Recurrent Cough and Expectoration for 10 Years: A Case Report.

Glob Pediatr Health. 2019;6:2333794X19833725

Authors: Huang T, Li C, Liu D

Abstract
Rationale. Most cases of cystic fibrosis occur in Europe, with only a few occurring in Asia. Pulmonary cystic fibrosis is not a rare disease, but in children it is a potentially life-threatening condition. Children suffering from pulmonary cystic fibrosis rarely survive to adulthood, and responses to treatment are generally poor. The most common cause of cystic fibrosis is a genetic mutation on chromosome 7. Patient concerns. A 15-year-old boy with healthy parents suffered from a recurrent cough and expectoration for nearly 10 years. Six years previously, a definitive diagnosis of pulmonary cystic fibrosis and hepatic cirrhosis was made at the Beijing Children's Hospital. The first occurrence of hematemesis occurred 1 year ago. The main symptoms, which caused this period of hospitalization, were cough, expectoration, and hematemesis. Diagnoses. The underlying cause was finally determined to be the cystic fibrosis transmembrane conductance regulator gene (p.G970D). After genetic and sweat testing performed at the Beijing Children's Hospital in 2012, a definitive diagnosis of cystic fibrosis was made. Interventions. The patient was administered hemostatic treatment, antibiotics, and cough relief and sputum reduction therapy. Outcomes. The patient's condition rapidly improved and continued to remain stable, though future relapse is possible following respiratory tract infections. Lessons. This case indicates that in the case of any child that presents a recurrent cryptogenic cough and expectoration, whether accompanied by hematemesis or not, pulmonary cystic fibrosis should be considered. In order to determine underlying causes and prepare for cystic fibrosis transmembrane conductance regulator modulator therapy, genetic and sweat testing are recommended to be conducted if available.

PMID: 30993151 [PubMed]

The CFTR gene variants in Japanese children with idiopathic pancreatitis.

Hum Genome Var. 2019;6:17

Authors: Iso M, Suzuki M, Yanagi K, Minowa K, Sakurai Y, Nakano S, Satou K, Shimizu T, Kaname T

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of CFTR have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey CFTR variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of PRSS1 and SPINK1. The entire CFTR gene was sequenced in the patients by combining LA-PCR and next-generation sequencing analysis. To determine a splice-affecting variant, CFTR expression was investigated in the nasal epithelial cells by RT-PCR. One (3.6%) and 15 (53.6%) of 28 patients had pathogenic and functionally affected variants in the CFTR gene, respectively. Two variants, p.Arg352Gln and p.Arg1453Trp, were found more frequently in the patients compared with one in Japanese healthy controls (p = 0.0078 and 0.044, respectively). We confirmed skipping of exon 10 in the nasal epithelial cells in one patient having a splice-affecting variant (c.1210-12 T(5)) in intron 9. Functionally affected variants of the CFTR gene are not so rare in Japanese paediatric patients with idiopathic pancreatitis. Surveying CFTR gene variants in a Japanese sample could help identify pancreatitis risk in these children.

PMID: 30992994 [PubMed]

Phenotyping ciliary dynamics and coordination in response to CFTR-modulators in Cystic Fibrosis respiratory epithelial cells.

Nat Commun. 2019 Apr 16;10(1):1763

Authors: Chioccioli M, Feriani L, Kotar J, Bratcher PE, Cicuta P

Abstract
Personalized approaches for systematically assessing ciliary beat dynamics and for drug testing would improve the challenging task of diagnosing and treating respiratory disorders. In this pilot study, we show how multiscale differential dynamic microscopy (multi-DDM) can be used to characterize collective ciliary beating in a non-biased automated manner. We use multi-DDM to assess the efficacy of different CFTR-modulating drugs in human airway epithelial cells derived from subjects with cystic fibrosis (ΔF508/ΔF508 and ∆F508/-) based on ciliary beat frequency and coordination. Similar to clinical observations, drug efficacy is variable across donors, even within the same genotype. We show how our assay can quantitatively identify the most efficient drugs for restoring ciliary beating for each individual donor. Multi-DDM provides insight into ciliary beating responses following treatment with drugs, and has application in the broader context of respiratory disease and for drug screening.

PMID: 30992452 [PubMed - in process]

Cystic Fibrosis Rapid Response: Translating Multi-omics Data into Clinically Relevant Information.

