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Thursday, April 30, 2009

Fluidosomes-tobramycin in drug development

Cystic Fibrosis Patients benefit from Orphan Drug Designation

Cystic fibrosis ­ Orphan drug designation for innovative treatment against lung infections by Axentis Pharma AG

Zurich, 30 April 2009 -- An innovative treatment for infections of the respiratory tract in cystic fibrosis patients has received orphan drug designation in the US. Axentis Pharma of Zurich, Switzerland announced today that this sought-after designation has been granted to its product candidate Fluidosomes-tobramycin, a therapeutic that will soon be tested in Phase II clinical trials. The company has now been granted orphan drug designation for this candidate in both Europe and the US.

Axentis Pharma (Switzerland) announced today that the Office of Orphan Products Development of the US Food and Drug Administration (FDA) has granted the orphan drug designation to its lead product candidate Fluidosomes?-tobramycin. This drug is a liposomal formulation of tobramycin, an innovative treatment for infections of the respiratory tract in patients with cystic fibrosis that is delivered directly to the site of infection via standard nebulizers. Pre-clinical and Phase I clinical studies support improved safety and efficacy profiles for Fluidosomes?-tobramycin as compared to currently marketed treatments for infections of the respiratory tract in patients with cystic fibrosis.

The orphan drug designation is granted with respect to treatment of pulmonary infections caused by Pseudomonas aeruginosa, a bacterium that is one of the most common causes of infections of the respiratory tract in patients with cystic fibrosis. Axentis Pharma¹s product candidate received the orphan drug designation for the US only two months after the application and less than one year after orphan designation in Europe was transferred to the company. Dr. Helmut Brunar, company CEO and President, comments: "The orphan drug designation for the US is very good news for affected patients as well as for Axentis Pharma's shareholders. Together with the Orphan Drug Designation that was already achieved last year in Europe, the US Designation puts Axentis Pharma in a favourable position to register Fluidosomes?-tobramycin in two major world markets with substantial support of the relevant authorities and at a cost advantage for the company. As a result, we will be able to deliver the product at competitive prices to patients once it has passed the final clinical test phase. In addition to this, the orphan drug designation grants Axentis several years of exclusive marketing rights once the product has been launched. That is a significant strengthening of Axentis Pharma market position as well as the company's value."

Fluidosomes?-tobramycin combines the company¹s proprietary Fluidosomes? technology with the well-established generic drug tobramycin. Utilising synthetic liposomes containing tobramycin, a standard nebulizer delivers the drug directly to the endobronchial sites of infection in cystic fibrosis patients. This may result in prolonged high local drug concentration in the lung, which in turn may lead to higher efficacy and may allow lower doses.

Currently, the company is initiating Phase II clinical trials that will assess the safety and tolerability of a new therapeutic formulation as well as the effects of two different doses of the new drug. Results of the clinical trial are expected early 2010.

About Axentis Pharma AG (www.axentispharma.com)

Axentis Pharma is a respiratory specialty pharmaceutical company which core competence is the application of a fully patented, encapsulating drug delivery system to already established and well-characterized therapeutic agents. Currently, the company is using this technology, named Fluidosome® technology, for the development of its lead product, a clinical stage treatment against cystic fibrosis (CF).

About Fluidosome technology

Axentis Pharma¹s Fluidosome? technology uses biocompatible lipids endogenous to the lung that are formulated into small liposomes. This nanocapsule platform offers wide-ranging potential for unmet medical needs, including other respiratory diseases. In the case of Fluidosome?-tobramycin, the interaction between tobramycin and the microbial cell is triggered when the liposomes attach to the outer cell membrane. Tobramycin then leaches into the inner cell compartment, which leads to rapid cell death.

About cystic fibrosis

Cystic fibrosis is the most common life-threatening hereditary disease amongst Caucasian populations. The disease is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene found on chromosome 7. This mutation causes increased secretion deposits on mucous membranes. Lung complications represent the most serious manifestation of the disease ­ and the reason for the high mortality rate amongst patients. Such complications often involve infection of the bronchi by the bacteria Pseudomonas aeruginosa. Chronic inflammations then cause lung functions to become blocked. As well as the breakdown of lung tissue, this also leads to bronchiectasis and lung failure.

