Cystic fibrosis patient care has advanced greatly in recent years and the mortality rate has improved.

Title: Gene Study Helps Advance Diagnosis of Cystic Fibrosis
Category: Health News
Created: 8/26/2013 2:36:00 PM
Last Editorial Review: 8/27/2013 12:00:00 AM

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Extract

In cystic fibrosis (CF), Pseudomonas aeruginosa acquisition represents a turning point in disease progression. The presence of chronic P. aeruginosa infection is associated with worsening lung function and increased risk of earlier death, whereas treatment substantially improves lung function and survival [1, 2]. Efforts to diagnose and eradicate early P. aeruginosa provide lasting benefits for children with CF [3, 4]. However, the timing of infection varies considerably between individuals with CF, treatment centres [5, 6], and different birth cohorts of people with the disease [7, 8].

Background

Pseudomonas aeruginosa is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing CFTR (CF transmembrane conductance regulator) variations contribute ~85% of the variation in chronic P. aeruginosa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to P. aeruginosa infection.

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The current standard of care includes informing women about prenatal testing and newborn screening for cystic fibrosis and providing genetic counseling to parents whose child is referred for sweat-testing. Despite counseling, early data identified some persistent confusion about residual risk.

Prenatal discussions about carrier testing and newborn screening for cystic fibrosis are not routine. Parental anxiety about abnormal results from a screen is decreased after speaking to a genetic counselor when scheduling the sweat test. Despite counseling, residual risk continues to be poorly understood. (Read the full article)

Registries have been established in a number of countries to monitor the health of patients with cystic fibrosis. Few international comparisons have been made between registries. International data registry comparisons may be useful for informing best practice and benchmarking.

Registry comparisons are feasible but are limited by factors such as nonstandardization of data collection. Lung function was lower in Australian children with cystic fibrosis compared with their US counterparts after adjusting for the benefits of diagnosis after newborn screening. (Read the full article)

Although it has been shown that cystic fibrosis newborn screening is beneficial, the strategies vary widely, and there has been uncertainty about the costs and consequences of different algorithms and whether screening methods/decisions should be based on assumed cost differences.

This study contributes by offering a comparison of both costs, assessed comprehensively, and the consequences associated with the 2 most popular screening methodologies, immunoreactive trypsinogen/immunoreactive trypsinogen and immunoreactive trypsinogen/DNA, by using a decision-tree framework allowing variation in the model parameters. (Read the full article)

Transition from pediatric to adult care is often reported to be unsuccessful. Little evidential research has examined the actual proportion of youth in pediatric versus adult care or impact on health status outcomes after transferring from pediatric to adult care.

Our article extends the literature by providing health transition outcome data, something that has been recognized as a critical gap to developing evidence-based programming and health care transition policy. (Read the full article)

Influenza leads to respiratory deteriorations in cystic fibrosis (CF) patients. In children, live attenuated influenza virus vaccine (LAIV) is more efficacious than inactivated influenza vaccines, which could be beneficial for CF. Data on the safety of LAIV in this population are scarce.

This study assesses LAIV’s safety in patients with CF and is necessary to determine whether the anticipated benefits associated with LAIV will outweigh potential risks. This can potentially lead to a recommendation for preferential LAIV use in this population. (Read the full article)

Infants with an inconclusive diagnosis of cystic fibrosis after newborn screening may turn out to have cystic fibrosis. However, little is known about the incidence, characteristics (phenotype and genotype), and outcomes of these infants to guide investigations and follow-up.

In this prospective longitudinal study, a proportion (11%) of infants with an initial inconclusive diagnosis were subsequently diagnosed with cystic fibrosis. This finding underscores the need for follow-up of this population. (Read the full article)

Little is known about the prevalence or outcomes of infants with indeterminate diagnostic results after a positive cystic fibrosis (CF) newborn screen (CF transmembrane conductance regulator–related metabolic syndrome [CRMS]).

CRMS accounted for 15.7% of newborn screened diagnoses in the CF Patient Registry from 2010 to 2012 (CRMS:CF ratio = 5.0:1.0). Although most infants were healthy, some infants demonstrated clinical features concerning for CF. (Read the full article)

Children with cystic fibrosis demonstrate gas exchange abnormalities and increased respiratory loads during sleep independent of lung function, age, and BMI. Assessment of breathing patterns during sleep provides an opportunity for detection of early lung disease progression.

Children with cystic fibrosis demonstrated increased respiratory loads and gas exchange abnormalities during sleep compared with controls. Based on these findings, sleep assessment in this patient population can identify markers for the early detection of lung disease progression. (Read the full article)

Philip M. Farrell
Jan 1, 2001; 107:1-13
ARTICLES

Title: Experimental Drug Offers Hope for Cystic Fibrosis Patients
Category: Health News
Created: 4/27/2010 6:10:00 PM
Last Editorial Review: 4/28/2010 12:00:00 AM

Title: Pigs Yield Clues to Cystic Fibrosis-Related Lung Disease
Category: Health News
Created: 4/28/2010 2:10:00 PM
Last Editorial Review: 4/29/2010 12:00:00 AM

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy and activates the transcription of dozens of genes, including that encoding the QS regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have recently shown that in CF isolates, the QS circuitry is often rewired such that RhlR acts in a LasR-independent manner. To begin understanding how QS activity differs in this rewired background, we characterized QS activation and RhlR-regulated gene expression in P. aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR include several that encode virulence factors. Some, but not all, of these genes are present in the QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 produces virulence factors at similar concentrations as PAO1, and in E90, RhlR plays a significant role in mediating cytotoxicity in a three-dimensional lung epithelium cell model. These data illuminate a rewired LasR-independent RhlR regulon in chronic infection isolates and suggest further investigation of RhlR as a possible target for therapeutic development in chronic infections.

