional residual capacity measured with infant whole-body plethysmography [FRC
pleth ] was 199% predicted; median ratio of residual volume to total lung capacity was 59% predicted) when compared with results in all evaluated groups of infants (P < .001), including multiple pairwise comparisons. Airflow limitation was demonstrated in infants with NEHI when compared with the infants in the spirometry control group but was similar to the two disease control groups. FRCpleth had the best discriminatory ability for NEHI diagnosis, with an FRCpleth ≥ 150% predicted demonstrating a ROC of 0.91 (95% CI, 0.82-1.00), sensitivity of 86.7% (95% CI, 59.5%-98.3%), and specificity of 95.5% (95% CI, 93.2%-97.3%)., Interpretation: Findings on iPFTs of markedly increased air trapping, out of proportion to the degree of airflow limitation, are characteristic of infants with NEHI. iPFT results demonstrating an FRCpleth ≥ 150% predicted are highly specific for NEHI and may aid in early diagnosis. Further research is required to confirm these findings in a prospective cohort and to understand the pathophysiologic explanation for these findings., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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15. Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation.
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Oren YS, Irony-Tur Sinai M, Golec A, Barchad-Avitzur O, Mutyam V, Li Y, Hong J, Ozeri-Galai E, Hatton A, Leibson C, Carmel L, Reiter J, Sorscher EJ, Wilton SD, Kerem E, Rowe SM, Sermet-Gaudelus I, and Kerem B
- Subjects
- Cells, Cultured, Humans, Mutation, RNA Splicing, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Drug Development, Oligonucleotides, Antisense
- Abstract
Background: Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene., Methods: We have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2'-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele., Results: A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2'-Methoxy Ethyl modification (2'MOE)., Conclusion: The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development., Competing Interests: Declaration of Competing Interest Batsheva Kerem has equity in SpliSense and is paid for consultancy. All other authors have no financial conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2021
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16. Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.
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Cohen-Cymberknoh M, Gindi Reiss B, Reiter J, Lechtzin N, Melo J, Pérez G, Blau H, Mussaffi H, Levine H, Bentur L, Gur M, Livnat G, Perez Miranda J, Polverino E, Blasi F, Aliberti S, Aviram M, Golan Tripto I, Picard E, Novoselsky M, Amsalem H, Hochner Celnikier D, Kerem E, and Shteinberg M
- Subjects
- Adolescent, Adult, Disease Progression, Female, Humans, Infant, Newborn, Infertility, Female etiology, Middle Aged, Pregnancy, Prognosis, Pseudomonas Infections complications, Respiratory Function Tests, Retrospective Studies, Severity of Illness Index, Cystic Fibrosis complications, Cystic Fibrosis physiopathology, Pregnancy Complications, Pregnancy Outcome
- Abstract
Background: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes., Aim: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression., Methods: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV
1 ) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter., Results: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants., Conclusion: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)- Published
- 2021
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17. Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations.
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Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N, Owen CA, and Wainwright C
- Subjects
- Adult, Alleles, Body Mass Index, Double-Blind Method, Drug Combinations, Female, Genotype, Humans, Male, Respiratory Function Tests, Aminophenols therapeutic use, Benzodioxoles therapeutic use, Chloride Channel Agonists therapeutic use, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Indoles therapeutic use, Quinolones therapeutic use
- Abstract
Background: Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro., Methods: Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV
1 ) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study., Results: At the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF., Conclusions: Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410)., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: DC, CAO, NA, and LTW are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated. AM: Coordinator for the Vertex tezacaftor/ivacaftor clinical trial 661-107 and fees for their institution (Robert Debré Hospital, Paris, France) during the conduct of the study; participation in advisory boards and educational meetings with Vertex Pharmaceuticals Incorporated outside of the submitted work. CW: Income on a per-patient basis derived from pharmaceutical studies (Vertex Pharmaceuticals Incorporated and Boehringer-Ingelheim); research grant from Novo Nordisk Pharmaceuticals for the P/L-CF-IDEA study; Vertex Pharmaceuticals P/L honorarium to attend the CF International Advisory Board Meeting in February 2014; Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014; Novartis Pharmaceuticals P/L honorarium to present a symposium at the National Pediatric Congress in Lebanon in May 2014; Vertex Pharmaceuticals P/L return travel and honorarium for lecture & discussions at the European CF Conference in Gothenburg in June 2014; DKBmed, LLC honorarium to present symposium at the North American CF Conference Georgia in October 2014; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015; Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings on the VX15-770-123 study in 2014; Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board-Innovative endpoints in CF in August 2015; University of Miami honorarium for meeting attendance in 2015; Thorax honorarium for associate editor duties in Q3/Q4 2015; BMJ honorarium for work as a reviewer; Vertex Pharmaceuticals 2015 Chicago return flight and accommodation for work as investigator in lumacaftor study; Vertex Pharmaceuticals 2015–2017 honorarium for being a speaker at Vertex-sponsored educational meeting series in Australia; Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in the Next Gen study; Vertex Pharmaceuticals December 2016 honoraria for work as a speaker at a Vertex-sponsored educational meeting in Liverpool, UK; DKBmed eCF review issue honoraria in January 2017; Vertex Pharmaceuticals March 2017 honoraria for being a speaker at TSANZ meeting; Vertex Pharmaceuticals Incorporated 2014–2018 honorarium for acting as a consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC 2018; Vertex Pharmaceuticals P/L honorarium to present as a speaker in an educational meeting at ECFC in Belgrade 2018; Vertex Pharmaceuticals Incorporated honorarium to attend the Next Gen Early Lifecycle Management Plan in London in 2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings, and conferences from October 2018 to present; Vertex Pharmaceuticals (Australia) P/L to attend as a steering committee member at the Medical Symposium Event (SHIFT 2019) in Perth in 2019; Vertex Pharmaceuticals P/L to attend the EU Real World Evidence steering committee in Amsterdam in 2019; Current board positions: International Advisory Board, Vertex Pharmaceuticals P/L; Associate Editor, Thorax; Associate Editor, Respirology. EK: Grants from Vertex Pharmaceuticals Incorporated during the conduct of the study; speaker honorarium and membership in scientific advisory board at Vertex Pharmaceuticals Incorporated outside the submitted work. HE: participated in an advisory board meeting with Vertex Pharmaceuticals Incorporated outside of the submitted work., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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18. Complicated pneumonia in children.
