•Adults with CF have smaller thigh muscles, compared to healthy controls.•Adults with CF have lower handgrip strength than healthy controls.•A subgroup of adults with CF has lower quadriceps strength ...than healthy controls.•Lower handgrip strength is associated with lower lung function in adults with CF.•Females with CF has lower handgrip strength than males with CF.
There is conflicting evidence regarding the presence of limb muscle impairments in adults with cystic fibrosis (CF), and the factors associated with these muscle impairments. The objectives of this study were to compare limb muscle size and function between adults with CF and healthy controls; and to examine their associations with demographic and clinical variables in adults with CF.
The systematic review was performed using PRISMA guidelines. Studies were included if they measured any aspect of limb muscle size or function in adults with CF. Meta-analyses were performed to compare muscle variables between CF and healthy controls; and to examine their associations with demographic and clinical variables.
Twenty-eight studies were included, with 747 adults with CF. The meta-analyses showed that adults with CF have smaller thigh muscles standardized mean difference (SMD) = 0.57, p<.0011, I2=0%, and lower handgrip strength (SMD = 0.89, p=.0034, I2=74.03%), which was weakly correlated with forced expiratory volume in one second (FEV1) (r=0.24, p=.035, I2=0%) and lower in females with CF (SMD = 2.05, p<.0001, I2=0%). There is no significant difference between adults with CF and controls in knee extensor strength (SMD = 0.25, p=.095, I2=42.79%).
Leg muscle atrophy and lower handgrip strength were noted. There may be a subgroup of adults with CF with knee extensor (quadriceps) weakness. Future studies are needed to better understand muscle impairments in people with CF; to explore the factors that can predict these muscle impairments; and to investigate their clinical significance in people with CF.
Overexpression of the receptor tyrosine kinase EphB4 is common in epithelial cancers and linked to tumor progression by promoting angiogenesis, increasing survival and facilitating invasion and ...migration. However, other studies have reported loss of EphB4 suggesting a tumor suppressor function in some cancers. These opposing roles may be regulated by (i) the presence of the primary ligand ephrin‐B2 that regulates pathways involved in tumor suppression or (ii) the absence of ephrin‐B2 that allows EphB4 signaling via ligand‐independent pathways that contribute to tumor promotion. To explore this theory, EphB4 was overexpressed in the prostate cancer cell line 22Rv1 and the mammary epithelial cell line MCF‐10A. Overexpressed EphB4 localized to lipid‐rich regions of the plasma membrane and confirmed to be ligand‐responsive as demonstrated by increased phosphorylation of ERK1/2 and internalization. EphB4 overexpressing cells demonstrated enhanced anchorage‐independent growth, migration and invasion, all characteristics associated with an aggressive phenotype, and therefore supporting the hypothesis that overexpressed EphB4 facilitates tumor promotion. Importantly, these effects were reversed in the presence of ephrin‐B2 which led to a reduction in EphB4 protein levels, demonstrating that ligand‐dependent signaling is tumor suppressive. Furthermore, extended ligand stimulation caused a significant decrease in proliferation that correlated with a rise in caspase‐3/7 and ‐8 activities. Together, these results demonstrate that overexpression of EphB4 confers a transformed phenotype in the case of MCF‐10A cells and an increased metastatic phenotype in the case of 22Rv1 cancer cells and that both phenotypes can be restrained by stimulation with ephrin‐B2, in part by reducing EphB4 levels.
In cystic fibrosis (CF), omalizumab has been used for difficult-to-treat asthma and allergic bronchopulmonary aspergillosis (ABPA) but safety and efficacy data are limited for this population.
We ...assessed patients receiving omalizumab for asthma or ABPA in the Toronto adult CF center between 2005 and 2017. We evaluated treatment safety and efficacy by analyzing changes in FEV1% predicted (FEV1pp) max value, slope and variability captured by the area under the curve (AUC), the cumulative dose of systemic corticosteroids (SCS), use of intravenous (IV) antibiotics and hospitalization days before omalizumab and up to 1 year after treatment initiation. Linear mixed effects model was used for FEV1pp slope and the trapezoidal rule for FEV1pp AUC.