For further information, please contact:

Dr. Helmut Brunar, Ph.D., CEO Axentis Pharma AG Limmatquai 138 CH-8001 Zurich, Switzerland T +41 44 202 7878 E board@axentispharma.com W www.axentispharma.com

Copy Editing Distribution: PR - Public Relations for Research Education Campus Vienna Biocenter 2 1030 Vienna Austria T +43 1 505 70 44 E contact@prd.at W www.prd.at


Tuesday, April 28, 2009

Rehabilitation and transition after lung transplantation in children.

Click here to read
Rehabilitation and transition after lung transplantation in children.

Burton JH, Marshall JM, Munro P, Moule W, Snell GI, Westall GP.

Pediatric Lung Transplant Service, The Alfred Hospital, Melbourne, Australia. J.burton@alfred.org.au

We describe the key components of an outpatient pediatric recovery and rehabilitation program set up within the adult lung transplant service at the Alfred Hospital, Melbourne. Following discharge, pediatric lung transplant recipients and their families participated in an intensive 3-month outpatient rehabilitation program. Weekly sessions included education regarding transplant issues, physiotherapy, and occupational therapy sessions. The overall aim of the program was to comprehensively address physical rehabilitation and psychosocial and educational needs. Sessions tailored to meet the individual needs of the child were presented at an appropriate cognitive level. Education sessions for both the children and parents focused on medications, identification of infection and rejection, nutrition, physiotherapy/rehabilitation, occupational roles and stress management, donor issues, psychosocial readjustment, and transition issues. Physiotherapy included a progressive aerobic and strength training program, postural reeducation, and core stability. We incorporate Age-appropriate play activities: running, dancing, jumping, ball skills, and so on. Occupational therapy sessions addressed the primary roles of patient, students, and player. Transitions such as returning to school, friends, and the community were explored. Issues discussed included adjustment to new health status, strategies to manage side effects of medications, and altered body image issues. Weekly multidisciplinary team meetings were used to discuss and plan the rehabilitation progress. School liaison and visits occurred prior to school commencement with follow-up offered to review the ongoing transition process. Both patients and parents have reported a high level of satisfaction with the rehabilitation program. We plan to formally evaluate the program in the future.

PMID: 19249539 [PubMed - indexed for MEDLINE]

Cystic fibrosis and the respiratory therapist: a 50-year perspective.

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Cystic fibrosis and the respiratory therapist: a 50-year perspective.

Volsko TA.

Department of Health Professions, Youngstown State University, One University Plaza, Youngstown OH 44555. tavolsko@ysu.edu.

The role of the respiratory therapist in the care of patients with cystic fibrosis has expanded throughout the years. As key members of the multidisciplinary team, respiratory therapists actively participate in the medical management of patients with cystic fibrosis along the continuum of care, from acute in-patient stays to the out-patient clinic and/or home setting. Through their involvement in diagnostic testing, administering therapy, or direct bedside care, patient and caregiver education, and disease management, respiratory therapists strive to preserve lung function, maintain overall health, and improve the patient's quality of life.

PMID: 19393103 [PubMed - in process]

Monitoring respiratory disease severity in cystic fibrosis

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Monitoring respiratory disease severity in cystic fibrosis.

Davies JC, Alton EW.

Department of Gene Therapy, Imperial College, Emmanuel Kaye Building, Manresa Road, London SW3 6NP, United Kingdom. j.c.davies@imperial.ac.uk.

Measurements of disease severity provide a guide for the physician to tailor therapies, for the patient and family to gauge progress, and are required for clinical trials. For many respiratory diseases, including cystic fibrosis, sensitive, noninvasive measurements are few, and some of those that are available are applicable only to certain subgroups of patients or lack sufficient sensitivity. We discuss currently available measurements in 4 groups: physiology, infection, inflammation, and radiology. For each group we highlight strengths and weaknesses, ask how we could improve upon these, and provide details of alternative methods.

PMID: 19393105 [PubMed - in process]

Pulmonary complications of cystic fibrosis.

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Pulmonary complications of cystic fibrosis.

Flume PA.

Departments of Medicine and Pediatrics, Medical University of South Carolina, 96 Jonathan Lucas Street, 812-CSB, Charleston SC 29425. flumepa@musc.edu.