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de Benedictis FM, Kerem E, Chang AB, Colin AA, Zar HJ, and Bush A
- Subjects
- Adrenal Cortex Hormones therapeutic use, Anti-Bacterial Agents therapeutic use, Child, Combined Modality Therapy, Community-Acquired Infections complications, Community-Acquired Infections diagnostic imaging, Community-Acquired Infections epidemiology, Community-Acquired Infections therapy, Drainage, Humans, Pneumonia, Bacterial diagnostic imaging, Pneumonia, Bacterial epidemiology, Risk Factors, Treatment Outcome, Pneumonia, Bacterial complications, Pneumonia, Bacterial therapy
- Abstract
Complicated community-acquired pneumonia in a previously well child is a severe illness characterised by combinations of local complications (eg, parapneumonic effusion, empyema, necrotising pneumonia, and lung abscess) and systemic complications (eg, bacteraemia, metastatic infection, multiorgan failure, acute respiratory distress syndrome, disseminated intravascular coagulation, and, rarely, death). Complicated community-acquired pneumonia should be suspected in any child with pneumonia not responding to appropriate antibiotic treatment within 48-72 h. Common causative organisms are Streptococcus pneumoniae and Staphylococcus aureus. Patients have initial imaging with chest radiography and ultrasound, which can also be used to assess the lung parenchyma, to identify pleural fluid; CT scanning is not usually indicated. Complicated pneumonia is treated with a prolonged course of intravenous antibiotics, and then oral antibiotics. The initial choice of antibiotic is guided by local microbiological knowledge and by subsequent positive cultures and molecular testing, including on pleural fluid if a drainage procedure is done. Information from pleural space imaging and drainage should guide the decision on whether to administer intrapleural fibrinolytics. Most patients are treated by drainage and more extensive surgery is rarely needed; in any event, in low-income and middle-income countries, resources for extensive surgeries are scarce. The clinical course of complicated community-acquired pneumonia can be prolonged, especially when patients have necrotising pneumonia, but complete recovery is the usual outcome., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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19. Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view.
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De Boeck K, Lee T, Amaral M, Drevinek P, Elborn JS, Fajac I, Kerem E, and Davies JC
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- Consensus, Cystic Fibrosis genetics, Humans, Research Design, Clinical Trials as Topic organization & administration, Cystic Fibrosis drug therapy, Cystic Fibrosis Transmembrane Conductance Regulator drug effects, Drug Development organization & administration
- Abstract
CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27
th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs., (Copyright © 2020. Published by Elsevier B.V.)- Published
- 2020
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20. Efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis not receiving chronic inhaled aminoglycosides: The international, randomized, double-blind, placebo-controlled Ataluren Confirmatory Trial in Cystic Fibrosis (ACT CF).
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Konstan MW, VanDevanter DR, Rowe SM, Wilschanski M, Kerem E, Sermet-Gaudelus I, DiMango E, Melotti P, McIntosh J, and De Boeck K
- Subjects
- Administration, Oral, Double-Blind Method, Female, Forced Expiratory Volume, Humans, Male, Respiratory Function Tests methods, Symptom Flare Up, Treatment Outcome, Codon, Nonsense, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Cystic Fibrosis physiopathology, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Drug Monitoring methods, Oxadiazoles administration & dosage, Oxadiazoles adverse effects
- Abstract
Background: Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides., Methods: Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV
1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48., Findings: 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (-0.8 vs -1.8) or Week 48 (-1.7 vs -2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI -1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported., Interpretation: Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive., Competing Interests: Declaration of Competing Interest JM is an employee of PTC Therapeutics, the funder of this clinical trial, and holds financial interests in the company. MWK, SMR, and DRV received compensation for consultant services from PTC Therapeutics prior to and/or during this study. EK, MW, IS-G, and KDB received compensation for travel expenses for meetings related to the study. All other authors declare no competing interests., (Copyright © 2020. Published by Elsevier B.V.)- Published
- 2020
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21. The future of cystic fibrosis care: a global perspective.
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Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O'Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, and Ratjen F
- Subjects
- Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator administration & dosage, Genetic Therapy methods, Global Health, Humans, Lung Transplantation methods, Cystic Fibrosis therapy, Delivery of Health Care trends, Disease Progression, Quality of Life
- Abstract
The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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22. Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery.
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Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T, Amaral MD, de Boeck K, Davies JC, Drevinek P, Elborn JS, Kerem E, and Lee T
- Subjects
- Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Humans, Mutation, Quality Improvement, Research Design standards, Clinical Trials as Topic methods, Clinical Trials as Topic standards, Cystic Fibrosis drug therapy, Drug Development organization & administration, Drug Development standards, Drug Discovery methods, Drug Discovery trends, Membrane Transport Modulators pharmacology
- Abstract
The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2019
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23. Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age.
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Shteinberg M, Lulu AB, Downey DG, Blumenfeld Z, Rousset-Jablonski C, Perceval M, Colombo A, Stein N, Livnat G, Gur M, Bentur L, Mussaffi H, Blau H, Sarouk I, Dagan A, Kerem E, Aviram M, Picard E, Aliberti S, Álvarez A, Miranda JP, Polverino E, Durieu I, Stuart Elborn J, and Cohen-Cymberknoh M
- Subjects
- Adult, Age Factors, Female, Humans, Prevalence, Retrospective Studies, Young Adult, Cystic Fibrosis complications, Exocrine Pancreatic Insufficiency complications, Infertility, Female epidemiology, Infertility, Female etiology
- Abstract
Objective: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF., Methods: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files., Results: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], p = .04) and older age (OR 3.9 [2.1-7.3] p < .0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility., Conclusions: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
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- 2019
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24. Sleep disorders in patients with primary ciliary dyskinesia, cystic fibrosis with and without pancreatic insufficiency.
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Cohen-Cymberknoh M, Atia O, Gileles-Hillel A, Kerem E, and Reiter J
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- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Hemoglobins analysis, Humans, Male, Middle Aged, Quality of Life, Surveys and Questionnaires, Young Adult, Ciliary Motility Disorders complications, Cystic Fibrosis complications, Exocrine Pancreatic Insufficiency complications, Sleep Wake Disorders complications
- Abstract
Background: Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are characterized by impaired mucociliary clearance causing sinopulmonary infections and airway inflammation. However, they differ in many aspects including multisystemic involvement and disease severity., Aim: To compare sleep disorders and their correlation with quality of life (QOL) in three distinct patient populations: CF and pancreatic insufficiency (CF-PI), pancreatic sufficiency (CF-PS) and PCD., Methods: Patients completed age appropriate sleep quality questionnaires (SDSC, PSQI), quality of life questionnaires (PedQL, QOL-BE) and the Epworth sleepiness scale (ESS). Medical records were reviewed for clinical data., Results: Eighty patients, 33 CF-PI, 27 CF-PS, and 20 PCD; 40 females; 41 adults and 39 children completed the study. In adults, 66% slept less than 7 h per night, and sleep quality was reduced in 26.5%, 53% reported night wakings and 47% nocturnal snoring or coughing. In children 78% slept more than 8 h, SDSC scores were mostly in the normal range. A significant correlation was found between sleep quality and QOL in both age groups. Global sleep scores were correlated with hemoglobin levels. Despite differences in disease severity and QOL, there were no significant differences in sleep quality between the three groups., Conclusion: Sleep disorders are common and correlate with QOL in CF and PCD. Despite differences in disease characteristics and severity, there are no differences in terms of sleep disorders between CF-PI, CF-PS and PCD patients, suggesting that they may represent indirect outcomes of disease., (Copyright © 2019. Published by Elsevier Ltd.)
