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Cystic Fibrosis
Current Awareness
Newsletter
June 2015
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Contents
Your Friendly Local Librarian… ................................................................................................................ 2
New Cochrane Library Systematic Reviews on Cystic Fibrosis ............................................................... 3
New from NICE ........................................................................................................................................ 3
Recent Literature Searches on Cystic Fibrosis ........................................................................................ 4
Current Awareness Database Articles on Cystic Fibrosis ........................................................................ 4
Medical................................................................................................................................................ 5
Microbiological.................................................................................................................................. 11
Psychological ..................................................................................................................................... 23
Other ................................................................................................................................................. 24
Journal Tables of Contents.................................................................................................................... 24
Journal of Cystic Fibrosis ................................................................................................................... 31
American Journal of Respiratory and Critical Care Medicine ........................................................... 31
Thorax ............................................................................................................................................... 31
Chest ................................................................................................................................................. 31
Your Friendly Local Librarian…
Whatever your information needs, the library is here to help. As your outreach librarian I offer
literature searching services as well as training and guidance in searching the evidence and critical
appraisal – just email me at library@uhbristol.nhs.uk
OUTREACH: Your Outreach Librarian can help facilitate evidence-based practise for all in the CF
team, as well as assisting with academic study and research. We can help with literature searching,
obtaining journal articles and books, and setting up individual current awareness alerts. We also
offer one-to-one or small group training in literature searching, accessing electronic journals, and
critical appraisal. Get in touch: library@uhbristol.nhs.uk
LITERATURE SEARCHING: We provide a literature searching service for any library member. For
those embarking on their own research it is advisable to book some time with one of the librarians
for a 1 to 1 session where we can guide you through the process of creating a well-focused literature
research and introduce you to the health databases access via NHS Evidence. Please email requests
to library@uhbristol.nhs.uk
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New from the Cochrane Library Systematic
Reviews on Cystic Fibrosis
Positive expiratory pressure physiotherapy for airway clearance in people with cystic fibrosis
Source: Cochrane Database of Systematic Reviews
Publication date: 17 June 2015
Abstract
Background: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in
people with cystic fibrosis. Positive expiratory pressure (PEP) devices provide back pressure to the
airways during expiration. This may improve clearance by building up gas behind mucus via collateral
ventilation and by temporarily increasing functional residual capacity. Given the widespread use of
PEP devices, there is a need to determine the evidence for their effect. This is an update of a
previously published review.
Objectives: To determine the effectiveness and acceptability of PEP devices compared to other
forms of physiotherapy as a means of improving mucus clearance and other outcomes in people
with cystic fibrosis.
Topical nasal steroids for treating nasal polyposis in people with cystic fibrosis
Source:
Cochrane Database of Systematic Reviews
Publication date:
22 June 2015
Abstract
Background: Nasal polyps frequently occur in people with cystic fibrosis. Sinus infections have been
shown to be a factor in the development of serious chest complications in these people. Nasal
polyps have been linked to a higher risk of lower respiratory tract infections with Pseudomonas
aeruginosa . Topical nasal steroids are of proven efficacy for treating nasal polyposis in the noncystic fibrosis population. There is no clear current evidence for the efficacy of topical steroids for
nasal polyps in people with cystic fibrosis. This is an updated version of a previously published
review.
Objectives: To assess the effectiveness of topical nasal steroids for treating symptomatic nasal
polyps in people with cystic fibrosis.
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New from NICE
Eyes on Evidence : life expectancy of people with cystic fibrosis
Source: National Institute for Health and Care Excellence - NICE
Publisher: National Institute for Health and Care Excellence (NICE)
Publication date: 11 May 2015
Abstract
A US cohort study reported that mortality rate among people with cystic fibrosis decreased by 1.8%
a year between 2000 and 2010, and estimated that children born and diagnosed with cystic fibrosis
in 2010 would be likely to survive to approximately 56 years if this trend were to continue.
This link will take you to the Eyes on Evidence commentary. Eyes on Evidence commentaries help
contextualise important new evidence, highlighting areas that could signal a change in clinical
practice. It does not constitute formal NICE guidance. The commentaries included are the opinions
of contributors and do not necessarily reflect the views of NICE.
Recent Literature Searches on Cystic Fibrosis
Below is a sample of literature searches carried out by librarians for UH Bristol members of staff
on the subject of Cystic Fibrosis. For further details get in touch: library@uhbristol.nhs.uk
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CF and instigating non-invasive ventilation
CF and dry powder antibiotics
Current Awareness Database Articles on
Cystic Fibrosis
Below is a selection of articles on cystic fibrosis recently added to the healthcare databases,
grouped in the following categories:
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Medical
Microbiological
Psychological
Other
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If you would like any of the following articles in full text, or if you would like a more focused
search on your own topic, then get in touch: library@uhbristol.nhs.uk
Medical
Title: Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis
Foundation Workshop Report.
Citation: Annals of the American Thoracic Society, Jun 2015, vol. 12, no. 6, p. 932-939
Author(s): Subbarao, Padmaja, Milla, Carlos, Aurora, Paul, Davies, Jane C, Davis, Stephanie D, Hall,
Graham L, Heltshe, Sonya, Latzin, Philipp, Lindblad, Anders, Pittman, Jessica E, Robinson, Paul D,
Rosenfeld, Margaret, Singer, Florian, Starner, Tim D, Ratjen, Felix, Morgan, Wayne
Abstract: The lung clearance index (LCI) is a lung function parameter derived from the multiplebreath washout (MBW) test. Although first developed 60 years ago, the technique was not widely
used for many years. Recent technological advances in equipment design have produced gains in
popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing
preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in
patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the
North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in
multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a
valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older
patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas,
and standardization across systems are key issues precluding its use as a clinical trial end point in
infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW
parameters in the routine clinical management of patients with CF.
Title: Multicenter Observational Study on Factors and Outcomes Associated with Various
Methicillin-Resistant Staphylococcus aureus Types in Children with Cystic Fibrosis.
Citation: Annals of the American Thoracic Society, Jun 2015, vol. 12, no. 6, p. 864-871
Author(s): Muhlebach, Marianne S, Heltshe, Sonya L, Popowitch, Elena B, Miller, Melissa B,
Thompson, Valeria, Kloster, Margaret, Ferkol, Thomas, Hoover, Wynton C, Schechter, Michael S,
Saiman, Lisa, STAR-CF Study Team
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in
patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of
strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in
the general population have different genotypic and phenotypic features than SCCmec II type. We
hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health
care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. To
determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from
patients not more than 18 years old at seven CF centers were typed and the association of potential
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risk factors and subsequent clinical course was assessed, using data provided by the CF Patient
Registry. Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%)
had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains.
SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03).
SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic
visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95%
confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged
in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care
increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics
were prescribed more frequently in those with SCCmec II strains and increased hospitalizations
occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted
difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had
an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior.
Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of
SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA
detection regardless of SCCmec type
Title: Recent advances in cystic fibrosis.
Citation: Current opinion in pediatrics, Jun 2015, vol. 27, no. 3, p. 317-324
Author(s): Milla, Carlos E, Moss, Richard B
Abstract: The field of cystic fibrosis (CF) continues to evolve at a fast pace thanks to novel
observations that have enabled deeper understanding of the disease pathophysiology. Parallel
groundbreaking developments in innovative therapies permit, for the first time, distinct disease
modification. This review highlights important discoveries in fluid homeostasis and mucus secretion
in CF that further informs the pathophysiology of the airway disease that characterizes CF. In
addition, current concepts and novel paradigms, such as 'theratypes' and 'CF transmembrane
conductance regulator chaperome', which will be important for the continued development of
disease modifying therapies, are reviewed. The rate of progress in the field continues to accelerate
with new knowledge informing the development of innovative therapies. This has already led to
tangible substantial and unprecedented clinical benefit for selected subsets of the CF patient
population. In the years ahead, further knowledge acquisition may motivate the extension of these
benefits to the larger population of people with CF.
Title: Multidisciplinary Treatment of Cystic Fibrosis-Related Recurrent Pyogenic Cholangitis (CFRPC).
Citation: Digestive diseases and sciences, Jun 2015, vol. 60, no. 6, p. 1801-1804
Author(s): Buxbaum, James, Nguyen, Nancy, Kulkarni, Sujit, Palmer, Suzanne, Rao, Adupa, Selby,
Robert
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Abstract: As the survival of cystic fibrosis patients improves due to better treatment of its
pulmonary manifestations, the management of hepatobiliary complications becomes increasingly
vital. While focal biliary cirrhosis is common, large duct manifestations are less frequently
encountered. We prospectively evaluated cases of large bile duct disease in a large adult cystic
fibrosis practice at the Keck Hospital of the University of Southern California. Over a 5-year period,
six patients presented with cholangiectasia, hepatolithiasis, and strictures. Their clinical presentation
and course closely resembled recurrent pyogenic cholangitis (RPC). Treatment of cholangitis and
strictures was primarily by endoscopic retrograde cholangiopancreatography, but major
hepatobiliary surgery following pulmonary optimization was required in 33 %. In adult populations,
CF-RPC may not be as unusual as previously reported and recognition allows optimal endoscopic,
medical, and surgical management
Title: Population pharmacokinetics of mycophenolic acid in lung transplant recipients with and
without cystic fibrosis.
