The implications and management of cystic fibrosis screen positive, inconclusive diagnosis patients.

Paediatr Respir Rev. 2019 Mar 12;:

Authors: Krishnananthan T, Pao C

Abstract
Newborn screening and extensive genetic analysis has led to the recognition of a cohort of infants with an equivocal diagnosis of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) disease. This paper reviews the comprehensive approach required for diagnosis of Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) and uses an illustrative case with p.Asp1152His (D1152H) mutation to examine the varying clinical phenotype seen amongst CFSPID patients. Whilst infants are well at diagnosis, uncertainties about cystic fibrosis (CF) disease progression indicate the importance of monitoring and early specialist involvement. However, over-medicalisation can cause significant psychosocial impact on patients' and families. The complexities underlying the surveillance and long-term management of patients with CFSPID are explored.

PMID: 31153793 [PubMed - as supplied by publisher]

The diagnosis of Cystic Fibrosis: Controversies and consensus on common grounds.

Paediatr Respir Rev. 2019 Mar 15;:

Authors: Jones AM

PMID: 31153792 [PubMed - as supplied by publisher]

Trials and tribulations: The highs and lows of running cystic fibrosis drug studies.

Paediatr Respir Rev. 2019 Mar 14;:

Authors: Davies JC

Abstract
So many new trials of drugs for CF are being conducted each year it can be difficult to keep up. Yet, almost as numerous are the review articles written about them. I have chosen therefore to use this paper to discuss some of the difficult ethical issues arising during trials, in particular how to fairly distribute opportunities to participate. Some of these issues may be specific to countries like my own with very limited access to genotype-specific CFTR modulators, others may apply more generally. We have made enormous progress as a community over the recent past, but there is still much more to do before all our patients are reaping health and quality of life benefits.

PMID: 31153791 [PubMed - as supplied by publisher]

Long needed guidelines: Referral to transplant for cystic fibrosis patients.

J Cyst Fibros. 2019 May;18(3):305-306

Authors: Chaparro C, Hopkins PM, Schwarz C

PMID: 31153582 [PubMed - in process]

Bespoke Babies: Genome Editing in Cystic Fibrosis Embryos.

Ann Thorac Surg. 2019 May 29;:

Authors: Brothers KB, Devereaux M, Sade RM

PMID: 31152729 [PubMed - as supplied by publisher]

Massive haemoptysis and ventilatory failure in pregnancy.

Thorax. 2019 May 31;:

Authors: Flight WG, Tang I, Gates A, Snowball J, Wrightson JM, Mackillop L, Chapman SJ

PMID: 31152092 [PubMed - as supplied by publisher]

Perceptions of safety monitoring in CF clinical studies and potential impact on future study participation.

J Cyst Fibros. 2019 May 28;:

Authors: Kern-Goldberger AS, Hill-Ricciuti AC, Zhou JJ, Savant AP, Rugg L, Dozor AJ, Welter J, Saiman L, Quittell LM

Abstract
BACKGROUND: Individuals with CF and their parents cite safety concerns as barriers to participating in clinical studies. We assessed whether a brochure/infographic describing patient safety monitoring processes could reduce knowledge and attitude barriers regarding safety monitoring. We also identified factors associated with likely participation in future CF studies.
METHODS: Respondents from three CF centers in the U.S. were randomly assigned to receive the safety monitoring brochure/infographic or an unrelated brochure. Fifty parents of children with CF <16, 50 adolescents with CF 16-21, and 50 adults with CF ≥22 years old were recruited to complete the study survey. Factors associated with survey responses and with reported likelihood of participating in future studies were assessed.
RESULTS: Overall the safety monitoring brochure/infographic was associated with increased likelihood of future participation in non-drug studies (aOR 2.30, CI95 1.01-5.28), but not in drug studies. Non-Hispanic respondents reported greater likelihood of participating in a future drug study than Hispanic respondents (aOR 3.18, CI95 1.30-7.74). Adults with CF (aOR 2.62, CI95 1.05-6.51) and parents (aOR 4.49, CI95 1.66-12.15) were more likely than adolescents to report they would ask their care team about clinical trials. Confidence in safety monitoring was associated with reported likelihood of future participation in drug studies.
CONCLUSIONS: Potential future participation in CF drug and/or non-drug studies was associated with respondent age and ethnicity, receiving the safety monitoring brochure/infographic, and confidence in safety monitoring. Our findings underscore the need for education about safety monitoring, with targeted approaches for the Hispanic CF population and adolescents.