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- 2019
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25. Take it personally: how personal we reach when we are so different from each other?
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Kerem E, Oren YS, and Kerem B
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- Canada, Humans, Cystic Fibrosis, Precision Medicine
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- 2019
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26. A quality improvement intervention to reduce emergency department radiography for bronchiolitis.
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Reiter J, Breuer A, Breuer O, Hashavya S, Rekhtman D, Kerem E, and Cohen-Cymberknoh M
- Subjects
- Bronchiolitis diagnosis, Bronchiolitis epidemiology, Cost-Benefit Analysis, Emergency Service, Hospital statistics & numerical data, Female, Humans, Infant, Israel epidemiology, Length of Stay statistics & numerical data, Male, Practice Guidelines as Topic, Prospective Studies, Quality Improvement economics, Radiography trends, Retrospective Studies, Bronchiolitis diagnostic imaging, Emergency Service, Hospital standards, Quality Improvement ethics, Radiation Exposure prevention & control, Radiography statistics & numerical data
- Abstract
Introduction: Bronchiolitis is one of the most common infectious diseases in children and the most frequent cause of hospitalization in infants. Clinical practice guidelines recommend that a chest X-ray (CXR) should not be routinely obtained in the diagnosis of bronchiolitis, as studies have shown that they do not affect clinical outcomes, but rather lead to overuse of pharmacological agents and a longer length of hospital stay., Objective: To determine whether active institution of bronchiolitis practice guidelines as part of a quality improvement project decreased the use of CXRs in the Pediatric Emergency Department (ED). Secondary outcomes included a decrease in the use of unnecessary medical interventions and a shorter mean hospital length of stay., Methods: The study was conducted at two Hadassah Medical Center Pediatric EDs. Guidelines were reviewed with the ED staff during departmental seminars by a senior pediatric pulmonologist, and posted at the physician computer stations in the ED. Prospective, post-intervention, data obtained during the study period was compared to retrospective, pre-intervention, data from the year prior to implementation of the intervention., Results: Post-intervention, 37% of patients vs. 58% in the retrospective cohort had a CXR via ED referral (p < 0.001). The use of hypertonic saline and bronchodilators decreased, while there was no significant change in antibiotic or corticosteroid use. There was a decrease in hospitalizations post-intervention (70% vs. 77%, p = 0.05)., Conclusion: This key intervention was successful in reinforcing the AAP guidelines, promoting greater cost-effectiveness, reducing radiation exposure, and saving valuable time and resources for the ED staff and the hospital., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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27. Attention deficit hyperactivity disorder symptoms in patients with cystic fibrosis.
- Author
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Cohen-Cymberknoh M, Tanny T, Breuer O, Blau H, Mussaffi H, Kadosh D, Gartner S, Salinas A, Bentur L, Nir V, Gur M, Reiter J, Shoseyov D, Kerem E, and Berger I
- Subjects
- Adolescent, Adult, Child, Cohort Studies, Cystic Fibrosis complications, Cystic Fibrosis therapy, Female, Health Status, Humans, Male, Prevalence, Symptom Assessment, Treatment Adherence and Compliance, Young Adult, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity epidemiology, Cystic Fibrosis psychology
- Abstract
Background: Cystic fibrosis (CF) is a chronic life-threatening disease. In patients who suffer from chronic disease, Attention Deficit Hyperactivity Disorder (ADHD) is associated with functional impairment that can affect adherence to treatment and consequently influence prognosis., Methods: CF patients filled in the ADHD Rating Scale (ADHD-RS) adapted to the DSM5 and were assessed on a continuous performance task (MOXO-CPT), a standardized-computerized test designed to evaluate several domains of attention., Results: Of the 175 patients (99 males), 18% presented ADHD symptoms, according to ADHD-RS; 16% in the younger group (<18years), and 18.9% in the adult group. The male to female ratio was 3:1 in children and 1:1 in adults., Conclusions: The occurrence of ADHD symptoms in patients with CF is substantially higher than in the general population and should be recognized as a co-morbidity of CF. As ADHD can impair adherence to therapy, further research is needed to investigate the effect of ADHD therapy on adherence., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
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28. Predictors of Prolonged Hospitalizations in Pediatric Complicated Pneumonia.
- Author
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Breuer O, Picard E, Benabu N, Erlichman I, Reiter J, Tsabari R, Shoseyov D, Kerem E, and Cohen-Cymberknoh M
- Subjects
- Child, Child, Preschool, Community-Acquired Infections, Decision Support Techniques, False Positive Reactions, Female, Glucose metabolism, Humans, L-Lactate Dehydrogenase metabolism, Length of Stay statistics & numerical data, Male, Pleura chemistry, Pleural Effusion complications, Pleural Effusion metabolism, Pneumonia, Bacterial complications, Pneumonia, Bacterial metabolism, Pneumonia, Bacterial therapy
- Abstract
Background: Pediatric community-acquired complicated pneumonia (PCACP) is characterized by a prolonged clinical course, but this may be highly variable., Methods: A multicenter observational study was conducted to develop and validate a clinical prediction tool for prolonged hospitalizations in PCACP. The derivation and validation cohorts consisted of 144 and 169 patients with PCACP, respectively, hospitalized between the years 1997 and 2017 in three tertiary care hospitals. Logistic regression analyses were used to identify parameters associated with a prolonged hospitalization and to develop and validate a prediction model for constructing a useful clinical tool., Results: Higher levels of lactate dehydrogenase (LDH) (P < .026) and lower levels of glucose (P = .018) in pleural fluid were significantly associated with prolonged hospitalization. A predictive stepwise logistic regression model was developed and applied to the validation cohort. The area under the receiver operating characteristic curve (AUROC) constructed indicated that the model retained good predictive value (AUROC for the derivation vs validation data, [0.77 (95% CI, 0.66-0.87) vs 0.82 (95% CI, 0.72-0.91)], respectively). From these data, a clinical tool was derived; the combination of pleural LDH >1,000 units/L and pleural glucose levels < 1 mmol/L or pleural LDH levels > 2,000 units/L and pleural glucose levels < 2 mmol/L or pleural LDH levels > 3,000 units/L and pleural glucose < 3 mmol/L predict prolonged hospitalization with positive and negative predictive values of 78% (95% CI, 0.71-0.85) and 73% (95% CI, 0.59-0.85), respectively., Conclusions: In children, pleural fluid LDH and glucose levels are useful parameters for assessing the severity of PCACP. The model developed in this study accurately predicts patients who will have prolonged hospitalization., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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29. Ivacaftor for the p.Ser549Arg (S549R) gating mutation - The Israeli experience.