MBio. 2019 Apr 16;10(2):

Authors: Cobián Güemes AG, Lim YW, Quinn RA, Conrad DJ, Benler S, Maughan H, Edwards R, Brettin T, Cantú VA, Cuevas D, Hamidi R, Dorrestein P, Rohwer F

Abstract
Pulmonary exacerbations are the leading cause of death in cystic fibrosis (CF) patients. To track microbial dynamics during acute exacerbations, a CF rapid response (CFRR) strategy was developed. The CFRR relies on viromics, metagenomics, metatranscriptomics, and metabolomics data to rapidly monitor active members of the viral and microbial community during acute CF exacerbations. To highlight CFRR, a case study of a CF patient is presented, in which an abrupt decline in lung function characterized a fatal exacerbation. The microbial community in the patient's lungs was closely monitored through the multi-omics strategy, which led to the identification of pathogenic shigatoxigenic Escherichia coli (STEC) expressing Shiga toxin. This case study illustrates the potential for the CFRR to deconstruct complicated disease dynamics and provide clinicians with alternative treatments to improve the outcomes of pulmonary exacerbations and expand the life spans of individuals with CF.IMPORTANCE Proper management of polymicrobial infections in patients with cystic fibrosis (CF) has extended their life span. Information about the composition and dynamics of each patient's microbial community aids in the selection of appropriate treatment of pulmonary exacerbations. We propose the cystic fibrosis rapid response (CFRR) as a fast approach to determine viral and microbial community composition and activity during CF pulmonary exacerbations. The CFRR potential is illustrated with a case study in which a cystic fibrosis fatal exacerbation was characterized by the presence of shigatoxigenic Escherichia coli The incorporation of the CFRR within the CF clinic could increase the life span and quality of life of CF patients.

PMID: 30992350 [PubMed - in process]

Promotion of physical activity for adolescents with cystic fibrosis: a qualitative study of UK multi disciplinary cystic fibrosis teams.

Physiotherapy. 2019 Jan 26;:

Authors: Denford S, Mackintosh KA, McNarry MA, Barker AR, Williams CA, Active Youth Unlimited Group

Abstract
BACKGROUND: The Cystic Fibrosis Trust recently published a standards of care document which stated that patients should be given a physical activity (PA) programme based on their motivations, fitness, and willingness to be active. However, there remains much debate regarding the roles and responsibilities for PA promotion, as well as "optimal" recommendations and advice. This study aimed to qualitatively explore cystic fibrosis (CF) multidisciplinary teams (MDTs) advice, recommendations and practices relating to PA promotion for adolescents with CF.
METHOD: Semi-structured interviews were conducted with fifteen members of CF MDTs (11 physiotherapists, two dieticians and two paediatricians). Thematic analysis was used to analyse the data.
RESULTS: Major themes identified were: (1) structure of MDTs, (2) recommendations relating to intensities, durations and types of PA, and (3) use of exercise testing. Participants reported variation between MDTs in terms of who is responsible for promoting and supporting PA, the nature of advice given to patients, and the use of exercise testing. Participants consistently lacked confidence in their own or others' knowledge to provide standardised recommendations to patients and highlighted that PA promotion and support was often overlooked during busy periods.
CONCLUSIONS: Despite its importance, PA support and promotion is not always prioritised. MDTs lack confidence in their ability to promote PA. Standardised advice and training relating to optimal intensities, durations and types of PA would provide a baseline from which to individualise advice to each patient and could increase confidence in PA promotion among MDTs.

PMID: 30992157 [PubMed - as supplied by publisher]

Carrier screening for spinal muscular atrophy with a simple test based on melting analysis.

J Hum Genet. 2019 May;64(5):387-396

Authors: Xia Z, Zhou Y, Fu D, Wang Z, Ge Y, Ren J, Guo Q

Abstract
Carrier screening of spinal muscular atrophy (SMA) can provide reproductive options for carriers and prevent the birth defects. Here, we developed a simple screening test based on melting analysis. The test comprises a duplex PCR with two primer pairs and three probes to simultaneous amplify SMN1, SMN2, and CFTR. By analyzing the melting profiles, we were able to determine the SMN1/SMN2 ratio and SMN1 + SMN2 copy number to subsequently determine the copy number of SMN1. Samples with one copy of SMN1 were considered as "high risk for carrier," while samples with ≥2 copies of SMN1 were considered as "low risk for carrier." We evaluated the clinical performance of this test using 215 clinical samples with various genotypes that had been previously confirmed by multiplex ligation-dependent probe amplification (MLPA). The test showed high sensitivity (100%) and specificity (97.1%) as well as high positive (97.3%) and negative (100%) predictive value, and was in perfect agreement with the gold standard test, MLPA (k = 0.97). Moreover, it is rapid, inexpensive, and easy to perform and automate, with high reproducibility and capacity. Therefore, we expect this test will advance carrier screening for SMA.