Citation: European journal of clinical pharmacology, Jun 2015, vol. 71, no. 6, p. 673-679
Author(s): Wang, Xiao-Xing, Feng, Meihua R, Nguyen, Hugh, Smith, David E, Cibrik, Diane M, Park,
Jeong M
Abstract: The objective of this work was to characterize and compare the population
pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic
fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug
mycophenolate mofetil (MMF) as an immunosuppressant. Three separate 12-h PK visits were
conducted for lung transplant patients with or without CF following repeated MPA treatment with at
least a 2-week break between the visits. A population PK model was developed using nonlinear
mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors
and time dependence of apparent oral clearance (CL/F) were assessed. For both CF and NCF
patients, MPA serum concentration-time profiles were best described by a two-compartment PK
model with first-order absorption. CF patients had a slower absorption rate (Ka), and elevated CL/F
and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of
body weight and CF disease to MPA CL/F, and both were included in the final model as covariates.
The population PK model developed from our study successfully characterizes the absorption,
distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The
decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution
(V2/F and V3/F) in the CF patients would suggest the importance of MPA therapeutic monitoring for
this group.
Title: Dose increase needed in most cystic fibrosis lung transplantation patients when changing
from twice- to once-daily tacrolimus oral administration.
Citation: European journal of clinical pharmacology, Jun 2015, vol. 71, no. 6, p. 715-722
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Author(s): Soto, Gustavo Adolfo Centeno, Ruiz-Antorán, Belén, Laporta, Rosalía, Sancho, Arantxa,
Lázaro, María Teresa, Herrera, Concepción Payares, Salcedo, Isabel, Cos, Maria Angeles, Torres,
Ferrán, Usetti, Piedad, Avendaño-Sola, Cristina
Abstract: The aim of this pharmacokinetic (PK) study was to evaluate tacrolimus (TAC) exposure in
stable cystic fibrosis (CF) lung transplant (LT) recipients, converted from TAC twice daily to TAC once
daily in an open-label, prospective, single-centre study. Eligible patients were post-transplant CF
patients (18-65 years) with stable lung function, on stable doses of TAC twice daily and who were
candidates to switch to TAC once daily. Twelve consecutive patients were included in the study.
Patients had their first PK analysis on day 1, still under the stable TAC twice-daily regimen, and were
converted to TAC once daily from day 2 onwards. The doses were adjusted according to clinical
judgement to achieve target levels, and a second 24-h PK period profile was obtained once the
patient was on a stable dosage on the therapeutic range. The mean total (SD) daily dose of TAC
twice daily at baseline upon enrolment was 0.17 (0.10) mg/kg/day. The mean (SD) daily dose of TAC
once daily after adjustments was 0.22 (0.12) mg/kg/day. In order to achieve target C min levels with
a similar AUC0-24, 82% of subjects who were converted to TAC once daily required an increase of
dose, in a range of 0-66.7%, with a mean dose increase of 28%. Our study results indicate that the
switch for conversion from TAC twice daily to TAC once daily in patients with CF may need dose
adjustment in order to reach levels within the therapeutic target.
Title: Reversibility of trapped air on chest computed tomography in cystic fibrosis patients.
Citation: European journal of radiology, Jun 2015, vol. 84, no. 6, p. 1184-1190
Author(s): Loeve, Martine, Rosenow, Tim, Gorbunova, Vladlena, Hop, Wim C J, Tiddens, Harm A W
M, de Bruijne, Marleen
Abstract: To investigate changes in trapped air volume and distribution over time and compare
computed tomography (CT) with pulmonary function tests for determining trapped air. Thirty
children contributed two CTs and pulmonary function tests over 2 years. Localized changes in
trapped air on CT were assessed using image analysis software, by deforming the CT at timepoint 2
to match timepoint 1, and measuring the volume of stable (TAstable), disappeared (TAdisappeared)
and new (TAnew) trapped air as a proportion of total lung volume. We used the difference between
total lung capacity measured by plethysmography and helium dilution, residual volume to total lung
capacity ratio, forced expiratory flow at 75% of vital capacity, and maximum mid-expiratory flow as
pulmonary function test markers of trapped air. Statistical analysis included Wilcoxon's signed rank
test and Spearman correlation coefficients. Median (range) age at baseline was 11.9 (5-17) years.
Median (range) of trapped air was 9.5 (2-33)% at timepoint 1 and 9.0 (0-25)% at timepoint 2
(p=0.49). Median (range) TAstable, TAdisappeared and TAnew were respectively 3.0 (0-12)%, 5.0 (122)% and 7.0 (0-20)%. Trapped air on CT correlated statistically significantly with all pulmonary
function measures (p<0.01), other than residual volume to total lung capacity ratio (p=0.37).
Trapped air on CT did not significantly progress over 2 years, may have a substantial stable
component, and is significantly correlated with pulmonary function markers. Copyright © 2015
Elsevier Ireland Ltd. All rights reserved
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Title: Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis: Is there
evidence?
Citation: International journal of immunopathology and pharmacology, Jun 2015, vol. 28, no. 2, p.
150-159,
Author(s): Snijders, D, Fernandez Dominguez, B, Calgaro, S, Bertozzi, I, Escribano Montaner, A,
Perilongo, G, Barbato, A
Abstract: Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. An
impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and treatment
involves antibiotics, mucoactive agents, and airway clearance techniques (ACTs). Traditional ACTs
have four components: postural drainage, percussion, vibration of the chest wall, and coughing.
Reviewing the international medical literature on the use of ACTs for patients with nCFb from 1989
to the present day, we retrieved 93 articles, of which 35 met our selection criteria for this analysis.
We reviewed active cycle of breathing techniques (ACBT), forced expiration techniques (FET),
autogenic drainage, postural drainage, oscillating positive expiratory pressure (OPep), high
frequency chest wall oscillation (HFCWO), and exercise or pulmonary rehabilitation. Overall, ACTs
appear to be safe for individuals (adults and children) with stable bronchiectasis; where there may
be improvements in sputum expectoration, selected measures of lung function, and health-related
quality of life. Unfortunately, there is a lack of RCTs in nCFb patients, especially in children.
Moreover, none of the studies describes long-term effects of ACTs. It should be noted that a single
intervention might not reflect the longer-term outcome and there is no evidence to recommend or
contest any type of ACTs in nCFb management. Multicenter RCTs are necessary to evaluate the
different techniques of ACTs especially in children with nCFb. © The Author(s) 2015.
Title: Inconclusive diagnosis of cystic fibrosis after newborn screening.
Citation: Pediatrics, Jun 2015, vol. 135, no. 6, p. e1377.
Author(s): Ooi, Chee Y, Castellani, Carlo, Keenan, Katherine, Avolio, Julie, Volpi, Sonia, Boland,
Margaret, Kovesi, Tom, Bjornson, Candice, Chilvers, Mark A, Morgan, Lenna, van Wylick, Richard,
Kent, Steven, Price, April, Solomon, Melinda, Tam, Karen, Taylor, Louise, Malitt, Kylie-Ann, Ratjen,
Felix, Durie, Peter R, Gonska, Tanja
Abstract: To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF)
identified by newborn screening (NBS; "CF screen positive, inconclusive diagnosis" [CFSPID]) for
disease manifestations. Infants with CFSPID and CF based on NBS from 8 CF centers were
prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum
trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and
between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria
for CF during the first 3 years of life. Eighty-two subjects with CFSPID and 80 subjects with CF were
enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation
rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2
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mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median
[interquartile range]:77 [61-106] vs 144 [105-199] μg/L; P < .0001) than did subjects with CF.
Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%,
respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID
(genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2).
Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months.
CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen
(P = .009) levels than did CFSPID→CFSPID patients. A proportion of infants with CFSPID will be
diagnosed with CF within the first 3 years. These findings underscore the need for clinical
monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping. Copyright © 2015 by
the American Academy of Pediatrics.
Title: Prevalence and impact of urinary incontinence in men with cystic fibrosis.
Citation: Physiotherapy, Jun 2015, vol. 101, no. 2, p. 166-170
Author(s): Burge, Angela T, Holland, Anne E, Sherburn, Margaret, Wilson, John, Cox, Narelle S,
Rasekaba, Tshepo M, McAleer, Rachael, Morton, Judith M, Button, Brenda M
Abstract: To determine the prevalence and impact of urinary incontinence (UI) in men with cystic
fibrosis (CF). Prospective observational study. Adult CF clinics at tertiary referral centres. Men with
CF (n=80) and age-matched men without lung disease (n=80). Validated questionnaires to identify
the prevalence and impact of UI. Prevalence of UI and relationship to disease specific factors,
relationship of UI with anxiety and depression. The prevalence of UI was higher in men with CF (15%)
compared to controls (10%) (p=0.339). Men with CF and UI had higher scores for anxiety than those
without UI (mean 9.1 (SD 4.8) vs 4.7 (4.1), p=0.003), with similar findings for depression (6.8 (4.6) vs
2.8 (3.4), p=0.002) using the Hospital Anxiety and Depression Scale. Incontinence is more prevalent
in adult men with CF than age matched controls, and may have an adverse effect on mental health.
The mechanisms involved are still unclear and may differ from those reported in women. Copyright
© 2014 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.
Title: Cystic Fibrosis below the Diaphragm: Abdominal Findings in Adult Patients.