Twenty-seven CF patients received omalizumab, 16 (59.3%) for asthma and 11 (40.7%) for ABPA. No significant omalizumab-related adverse effects were observed. In the asthmatic group, the max value of FEV1pp improved on omalizumab and the cumulative dose of SCS decreased. In the ABPA group, the rate of FEV1pp decline (slope) and the variability of FEV1pp (AUC) improved on omalizumab. In ABPA patients, the cumulative SCS dose was not significantly different but 4 (36%) patients decreased their SCS dose by >50% compared to baseline. Days on IV antibiotics and hospital days did not differ significantly before and while on omalizumab therapy.
In adult CF patients with difficult-to-treat asthma or ABPA, omalizumab should be considered. Larger studies are needed to identify patient characteristics that may predict response to omalizumab.
•In adult CF patients with severe ABPA or asthma, the safety and efficacy of omalizumab are not known.•Omalizumab was well tolerated and no significant drug-related adverse effects were observed.•In CF-asthma, the max FEV1pp improved on omalizumab and the cumulative SCS dose decreased.•In ABPA, the rate of FEV1pp decline (slope) and the variability of FEV1pp improved on omalizumab.
•Lung function increases in the first year and decline is mitigated following liver transplantation.•Rates of pulmonary exacerbations decrease despite the use of immunosuppression.•There is a trend ...towards increased body mass index following liver transplant.•The development of diabetes is common post-transplant.•One-year survival ranged from 75 to 100 % while five-year survival was lower at 64–89 %.
Data on the impact of liver transplantation (LT) in cystic fibrosis (CF) on lung function and exacerbations are limited. The objective of this study was to summarize the literature on lung function, nutritional status, survival, and complications following LT in people with CF.
Three databases were searched until September 2023, to identify the impact of LT in CF. Lung transplant prior to LT and simultaneous liver-lung transplant were excluded. Pooled hazard ratios were calculated using random-effects models.
Thirty studies were included in this review, with 3 and 9 studies included in meta-analyses for nutritional status and lung function, respectively. Eighty-three percent of the studies used data that was more than a decade old. There was a significant increase in percent-predicted forced expiratory volume with mean change of 7.16 % (2.13, 12.19; p = 0.005) one year post-LT. Pulmonary exacerbations decreased in the short-term, however there was no significant change in body mass index (BMI). One-year survival post-LT ranged between 75 and 100 %, while five-year survival was lower at 64–89 %.
Existing data suggest that LT improves lung function in the short term and does not increase the likelihood of pulmonary exacerbations, despite ongoing immunosuppression in the setting of chronic lung infection.
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France implemented a high emergency lung transplantation (HELT) programme nationally in 2007. A similar programme does not exist in Canada. The objectives of our study were to compare health outcomes ...within France as well as between Canada and France before and after the HELT programme in a population with cystic fibrosis (CF).
This population-based cohort study utilised data from the French and Canadian CF registries. A cumulative incidence curve assessed time to transplant with death without transplant as competing risks. The Kaplan-Meier method was used to estimate post-transplant survival.
Between 2002 and 2016, there were 1075 (13.0%) people with CF in France and 555 (10.2%) people with CF in Canada who underwent lung transplantation. The proportion of lung transplants increased in France after the HELT programme was initiated (4.5%
10.1%), whereas deaths pre-transplant decreased from 85.3% in the pre-HELT period to 57.1% in the post-HELT period. Between 2008 and 2016, people in France were significantly more likely to receive a transplant (hazard ratio (HR) 1.56, 95% CI 1.37-1.77; p<0.001) than die (HR 0.55, 95% CI 0.46-0.66; p<0.001) compared with Canada. Post-transplant survival was similar between the countries, and there was no difference in survival when comparing pre- and post-HELT periods in France.
Following the implementation of the HELT programme, people living with CF in France were more likely to receive a transplant than die. Post-transplant survival in the post-HELT period in France did not change compared with the pre-HELT period, despite potentially sicker patients being transplanted, and was comparable to Canada.
•Obstructive sleep apnea is more common among adults with CF than previously thought.•Positive airway pressure and supplemental oxygen are being under-utilized for sleep breathing disorder among ...adults with CF.•Traditional risk factors do not predict sleep breathing disorder in adults with CF.•CF-related markers of poor lung health do not predict sleep breathing disorder.
Our understanding of the epidemiology of sleep breathing disorders among adults with cystic fibrosis (CF) is limited. Our purpose was to describe the frequency, risk factors and treatment of sleep breathing disorders among adults with CF.