PMID: 30765868 [PubMed - indexed for MEDLINE]

Opportunities for Outpatient Pharmacy Services for Patients with Cystic Fibrosis: Perceptions of Healthcare Team Members.

Pharmacy (Basel). 2019 Apr 03;7(2):

Authors: Abraham O, Morris A

Abstract
Cystic fibrosis (CF) is one of the most common life-threatening, genetic conditions. People with CF follow complex, time-consuming treatment regimens to manage their chronic condition. Due to the complexity of the disease, multidisciplinary care from CF Foundation (CFF)-accredited centers is recommended for people with CF. These centers include several types of healthcare professionals specializing in CF; however, pharmacists are not required members. The purpose of this study was to identify the outpatient care needs of people living with CF that pharmacists could address to improve their quality of care. Healthcare members from a CFF accredited center and pharmacists were recruited to participate in semi-structured, audio-recorded interviews. Prevalent codes were identified and data analysis was conducted, guided by the systems engineering initiative for patient safety (SEIPS) model. The objective was to understand the medication and pharmacy-related needs of patients with CF and care team perspectives on pharmacists providing support for these patients. From the themes that emerged, pharmacists can provide support for people living with CF (medication burden, medication access, medication education) and the CF care team (drug monitoring and adherence, prior authorizations and insurance coverage, refill history). Pharmacists are well-positioned to address these difficulties to improve quality of care for people living with cystic fibrosis.

PMID: 30987260 [PubMed]

Mucin Binding To Therapeutic Molecules: The Case Of Antimicrobial Agents Used In Cystic Fibrosis.

Int J Pharm. 2019 Apr 13;:

Authors: Butnarasu C, Barbero N, Pacheco D, Petrini P, Visentin S

Abstract
Mucin is a complex glycoprotein consisting of a wide variety of functional groups that can interact with exogenous agents. The binding to mucin plays a crucial role in drug pharmacokinetics especially in diseases, such as cystic fibrosis (CF), where mucin is overexpressed. In this study, we have investigated the interaction between mucin and several drugs used in CF therapy. Protein-drug interaction was carried out by UV-Vis and fluorescence spectroscopy; quenching mechanism, binding constants, number of binding sites, thermodynamic parameters and binding distance of the interaction were obtained.

PMID: 30991132 [PubMed - as supplied by publisher]

Noninvasive Ventilation-Facilitated Bronchofiberoscopy in Patients with Respiratory Failure.

Adv Exp Med Biol. 2019 Apr 16;:

Authors: Skoczyński S, Minarowski Ł, Tobiczyk E, Oraczewska A, Glinka K, Ficek K, Mróz R, Barczyk A

Abstract
Respiratory failure is one of the most important risk factors for diagnostic bronchofiberoscopy (BF), whereas therapeutic bronchoscopies are typically performed in intubated patients. Only a few published studies analyzed the outcomes of noninvasive mechanical ventilation (NIV)-facilitated BF. In this case series, we present our experiences with NIV-facilitated diagnostic and therapeutic BF performed in patients with respiratory failure that was associated with acute interstitial pulmonary disease, chronic obstructive pulmonary disease, cystic fibrosis exacerbation, foreign body aspiration, tracheal stenosis, pneumonia, and in a patient with a neuromuscular disease. All of the patients were initially hypoxic and some had PaO2/FiO2 < 200, which corresponded to moderate-to-acute respiratory distress syndrome (ARDS). NIV-facilitated BF were performed for the diagnostic or therapeutic purposes. The former consisted of bronchoalveolar lavage and bacterial sampling in a patient with impaired cough reflex, airway assessment in otherwise unexplained respiratory failure and hemoptysis, and the latter of mucous plugs resolution, foreign body removal, and assistance in weaning from mechanical ventilation. All procedures were carried out using NIV in the spontaneous timed (ST) or average volume assured pressure support (AVAPS) mode with oxygen supplementation. There were no procedure-related complications noticed during NIV-facilitated BF. We conclude that NIV is a useful and safe tool that facilitates the performance of BF in severe pulmonary diseases. Prospective studies are required to set the recommendations for the procedure and to define the optimum ventilatory modes to be used.