Citation: Radiographics : a review publication of the Radiological Society of North America, Inc, May
2015, vol. 35, no. 3, p. 680-695
Author(s): Lavelle, Lisa P, McEvoy, Sinead H, Ni Mhurchu, Elaine, Gibney, Robert G, McMahon, Colm
J, Heffernan, Eric J, Malone, Dermot E
Abstract: Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the white
population. Mutation of the CF transmembrane conductance regulator gene on chromosome 7
results in production of abnormally viscous mucus and secretions in the lungs of patients with CF. A
similar pathologic process occurs in the gastrointestinal tract, pancreas, and hepatobiliary system.
Inspissated mucus causes luminal obstruction and resultant clinical and radiologic complications
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associated with the disease process. Pancreatic involvement can result in exocrine and endocrine
insufficiency, pancreatic atrophy, fatty replacement, or lipomatous pseudohypertrophy. Acute and
chronic pancreatitis, pancreatic calcification, cysts, and cystosis also occur. Hepatic manifestations
include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary
complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. The entire digestive
tract can be involved. Distal ileal obstruction syndrome, intussusception, appendicitis, chronic
constipation, colonic wall thickening, fibrosing colonopathy, pneumatosis intestinalis,
gastroesophageal reflux, and peptic ulcer disease have been described. Renal manifestations include
nephrolithiasis and secondary amyloidosis. The educational objectives of this review are to reveal
the abdominal manifestations of CF to facilitate focused analysis of cross-sectional imaging in adult
patients. Life expectancy in patients with CF continues to improve because of a combination of
aggressive antibiotic treatment, improved emphasis on nutrition and physiotherapy, and
development of promising new CF transmembrane conductance regulator modulators. As lung
function and survival improve, extrapulmonary conditions, including hepatic and gastrointestinal
malignancy, will be an increasing cause of morbidity and mortality. Awareness of the expected
abdominal manifestations of CF may assist radiologists in identifying acute inflammatory or
neoplastic conditions. (©)RSNA, 2015.
Microbiological
Title: Utilization of antibiotics for methicillin-resistant Staphylococcus aureus infection in cystic
fibrosis.
Citation: Pediatric pulmonology, Jun 2015, vol. 50, no. 6, p. 552-559
Author(s): Zobell, Jeffery T, Epps, Kevin L, Young, David C, Montague, Madison, Olson, Jared,
Ampofo, Krow, Chin, Melissa J, Marshall, Bruce C, Dasenbrook, Elliott
Abstract: The purpose of this study was to characterize the utilization of antibiotics for chronic
methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients with
acute pulmonary exacerbations (PEx). An anonymous national cross-sectional survey of CF
Foundation accredited care programs was performed using an electronic survey tool. Fifty-eight
percent (152/261) CF Foundation accredited programs completed the survey. Ninety-eight percent
(149/152) of respondents reported using antibiotics (oral or intravenous) against MRSA. Variability
exists in the use of antibiotics amongst the programs and in the dosages utilized. For oral outpatient
treatment, sulfamethoxazole/trimethoprim was the most commonly utilized antibiotic by both
pediatric (109/287, 38%) and adult (99/295, 34%) respondents, of which, ten percent of reported to
use it in combination with rifampin. For inpatient treatment, linezolid (both intravenous (IV) and
oral) was most commonly utilized in both pediatric (IV 35/224, 16%; oral 41/224, 18%), and adult (IV
44/235, 19%; oral 38/235, 16%) respondents for inpatient treatment. IV vancomycin was the second
most commonly utilized antibiotic by pediatric (70/224, 31%) and adult (71/235, 30%) respondents.
Most respondents reported dose titration to achieve a vancomycin trough level of 15-20 mg/L
(150/179, 84%). Topical or inhaled antibiotic utilization was reported to be an uncommon practice
with approximately 70% of pediatric and adult respondents reporting to use them either rarely or
never. The concomitant use of anti-MRSA and anti-pseudomonal antibiotics was common with 96%
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of pediatric and 99% of adult respondents answering in the affirmative. We conclude that anti-MRSA
antibiotics are utilized via various dosage regimens by a majority of CF Foundation accredited care
programs for the treatment of chronic MRSA in PEx, and there is no consensus on the best
treatment approach. © 2015 Wiley Periodicals, Inc.
Title: Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome.
Citation: Mammalian genome : official journal of the International Mammalian Genome Society, Jun
2015, vol. 26, no. 5-6, p. 222-234
Author(s): Bazett, Mark, Honeyman, Lisa, Stefanov, Anguel N, Pope, Christopher E, Hoffman, Lucas
R, Haston, Christina K
Abstract: Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator
(Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether
these changes are model-dependent and whether the intestinal microbiome is altered in cystic
fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with
the clinically common ΔF508 Cftr mutation (FVB/N Cftr (tm1Eur)) and with Cftr null mutations
(BALB/c Cftr (tm1UNC) and C57BL/6 Cftr (tm1UNC)). Intestinal disease in 12-week-old CF mice,
relative to wild-type strain controls, was measured histologically. The microbiome was characterized
by pyrosequencing of the V4-V6 region of the 16S rRNA gene and intestinal load was measured by
RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention,
goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and
C57BL/6 Cftr (tm1UNC) mice than in the FVB/N Cftr (tm1Eur) mice. Intestinal bacterial load was
significantly increased in all CF models, compared to levels in controls, and positively correlated with
circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified
Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall
bacterial frequencies were not common to the three CF strains and were not correlative of major
histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and
dysbiosis were each more severe in BALB/c and C57BL/6 Cftr (tm1UNC) mice than in the FVB/N Cftr
(tm1Eur) mice. The intestinal microbiome differed among the three CF mouse models.
Title: Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of
the chloride transport defect in cystic fibrosis.
Citation: European journal of medicinal chemistry, Jun 2015, vol. 99, p. 14-35
Author(s): Pesce, Emanuela, Bellotti, Marta, Liessi, Nara, Guariento, Sara, Damonte, Gianluca,
Cichero, Elena, Galatini, Andrea, Salis, Annalisa, Gianotti, Ambra, Pedemonte, Nicoletta, ZegarraMoran, Olga, Fossa, Paola, Galietta, Luis J V, Millo, Enrico
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel
present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis
(CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing
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and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect.
Processing and gating defects can be targeted by small molecules called generically correctors and
potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds
that includes molecules with dual activity, as correctors and potentiators. With the aim to improve
the activity profile of AATs, we have now designed and synthesized a library of novel compounds in
order to establish an initial SAR that may provide indications about the chemical groups that are
beneficial or detrimental for rescue activity. The new compounds were tested as correctors and
potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound,
AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector
VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in
nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new
analogues with possibly improved activity. Copyright © 2015. Published by Elsevier Masson SAS.
Title: Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of
the chloride transport defect in cystic fibrosis.
Citation: European journal of medicinal chemistry, Jun 2015, vol. 99, p. 14-35
Author(s): Pesce, Emanuela, Bellotti, Marta, Liessi, Nara, Guariento, Sara, Damonte, Gianluca,
Cichero, Elena, Galatini, Andrea, Salis, Annalisa, Gianotti, Ambra, Pedemonte, Nicoletta, ZegarraMoran, Olga, Fossa, Paola, Galietta, Luis J V, Millo, Enrico
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel
present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis
(CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing
and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect.
Processing and gating defects can be targeted by small molecules called generically correctors and
potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds
that includes molecules with dual activity, as correctors and potentiators. With the aim to improve
the activity profile of AATs, we have now designed and synthesized a library of novel compounds in
order to establish an initial SAR that may provide indications about the chemical groups that are
beneficial or detrimental for rescue activity. The new compounds were tested as correctors and
potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound,
AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector
VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in
nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new
analogues with possibly improved activity. Copyright © 2015. Published by Elsevier Masson SAS.
Title: The Fifth Transmembrane Segment of Cystic Fibrosis Transmembrane Conductance
Regulator Contributes to Its Anion Permeation Pathway.
Citation: Biochemistry, Jun 2015, vol. 54, no. 24, p. 3839-3850
Author(s): Zhang, Jingyao, Hwang, Tzyh-Chang
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Abstract: Previous studies have identified several transmembrane segments (TMs), including TM1,
TM3, TM6, TM9, TM11, and TM12, as pore-lining segments in cystic fibrosis transmembrane
conductance regulator (CFTR), but the role of TM5 in pore construction remains controversial. In this
study, we employed substituted cysteine accessibility methodology (SCAM) to screen the entire TM5
defined by the original topology model and its cytoplasmic extension in a Cysless background. We
found six positions (A299, R303, N306, S307, F310, and F311) where engineered cysteines react to
intracellular 2-sulfonatoethyl methanethiosulfonate (MTSES(-)). Quantification of the modification
rate of engineered cysteines in the presence or absence of ATP suggests that these six residues are
accessible in both the open and closed states. Whole-cell experiments with external MTSES(-)
identified only two positive positions (L323 and A326), resulting in a segment containing 11
consecutive amino acids, where substituted cysteines respond to neither internal nor external
MTSES(-), a unique feature not seen previously in CFTR's pore-lining segments. The observation that
these positions are inaccessible to channel-permeant thiol-specific reagent [Au(CN)2](-) suggests
that this segment of TM5 between F311 and L323 is concealed from the pore by other TMs and/or
lipid bilayers. In addition, our data support the idea that the positively charged arginine at position
303 poses a pure electrostatic action in determining the single-channel current amplitude of CFTR
and the effect of an open-channel blocker glibencalmide. Collectively, we conclude that the
cytoplasmic portion of CFTR's TM5 lines the pore. Our functional data are remarkably consistent
with predicted structural arrangements of TM5 in some homology models of CFTR.