PMID: 31151855 [PubMed - as supplied by publisher]

Congenital and acquired diseases related to stone formation.

Curr Opin Urol. 2018 09;28(5):414-419

Authors: Veser J, Özsoy M, Seitz C

Abstract
PURPOSE OF REVIEW: To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis.
RECENT FINDINGS: Urolithiasis is related to a broad spectrum of congenital and acquired diseases and its management varies according to the stone type, underlying disease or recurrence rate, but it also changes according to recent findings and developments. As prevalence of urolithiasis is constantly increasing, identification of high-risk stone formers and early treatment is essential. Therefore, genetic evaluation like whole exome sequencing becomes a pertinent part of further diagnostics.
SUMMARY: Stone formation is a very heterogeneous pathomechanism. This prompt us to look at every patient individually particularly in high-risk patients, including stone and 24-h-urine analysis and additional diagnostic work-up based on stone type or underlying disease.

PMID: 29957682 [PubMed - indexed for MEDLINE]

Allergic contact dermatitis caused by a polyurethane catheter.

Contact Dermatitis. 2018 11;79(5):313-314

Authors: Milanesi N, Gola M, Francalanci S

PMID: 29923607 [PubMed - indexed for MEDLINE]

Extracellular DNA release, quorum sensing, and PrrF1/F2 small RNAs are key players in Pseudomonas aeruginosa tobramycin-enhanced biofilm formation.

NPJ Biofilms Microbiomes. 2019;5:15

Authors: Tahrioui A, Duchesne R, Bouffartigues E, Rodrigues S, Maillot O, Tortuel D, Hardouin J, Taupin L, Groleau MC, Dufour A, Déziel E, Brenner-Weiss G, Feuilloley M, Orange N, Lesouhaitier O, Cornelis P, Chevalier S

Abstract
Biofilms are structured microbial communities that are the leading cause of numerous chronic infections which are difficult to eradicate. Within the lungs of individuals with cystic fibrosis (CF), Pseudomonas aeruginosa causes persistent biofilm infection that is commonly treated with aminoglycoside antibiotics such as tobramycin. However, sublethal concentrations of this aminoglycoside were previously shown to increase biofilm formation by P. aeruginosa, but the underlying adaptive mechanisms still remain elusive. Herein, we combined confocal laser scanning microscope analyses, proteomics profiling, gene expression assays and phenotypic studies to unravel P. aeruginosa potential adaptive mechanisms in response to tobramycin exposure during biofilm growth. Under this condition, we show that the modified biofilm architecture is related at least in part to increased extracellular DNA (eDNA) release, most likely as a result of biofilm cell death. Furthermore, the activity of quorum sensing (QS) systems was increased, leading to higher production of QS signaling molecules. We also demonstrate upon tobramycin exposure an increase in expression of the PrrF small regulatory RNAs, as well as expression of iron uptake systems. Remarkably, biofilm biovolumes and eDNA relative abundances in pqs and prrF mutant strains decrease in the presence of tobramycin. Overall, our findings offer experimental evidences for a potential adaptive mechanism linking PrrF sRNAs, QS signaling, biofilm cell death, eDNA release, and tobramycin-enhanced biofilm formation in P. aeruginosa. These specific adaptive mechanisms should be considered to improve treatment strategies against P. aeruginosa biofilm establishment in CF patients' lungs.

PMID: 31149345 [PubMed - in process]

Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia.