- Author
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Dagan A, Cohen-Cymberknoh M, Shteinberg M, Levine H, Vilozni D, Bezalel Y, Bar Aluma BE, Sarouk I, Ashkenazi M, Lavie M, Tsabari R, Blau H, Kerem E, Bentur L, Efrati O, and Livnat G
- Subjects
- Adolescent, Adult, Blood Glucose metabolism, Body Mass Index, Child, Cohort Studies, Cystic Fibrosis genetics, Cystic Fibrosis metabolism, Cystic Fibrosis physiopathology, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Female, Forced Expiratory Volume, Glucose Tolerance Test, Humans, Israel, Male, Mutation, Retrospective Studies, Sweat chemistry, Treatment Outcome, Vital Capacity, Young Adult, Aminophenols therapeutic use, Chloride Channel Agonists therapeutic use, Cystic Fibrosis drug therapy, Quinolones therapeutic use
- Abstract
Background: Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse., Aim: Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation., Methods: Data obtained from CF patients receiving ivacaftor for one year., Results: Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV
1 , increasing from 74% to 88% (p < 0.001), FVC, 89% to 101% (p = 0.019), and FEF25-75 , 59%-76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p < 0.001), and BMI increased from 20 ± 3 to 22 ± 4 (p = 0.003). Glucose tolerance improved in five patients. There was no significant change in bacterial colonization., Conclusions: Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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30. Clinical impact of Pseudomonas aeruginosa colonization in patients with Primary Ciliary Dyskinesia.
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Cohen-Cymberknoh M, Weigert N, Gileles-Hillel A, Breuer O, Simanovsky N, Boon M, De Boeck K, Barbato A, Snijders D, Collura M, Pradal U, Blau H, Mussaffi H, Price M, Bentur L, Gur M, Aviram M, Picard E, Shteinberg M, Livnat G, Rivlin J, Hiller N, Shoseyov D, Amirav I, and Kerem E
- Subjects
- Adolescent, Adult, Aged, Carrier State diagnostic imaging, Child, Child, Preschool, Disease Progression, Female, Forced Expiratory Volume, Humans, Infant, Infant, Newborn, Kartagener Syndrome diagnostic imaging, Kartagener Syndrome physiopathology, Male, Middle Aged, Pseudomonas Infections diagnostic imaging, Retrospective Studies, Severity of Illness Index, Tomography, X-Ray Computed, Young Adult, Carrier State physiopathology, Kartagener Syndrome microbiology, Pseudomonas Infections physiopathology, Pseudomonas aeruginosa, Sputum microbiology
- Abstract
Background: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD., Methods: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters., Results: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV
1 ) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results., Conclusions: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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31. Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis.
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Breuer O, Daum H, Cohen-Cymberknoh M, Unger S, Shoseyov D, Stepensky P, Keller B, Warnatz K, and Kerem E
- Subjects
- Adult, B-Lymphocytes cytology, B-Lymphocytes immunology, Bronchiectasis diagnostic imaging, Bronchiectasis epidemiology, Bronchiectasis immunology, Candidiasis, Chronic Mucocutaneous diagnostic imaging, Candidiasis, Chronic Mucocutaneous genetics, Candidiasis, Chronic Mucocutaneous immunology, Candidiasis, Chronic Mucocutaneous microbiology, Cystic Fibrosis diagnosis, Cystic Fibrosis genetics, Female, Humans, Interferon-gamma immunology, Kartagener Syndrome diagnosis, Male, Nitric Oxide, Phosphorylation, Prevalence, STAT1 Transcription Factor metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, Tomography, X-Ray Computed, United States epidemiology, Bronchiectasis genetics, Mutation, STAT1 Transcription Factor genetics, Exome Sequencing methods
- Abstract
Background: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown., Objective: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis., Methods: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping., Results: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen., Conclusions: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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32. Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis.
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Cohen-Cymberknoh M, Gilead N, Gartner S, Rovira S, Blau H, Mussaffi H, Rivlin J, Gur M, Shteinberg M, Bentur L, Livnat G, Aviram M, Picard E, Tenenbaum A, Armoni S, Breuer O, Shoseyov D, and Kerem E
- Subjects
- Adolescent, Adult, Child, Drug Resistance, Multiple, Bacterial, Female, Humans, Infant, Israel epidemiology, Male, Medication Therapy Management, Middle Aged, Outcome and Process Assessment, Health Care, Anti-Bacterial Agents classification, Anti-Bacterial Agents therapeutic use, Cystic Fibrosis complications, Cystic Fibrosis epidemiology, Cystic Fibrosis microbiology, Cystic Fibrosis therapy, Infection Control methods, Infection Control statistics & numerical data, Pseudomonas Infections diagnosis, Pseudomonas Infections drug therapy, Pseudomonas Infections epidemiology, Pseudomonas Infections etiology, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa isolation & purification, Pseudomonas aeruginosa pathogenicity
- Abstract
Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients., Objectives: To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure., Methods: In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year., Results: Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken., Conclusions: Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
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33. Equitable CF care as a basic human right.