Title: Functional Architecture of the Cytoplasmic Entrance to the Cystic Fibrosis Transmembrane
Conductance Regulator Chloride Channel Pore.
Citation: The Journal of biological chemistry, Jun 2015, vol. 290, no. 25, p. 15855-15865
Author(s): El Hiani, Yassine, Linsdell, Paul
Abstract: As an ion channel, the cystic fibrosis transmembrane conductance regulator must form a
continuous pathway for the movement of Cl(-) and other anions between the cytoplasm and the
extracellular solution. Both the structure and the function of the membrane-spanning part of this
pathway are well defined. In contrast, the structure of the pathway that connects the cytoplasm to
the membrane-spanning regions is unknown, and functional roles for different parts of the protein
forming this pathway have not been described. We used patch clamp recording and substituted
cysteine accessibility mutagenesis to identify positively charged amino acid side chains that attract
cytoplasmic Cl(-) ions to the inner mouth of the pore. Our results indicate that the side chains of Lys190, Arg-248, Arg-303, Lys-370, Lys-1041, and Arg-1048, located in different intracellular loops of the
protein, play important roles in the electrostatic attraction of Cl(-) ions. Mutation and covalent
modification of these residues have charge-dependent effects on the rate of Cl(-) permeation,
demonstrating their functional role in maximization of Cl(-) flux. Other nearby positively charged side
chains were not involved in electrostatic interactions with Cl(-). The location of these Cl(-)-attractive
residues suggests that cytoplasmic Cl(-) ions enter the pore via a lateral portal located between the
cytoplasmic extensions to the fourth and sixth transmembrane helices; a secondary, functionally less
relevant portal might exist between the extensions to the 10th and 12th transmembrane helices.
These results define the cytoplasmic mouth of the pore and show how it attracts Cl(-) ions from the
cytoplasm. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
15
Title: Mutation and new polymorphisms insight in introns 11 to 14a of CFTR gene of northern
Iranian cystic fibrosis patients.
Citation: Gene, Jun 2015, vol. 564, no. 2, p. 193-196
Author(s): Esmaeili Dooki, Mohammad Reza, Tabaripour, Reza, Rahimi, Razieh, Akhavan-Niaki, Haleh
Abstract: Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, caused
by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). The type and
distribution of mutations vary widely between different countries and ethnic groups. We therefore
aimed to perform a comprehensive analysis of the CFTR gene in northern Iranian CF patients. Forty
northern Iranian CF patients were analyzed for mutations in introns 11 to 14a of their CFTR genes,
using sequencing and reverse dot blot methods. Five normal subjects were also analyzed as normal
control. One mutation and seven polymorphisms were identified. Of the eighty alleles studied,
c.2043delG in exon 13 represented 12.5% of mutant alleles and was associated with two distinct
haplotypes. rs1042077T>G, rs4148712delAT, rs4148711T>A and rs3808183 T>C with frequencies
varying between 29.2% and 6.9% for the least common allele, as well as three new polymorphisms
c.1680-224C>A (11.1%), c.2491-275T>G (14.1%) and c.2491-274C>G (35.9%) were detected. These
findings suggest a founder effect for c.2043delG in the Middle East and will assist in genetic
counseling, prenatal diagnosis and future screening of CF in Iran. Copyright © 2015 Elsevier B.V. All
rights reserved.
Title: Defective innate immunity and hyperinflammation in newborn cystic fibrosis
transmembrane conductance regulator-knockout ferret lungs.
Citation: American journal of respiratory cell and molecular biology, Jun 2015, vol. 52, no. 6, p. 683694
Author(s): Keiser, Nicholas W, Birket, Susan E, Evans, Idil A, Tyler, Scott R, Crooke, Adrianne K, Sun,
Xingshen, Zhou, Weihong, Nellis, Joseph R, Stroebele, Elizabeth K, Chu, Kengyeh K, Tearney,
Guillermo J, Stevens, Mark J, Harris, J Kirk, Rowe, Steven M, Engelhardt, John F
Abstract: Mucociliary clearance (MCC) and submucosal glands are major components of airway
innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense
systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the
presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated
several components of airway innate immunity and inflammation in the early CF ferret lung. At birth,
the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface
liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of
age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly
introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF
bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against
Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid
chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-
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sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8,
TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement
system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation
factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF,
despite no genotypic difference in bacterial load shortly after birth. These results suggest that
newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be
important in the early onset and progression of lung disease in these animals.
Title: Detection of KI WU and Merkel cell polyomavirus in respiratory tract of cystic fibrosis
patients.
Citation: Clinical microbiology and infection : the official publication of the European Society of
Clinical Microbiology and Infectious Diseases, Jun 2015, vol. 21, no. 6, p. 603.e9
Author(s): Iaria, M, Caccuri, F, Apostoli, P, Giagulli, C, Pelucchi, F, Padoan, R F, Caruso, A, Fiorentini, S
Abstract: In the last few years, many reports have confirmed the presence of WU, KI and Merkel cell
(MC) polyomaviruses (PyV) in respiratory samples wordwide, but their pathogenic role in patients
with underlying conditions such as cystic fibrosis is still debated. To determine the prevalence of
MCPyV, WUPyV and KIPyV, we conducted a 1-year-long microbiological testing of respiratory
specimens from 93 patients with cystic fibrosis in Brescia, Italy. We detected PyV DNA in 94 out of
337 analysed specimens. KIPyV was the most common virus detected (12.1%), followed by WUPyV
(8.9%) and MCPyV (6.8%). We found an intriguing association between the presence of MCPyV and
the concurrent isolation of Pseudomonas aeruginosa, as well as with the patient status, classified as
chronically colonized with P. aeruginosa. Our study adds perspective on the prevalence and the
potential pathogenic role of PyV infections. Copyright © 2015 European Society of Clinical
Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Title: Quantitative analysis of volatile metabolites released in vitro by bacteria of the genus
Stenotrophomonas for identification of breath biomarkers of respiratory infection in cystic
fibrosis.
Citation: Journal of breath research, Jun 2015, vol. 9, no. 2, p. 027104.
Author(s): Shestivska, Violetta, Dryahina, Kseniya, Nunvář, Jaroslav, Sovová, Kristýna, Elhottová,
Dana, Nemec, Alexandr, Smith, David, Španěl, Patrik
Abstract: The aim of the present study was to characterize the volatile metabolites produced by
genotypically diverse strains of the Stenotrophomonas genus in order to evaluate their potential as
biomarkers of lung infection by non-invasive breath analysis. Volatile organic compounds (VOCs)
emitted from 15 clinical and five environmental strains belonging to different genogroups of
Stenotrophomonas maltophilia (n = 18) and Stenotrophomonas rhizophila (n = 2) cultured in
Mueller-Hinton Broth (MHB) liquid media were analysed by gas chromatography mass spectrometry
(GC-MS) and selected ion flow tube mass spectrometry (SIFT-MS). Several VOCs were detected in
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high concentration, including ammonia, propanol, dimethyl disulphide propanol and dimethyl
disulphide. The GC-MS measurements showed that all 15 clinical strains produced similar headspace
VOCs compositions, and SIFT-MS quantification showed that the rates of production of the VOCs by
the genotypically distinct strains were very similar. All in vitro cultures of both the
Stenotrophomonas species were characterised by efficient production of two isomers of methyl
butanol, which can be described by known biochemical pathways and which is absent in other
pathogens, including Pseudomonas aeruginosa. These in-vitro data indicate that methyl butanol
isomers may be exhaled breath biomarkers of S. maltophilia lung infection in patients with cystic
fibrosis.
Title: Localization of cystic fibrosis transmembrane conductance regulator signaling complexes in
human salivary gland striated duct cells.
Citation: European journal of oral sciences, Jun 2015, vol. 123, no. 3, p. 140-148
Author(s): Zinn, Vina Z, Khatri, Aditi, Mednieks, Maija I, Hand, Arthur R
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMPdependent protein kinase (PKA)-regulated Cl(-) channel, crucial for epithelial cell regulation of salt
and water transport. Previous studies showed that ezrin, an actin binding and A-kinase anchoring
protein (AKAP), facilitates association of PKA with CFTR. We used immunohistochemistry and
immunogold transmission electron microscopy to localize CFTR, ezrin, and PKA type II regulatory (RII)
and catalytic (C) subunits in striated duct cells of human parotid and submandibular glands.
Immunohistochemistry localized the four proteins mainly to the apical membrane and the apical
cytoplasm of striated duct cells. In acinar cells, ezrin localized to the luminal membrane, and PKA RII
subunits were present in secretory granules, as previously described. Immunogold labeling showed
that CFTR and PKA RII and C subunits were localized to the luminal membrane and associated with
apical granules and vesicles of striated duct cells. Ezrin was present along the luminal membrane, on
microvilli and along the junctional complexes between cells. Double labeling showed specific protein
associations with apical granules and vesicles and along the luminal membrane. Ezrin, CFTR, and PKA
RII and C subunits are co-localized in striated duct cells, suggesting the presence of signaling
complexes that serve to regulate CFTR activity. © 2015 Eur J Oral Sci.
Title: Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting
Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.
Citation: PLoS genetics, Jun 2015, vol. 11, no. 6, p. e1005273.