J Clin Invest. 2019 May 30;130:

Authors: Borcherding DC, Siefert ME, Lin S, Brewington J, Sadek H, Clancy JP, Plafker SM, Ziady AG

Abstract
Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that approved F508del CFTR correctors VX809/VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del-CFTR. Mechanistically, F508del-CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CBP. Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.

PMID: 31145101 [PubMed - in process]

Employment after lung transplantation in Poland - a single center study.

Int J Occup Med Environ Health. 2019 May 29;:

Authors: Ochman M, Latos M, Orzeł G, Pałka P, Urlik M, Nęcki M, Stącel T, Zembala M

Abstract
OBJECTIVES: Lung transplantation not only saves a patient's life but also creates the opportunity for becoming more self-reliant and getting back to work. The aim of this single center study was to assess the prospects of employment, as well as its influence on the quality of life and physical activity, of the lung transplant recipients of the Silesian Center for Heart Diseases in Zabrze, Poland.
MATERIAL AND METHODS: A retrospective study covered 67 lung transplant recipients of the Silesian Center of Heart Diseases. Only patients with ≥ 6-month follow-up were included. All of the patients gave their written consent to be included in the study before filling out the questionnaire containing questions about employment, income, education and how work affected their quality of life before and after lung transplantation. A physical capability assessment was performed by climbing flights of stairs and by means of a 6-min walk test, and spirometry parameters were also measured.
RESULTS: Twenty of the patients included in the study (31.7%) were employed after lung transplantation, 63.2% of whom worked full-time. Profession was changed by 2 patients (14.3%). The patients diagnosed with cystic fibrosis were found to have the highest chance of finding employment after lung transplantation. The statistical analysis revealed that the employed patients were able to cover longer distances during the 6-min walk test (556 m, on average) than the unemployed ones (494 m, on average).
CONCLUSIONS: One in 3 patients finds employment after lung transplantation. Work improves the quality of life of the majority of lung transplant recipients. The patients who are employed are also in a better physical condition, and they are more self-reliant in comparison to those who remain unemployed. Lung transplant recipients with cystic fibrosis are most likely to find employment, and so are patients with higher education.

PMID: 31144676 [PubMed - as supplied by publisher]

Regional variations in longitudinal pulmonary function: A comparison of Hispanic and non-Hispanic subjects with cystic fibrosis in the United States.

Pediatr Pulmonol. 2019 May 29;:

Authors: McGarry ME, Neuhaus JM, Nielson DW, Ly NP

Abstract
BACKGROUND: Hispanic subjects with cystic fibrosis (CF) have increased morbidity and mortality than non-Hispanic white subjects. The ethnic disparity in mortality varies by region. Factors influencing pulmonary function vary by both ethnicity and region.
OBJECTIVE: To determine if the ethnic difference in pulmonary function varies by region.
METHODS: This retrospective cohort study compared differences in longitudinal pulmonary function (percent-predicted forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1 ], forced expiratory flow at 25% to 75% [FEF25-75 ], FEV1 /FVC, and FEV1 decline) between Hispanic and non-Hispanic white subjects with CF by Census region of the United States (West, South, Midwest, and Northeast). Subjects were of ages 6 to 25 years and in the CF Foundation Patient Registry from 2008 to 2013. We used linear mixed effects models with subject-specific slopes and intercepts, adjusting for 14 demographic and clinical variables.
RESULTS: Of 14 932 subjects, 1433 (9.6%) were Hispanic and 13 499 (90.4%) were non-Hispanic white. Hispanic subjects' FEV1 was 9.0% (8.3%-9.8%) lower than non-Hispanic white subjects in the West, while Hispanic subjects' FEV1 was only 4.0% (3.0%-5.0%) lower in the Midwest, 4.4% (3.1%-5.7%) lower in the Northeast, and 4.4% (3.2%-5.5%) lower in the South. Similarly, FVC and FEF25-75 were lower among Hispanic subjects compared to non-Hispanic white subjects in all US regions, with the biggest differences in the West. Only in the West was FEV1 /FVC significantly lower in Hispanic subjects (-0.019; -0.022 to -0.015). FEV1 decline was not significantly different between ethnicities in any region.
CONCLUSIONS: In CF, Hispanic subjects have lower pulmonary function than non-Hispanic white subjects in all geographic regions with the largest difference in occurring in the West.