Earlier diagnosis, treatment of exacerbations, and the use of long-term therapies have all improved the lifespan of patients with cystic fibrosis (CF). However, the natural history of CF airways disease remains one of worsening bronchiectasis and obstructive airways impairment. The progression of airways disease leads to eventual respiratory failure, but some will suffer other acute respiratory complications that require intervention, including pneumothorax, massive hemoptysis, and respiratory failure. Here I discuss the pathophysiology of these complications and the patient-related and treatment-related factors associated with their occurrence. Knowledge of these associations may play great importance in treatment decisions regarding the care of the patient and the respiratory therapist should be aware of the implications. Since disease severity is associated with all 3 conditions, aggressive treatment of the underlying condition is imperative, which includes the performance of airway-clearance therapies. Though some might argue that airway-clearance therapies might aggravate or even precipitate complications such as hemoptysis and pneumothorax, others will defend that there are airway-clearance therapies that might be safely performed. Aerosolized medications such as dornase alfa and tobramycin have been associated with a lower incidence of massive hemoptysis and are recommended therapies for patients with advanced airways disease, yet they are also associated with a higher incidence of pneumothorax, which suggests careful assessment of their potential bronchospastic effect in patients with advanced airways disease. The respiratory therapist also plays a key role in the care of the patient with respiratory failure. Here is also discussed the role of ventilatory support and airway-clearance therapies in the patient with advanced stage disease. Now, more than ever, the patient needs caregivers with the knowledge and sensitivity to provide appropriate palliative care.

PMID: 19393106 [PubMed - in process]

***Full text of the article to be available soon...

Infection control in cystic fibrosis: cohorting, cross-contamination, and the respiratory therapist.

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Infection control in cystic fibrosis: cohorting, cross-contamination, and the respiratory therapist.

O'Malley CA.

Department of Respiratory Care, Children's Memorial Hospital, 2300 Children's Plaza, Box 58, Chicago IL 60614. comalley@childrensmemorial.org.

Cystic fibrosis (CF) is a complex genetic disease characterized by lung infections that lead to early morbidity and death. Pathogens that commonly infect the lungs of patients with CF include Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia cepacia. Aggressively treating pulmonary infection with antibiotics has contributed to improved survival in patients with CF but has also promoted multiple-drug-resistant bacteria. Other complexities include the ability of bacteria to form biofilms, which makes them more resistant to antibiotics, and emerging pathogens in CF, of which the clinical importance is not yet clear. Increasing evidence of patient-to-patient transmission of CF pathogens led the Cystic Fibrosis Foundation to produce evidence-based infection-control recommendations, which stress 4 principles: standard precautions, transmission-based precautions, hand hygiene, and care of respiratory equipment. Respiratory therapists need to know and follow these infection-control recommendations. Cohorting patients infected with B. cepacia complex is one of several interventions successful at keeping the spread of this pathogen low, but cohorting patients who are infected/colonized with other microbes is controversial, the main argument of which is not being certain of a patient's present respiratory culture status at any given patient visit.

PMID: 19393108 [PubMed - in process]

***Full text of the article should be available shorty.....

Bugs, biofilms, and resistance in cystic fibrosis

Click here to read
Bugs, biofilms, and resistance in cystic fibrosis.

Davies JC, Bilton D.

Department of Gene Therapy, Imperial College, Emmanuel Kaye Building, Manresa Road, London SW3 6NP, United Kingdom. j.c.davies@imperial.ac.uk.

Bacteria infect the respiratory tract early in the course of cystic fibrosis disease, often fail to be eradicated, and together with an aggressive host inflammatory response, are thought to be key players in the irreversible airway damage from which most patients ultimately die. Although incompletely understood, certain aspects of the cystic fibrosis airway itself appear to favor the development of chronic modes of survival, in particular biofilm formation; this and the development of antibiotic resistance following exposure to multiple antibiotic courses lead to chronic, persistent infection. In addition to the common cystic fibrosis pathogens, such as Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa, several newer species are becoming more common. Furthermore, new molecular techniques have led to the identification of multiple different organisms within respiratory secretions, many of which are not cultured with conventional tools. Future work should aim to develop clinically applicable methods to identify these and to determine which have the potential to impact pulmonary health. We outline the basic tenets of infection control and treatment.

*Full text should be up and running soon.....

Aerosol antibiotics in cystic fibrosis.

Aerosol antibiotics in cystic fibrosis.

Geller DE.