Author(s): Emond, Mary J, Louie, Tin, Emerson, Julia, Chong, Jessica X, Mathias, Rasika A, Knowles,
Michael R, Rieder, Mark J, Tabor, Holly K, Nickerson, Debbie A, Barnes, Kathleen C, NHLBI GO Exome
Sequencing Project, Go, Lung, Gibson, Ronald L, Bamshad, Michael J
Abstract: Discovery of rare or low frequency variants in exome or genome data that are associated
with complex traits often will require use of very large sample sizes to achieve adequate statistical
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power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype
distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently
validated empirically with the discovery of variants in DCTN4 that influence the natural history of P.
aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing
availability of large exome/genome sequence datasets that serve as proxies for population-based
controls affords the opportunity to test an alternative, potentially more powerful and generalizable
strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared
to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we
applied this approach to search for variants associated with risk for age-of-onset of chronic P.
aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6
that were significantly associated with group status. These results were validated using a large,
prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with
increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88])
and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95%
CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95%
CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant.
Neither gene showed a significant association using an extreme phenotypes design, and conditions
for which the power of an extreme phenotype vs. control population design was greater than that
for the extreme phenotypes design were explored.
Title: Deleterious impact of Pseudomonas aeruginosa on cystic fibrosis transmembrane
conductance regulator function and rescue in airway epithelial cells.
Citation: The European respiratory journal, Jun 2015, vol. 45, no. 6, p. 1590-1602
Author(s): Trinh, Nguyen Thu Ngan, Bilodeau, Claudia, Maillé, Émilie, Ruffin, Manon, Quintal, MarieClaude, Desrosiers, Martin-Yvon, Rousseau, Simon, Brochiero, Emmanuelle
Abstract: The epithelial response to bacterial airway infection, a common feature of lung diseases
such as chronic obstructive pulmonary disease and cystic fibrosis, has been extensively studied.
However, its impact on cystic fibrosis transmembrane conductance regulator (CFTR) channel
function is not clearly defined. Our aims were, therefore, to evaluate the effect of Pseudomonas
aeruginosa on CFTR function and expression in non-cystic fibrosis airway epithelial cells, and to
investigate its impact on ΔF508-CFTR rescue by the VRT-325 corrector in cystic fibrosis cells. CFTR
expression/maturation was evaluated by immunoblotting and its function by short-circuit current
measurements. A 24-h exposure to P. aeruginosa diffusible material (PsaDM) reduced CFTR currents
as well as total and membrane protein expression of the wildtype (wt) CFTR protein in CFBE-wt cells.
In CFBE-ΔF508 cells, PsaDM severely reduced CFTR maturation and current rescue induced by VRT325. We also confirmed a deleterious impact of PsaDM on wt-CFTR currents in non-cystic fibrosis
primary airway cells as well as on the rescue of ΔF508-CFTR function induced by VRT-325 in primary
cystic fibrosis cells. These findings show that CFTR function could be impaired in non-cystic fibrosis
patients infected by P. aeruginosa. Our data also suggest that CFTR corrector efficiency may be
affected by infectious components, which should be taken into account in screening assays of
correctors. Copyright ©ERS 2015.
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Title: Lytic activity by temperate phages of Pseudomonas aeruginosa in long-term cystic fibrosis
chronic lung infections.
Citation: The ISME journal, Jun 2015, vol. 9, no. 6, p. 1391-1398
Author(s): James, Chloe E, Davies, Emily V, Fothergill, Joanne L, Walshaw, Martin J, Beale, Colin M,
Brockhurst, Michael A, Winstanley, Craig
Abstract: Pseudomonas aeruginosa is the most common bacterial pathogen infecting the lungs of
cystic fibrosis (CF) patients. The transmissible Liverpool epidemic strain (LES) harbours multiple
inducible prophages (LESφ2; LESφ3; LESφ4; LESφ5; and LESφ6), some of which are known to confer a
competitive advantage in an in vivo rat model of chronic lung infection. We used quantitative PCR
(Q-PCR) to measure the density and dynamics of all five LES phages in the sputa of 10 LES-infected
CF patients over a period of 2 years. In all patients, the densities of free-LES phages were positively
correlated with the densities of P. aeruginosa, and total free-phage densities consistently exceeded
bacterial host densities 10-100-fold. Further, we observed a negative correlation between the
phage-to-bacterium ratio and bacterial density, suggesting a role for lysis by temperate phages in
regulation of the bacterial population densities. In 9/10 patients, LESφ2 and LESφ4 were the most
abundant free phages, which reflects the differential in vitro induction properties of the phages.
These data indicate that temperate phages of P. aeruginosa retain lytic activity after prolonged
periods of chronic infection in the CF lung, and suggest that temperate phage lysis may contribute to
regulation of P. aeruginosa density in vivo.
Title: Azithromycin use in patients with cystic fibrosis.
Citation: European journal of clinical microbiology & infectious diseases : official publication of the
European Society of Clinical Microbiology, Jun 2015, vol. 34, no. 6, p. 1071-1079
Author(s): Principi, N, Blasi, F, Esposito, S
Abstract: Rational antimicrobial administration is still considered to be the most effective
therapeutic approach in cystic fibrosis (CF), and long-term treatment with azithromycin (Az) is
included in the current guidelines for CF patients aged ≥ 6 years. Az has microbiological,
immunomodulatory and anti-inflammatory properties that can reduce some of the biological
problems that are among the causes of the progressive lung damage associated with CF. Moreover,
although it is not active against Pseudomonas aeruginosa (the most important bacterial pathogen
responsible for infectious exacerbations), it can be efficiently used in the case of P. aeruginosa
infections because sub-inhibitory concentrations can reduce their pathogenic role by interfering with
some bacterial activities and increasing their susceptibility to antibiotics. Az also has anti-viral
activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after
apparently mild viral infections. The available data seem to indicate that it is effective during its first
year of administration, but the impact of longer treatment is debated. Other still undefined aspects
of the use of Az include the possible emergence of antibiotic resistance in the other bacterial
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pathogens that usually colonise CF patients, the real incidence of adverse events and the drug's
potential interference with other routine therapies.
Title: Spray-dried amikacin sulphate powder for inhalation in cystic fibrosis patients: The role of
ethanol in particle formation.
Citation: European journal of pharmaceutics and biopharmaceutics : official journal of
Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V, Jun 2015, vol. 93, p. 165-172
Author(s): Belotti, Silvia, Rossi, Alessandra, Colombo, Paolo, Bettini, Ruggero, Rekkas, Dimitrios,
Politis, Stavros, Colombo, Gaia, Balducci, Anna Giulia, Buttini, Francesca
Abstract: A Central Composite Design (CCD) was applied in order to identify positive combinations of
the production parameters of amikacin sulphate spray-dried powders for inhalation, with the intent
to expand the experimental space defined in a previous half-fractional factorial design. Three
factors, namely drying temperature, feed rate and ethanol proportion, have been selected out of the
initial five. In addition, the levels of these factors were increased from two to three and their effect
on amikacin respirability was evaluated. In particular, focus was given on the role of ethanol
presence on the formation of the microparticles for inhalation. The overall outcome of the CCD was
that amikacin respirability was not substantially improved, as the optimum region coincided with
areas already explored with the fractional factorial design. However, expanding the design space
towards smaller ethanol levels, including its complete absence, revealed the crucial role of this
solvent on the morphology of the produced particles. Peclet number and drug solubility in the
spraying solution helped to understand the formation mechanism of these amikacin sulphate spraydried particles. Copyright © 2015 Elsevier B.V. All rights reserved.
Title: N-acetylcysteine and azithromycin affect the innate immune response in cystic fibrosis
bronchial epithelial cells in vitro.
Citation: Experimental lung research, Jun 2015, vol. 41, no. 5, p. 251-260
Author(s): Hussain, Shahida, Varelogianni, Georgia, Särndahl, Eva, Roomans, Godfried M
Abstract: We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin
(AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE)
cells with the ΔF508 homozygous mutation in vitro. In the present paper, we further investigated
possible immunomodulatory effects of these drugs on the regulation of the innate immune system
by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin
(IL)-6 production in CFBE cells. Under basal conditions, PCR and Western Blot data indicate that the
NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that
the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2
while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production
was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not
Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6
upregulation is independent of NLRC1, but involves the activation of NLRC2. Overall, the results
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indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a
weakly strengthening effect on the innate immune system.
Title: Intrapatient diversity of Achromobacter spp. involved in chronic colonization of Cystic
Fibrosis airways.
Citation: Infection, genetics and evolution : journal of molecular epidemiology and evolutionary
genetics in infectious diseases, Jun 2015, vol. 32, p. 214-223
Author(s): Dupont, Chloé, Michon, Anne-Laure, Jumas-Bilak, Estelle, Nørskov-Lauritsen, Niels,
Chiron, Raphaël, Marchandin, Hélène
Abstract: Achromobacter spp. are increasingly identified in Cystic Fibrosis (CF) patients and their
ability to persistently colonize the CF respiratory tract (CFRT) suggests that Achromobacter species
possess adaptive characteristics. We studied genome dynamics in 118 isolates recovered from 13
patients with Achromobacter chronic colonization (5-26 isolates per patient recovered over 13-61
months). Isolates were identified to species level by nrdA gene sequencing, subjected to Pulsed-Field
Gel Electrophoresis (PFGE) and multiplex rep-PCR (MR-PCR), and rrs intragenomic diversity was
studied by PCR-Temporal Temperature Gel Electrophoresis (TTGE). Intrapatient diversity was
assessed: (i) from dynamics of XbaI and/or SpeI-based pulsotypes, (ii) from comparison of MR-PCR
profiles, and (iii) by longitudinal analysis of rrs intragenomic diversity. Patients were chronically
colonized by Achromobacter xylosoxidans (n=10), Achromobacter dolens (n=1) or Achromobacter
insuavis (n=2). All strains displayed genomic diversification over time but A. insuavis showed higher
pulsotype diversity compared to other species. Intragenomic rrs heterogeneity was found in strains
from 6 of 13 patients and may be persistently observed. Achromobacter genome evolution observed
during chronic colonization of the CFRT warrants further investigation of the adaptation features of
the different species, as well as of the selective forces driving this adaptation in the CFRT. Copyright
© 2015 Elsevier B.V. All rights reserved.