PMID: 31144477 [PubMed - as supplied by publisher]

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome.

J Clin Immunol. 2019 May 29;:

Authors: Volpi S, Insalaco A, Caorsi R, Santori E, Messia V, Sacco O, Terheggen-Lagro S, Cardinale F, Scarselli A, Pastorino C, Moneta G, Cangemi G, Passarelli C, Ricci M, Girosi D, Derchi M, Bocca P, Diociaiuti A, El Hachem M, Cancrini C, Tomà P, Granata C, Ravelli A, Candotti F, Picco P, DeBenedetti F, Gattorno M

Abstract
OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib.
METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis.
RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease.
CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

PMID: 31144250 [PubMed - as supplied by publisher]

The Number of X Chromosomes Influences Inflammatory Cytokine Production Following Toll-Like Receptor Stimulation.

Front Immunol. 2019;10:1052

Authors: Lefèvre N, Corazza F, Valsamis J, Delbaere A, De Maertelaer V, Duchateau J, Casimir G

Abstract
Sex differences are observed in the evolution of numerous inflammatory conditions. Women exhibit better clinical courses compared to men in acute inflammatory processes, yet worse prognosis in several chronic inflammatory diseases. Inflammatory markers are significantly different between prepubertal boys and girls, whose sex steroid levels are very low, suggesting genetics play a role. To evaluate the potential influence of the X chromosome, we studied cytokine production and protein phosphorylation following Toll-like receptor (TLR) activation in whole blood and purified neutrophils and monocytes of healthy adults of both sexes as well as subjects with Klinefelter syndrome. We recorded higher levels of inflammatory cytokines in men compared to both women and patients with Klinefelter syndrome following whole blood stimulation. In purified monocytes, production of inflammatory cytokines was also higher in men compared to women, while Klinefelter subjects expressed the same pattern of cytokine production as males, in contrast with whole blood analyses. These differences remained after adjusting for sex steroid levels. Our study revealed higher cytokine inflammatory responses in men than women, yet also compared to subjects with Klinefelter syndrome, who carry two copies of the X chromosome, like women, and thus potentially benefit from the cellular mosaicism of X-linked genes.

PMID: 31143188 [PubMed - in process]

Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators.

Front Pharmacol. 2019;10:514

Authors: de Wilde G, Gees M, Musch S, Verdonck K, Jans M, Wesse AS, Singh AK, Hwang TC, Christophe T, Pizzonero M, Van der Plas S, Desroy N, Cowart M, Stouten P, Nelles L, Conrath K

Abstract
The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

PMID: 31143125 [PubMed]

Cystic Fibrosis and Pseudomonas aeruginosa: the Host-Microbe Interface.

Clin Microbiol Rev. 2019 Jun 19;32(3):

Authors: Malhotra S, Hayes D, Wozniak DJ

Abstract
SUMMARYIn human pathophysiology, the clash between microbial infection and host immunity contributes to multiple diseases. Cystic fibrosis (CF) is a classical example of this phenomenon, wherein a dysfunctional, hyperinflammatory immune response combined with chronic pulmonary infections wreak havoc upon the airway, leading to a disease course of substantial morbidity and shortened life span. Pseudomonas aeruginosa is an opportunistic pathogen that commonly infects the CF lung, promoting an accelerated decline of pulmonary function. Importantly, P. aeruginosa exhibits significant resistance to innate immune effectors and to antibiotics, in part, by expressing specific virulence factors (e.g., antioxidants and exopolysaccharides) and by acquiring adaptive mutations during chronic infection. In an effort to review our current understanding of the host-pathogen interface driving CF pulmonary disease, we discuss (i) the progression of disease within the primitive CF lung, specifically focusing on the role of host versus bacterial factors; (ii) critical, neutrophil-derived innate immune effectors that are implicated in CF pulmonary disease, including reactive oxygen species (ROS) and antimicrobial peptides (e.g., LL-37); (iii) P. aeruginosa virulence factors and adaptive mutations that enable evasion of the host response; and (iv) ongoing work examining the distribution and colocalization of host and bacterial factors within distinct anatomical niches of the CF lung.