Aerosol Research Laboratory and Cystic Fibrosis Center, Nemours Children's Clinic, 496 S Delaney Avenue, Suite 406A, Orlando FL 32801. dgeller'nemours.org.

Chronic airways infection and inflammation is the greatest source of morbidity and mortality in cystic fibrosis (CF) patients. Many organisms can be found in the lower respiratory tract of CF patients, but infection with mucoid Pseudomonas aeruginosa is common, is associated with poorer outcomes, and is the main target for antimicrobial strategies in CF. Aerosol antibiotics achieve high local concentrations in the airways, reduce systemic toxicity, and have been used successfully for chronic suppressive treatment for established P. aeruginosa infections. Eradication of early P. aeruginosa airway infection has also been tried with aerosol antibiotics, though the ideal treatment strategy is still being investigated. There are several variables to consider when choosing an antibiotic formulation to develop for topical inhalation. Tobramycin solution for inhalation (TSI) is currently the only approved inhaled antibiotic in the United States. The time burden for patients to administer TSI by jet nebulizer is substantial, so efforts have focused on more efficient, faster delivery methods. Novel formulations of aerosol antibiotics are being studied for CF, including beta-lactams, fluoroquinolones and aminoglycosides. Phase-3 studies of aztreonam lysinate for inhalation delivered via a proprietary eFlow nebulizer showed improved outcomes and a short (< 3 min) delivery time. Liposome formulations are being studied as a way to penetrate mucoid biofilms and prolong the residence time of the antibiotic in the lungs. Light, porous, dry-powder formulations are also in clinical trials to reduce delivery time. These new formulations and delivery systems promise to expand our armamentarium against microbes while reducing the time burden for patients.

PMID: 19393109 [PubMed - in process]

The antimicrobial efficacy of sustained release silver–carbene complex-loaded l-tyrosine polyphosphate nanoparticles

Khadijah M. Hindia, Andrew J. Dittob, Matthew J. Panznera, Douglas A. Medvetza, Daniel S. Hanc, Christine E. Hovisc, Julia K. Hilliardc, Jane B. Taylorc, Yang H. Yunb, Corresponding Author Contact Information, E-mail The Corresponding Author, Carolyn L. Cannonc, Corresponding Author Contact Information, E-mail The Corresponding Author and Wiley J. Youngsa, Corresponding Author Contact Information, E-mail The Corresponding Author

aDepartment of Chemistry, University of Akron, Akron, OH 44325-3601, USA

bDepartment of Biomedical Engineering, University of Akron, Akron, OH 44325-0302, USA

cDepartment of Pediatrics, Washington University School of Medicine, St. Louis, MI 63110-1002, USA

Received 19 January 2009;
accepted 17 March 2009.
Available online 23 April 2009.

The pressing need to treat multi-drug resistant bacteria in the chronically infected lungs of cystic fibrosis (CF) patients has given rise to novel nebulized antimicrobials. We have synthesized a silver–carbene complex (SCC10) active against a variety of bacterial strains associated with CF and chronic lung infections. Our studies have demonstrated that SCC10-loaded into l-tyrosine polyphosphate nanoparticles (LTP NPs) exhibits excellent antimicrobial activity in vitro and in vivo against the CF relevant bacteria Pseudomonas aeruginosa. Encapsulation of SCC10 in LTP NPs provides sustained release of the antimicrobial over the course of several days translating into efficacious results in vivo with only two administered doses over a 72 h period.


Better use should be made of current cystic fibrosis treatments

Current treatments for cystic fibrosis (CF) must be used while newer therapies remain under development.

These are the views of Dr Brian O’Sullivan, University of Massachusetts Medical School, USA, and Dr Steven Freedman, Harvard Medical School, Boston, USA, published in Online First (see link for this at the end of this post) and an upcoming edition of The Lancet.

CF is the most common lethal genetic disease in the white population, affecting some 1 in 3000 North Europeans and white Americans. Life expectancy of CF patients has increased from 31 to 37 years in the past decade; and a UK model predicts that a child born with CF today will live to age 50.

The authors say that of the treatments available for CF, hypertonic saline, macrolide antibiotics, and ibuprofen deserve a special mention. Patients given 7% hypertonic saline via nebulisation have better lung function than those given standard saline, because it draws water into the airways and leads to sustained airway hydration, preventing infection.

Azithromycin (a macrolide antibiotic) works by preventing P aeruginosa from forming films and killing it even within its films. It also has anti-inflammatory properties.