PMID: 30989590 [PubMed - as supplied by publisher]

Hypercalcaemia: A portent of sarcoidosis in cystic fibrosis.

Sultan Qaboos Univ Med J. 2018 Nov;18(4):e533-e536

Authors: Jayakrishnan B, Al-Mubaihsi SM, Kashoub MS, George J

Abstract
The coexistence of cystic fibrosis (CF) and sarcoidosis is rare. We report a 22-year-old male cystic fibrosis patient who presented multiple times to the Sultan Qaboos University Hospital, Muscat, Oman, in 2013. He was diagnosed with non-parathyroid-related hypercalcaemia and anterior uveitis, while computed tomography revealed mediastinal and abdominal lymphadenopathy and mild hepatosplenomegaly. These findings, in addition to the presence of calciuria and a high angiotensin-converting enzyme (ACE) level, confirmed a clinical diagnosis of sarcoidosis. The patient responded well to treatment with oral prednisolone which, over the course of two years, resulted in the near-complete resolution of parenchymal nodular infiltrates, regression of hilar lymphadenopathy, resolution of hypercalcaemia and the normalisation of his ACE levels. Diagnosing pulmonary sarcoidosis in CF can be challenging as most adult patients already have extensive lung disease. Physicians should be aware that hypercalcaemia may be an early manifestation of sarcoidosis in such cases.

PMID: 30988976 [PubMed - in process]

Question 13: Can we predict the need for lung transplantation in children with cystic fibrosis?

Paediatr Respir Rev. 2019 Feb 19;:

Authors: Piper N, Bajic M, Selvadurai H, Robinson P, Zurynski Y, Fitzgerald DA

PMID: 30987796 [PubMed - as supplied by publisher]

Abstracts from the 24th Congress of the Italian Society of Cystic Fibrosis and the 14th National Congress of Cystic Fibrosis Italian Society : Salerno, Italy. 8 -10 November 2018.

Ital J Pediatr. 2019 Apr 16;45(Suppl 1):43

Authors:

PMID: 30987649 [PubMed - in process]

Lactoferrin in Aseptic and Septic Inflammation.

Molecules. 2019 Apr 03;24(7):

Authors: Lepanto MS, Rosa L, Paesano R, Valenti P, Cutone A

Abstract
Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer's disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in Chlamydia trachomatis infection, cystic fibrosis and inflammatory bowel disease, Lf, besides the anti-inflammatory activity, exerts a significant activity against bacterial adhesion, invasion and colonization. Lastly, a critical analysis of literature in vitro data reporting contradictory results on the Lf role in inflammatory processes, ranging from pro- to anti-inflammatory activity, highlighted that they depend on cell models, cell metabolic status, stimulatory or infecting agents as well as on Lf iron saturation degree, integrity and purity.

PMID: 30987256 [PubMed - in process]

Trial Refresh: A Case for an Adaptive Platform Trial for Pulmonary Exacerbations of Cystic Fibrosis.

Front Pharmacol. 2019;10:301

Authors: Schultz A, Marsh JA, Saville BR, Norman R, Middleton PG, Greville HW, Bellgard MI, Berry SM, Snelling T

Abstract
Cystic fibrosis is a genetic disease typically characterized by progressive lung damage and premature mortality. Pulmonary exacerbations, or flare-ups of the lung disease, often require hospitalization for intensive treatment. Approximately 25% of patients with cystic fibrosis do not recover their baseline lung function after pulmonary exacerbations. There is a relative paucity of evidence to inform treatment strategies for exacerbations. Compounding this lack of evidence, there are a large number of treatment options already as well as becoming available. This results in significant variability between medication regimens prescribed by different physicians, treatment centers and regions with potentially adverse impact to patients. The conventional strategy is to undertake essential randomized clinical trials to inform treatment decisions and improve outcomes for patients with exacerbations. However, over the past several decades, clinical trials have generally failed to provide information critical to improved treatment and management of exacerbations. Bayesian adaptive platform trials hold the promise of addressing clinical uncertainties and informing treatment. Using modeling and response adaptive randomization, they allow for the evaluation of multiple treatments across different management domains, and progressive improvement in patient outcomes throughout the course of the trial. Bayesian adaptive platform trials require substantial amounts of preparation. Basic preparation includes extensive stakeholder involvement including elicitation of consumer preferences and clinician understanding of the research topic, defining the research questions, determining the best outcome measures, delineating study sub-groups, in depth statistical modeling, designing end-to-end digital solutions seamlessly supporting clinicians, researchers and patients, constructing randomisation algorithms and importantly, defining pre-determined intra-study end-points. This review will discuss the motivation and necessary steps required to embark on a Bayesian adaptive platform trial to optimize medication regimens for the treatment of pulmonary exacerbations of cystic fibrosis.