Title: Pseudomonas aeruginosa and Periodontal Pathogens in the Oral Cavity and Lungs of Cystic
Fibrosis Patients: a Case-Control Study.
Citation: Journal of clinical microbiology, Jun 2015, vol. 53, no. 6, p. 1898-1907
Author(s): Rivas Caldas, Rocio, Le Gall, Florence, Revert, Krista, Rault, Gilles, Virmaux, Michèle,
Gouriou, Stephanie, Héry-Arnaud, Geneviève, Barbier, Georges, Boisramé, Sylvie
Abstract: Cystic fibrosis (CF) is the most frequent lethal genetic disease in the Caucasian population.
Lung destruction is the principal cause of death by chronic Pseudomonas aeruginosa colonization.
There is a high prevalence of oropharyngeal anaerobic bacteria in sputum of CF patients. This study
was carried out due to the lack of results comparing subgingival periodontal pathogenic bacteria
between the oral cavity and lungs in patients with CF in relation with P. aeruginosa presence. Our
first goal was to detect P. aeruginosa in oral and sputum samples by culture and molecular methods
and to determine clonality of isolates. In addition, subgingival periodontal anaerobic bacteria were
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searched for in sputum. A cross-sectional pilot case-control study was conducted in the CF Reference
Center in Roscoff, France. Ten CF patients with a ΔF508 homozygous mutation (5 chronically
colonized [CC] and 5 not colonized [NC]) were enrolled. P. aeruginosa was detected in saliva,
sputum, and subgingival plaque samples by real-time quantitative PCR (qPCR). Subsequently,
periodontal bacteria were also detected and quantified in subgingival plaque and sputum samples by
qPCR. In CC patients, P. aeruginosa was recovered in saliva and subgingival plaque samples. Sixteen
P. aeruginosa strains were isolated in saliva and sputum from this group and compared by pulsedfield gel electrophoresis (PFGE). Subgingival periodontal anaerobic bacteria were found in sputum
samples. A lower diversity of these species was recovered in the CC patients than in the NC patients.
The presence of the same P. aeruginosa clonal types in saliva and sputum samples underlines that
the oral cavity is a possible reservoir for lung infection. Copyright © 2015, American Society for
Microbiology. All Rights Reserved.
Title: Mature cystic fibrosis airway neutrophils suppress T cell function: evidence for a role of
arginase 1 but not programmed death-ligand 1.
Citation: Journal of immunology (Baltimore, Md. : 1950), Jun 2015, vol. 194, no. 11, p. 5520-5528
Author(s): Ingersoll, Sarah A, Laval, Julie, Forrest, Osric A, Preininger, Marcela, Brown, Milton R,
Arafat, Dalia, Gibson, Greg, Tangpricha, Vin, Tirouvanziam, Rabindra
Abstract: Bacteria colonize cystic fibrosis (CF) airways, and although T cells with appropriate Ag
specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To
account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited
massively into the CF airway lumen and actively exocytosing primary granules, also suppress T cell
function therein. Programmed death-ligand 1 (PD-L1), which exerts T cell suppression at a late step,
was expressed bimodally on CF airway PMNs, delineating PD-L1(hi) and PD-L1(lo) subsets, whereas
healthy control (HC) airway PMNs were uniformly PD-L1(hi). Blood PMNs incubated in CF airway
fluid lost PD-L1 over time; in coculture, Ab blockade of PD-L1 failed to inhibit the suppression of T
cell proliferation by CF airway PMNs. In contrast with PD-L1, arginase 1 (Arg1), which exerts T cell
suppression at an early step, was uniformly high on CF and HC airway PMNs. However, arginase
activity was high in CF airway fluid and minimal in HC airway fluid, consistent with the fact that Arg1
activation requires primary granule exocytosis, which occurs in CF, but not HC, airway PMNs. In
addition, Arg1 expression on CF airway PMNs correlated negatively with lung function and positively
with arginase activity in CF airway fluid. Finally, combined treatment with arginase inhibitor and
arginine rescued the suppression of T cell proliferation by CF airway fluid. Thus, Arg1 and PD-L1 are
dynamically modulated upon PMN migration into human airways, and, Arg1, but not PD-L1,
contributes to early PMN-driven T cell suppression in CF, likely hampering resolution of infection and
inflammation. Copyright © 2015 by The American Association of Immunologists, Inc.
Title: Estrogen and progesterone differentially regulate the levels of cystic fibrosis transmembrane
regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono-phosphate (cAMP) in the rat
cervix.
23
Citation: Molecular reproduction and development, Jun 2015, vol. 82, no. 6, p. 463-474
Author(s): Ismail, Nurain, Giribabu, Nelli, Muniandy, Sekaran, Salleh, Naguib
Abstract: The consistency of the cervical mucus changes with the reproductive cycle, which we
hypothesized involved changing levels of cystic fibrosis transmembrane regulator (CFTR), adenylate
cyclase (AC), and cyclic adenosine mono-phosphate (cAMP). We therefore measured the abundance
of each in the rat cervix under estrogen and progesterone influence to determine if the activity of
these components could explain the changes in the consistency of cervical mucus. Ovariectomised
adult female rats were treated with three days of either estrogen (1 μg/kg/day) or progesterone (20
mg/kg/day), or three days of estrogen followed by two days of either vehicle or progesterone or
estrogen plus progesterone. In some groups, mifepristone (7 mg/kg/day) was concurrently given
with progesterone. Animals were then sacrificed, and the cervix was harvested for protein and
mRNA expression analyses by Western blot and real-time PCR, respectively. The distribution of
proteins was investigated by immunohistochemistry, and levels of cAMP were determined by
enzyme-linked immunosorbent assay (ELISA). Cftr mRNA, AC protein, and cAMP levels in cervical
homogenates as well as the tissue distribution of CFTR and AC in endocervical epithelia were highest
under estrogen influence; the opposite pattern was seen under progesterone influence. Cervical
lumen circumference was highest under estrogen and lowest under progesterone. The effects of
progesterone were antagonized by mifepristone. Therefore, increased abundance of CFTR, AC, and
cAMP under estrogen influence could account for the increased fluid accumulation within the
cervical lumen, which would contribute to lower cervical mucus consistency, whereas progesterone
reverses this effect at the molecular and organ level. Mol. Reprod. Dev. 82: 463-474, 2015. © 2015
Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
Psychological
Title: Adherence Determinants in Cystic Fibrosis: Cluster Analysis of Parental Psychosocial,
Religious, and/or Spiritual Factors.
Citation: Annals of the American Thoracic Society, Jun 2015, vol. 12, no. 6, p. 838-846 (June 2015)
Author(s): Grossoehme, Daniel H, Szczesniak, Rhonda D, Britton, LaCrecia L, Siracusa, Christopher M,
Quittner, Alexandra L, Chini, Barbara A, Dimitriou, Sophia M, Seid, Michael
Abstract: Cystic fibrosis is a progressive disease requiring a complex, time-consuming treatment
regimen. Nonadherence may contribute to an acceleration of the disease process. Spirituality
influences some parental healthcare behaviors and medical decision-making. We hypothesized that
parents of children with cystic fibrosis, when classified into groups based on adherence rates, would
share certain psychosocial and religious and/or spiritual variables distinguishing them from other
adherence groups. We conducted a multisite, prospective, observational study focused on parents of
children younger than 13 years old at two cystic fibrosis center sites (Site 1, n = 83; Site 2, n = 59).
Religious and/or spiritual constructs, depression, and marital adjustment were measured by using
previously validated questionnaires. Determinants of adherence included parental attitude toward
treatment, perceived behavioral norms, motivation, and self-efficacy. Adherence patterns were
24
measured with the Daily Phone Diary, a validated instrument used to collect adherence data. Cluster
analysis identified discrete adherence patterns, including parents' completion of more treatments
than prescribed. For airway clearance therapy, four adherence groups were identified: median
adherence rates of 23%, 52%, 77%, and 120%. These four groups differed significantly for parental
depression, sanctification of their child's body, and self-efficacy. Three adherence groups were
identified for nebulized medications: median adherence rates of 35%, 82%, and 130%. These three
groups differed significantly for sanctification of their child's body and self-efficacy. Our results
indicated that parents in each group shared psychosocial and religious and/or spiritual factors that
differentiated them. Therefore, conversations about adherence likely should be tailored to baseline
adherence patterns. Development of efficacious religious and/or spiritual interventions that
promote adherence by caregivers of children with cystic fibrosis may be useful.
Other
Title: Patient experience in cystic fibrosis care: Development of a disease-specific questionnaire.
Citation: Chronic illness, Jun 2015, vol. 11, no. 2, p. 108-125
Author(s): Stahl, Katja, Steinkamp, Gratiana, Ullrich, Gerald, Schulz, Wolfgang, van KoningsbruggenRietschel, Silke, Heuer, Hans-Eberhard, Ellemunter, Helmut, Schwarz, Carsten
Abstract: The aim of this study was to develop valid and reliable disease-specific questionnaires for
adult patients with cystic fibrosis and for parents of minors with cystic fibrosis for assessing patient
experience with cystic fibrosis care. The pilot versions of the questionnaires were developed based
on a literature review, interviews with health professionals and focus groups. A postal survey with
two reminders was conducted in 56 German cystic fibrosis centres recruiting 2874 participants.