This was a retrospective analysis of linked data from laboratory-based diagnostic polysomnography (PSG) undertaken at St. Michael's Hospital (Toronto, Canada) and the Canadian CF Registry. Adults (≥19 years old) with CF that underwent a diagnostic PSG at St. Michael's Hospital between 2002 and 2021 were included. Sleep breathing disorder frequency, risk factors, and treatment were described, using descriptive statistics and logistic regression.
There were 42 patients included (33.3 % women and median age at diagnostic PSG was 34.7 years). Obstructive sleep apnea OSA was the most commonly observed sleep breathing disorder (found in 64.3 %), followed by sustained nocturnal hypoxemia (16.7 %), and sleep hypoventilation (9.5 %). Only 41 % of individuals with an elevated total apnea-hypopnea index were receiving positive airway pressure PAP therapy. Corticosteroid use (either oral or inhaled) was the only factor with a significant positive association with presence of any sleep breathing disorder (odds ratio 5.00, 95 % confidence interval 1.28-22.78).
Among adults with CF, OSA occurs more commonly than previously appreciated and the majority of sleep breathing disorders were not being treated with PAP or supplemental oxygen. Management of sleep breathing disorders among adults with CF reflects a potentially important care gap, but further research is needed to determine the health impacts of treating sleep breathing disorders in CF.
Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications.
What are rates ...of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV
< 40% predicted?
This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV
measurements < 40% predicted within a 5-year period, age ≥ 6 years, without prior LTx were included. Multivariable competing risk regression for time to death without LTx (LTx as a competing risk) and time to LTx (death as a competing risk) was performed.
There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV
< 40% predicted living in the United States and Canada, respectively. Multivariable competing risk regression models identified an increased risk of death without LTx (hazard ratio HR, 1.79; 95% CI, 1.52-2.1) and decreased LTx (HR, 0.66; 95% CI, 0.58-0.74) among individuals in the United States compared with Canada. More pronounced differences were seen in the patients in the United States with Medicaid/Medicare insurance compared with Canadians (multivariable HR for death without LTx, 2.24 95% CI, 1.89-2.64; multivariable HR for LTx, 0.54 95% CI, 0.47-0.61). Patients of nonwhite race were also disadvantaged (multivariable HR for death without LTx, 1.56 95% CI, 1.32-1.84; multivariable HR for LTx, 0.47 95% CI, 0.36-0.62).
There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV
< 40% predicted compared with Canadian patients. Findings are more striking among US patients with CF with Medicaid/Medicare health insurance, and nonwhite patients in both countries, raising concerns about underuse of LTx among vulnerable populations.
The existence of pleiotropy in disorders with multi-organ involvement can suggest therapeutic targets that could ameliorate overall disease severity. Here we assessed pleiotropy of modifier genes in ...cystic fibrosis (CF). CF, caused by mutations in the cystic fibrosis transmembrane conductance regulator (
CFTR)
gene, affects the lungs, liver, pancreas and intestines. However, modifier genes contribute to variable disease severity across affected organs, even in individuals with the same
CFTR
genotype. We sought to determine whether
SLC26A9
,
SLC9A3
and
SLC6A14,
that contribute to meconium ileus in CF, are pleiotropic for other early-affecting CF co-morbidities. In the Canadian CF population, we assessed evidence for pleiotropic effects on (1) pediatric lung disease severity (
n
= 815), (2) age at first acquisition of
Pseudomonas aeruginosa
(
P. aeruginosa
) (
n
= 730), and (3) prenatal pancreatic damage measured by immunoreactive trypsinogen (
n
= 126). A multiple-phenotype analytic strategy assessed evidence for pleiotropy in the presence of phenotypic correlation. We required the same alleles to be associated with detrimental effects.
SLC26A9
was pleiotropic for meconium ileus and pancreatic damage (
p
= 0.002 at rs7512462),
SLC9A3
for meconium ileus and lung disease (
p
= 1.5 × 10
−6
at rs17563161), and
SLC6A14
for meconium ileus and both lung disease and age at first
P. aeruginosa
infection (
p
= 0.0002 and
p
= 0.006 at rs3788766, respectively). The meconium ileus risk alleles in
SLC26A9
,
SLC9A3
and
SLC6A14
are pleiotropic, increasing risk for other early CF co-morbidities. Furthermore, co-morbidities affecting the same organ tended to associate with the same genes. The existence of pleiotropy within this single disorder suggests that complementary therapeutic strategies to augment solute transport will benefit multiple CF-associated tissues.
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