- Author
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De Boeck K and Kerem E
- Subjects
- Humans, Cystic Fibrosis, Human Rights
- Published
- 2016
- Full Text
- View/download PDF
34. Primary ciliary dyskinesia in Israel: Prevalence, clinical features, current diagnosis and management practices.
- Author
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Abitbul R, Amirav I, Blau H, Alkrinawi S, Aviram M, Shoseyov D, Bentur L, Avital A, Springer C, Lavie M, Prais D, Dabbah H, Elias N, Elizur A, Goldberg S, Hevroni A, Kerem E, Luder A, Roth Y, Cohen-Cymberknoh M, Ben Ami M, Mandelberg A, Livnat G, Picard E, Rivlin J, Rotschild M, Soferman R, Loges NT, Olbrich H, Werner C, Wolter A, Herting M, Wallmeier J, Raidt J, Omran H, and Mussaffi H
- Subjects
- Adolescent, Adult, Child, Cilia genetics, Cilia ultrastructure, Female, Humans, Israel epidemiology, Kartagener Syndrome ethnology, Kartagener Syndrome therapy, Male, Microscopy, Electron, Transmission methods, Nitric Oxide metabolism, Prospective Studies, Young Adult, Cilia immunology, Kartagener Syndrome diagnosis, Kartagener Syndrome epidemiology, Prevalence
- Abstract
Background: Primary Ciliary Dyskinesia (PCD) is rare and its features in Israel have not been described., Aims: to assess prevalence utilizing state-of-the-art diagnostic techniques, and describe clinical features, diagnostic and management practices in Israel., Methods: A national multicenter study from 2012 to 2013 recruited patients diagnosed or suspected of having PCD. Diagnosis was verified using: nasal Nitric Oxide (nNO); High-speed Video Microscope Analysis (HVMA); Transmission Electron Microscopy (TEM) of cilia; Immuno-fluorescence staining (IF) for ciliary proteins, and genetic analysis., Results: Of the 203 patients recruited from 14 pediatric centers, 150 had a PCD diagnosis verified. Median age was 15.05y, with range 0.15-60.5y. PCD prevalence was 1:54,000 for the general population and 1:25,000 in children (5-14 y). For the non-Jewish (mainly Druze and Arab Moslem) compared to Jewish populations, prevalence was 1:16,500 and 1:139,000 respectively (p < 0.0001) and parental consanguinity was 85.4% and 21.9% respectively (p < 0.0001). Clinical features included bronchiectasis (88%), rhinitis (81%), recurrent pneumonia (78%), recurrent otitis (62%), neonatal pneumonia (60%) and situs inversus (42%). Prior diagnostic practices varied widely between centers with TEM assessed in 55% and abnormal in 61% of these. Management included antibiotics and airway clearance. Diagnostic verification revealed for 150 PCD patients: 81% nNO<233 ppb, 62% abnormal HVMA, 51% diagnostic TEM, 58% diagnostic IF and, 57% genetic diagnosis., Conclusions: PCD in Israel is rare, with comprehensive diagnostic tests showing prevalence in children similar to Europe. Prevalence was higher in non-Jews, associated with parental consanguinity. Diagnostic and management practices vary. Referral centers providing comprehensive diagnostic and care capabilities should be established., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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35. Reversible airway obstruction in cystic fibrosis: Common, but not associated with characteristics of asthma.
- Author
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Levine H, Cohen-Cymberknoh M, Klein N, Hoshen M, Mussaffi H, Stafler P, Breuer O, Kerem E, and Blau H
- Subjects
- Adolescent, Age Factors, Aged, Biological Availability, Bronchial Hyperreactivity diagnosis, Bronchial Hyperreactivity drug therapy, Bronchial Hyperreactivity etiology, Bronchial Hyperreactivity physiopathology, Child, Preschool, Diagnosis, Differential, Female, Forced Expiratory Volume, Glucocorticoids administration & dosage, Glucocorticoids pharmacokinetics, Humans, Israel epidemiology, Male, Retrospective Studies, Spirometry methods, Statistics as Topic, Airway Obstruction diagnosis, Airway Obstruction etiology, Airway Obstruction physiopathology, Asthma diagnosis, Bronchodilator Agents administration & dosage, Bronchodilator Agents pharmacokinetics, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Cystic Fibrosis epidemiology, Cystic Fibrosis physiopathology
- Abstract
Background: As asthma-like symptoms are common in CF, we evaluated reversible airway obstruction and associated characteristics., Methods: Retrospective analysis of charts including spirometry and bronchodilator response., Results: Of 190 CF patients (103 at Schneider's, 87 at Hadassah), aged 14.4 (4-76) years, median (range), 39% had reversible obstruction (ΔFEV1% predicted ≥12%), associated with younger age (p=0.01) and severe genotype (p=0.02). There was no association with family history of asthma, serum IgE, blood eosinophils, pancreatic status, FEV1<40% predicted, Aspergillus or pseudomonas infection. Of patients with reversible obstruction, 74% were on bronchodilator and 68% on inhaled corticosteroid therapy but 54% and 57% respectively receiving these therapies did not have reversible obstruction., Conclusions: Reversible airway obstruction is common in CF, more frequent in younger patients and with severe genotype, with no correlation to markers of atopy or CF clinical severity. Bronchodilator and inhaled corticosteroid therapies are commonly prescribed even without reversible obstruction., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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36. The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.
- Author
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Stafler P, Mei-Zahav M, Wilschanski M, Mussaffi H, Efrati O, Lavie M, Shoseyov D, Cohen-Cymberknoh M, Gur M, Bentur L, Livnat G, Aviram M, Alkrinawi S, Picard E, Prais D, Steuer G, Inbar O, Kerem E, and Blau H
- Subjects
- Adult, Birth Rate, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Family Health, Female, Genetic Carrier Screening methods, Genetic Carrier Screening statistics & numerical data, Genetic Counseling organization & administration, Humans, Infant, Infant, Newborn, Israel epidemiology, Male, Mutation, National Health Programs statistics & numerical data, Pregnancy, Risk Assessment methods, Cystic Fibrosis diagnosis, Cystic Fibrosis ethnology, Cystic Fibrosis genetics, Neonatal Screening methods, Neonatal Screening trends, Prenatal Diagnosis methods, Prenatal Diagnosis trends
- Abstract
Background: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact., Methods: A retrospective review of governmental databanks, the national CF registry and CF centers., Results: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population., Conclusions: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
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37. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients.
- Author
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Flume PA, VanDevanter DR, Morgan EE, Dudley MN, Loutit JS, Bell SC, Kerem E, Fischer R, Smyth AR, Aaron SD, Conrad D, Geller DE, and Elborn JS
- Subjects
- Administration, Inhalation, Adolescent, Adult, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents adverse effects, Chronic Disease, Double-Blind Method, Drug Monitoring methods, Female, Forced Expiratory Volume, Humans, Male, Symptom Assessment, Symptom Flare Up, Treatment Outcome, Cystic Fibrosis diagnosis, Cystic Fibrosis drug therapy, Cystic Fibrosis microbiology, Cystic Fibrosis psychology, Levofloxacin administration & dosage, Levofloxacin adverse effects, Pseudomonas Infections diagnosis, Pseudomonas Infections drug therapy, Pseudomonas Infections physiopathology, Pseudomonas aeruginosa drug effects, Pseudomonas aeruginosa isolation & purification, Quality of Life
- Abstract
Rationale: For patients with cystic fibrosis (CF), the use of inhaled antibiotics has become standard of care to suppress chronic Pseudomonas airways infection. There are limited antibiotic options formulated and approved for inhaled use and antibiotic efficacies attenuate over time, making additional inhaled antibiotic classes desirable. APT-1026 (levofloxacin inhalation solution, LIS) is a fluoroquinolone in development for management of chronic P. aeruginosa airways infection in patients with CF., Objectives: To compare the safety and efficacy of a 28-day course of treatment with LIS 240mg or placebo BID in persons ≥12years old with CF and chronic P. aeruginosa infection., Methods: A multinational, randomized (2:1), double-blinded study of LIS and placebo over 28days in CF patients ≥12years with chronic P. aeruginosa infection. Time to exacerbation was the primary endpoint. FEV1 (% predicted) and patient-reported quality of life were among secondary endpoints., Main Results: Baseline demographics for 330 subjects (LIS=220) were similar although significantly more patients randomized to LIS had experienced multiple exacerbations in the year prior to study entry. There was no statistically significant difference in protocol-defined pulmonary exacerbations between treatment arms. Relative change in FEV1% predicted from baseline was significantly greater for patients randomized to LIS compared to those randomized to placebo (mean difference 1.31%, p=0.01 [95% CI 0.27, 2.34%]). LIS was well-tolerated, with dysguesia the most frequent adverse event., Conclusions: LIS did not demonstrate a difference in time to next exacerbation when compared to placebo. Reasons for this result are discussed but may be due to an imbalance in the frequency of prior pulmonary exacerbations between the two groups. An improvement in FEV1 (% predicted) at 28days was observed and LIS was well tolerated. LIS is safe and has a potential role in the management of CF patients with chronic P. aeruginosa., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
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38. CFTR potentiator therapy ameliorates impaired insulin secretion in CF patients with a gating mutation.