IMPORTANCE Pseudomonas aeruginosa is a prominent cystic fibrosis (CF) pathogen that uses quorum sensing (QS) to regulate virulence. In laboratory strains, the key QS regulator is LasR. Many isolates from patients with chronic CF infections appear to use an alternate QS circuitry in which another transcriptional regulator, RhlR, mediates QS. We show that a LasR-null CF clinical isolate engages in QS through RhlR and remains capable of inducing cell death in an in vivo-like lung epithelium cell model. Our findings support the notion that LasR-null clinical isolates can engage in RhlR QS and highlight the centrality of RhlR in chronic P. aeruginosa infections.

BACKGROUND:Patients with cystic fibrosis develop decreased exercise capacity. However, the main factors responsible for this decline are still unclear. Thus, the objective of this study was to evaluate the factors influencing exercise capacity assessed with the modified shuttle test (MST) in individuals with cystic fibrosis.METHODS:A cross-sectional study was carried out in subjects with a diagnosis of cystic fibrosis who were 6–26 y old and were regularly monitored at 2 cystic fibrosis reference centers in Brazil. Individuals who were unable to perform the tests or who exhibited hemodynamic instability and exacerbation of respiratory symptoms were excluded. Anthropometric, clinical, and genotype data were collected. In addition, lung function and exercise capacity were evaluated with the MST.RESULTS:73 subjects (mean age 12.2 ± 4.9 y and FEV1 76.8 ± 23.3%) were included. The mean distance achieved in the MST was 765 ± 258 m (71.6% of predicted). The distance achieved on the MST correlated significantly with age (r = 0.49, P < .001), body mass index (r = 0.41, P < .001), resting heart rate (r = −0.51, P < .001), and FEV1 (r = 0.24, P = .042). Subjects with FEV1 > 67% of predicted (P = .02) and those with resting heart rate < 100 beats/min (P = .01) had a greater exercise capacity. Resting heart rate, age, and FEV1 (%) were found as significant variables to explain the distance achieved on the MST (R2 = 0.48, standard error = 191.0 m).CONCLUSIONS:The main determinants of exercise capacity assessed with the MST in individuals with cystic fibrosis were resting heart rate, age, and lung function.

Management of cystic fibrosis has been revolutionised by the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. These compounds treat the underlying molecular basis of the disease by increasing activity of defective CFTR channels, which improves many clinical parameters and enhances patient quality of life [1]. Next-generation modulators, also known as triple combination therapy, promise to be highly efficacious in up to 90% of patients [2] and will likely dramatically change the landscape of cystic fibrosis disease. Studies examining individuals before and after initiation of CFTR modulators have revealed novel functions of CFTR and shown that CFTR modulators do not reverse all disease manifestations [3–5]. Thus, knowledge of the post-modulator cystic fibrosis disease state is crucial for understanding what continued therapies will be needed for people with cystic fibrosis and what new challenges may arise.

Pseudomonas aeruginosa exploits intrinsic and acquired resistance mechanisms to resist almost every antibiotic used in chemotherapy. Antimicrobial resistance in P. aeruginosa isolates recovered from cystic fibrosis (CF) patients is further enhanced by the occurrence of hypermutator strains, a hallmark of chronic infections in CF patients. However, the within-patient genetic diversity of P. aeruginosa populations related to antibiotic resistance remains unexplored. Here, we show the evolution of the mutational resistome profile of a P. aeruginosa hypermutator lineage by performing longitudinal and transversal analyses of isolates collected from a CF patient throughout 20 years of chronic infection. Our results show the accumulation of thousands of mutations, with an overall evolutionary history characterized by purifying selection. However, mutations in antibiotic resistance genes appear to have been positively selected, driven by antibiotic treatment. Antibiotic resistance increased as infection progressed toward the establishment of a population constituted by genotypically diversified coexisting sublineages, all of which converged to multidrug resistance. These sublineages emerged by parallel evolution through distinct evolutionary pathways, which affected genes of the same functional categories. Interestingly, ampC and ftsI, encoding the β-lactamase and penicillin-binding protein 3, respectively, were found to be among the most frequently mutated genes. In fact, both genes were targeted by multiple independent mutational events, which led to a wide diversity of coexisting alleles underlying β-lactam resistance. Our findings indicate that hypermutators, apart from boosting antibiotic resistance evolution by simultaneously targeting several genes, favor the emergence of adaptive innovative alleles by clustering beneficial/compensatory mutations in the same gene, hence expanding P. aeruginosa strategies for persistence.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has given its recommendation for the approval of Kalydeco for the treatment of children and adolescents with cystic fibrosis in a new indication, Vertex has revealed.

Vertex Pharmaceuticals announced a plan late Tuesday to begin trials before the end of the year of the third in its so-called “triple combo” of pills designed to treat as much as 90 percent of the 75,000 patients worldwide who suffer from cystic fibrosis. That news, announced in conjunction with the Boston-based drugmaker’s third-quarter financial results last night, spurred a 6 percent stock increase after hours, implying the company’s market cap could increase by about half a billion dollars…

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Totowa, N.J. : Humana Press, [2002]

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