PMID: 30983998 [PubMed]

Review of Cystic Fibrosis.

Pediatr Ann. 2019 Apr 01;48(4):e154-e161

Authors: Goetz D, Ren CL

Abstract
Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF. CF is a lifelong, life-limiting disease, but an organized care center network with multidisciplinary approach, quality improvement initiatives, and research has led to markedly increased survival and development of adult CF care programs. In the past few years, medications that directly target the underlying CF defect have been developed, which should result in even greater survival benefits. [Pediatr Ann. 2019;48(4):e154-e161.].

PMID: 30986316 [PubMed - in process]

CFTR interacts with Hsp90 and regulates the phosphorylation of AKT and ERK1/2 in colorectal cancer cells.

FEBS Open Bio. 2019 Apr 15;:

Authors: Liu K, Jin H, Guo Y, Liu Y, Wan Y, Zhao P, Zhou Z, Wang J, Wang M, Zou C, Wu W, Cheng Z, Dai Y

Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF cells and tissues exhibit various mitochondrial abnormalities. However, the underlying molecular mechanisms remain elusive. Here, we examined the mechanisms through which CFTR regulates Bcl-2 family proteins, which in turn regulate permeabilization of the mitochondrial outer membrane. Notably, inhibition of CFTR activated Bax and Bad, but inhibited Bcl-2. Moreover, degradation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT increased significantly in CFTR-knockdown cells. Dysfunction of CFTR decreased heat-shock protein 90 (Hsp90) mRNA levels, and CFTR was found to interact with Hsp90. Inhibition of Hsp90 by SNX-2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco2 and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF-related diseases.

PMID: 30985981 [PubMed - as supplied by publisher]

Impact of CYP3A5 phenotype on tacrolimus concentrations after sublingual and oral administration in lung transplant.

Pharmacogenomics. 2019 Apr 15;:

Authors: Pasternak AL, Kidwell KM, Dempsey JM, Gersch CL, Pesch A, Sun Y, Rae JM, Hertz DL, Park JM

Abstract
AIM: This study evaluated the impact of CYP3A5 genotype and other patient characteristics on sublingual (SL) tacrolimus exposure and compared the relationship with oral administration.
PATIENTS & METHODS: Tacrolimus concentrations were retrospectively collected for adult lung transplant recipients, who were genotyped for CYP3A5*3, CYP3A4*22, CYP3A7*1C, and POR*28. Regression analyses were performed to determine covariates that impacted the SL and oral tacrolimus concentration/dose ratios.
RESULTS: An interaction of CYP3A5 genotype and CYP3A inhibitor increased the SL concentration/dose, while cystic fibrosis decreased the SL concentration/dose. The oral concentration/dose was independently associated with these covariates and was increased by serum creatinine and number of tacrolimus doses.
CONCLUSION: This study suggests personalized dosing strategies for tacrolimus likely need to consider characteristics beyond CYP3A5 genotype.

PMID: 30983501 [PubMed - as supplied by publisher]

[Chronic rhinosinusitis and cystic fibrosis in adult].

Rev Prat. 2019 Mar;69(3):279-280

Authors: Mortuaire G

PMID: 30983252 [PubMed - in process]

[Problems posed by genetic diseases, concerning: chromosomal disorders, trisomy 21; genetic diseases, cystic fibrosis, DNA instability disorders: fragile X syndrome].

Rev Prat. 2019 Feb;69(2):e47-e54

Authors: Yauy K, Geneviève D

PMID: 30983237 [PubMed - in process]

Effectiveness of ivacaftor in cystic fibrosis: Improvement of liver cirrhosis, nutritional status and respiratory function.

Med Clin (Barc). 2019 Apr 11;:

Authors: Martín de Vicente C, García Romero R

PMID: 30982531 [PubMed - as supplied by publisher]