- Author
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Tsabari R, Elyashar HI, Cymberknowh MC, Breuer O, Armoni S, Livnat G, Kerem E, and Zangen DH
- Subjects
- Blood Glucose analysis, Chloride Channel Agonists administration & dosage, Chloride Channel Agonists pharmacokinetics, Cystic Fibrosis genetics, Cystic Fibrosis metabolism, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Female, Humans, Insulin Secretion, Male, Mutation, Siblings, Treatment Outcome, Young Adult, Aminophenols administration & dosage, Aminophenols pharmacokinetics, Cystic Fibrosis drug therapy, Insulin metabolism, Quinolones administration & dosage, Quinolones pharmacokinetics
- Abstract
Objective: To investigate the effect of treatment with ivacaftor on insulin secretion in patients with cystic fibrosis (CF) (ΔF508\S549R) having CFRD/impaired insulin secretion., Methods: A standard OGTT was performed before and after 16weeks of treatment with ivacaftor in 2 sibling patients with CF carrying the S549R gating mutation. The area under the curve (AUC) for glucose and insulin was calculated using the trapezoidal estimation., Results: Before treatment, the OGTT of case 1 showed indeterminate glycemia; the OGTT of case 2 indicated CFRD. After ivacaftor treatment the OGTT demonstrated improved insulin secretion pattern mainly by increased first phase early insulin secretion, resulting in reduction of the AUC of glucose in both cases., Conclusions: The treatment with ivacaftor in patients with CF carrying gating mutation can ameliorate impaired insulin secretion. Further studies and larger cohorts are needed to evaluate the impact of ivacaftor on insulin secretion in patients with CF carrying gating or other mutations., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
39. Treatment of cystic fibrosis in low-income countries.
- Author
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Cohen-Cymberknoh M, Shoseyov D, Breuer O, Shamali M, Wilschanski M, and Kerem E
- Subjects
- Anti-Bacterial Agents economics, Chest Wall Oscillation economics, Cystic Fibrosis economics, Delivery of Health Care economics, Delivery of Health Care organization & administration, Enzyme Replacement Therapy economics, Humans, Patient Compliance, Respiratory Therapy economics, Respiratory Therapy methods, Vitamin A therapeutic use, Vitamin D therapeutic use, Vitamin E therapeutic use, Vitamins economics, Anti-Bacterial Agents therapeutic use, Carrier State drug therapy, Chest Wall Oscillation methods, Cystic Fibrosis therapy, Developing Countries, Enzyme Replacement Therapy methods, Pseudomonas Infections drug therapy, Vitamins therapeutic use
- Published
- 2016
- Full Text
- View/download PDF
40. Disparities in Cystic Fibrosis Care and Outcome: Socioeconomic Status and Beyond.
- Author
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Kerem E and Cohen-Cymberknoh M
- Subjects
- Female, Humans, Male, Cystic Fibrosis mortality, Hispanic or Latino, Outcome Assessment, Health Care methods, White People
- Published
- 2016
- Full Text
- View/download PDF
41. Hepatopulmonary Syndrome in Patients With Cystic Fibrosis and Liver Disease.
- Author
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Breuer O, Shteyer E, Wilschanski M, Perles Z, Cohen-Cymberknoh M, Kerem E, and Shoseyov D
- Subjects
- Adolescent, Cystic Fibrosis complications, Diagnosis, Differential, Forced Expiratory Volume, Hepatopulmonary Syndrome etiology, Humans, Liver Cirrhosis etiology, Male, Tomography, X-Ray Computed, Cystic Fibrosis diagnosis, Hepatopulmonary Syndrome diagnosis, Liver Cirrhosis diagnosis
- Abstract
Hepatopulmonary syndrome (HPS) is a liver-induced lung disorder defined as a triad of liver disease, pulmonary vascular dilatation, and a defect in oxygenation. It can complicate chronic liver disease of any etiology, but is most commonly associated with portal hypertension. Severe liver disease with portal hypertension is present in 2% to 8% of patients with cystic fibrosis (CF), but to date, to our knowledge, only one patient with CF has been reported to suffer from HPS. Here, we describe two patients with CF diagnosed with HPS, one subsequent to unresolved hypoxemia and the other following screening for HPS performed in our center. We speculate that HPS is underdiagnosed in patients with CF because of their coexisting respiratory morbidity, and we advocate routine screening for every patient with CF who has liver disease and portal hypertension., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
42. A phase 3, open-label, randomized trial to evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients.
- Author
-
Stuart Elborn J, Geller DE, Conrad D, Aaron SD, Smyth AR, Fischer R, Kerem E, Bell SC, Loutit JS, Dudley MN, Morgan EE, VanDevanter DR, and Flume PA
- Subjects
- Administration, Inhalation, Adolescent, Adult, Chronic Disease, Cystic Fibrosis microbiology, Female, Forced Expiratory Volume, Humans, Male, Pseudomonas Infections complications, Quality of Life, Treatment Outcome, Young Adult, Anti-Bacterial Agents administration & dosage, Cystic Fibrosis drug therapy, Levofloxacin administration & dosage, Pseudomonas Infections drug therapy, Pseudomonas aeruginosa, Tobramycin administration & dosage
- Abstract
Background: Inhaled antibiotics are standard of care for persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infection. APT-1026 (levofloxacin inhalation solution, LIS) is fluoroquinolone in development. We compared the safety and efficacy of LIS to tobramycin inhalation solution (TIS) in persons ≥12 years old with CF and chronic P. aeruginosa infection., Methods: This multinational, randomized (2:1), non-inferiority study compared LIS and TIS over three 28-day on/off cycles. Day 28 FEV(1) % predicted relative change was the primary endpoint. Time to exacerbation and patient-reported quality of life were among secondary endpoints., Results: Baseline demographics for 282 subjects were comparable. Non-inferiority was demonstrated (1.86% predicted mean FEV(1) difference [95% CI -0.66 to 4.39%]). LIS was well-tolerated, with dysgeusia (taste distortion) as the most frequent adverse event., Conclusions: LIS is a safe and effective therapy for the management of CF patients with chronic P. aeruginosa infection., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