Psychometric evaluation was done via exploratory factor analysis and reliability and regression
analysis. The questionnaires' ability to differentiate between subgroups and between cystic fibrosis
centres was evaluated. Response rates were 74% for both adult patients and parents. Ten factors
were extracted for both the adult and the parents' models (Cronbach's alpha between 0.6 and 0.9),
explaining 50% and 48% of the variance, respectively. The factors organisation & access and the
doctor-patient/parent-interaction had the highest relevance for a good overall care experience. The
questionnaires were able to distinguish between different cystic fibrosis centres. The questionnaires
are well suited for use in internal and external quality management of cystic fibrosis care due to
their good psychometric properties, the ability to differentiate between centres and its
practicability. © The Author(s) 2014 Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav.
Title: Assessment of Parental Understanding of Positive Newborn Screening Results and Carrier
Status for Cystic Fibrosis with the use of a Short Educational Video.
Citation: Journal of genetic counseling, Jun 2015, vol. 24, no. 3, p. 473-481
Author(s): Temme, R, Gruber, A, Johnson, M, Read, L, Lu, Y, McNamara, J
25
Abstract: Many children are identified as unaffected carriers for cystic fibrosis (CF) through newborn
screening (NBS) programs. The aim of this study was to improve parental understanding of positive
NBS results using an educational video in addition to genetic counseling. One hundred parents of
infants identified as CF carriers through NBS were randomly assigned by household to either a
genetic counseling only group or a genetic counseling and video group. All participants completed a
knowledge-based questionnaire before, immediately after, and six weeks following genetic
counseling. This included questions about resources accessed before and after the appointment.
Seventy-two percent of participants accessed resources on their own prior to genetic counseling;
these participants scored significantly higher on the pre-counseling questionnaire (p = 0.03). Postcounseling knowledge scores for both groups significantly improved after genetic counseling (p <
0.001). Post-counseling scores were significantly higher in the video group compared to the nonvideo group (p = 0.02). Knowledge was retained six weeks following genetic counseling. This study
demonstrates the effectiveness of an educational video and reinforces the importance of genetic
counseling following positive NBS results for CF.
Title: Differences in hyperpolarized (3) He ventilation imaging after 4 years in adults with cystic
fibrosis.
Citation: Journal of magnetic resonance imaging : JMRI, Jun 2015, vol. 41, no. 6, p. 1701-1707
Author(s): Paulin, Gregory A, Svenningsen, Sarah, Jobse, Brian N, Mohan, Sindu, Kirby, Miranda,
Lewis, James F, Parraga, Grace
Abstract: To evaluate cystic fibrosis (CF) subjects over 4 years using (3) He magnetic resonance
imaging (MRI), pulmonary function tests, and track hospitalization and physician visits. Five CF adults
provided written informed consent to an approved protocol and underwent MRI, spirometry, and
plethysmography at baseline, 7 days, and 4 ± 1 years later. (3) He MRI ventilation defect percent
(VDP) was generated for all subjects and timepoints. After 4 years, mean forced expiratory volume in
1 second / forced vital capacity (FEV1 /FVC) was lower (P = 0.01) in all subjects and there were no
other pulmonary function test changes. Two CF adults showed significantly elevated (worse) (3) He
VDP at baseline and after 4 years they had significantly greater (worsened) VDP (P = 0.02), without a
significant FEV1 decline (P = 0.06) but with a greater number of exacerbations (P < 0.05). Baseline
VDP strongly correlated with FEV1 (r(2) = 0.98, P = 0.0007) at 4-year follow-up. For two CF subjects,
VDP was significantly worse at baseline and worsened over 4 years, which was in agreement with a
greater number of hospitalizations and clinic visits. These results are limited by the very small
sample size, but the strong VDP correlation with longitudinal changes in FEV1 generates the
hypothesis that abnormal VDP may temporally precede FEV1 decline in CF subjects; this must be
tested in a larger CF study. J. Magn. Reson. Imaging 2015;41:1701-1707. © 2014 Wiley Periodicals,
Inc. © 2014 Wiley Periodicals, Inc.
Title: Oral reduced L-glutathione improves growth in pediatric cystic fibrosis patients.
Citation: Journal of pediatric gastroenterology and nutrition, Jun 2015, vol. 60, no. 6, p. 802-810
26
Author(s): Visca, Alfredo, Bishop, Clark T, Hilton, Sterling, Hudson, Valerie M
Abstract: Consensus nutritional guidelines for patients with cystic fibrosis (CF) recommend
aggressive treatment of growth failure. Oral reduced glutathione (GSH) has been shown to improve
cachexia and case reports have demonstrated improved growth in pediatric patients with CF. No
controlled studies using oral GSH in CF have, however, been reported. The aim of the study was to
determine whether oral GSH could improve growth in CF. Secondarily, to determine whether oral
GSH could improve other systemic clinical markers. We performed a placebo-controlled,
randomized, double-blind, repeated-measures clinical trial in 44 pediatric patients with CF ages 18
months to 10 years. Primary outcomes were change in weight percentile, body mass index (BMI)
percentile, height percentile, and fecal calprotectin. Secondary outcomes included liver function
tests and measures of systemic inflammation. Each participant was studied for 6 months, with data
obtained at baseline, 3 months, and 6 months. Blood samples were obtained on the baseline and 6month visits. Subjects were treated with oral GSH or placebo (calcium citrate), each 65 mg · kg · day
divided into 3 doses per day at mealtimes, and administered daily for 6 months. The GSH treatment
group gained an average of 0.67 standard deviation (SD) in weight-for-age-and sex z score (wfaszs),
(19.1 weight percentile points) during the course of 6 months, with no adverse effects (vs placebo
with an increase of 0.1 SD in wfaszs [2.1 weight percentile points], P < 0.0001). Fecal calprotectin
improved, GSH -52.0 vs placebo 0.5), also BMI for GSH improved 0.69 SD BMI-adjusted-for-age-andsex z score versus placebo 0.22 SD (BMI percentile 21.7 GSH vs 5.2 placebo), and height 0.2 SD in
height-for-age-and-sex z score (hfaszs) GSH versus -0.06 SD hfaszs placebo [height percentile 7.0
GSH vs -2.6 placebo], all P < 0.0001). Secondary outcomes improved significantly, as well. Oral
reduced L-GSH significantly improves measures of growth status and gut inflammation in CF.
Title: Changes in Pulmonary Function and Controlled Ventilation-High Resolution CT of Chest After
Antibiotic Therapy in Infants and Young Children with Cystic Fibrosis.
Citation: Lung, Jun 2015, vol. 193, no. 3, p. 421-428
Author(s): Sheikh, Shahid I, Long, Frederick R, Flucke, Robert, Ryan-Wenger, Nancy A, Hayes, Don,
McCoy, Karen S
Abstract: Infants with cystic fibrosis (CF) develop early progressive lung disease which may be
asymptomatic. Infant pulmonary function tests (IPFT) and controlled ventilation-high resolution
computed tomography (CV-HRCT) of chest can detect early asymptomatic lung disease. It is not well
established that these objective measures can detect changes in lung disease after clinical
interventions. The purpose of this study was to evaluate usefulness of IPFT and CV-HRCT to detect
changes in lung disease after intravenous (IV) antibiotic therapy in infants with early CF-related lung
disease. IPFTs and CV-HRCT done before and after 2 weeks of IV antibiotics in infants at our
institution over the last 12 years were compared. CV-HRCTs were compared using the modified
Brody scoring system. The sample included 21 infants, mean age 85.2 ± 47.6 weeks. Mean change in
weight was 0.4 ± 0.38 kg (p = 0.001). Significant changes in IPFT included mean % predicted FEV0.5
(+13.5 %, p = 0.043), mean %FEF25-75 (+30.2 %, p = 0.008), mean %RV/TLC (-11.2 %, p = 0.008), and
mean %FRC/TLC (-4.5 %, p = 0.001). Total Brody scores improved from a median of 10 to 5 (p <
0.001) as did mean scores for airway wall thickening (p = 0.050), air trapping (p < 0.001), and
27
parenchymal opacities (p = 0.003). IPFT and CV-HRCT can be used as objective measures of
improvement in lung disease for infants with CF treated with antibiotics.
Title: Prenatal diagnosis of cystic fibrosis: 10-years experience.
Citation: Pathologie-biologie, Jun 2015, vol. 63, no. 3, p. 126-129
Author(s): Hadj Fredj, S, Ouali, F, Siala, H, Bibi, A, Othmani, R, Dakhlaoui, B, Zouari, F, Messaoud, T
Abstract: We present in this study our 10years experience in prenatal diagnosis of cystic fibrosis
performed in the Tunisian population. Based on family history, 40 Tunisian couples were selected for
prenatal diagnosis. Fetal DNA was isolated from amniotic fluid collected by transabdominal
amniocentesis or from chronic villi by transcervical chorionic villus sampling. The genetic analysis for
cystic fibrosis mutations was performed by denaturant gradient gel electrophoresis and denaturing
high-pressure liquid phase chromatography. We performed microsatellites analysis by capillary
electrophoresis in order to verify the absence of maternal cell contamination. Thirteen fetuses were
affected, 21 were heterozygous carriers and 15 were healthy with two normal alleles of CFTR gene.