PMID: 31142499 [PubMed - in process]

Unexpected analytical interference in isavuconazole UV determination in a child in therapy with lumacaftor/ivacaftor for cystic fibrosis.

Clin Chem Lab Med. 2019 May 29;:

Authors: Baldelli S, Fusi M, Cozzi V, Clementi E, Faelli NML, Russo M, Colombo C, Cattaneo D

PMID: 31141479 [PubMed - as supplied by publisher]

Heel prick test: maternal-fetal conditions that may have an effect on the test results in newborns admitted to the intensive care unit.

Rev Bras Ter Intensiva. 2019 May 23;:

Authors: Rodrigues LP, Tanaka SCSV, Haas VJ, Cunali VCA, Marqui ABT

Abstract
OBJECTIVE: To describe the characteristics of the heel prick test in newborns admitted to the intensive care unit of a university hospital as well as to determine whether maternal and fetal conditions could have affected the results of this test.
METHODS: Retrospective longitudinal study with a quantitative approach that evaluated 240 medical records. The data collected were analyzed by descriptive statistical analysis.
RESULTS: There was a predominance of pregnant women aged 20 to 34 years who had a complete secondary education and who had more than six prenatal care visits. Maternal complications or pathologies occurred in 60% of the mothers, and most (67.5%) did not present any condition that could have affected the heel prick test results. Most newborns were premature and exhibited low birth weight. Approximately 90% of newborns exhibited conditions that could have influenced the test, especially prematurity, parenteral nutrition and blood transfusion. Of the 240 newborns, 25% had abnormal heel prick test results, especially for cystic fibrosis and congenital adrenal hyperplasia.
CONCLUSION: There are maternal and neonatal conditions that can affect heel prick test results, and therefore, their investigation is essential, aiming to guide measures that promote mother and child health and consolidate neonatal screening in this population.

PMID: 31141086 [PubMed - as supplied by publisher]

Gene modifiers of cystic fibrosis lung disease: A systematic review.

Pediatr Pulmonol. 2019 May 29;:

Authors: Shanthikumar S, Neeland MN, Saffery R, Ranganathan S

Abstract
BACKGROUND: Lung disease is the major source of morbidity and mortality in cystic fibrosis (CF), with large variability in severity between patients. Although accurate prediction of lung disease severity would be extremely useful, no robust methods exist. Twin and sibling studies have highlighted the importance of non-cystic fibrosis transmembrane conductance regulator (CFTR) genes in determining lung disease severity but how these impact on the severity in CF remains unclear.
METHODS: A systematic review was undertaken to answer the question "In patients with CF which non-CFTR genes modify the severity of lung disease?" The method for this systematic review was based upon the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" statement, with a narrative synthesis of results planned.
RESULTS: A total of 1168 articles were screened for inclusion, with 275 articles undergoing detailed assessment for inclusion. One hundred and forty articles were included. Early studies focused on candidate genes, whereas more recent studies utilized genome-wide approaches and also examined epigenetic mechanisms, gene expression, and therapeutic response.
DISCUSSION: A large body of evidence regarding non-CFTR gene modifiers of lung disease severity has been generated, examining a wide array of genes. Limitations to existing studies include heterogeneity in outcome measures used, limited replication, and relative lack of clinical impact. Future work examining non-CFTR gene modifiers will have to overcome these limitations if gene modifiers are to have a meaningful role in the care of patients with CF.

PMID: 31140758 [PubMed - as supplied by publisher]