43. Is infection with hypermutable Pseudomonas aeruginosa clinically significant?
- Author
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Auerbach A, Kerem E, Assous MV, Picard E, and Bar-Meir M
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Chronic Disease, Cystic Fibrosis microbiology, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Infant, Male, Middle Aged, Prospective Studies, Pseudomonas Infections microbiology, Pseudomonas aeruginosa isolation & purification, Sputum microbiology, Young Adult, Cystic Fibrosis complications, DNA, Bacterial genetics, Lung microbiology, Mutation, Pseudomonas Infections complications, Pseudomonas aeruginosa genetics
- Abstract
Background: Hypermutable Pseudomonas aeruginosa (HPA) with high mutation rate due to defects in the DNA mismatch repair genes are frequently isolated in the sputum of cystic fibrosis (CF) patients. These isolates tend to be multidrug resistant and may be better adapted to the CF lung environment. However, the clinical significance of this infection has not been determined., Methods: This prospective study enrolled patients with PA infection attending CF clinics in Jerusalem between 2010 and 2011. Mutation frequency of pseudomonas isolates was determined by quantification of colonies resistant to rifampicin., Results: Of the 73 patients enrolled, 22 (30%) were infected with HPA. Average mutation frequency was 2.95×10(-4) in HPA and 1×10(-7) in non-HPA. Pulmonary function tests, number of pulmonary exacerbations and the response to antibiotic therapy were similar between patients infected with HPA and non-HPA isolates. The only predictors for infection with HPA were resistance to multiple antimicrobial categories (OR=4.8, 95% CI: 1.8-12.4) and previous use of inhaled colistin (OR=8.1, 95% CI: 2-30). Resistant mutant subpopulation analysis was a poor screening test for identifying HPA isolates., Conclusions: Infection with hypermutable strains represents the marked ability of PA to adapt to the lung environment, but was not associated with worse clinical outcome., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
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44. Contamination of hypertonic saline solutions in use by cystic fibrosis patients in Israel.
- Author
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Peled O, Kalamaro V, Kerem E, Shoseyov D, Blau H, Efrati O, and Block C
- Subjects
- Burkholderia cenocepacia isolation & purification, Humans, Israel, Mycobacterium isolation & purification, Pseudomonas aeruginosa isolation & purification, Cystic Fibrosis therapy, Drug Contamination, Saline Solution, Hypertonic adverse effects
- Abstract
Background: Treatment of cystic fibrosis (CF) patients with inhaled hypertonic saline (HS) solutions is safe, beneficial and reduces exacerbation rates. We studied contamination of solutions used by Israeli CF patients for prolonged periods., Methods: The study addressed whether daily opening of previously unopened solutions caused contamination, survival of 6 CF-associated bacteria in artificially inoculated solutions, in-use contamination of solutions and patterns of their use by patients., Results: Repeated opening did not contaminate solutions and survival of indicator bacteria was variable. Mycobacterium abscessus survived in 3% HS solution for 6 weeks and Burkholderia cenocepacia and Pseudomonas aeruginosa were longer. In 30/76 (39.5%) of used solutions 49 contaminants were found, none being common CF-associated pathogens., Conclusions: Most CF-related bacteria survived to some degree in HS. Approximately 40% of solutions used by patients were contaminated by organisms of uncertain significance. Our findings highlight the potential risk posed by contamination of HS solutions and support recommendations to use sterile unit-dose formulations., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2014
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45. Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.
- Author
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Kerem E, Konstan MW, De Boeck K, Accurso FJ, Sermet-Gaudelus I, Wilschanski M, Elborn JS, Melotti P, Bronsveld I, Fajac I, Malfroot A, Rosenbluth DB, Walker PA, McColley SA, Knoop C, Quattrucci S, Rietschel E, Zeitlin PL, Barth J, Elfring GL, Welch EM, Branstrom A, Spiegel RJ, Peltz SW, Ajayi T, and Rowe SM
- Subjects
- Acute Kidney Injury chemically induced, Adolescent, Adult, Anti-Bacterial Agents administration & dosage, Child, Chlorides analysis, Codon, Nonsense, Cystic Fibrosis physiopathology, Disease Progression, Double-Blind Method, Female, Forced Expiratory Volume, Humans, Male, Middle Aged, Oxadiazoles adverse effects, Sweat chemistry, Tobramycin administration & dosage, Young Adult, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Oxadiazoles therapeutic use
- Abstract
Background: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis., Methods: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205., Findings: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group., Interpretation: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin., Funding: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
46. European Cystic Fibrosis Society Standards of Care: a road map to improve CF outcome.
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Kerem E and Webb AK
- Subjects
- Europe, Humans, Cystic Fibrosis therapy, Societies, Medical, Standard of Care standards
- Published
- 2014
- Full Text
- View/download PDF
47. Differences in disease expression between primary ciliary dyskinesia and cystic fibrosis with and without pancreatic insufficiency.
- Author
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Cohen-Cymberknoh M, Simanovsky N, Hiller N, Hillel AG, Shoseyov D, and Kerem E
- Subjects
- Adolescent, Cross-Sectional Studies, Female, Humans, Male, Cystic Fibrosis complications, Cystic Fibrosis diagnosis, Exocrine Pancreatic Insufficiency complications, Exocrine Pancreatic Insufficiency diagnosis, Kartagener Syndrome complications, Kartagener Syndrome diagnosis
- Abstract
Background: Impaired mucociliary clearance causes pulmonary disease in primary ciliary dyskinesia (PCD) and contributes to cystic fibrosis (CF) lung disease. Although the sinopulmonary disease is similar, morbidity and mortality are different. Both patients with PCD and patients with CF with pancreatic sufficiency (CF-PS) show no nutrient malabsorption and are diagnosed at a later age compared with patients with CF with pancreatic insufficiency (CF-PI)., Methods: Clinical status, microbiology, FEV1, and high-resolution CT (HRCT) scans presented as total Brody score (CT-TBS) were compared for patients with PCD, CF-PI, and CF-PS, all treated at the same medical center, by the same team, and by a similar routine follow-up., Results: One hundred sixty-four patients, 34 with PCD, 88 with CF-PI, and 42 with CF-PS were enrolled. PCD was diagnosed at a similar age as CF-PS but significantly later than CF-PI. Mean FEV1 % predicted was similar for the three groups. The rate of FEV1 change with age in PCD was similar to CF-PS but significantly lower than in CF-PI. Severity of structural lung disease (CT-TBS) was similar for PCD and CF-PS and significantly higher in CF-PI. No correlation between TBS or Pseudomonas aeruginosa infection and FEV1 in PCD was seen, whereas a negative correlation with FEV1 was observed for both CF groups., Conclusions: Although in our study PCD was similar to CF-PS, the lack of correlation between FEV1 and age, CT-TBS, and P aeruginosa infection in PCD suggests that impaired mucociliary clearance is not the only cause for inducing pulmonary damage in these diseases. Furthermore, a comparison of disease characteristics for PCD and CF should distinguish between CF-PI and CF-PS as different entities.