Ten couples opted for therapeutic abortion. The microsatellites genotyping showed the absence of
contamination of the fetal DNA by maternal DNA in 93.75%. Our diagnostic strategy provides rapid
and reliable prenatal diagnosis at risk families of cystic fibrosis. Copyright © 2015 Elsevier Masson
SAS. All rights reserved.
Title: Improving nutritional status in a pediatric cystic fibrosis center.
Citation: Pediatric pulmonology, Jun 2015, vol. 50, no. 6, p. 544-551
Author(s): Ramírez, Ixsy, Filbrun, Amy, Hasan, Aws, Kidwell, Kelley M, Nasr, Samya Z
Abstract: The nutritional status of patients with cystic fibrosis (CF) is strongly associated with
pulmonary function, respiratory status and survival. Malnutrition could result from a discrepancy
between energy needs and food intake while malabsorption results from pancreatic insufficiency
which occurs in 85% of people with CF. A quality improvement (QI) project was designed to improve
the nutritional status of patients with CF with low Body Mass Index (BMI) between 3 and 19 years of
age. An algorithm was developed which included clinic-based assessments of patients' nutritional
status and periodic assessment by a dietitian, social worker and/or psychologist during the project.
Gastrostomy tube placement and feeding was offered as a last resort to improve caloric intake. 173
patients seen during January-June, 2010, were included in this project. They were classified into four
BMI groups and data were collected quarterly through June, 2012. The project target population
(BMI percentile ≤ 24) had a median BMI percentile at the start of the project of 11.8. At the end of
the project median BMI percentile was 22 (46% improvement). Improving nutrition and BMI for
patients with CF is achievable. There must be a motivated, multi-disciplinary team that includes
patients and families. A patient-specific combination of interventions must be used. These
interventions could be quite basic for patients with BMI percentile ≥ 25, yet more elaborate for
28
patients with BMI percentile <25. Clinic-based algorithms such as ours can successfully improve the
BMI percentile in patients with CF. © 2014 Wiley Periodicals, Inc.
Title: Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn
screening.
Citation: Pediatrics, Jun 2015, vol. 135, no. 6, p. e1386.
Author(s): Ren, Clement L, Fink, Aliza K, Petren, Kristofer, Borowitz, Drucy S, McColley, Susanna A,
Sanders, Don B, Rosenfeld, Margaret, Marshall, Bruce C
Abstract: Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)
describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but
inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of
CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term
outcomes of infants with CRMS. We analyzed data from the US CF Foundation Patient Registry
(CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care
utilization, microbiology, and treatment characteristics between infants with CF and infants with
CRMS. There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR.
By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and
CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into
the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional
indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory
tract culture in the first year of life. CRMS is a common outcome of CF NBS, and some infants with
CRMS may develop features concerning for CF disease. A substantial proportion of infants with
CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features
not collected in the CFFPR. Copyright © 2015 by the American Academy of Pediatrics.
Title: Non cystic fibrosis bronchiectasis: A longitudinal retrospective observational cohort study of
Pseudomonas persistence and resistance.
Citation: Respiratory medicine, Jun 2015, vol. 109, no. 6, p. 716-726 (June 2015)
Author(s): McDonnell, Melissa J, Jary, Hannah R, Perry, Audrey, MacFarlane, James G, Hester, Katy L
M, Small, Therese, Molyneux, Catherine, Perry, John D, Walton, Katherine E, De Soyza, Anthony
Abstract: The hallmark of non-cystic fibrosis bronchiectasis is recurrent bronchial infection, yet there
are significant gaps in our understanding of pathogen persistence, resistance and exacerbation
frequencies. Pseudomonas aeruginosa is a key pathogen thought to be a marker of disease severity
and progression, yet little is known if the infection risk is seen in those with milder disease or if there
is any potential for eradication. These data are important in determining risk stratification and follow
up. A retrospective review of consecutive adult patients attending a specialist UK bronchiectasis
clinic over a two-year recruitment period between July 2007 and June 2009 was performed. Analysis
of our primary outcome, longitudinal microbiological status, was recorded based on routine clinical
29
follow-up through to data capture point or date of death. Patients were stratified by lung function
and infecting organism. 155 patients (mean (SD) age 62.2 (12.4) years; 60.1% female) were identified
from clinic records with microbiological data for a median (IQR) follow up duration of 46 (35-62)
months. Baseline mean FEV1% predicted was 60.6% (24.8) with mean exacerbation frequency of
4.42/year; 73.6% reported 3 or more exacerbations/year. Haemophilus influenzae was isolated in 90
(58.1%) patients and P. aeruginosa in 78 (50.3%) patients with persistent infection in 51 (56.7%) H.
influenzae and 47 (60.3%) P. aeruginosa, respectively. Of the P. aeruginosa colonised patients, 16
(34%) became culture negative on follow-up with a mean of 5.2 negative sputum cultures/patient. P.
aeruginosa was isolated from 5 out of 39 patients (12.8%) with minimal airflow limitation as
compared to 18 out of 38 patients (47.4%) with severe airflow limitation. Although hospital
admissions were significantly higher in the P. aeruginosa infected group (1.3 vs. 0.7 admissions per
annum, p = 0.035), overall exacerbation rates were the same (4.6 vs. 4.3, p = 0.58). Independent
predictors of P. aeruginosa colonisation were low FEV1% predicted (OR 2.46; 95% CI 1.27-4.77) and
polymicrobial colonisation (OR 4.07; 95% CI 1.56-10.58). 17 (11%) patients were infected with multiresistant strains; however, none were pan-resistant. P. aeruginosa is associated with greater
persistent infection rates and more hospital admissions than H. influenzae. Exacerbation rates,
however, were similar; therefore H. influenzae causes significant out-patient morbidity. P.
aeruginosa infection occurs across all strata of lung function impairment but is infrequently multiresistant in bronchiectasis. Careful microbiology follow up is required even in those with wellpreserved lung function. Copyright © 2014 Elsevier Ltd. All rights reserved.
Title: Patient experience in cystic fibrosis care: Development of a disease-specific questionnaire
Citation: Chronic Illness, Jun 2015, vol. 11, no. 2, p. 108-125, 1742-3953
Author(s): Stahl, Katja, Steinkamp, Gratiana, Ullrich, Gerald, Schulz, Wolfgang, Van KoningsbruggenRietschel, Silke, Heuer, Hans-Eberhard, Ellemunter, Helmut, Schwarz, Carsten
Abstract: Objectives The aim of this study was to develop valid and reliable disease-specific
questionnaires for adult patients with cystic fibrosis and for parents of minors with cystic fibrosis for
assessing patient experience with cystic fibrosis care. Methods The pilot versions of the
questionnaires were developed based on a literature review, interviews with health professionals
and focus groups. A postal survey with two reminders was conducted in 56 German cystic fibrosis
centres recruiting 2874 participants. Psychometric evaluation was done via exploratory factor
analysis and reliability and regression analysis. The questionnaires' ability to differentiate between
subgroups and between cystic fibrosis centres was evaluated. Results Response rates were 74% for
both adult patients and parents. Ten factors were extracted for both the adult and the parents'
models (Cronbach's alpha between 0.6 and 0.9), explaining 50% and 48% of the variance,
respectively. The factors organisation & access and the doctor-patient/parent-interaction had the
highest relevance for a good overall care experience. The questionnaires were able to distinguish
between different cystic fibrosis centres. Discussion The questionnaires are well suited for use in
internal and external quality management of cystic fibrosis care due to their good psychometric
properties, the ability to differentiate between centres and its practicability. [PUBLICATION] Cannot
see references
30
Title: Pregnancy outcomes in cystic fibrosis: a 10-year experience from a UK centre
Citation: Obstetric Medicine, Jun 2015, vol. 8, no. 2, p. 99-101, 1753-495X
Author(s): Renton, M, Priestley, L, Bennett, L, Mackillop, L, Chapman, SJ
Abstract: Background: Cystic fibrosis manifests as a multisystem disease, despite this female fertility
is relatively preserved with levels approaching that of the non-cystic fibrosis population. We
reviewed pregnancies in cystic fibrosis patients over a 10-year period from a UK adult cystic fibrosis
centre by considering maternal and fetal outcomes. Methods: We conducted a retrospective casenote review of pregnancies during 2003-2013 using respiratory and obstetric records. Results: We
observed moderate falls in lung function immediately after delivery, which persisted at 12 months
postpartum. We found that a decline in lung function at delivery was a marker for further decline in
function during the subsequent postpartum period. We found baseline lung function was predictive
of gestational age at delivery. We observed a high incidence of haemoptysis. Conclusion: Consistent
with current guidance we found pregnancy is feasible and well tolerated in the majority of patients
with cystic fibrosis. There was a high incidence of haemoptysis, which warrants further study.
[PUBLICATION]
31
Journal Tables of Contents
The most recent issues of the following journals:




Journal of Cystic Fibrosis
American Journal of Respiratory and Critical Care Medicine
Thorax
Chest
Click on the links for abstracts. If you would like any of these papers in full text then get in touch:
library@uhbristol.nhs.uk
Journal of Cystic Fibrosis
American Journal of
Respiratory and Critical Care
Medicine
Vol. 14, iss. 4, July 2015
Vol. 192, iss. 81 1 July 2015
Thorax
Chest
Vol. 70, iss. 7, July 2015
Vol. 148 iss. 1, July 2015
32
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