- Published
- 2014
- Full Text
- View/download PDF
48. Mitochondrial OXPHOS function is unaffected by chronic azithromycin treatment.
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Negari SB, Aouizerat T, Tenenbaum A, Cohen-Cymberknoh M, Shoseyov D, Kerem E, and Saada A
- Subjects
- Adolescent, Child, Cystic Fibrosis metabolism, Female, Humans, Male, Anti-Bacterial Agents therapeutic use, Azithromycin therapeutic use, Cystic Fibrosis drug therapy, Electron Transport Complex I metabolism, Electron Transport Complex II metabolism, Lymphocytes metabolism, Mitochondria physiology, Oxidative Phosphorylation
- Abstract
Background: Certain antibiotics may cause unwanted side effects due to the similarity of the mitochondrial translation system to the prokaryotic one. Children with cystic fibrosis (CF) are vulnerable to recurrent respiratory tract infections and azithromycin, a translation targeted antibiotic, is often used chronically to treat CF patients. No major clinical side effects were found with chronic treatment. However, mitochondrial function was not previously assessed. We evaluated oxidative phosphorylation (OXPHOS) in lymphocytes from children with CF receiving chronic azithromycin treatment using an improved ATP production assay., Method: Enzymatic activities of respiratory chain complexes II-IV and ATP production were measured in lymphocytes., Results: Relative to controls and to CF patients without azithromycin treatment, no significant difference in mitochondrial respiratory chain complexes II-IV was detected, and ATP production with pyruvate, glutamate and succinate, did not disclose any differences between the groups., Conclusion: We suggest that chronic treatment with azithromycin does not significantly affect OXPHOS function., (Copyright © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. Differences in the pattern of structural abnormalities on CT scan in patients with cystic fibrosis and pancreatic sufficiency or insufficiency.
- Author
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Simanovsky N, Cohen-Cymberknoh M, Shoseyov D, Gileles-Hillel A, Wilschanski M, Kerem E, and Hiller N
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Comorbidity, Cystic Fibrosis genetics, Female, Genotype, Humans, Linear Models, Male, Middle Aged, Retrospective Studies, Severity of Illness Index, Tomography, X-Ray Computed, Young Adult, Cystic Fibrosis diagnostic imaging, Cystic Fibrosis epidemiology, Exocrine Pancreatic Insufficiency epidemiology, Lung diagnostic imaging
- Abstract
Background: Cystic fibrosis (CF) genotypes characterized by pancreatic sufficiency (PS) are generally associated with milder disease vs genotypes characterized by pancreatic insufficiency (PI); however, the correlation between pancreatic status and type and severity of structural lung changes has not been studied. We aimed to evaluate differences in the severity and distribution of pulmonary manifestations of CF in patients with PS vs PI., Methods: We retrospectively evaluated changes in individual lobes and the whole lung on chest CT scan with the modified Brody score. The study population included 84 (39 female, 45 male) patients with CF aged 4 to 68 years (mean, 20.5) treated from 2000 to 2010. Our institutional review board waived the requirement for informed consent. The severity of lung changes and distribution of pulmonary disease were compared by Student t test, nonparametric Pearson χ2 test, or mixed-design analysis of variance for 28 patients with CF-PS and 56 with CF-PI. Correlations were evaluated with the Pearson (continuous variables) or Spearman ρ (nonparametric variables) tests. A linear regression model was used for multivariate analyses., Results: Compared with patients with CF-PS, those with CF-PI had more-severe lung disease (P=.001) with predominant upper lobe involvement (P=.002) and significant differences in Brody scores for bronchiectasis and bronchial wall thickening. Lung manifestations in patients with CF-PS did not show predominant involvement of any one area (P=.133)., Conclusions: In patients with CF-PI, structural lung changes are more severe with upper lobe predominance, prominent bronchiectasis, and bronchial wall thickening vs lower severity and more general distribution of changes in those with CF-PS.
- Published
- 2013
- Full Text
- View/download PDF
50. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis.
- Author
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Moss RB, Mistry SJ, Konstan MW, Pilewski JM, Kerem E, Tal-Singer R, and Lazaar AL
- Subjects
- Adolescent, Adult, Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Phenylurea Compounds adverse effects, Sulfonamides adverse effects, Young Adult, Cystic Fibrosis drug therapy, Phenylurea Compounds therapeutic use, Receptors, Interleukin-8B antagonists & inhibitors, Sulfonamides therapeutic use
- Abstract
Background: It is hypothesized that a CXCR2 receptor antagonist would inhibit the recruitment and activation of neutrophils and other inflammatory cells into the lung in subjects with cystic fibrosis. The objective of this study was to evaluate the safety, tolerability and pharmacodynamics of SB-656933, an oral CXCR2 antagonist., Methods: 146 adult CF patients were randomized to receive either placebo or SB-656933 20mg or 50mg once daily for 28days. The primary endpoint was safety; secondary endpoints included pharmacokinetics, blood and sputum biomarkers, sputum microbiology, pulmonary function and respiratory symptoms., Results: SB-656933 was generally well tolerated. The most frequent adverse event was headache. Five subjects were withdrawn due to adverse events. In subjects receiving SB-656933 50mg, sputum neutrophils and elastase were reduced compared to baseline (probability of a true reduction, 0.889 and 0.882 respectively), and free DNA reduced compared to placebo (probability of a true reduction, 0.967), while blood levels of fibrinogen, CRP and CXCL8 were increased. There were no changes in lung function or respiratory symptoms. Average plasma concentrations of SB-656933 were lower than predicted based on previous studies, only breaching IC50 for ~4h at the 50mg dose., Conclusions: SB-656933 was well-tolerated in adult patients with cystic fibrosis. Patients receiving a daily dose of 50mg showed trends for improvement in sputum inflammatory biomarkers despite potential blunting of effects by lower than expected plasma concentrations. Although the increase in systemic inflammatory markers requires further evaluation, CXCR2 antagonism may be a useful approach for modulating airway inflammation in patients with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT00903201)., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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