Ibuprofen treatment seems to be most effective in younger patients (aged 5-13 years), ie, started before the development of inflammation and severe pathological changes in the lung.

As well as these interventions, airway clearance techniques are used to clear airway secretions. These include percussion (chest massage), and special breathing devices which exert pressure.

Nutrition is also key, with the authors saying: “The benefits of maintaining good nutrition in regard to long-term survival and lung health cannot be overstated.” When pancreatic insufficiency occurs, supplements of both pancreatic enzymes and fat-soluble vitamins must be used.

New horizons for CF treatment are focussing on two classes of drugs in development. "Correctors" transfer more of the mutated CFTR from the cell’s genetic machinery to its correct location on cell membranes, on the basis that it is better to have much more partly-functioning CFTR in place than none at all.

"Potentiators" improve the function of CFTR at the cell membrane.

The authors say: “A cocktail of a corrector and a potentiator might be the ultimate treatment for most patients with cystic fibrosis.”

However, treatment which would correct the actual CFTR mutation — known as gene therapy — has so far been disappointing. This would work via insertion of one copy of normal DNA into the affected cells — but has met with problems due to the poor performance of vectors to transfer the DNA.
Future development of new vectors and better methods of delivery are pre-requisites for gene therapy success.

But the authors say the prospect of gene therapy remains a hope more than a reality.

“The goal in 2009 is to preserve lung function by maximising current treatment regimens, so that patients can benefit fully from future therapies that could correct the basic defect and turn cystic fibrosis into a manageable disease," they conclude.


Efficacy and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-Mutation-Mediated Cystic Fibrosis

Efficacy and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-Mutation-Mediated Cystic Fibrosis (CF)
This study is not yet open for participant recruitment.
Verified by Hadassah Medical Organization, April 2009
First Received: April 20, 2009 Last Updated: April 27, 2009 History of Changes
Sponsored by: Hadassah Medical Organization
Information provided by: Hadassah Medical Organization
ClinicalTrials.gov Identifier: NCT00889434
  • Working Hypothesis: EGCG and Tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts.
  • Aims of the Study: To determine in patients with CF if oral administration of EGCG and Tocotrienol, both separate and in combination, modify CFTR splicing towards normal splicing as evaluated by improved Transepithelial Potential Difference (TEPD) assessment of chloride secretion.

To assess the effect of EGCG and Tocotrienol, both separate and in combination, on (1) additional TEPD measures of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) changes in pulmonary function over the course of the study.

  • Potential Implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as ~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.
  • Contribution of the expected outcome to society Today genetic diseases can be treated but not healed. This proposal may be a step in the direction of finding a cure for patients carrying splicing mutations.

Condition Intervention
Cystic Fibrosis
Dietary Supplement: ECGC
Dietary Supplement: Tocotrienol
Dietary Supplement: EGCG + Tocotrienol

Study Type: Interventional
Study Design: Treatment, Open Label, Dose Comparison, Crossover Assignment, Safety/Efficacy Study
Official Title: Single-Site, Open-Label, Dose-Ranging, Efficacy, and Safety Study of EGCG/Tocotrienol in 18 Patients With Splicing-Mutation-Mediated CF

Further study details as provided by Hadassah Medical Organization:

Primary Outcome Measures:
  • Changes in nasal chloride secretion as assessed by TEPD, with assessment of mean changes in TEPD by drug compared to baseline and the proportion of patients with a chloride secretion response by drug compared to baseline [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pulmonary function testing: forced expiratory volume in 1 sec [FEV1], forced vital capacity [FVC], and maximal expiratory flow25-75 [MEF25-75] [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 18
Study Start Date: September 2009
Estimated Study Completion Date: June 2011
Estimated Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
EGCG: Active Comparator
Two cycles comprising 28 days of continuous daily treatment with EGCGgiven 2 times/6 soft gel capsules (total 600 mg) /day (BID) in the morning and in the evening with food followed by a 14 day wash out period without drug.
Dietary Supplement: ECGC
1 cycle will comprise 28 days of continuous daily treatment with EGCG given once/day(total 375 mg) /day in the morning with food followed by a 14 day wash out period without drug.
Tocotrienol: Active Comparator Dietary Supplement: Tocotrienol
One cycle will comprise 28 days of continuous daily treatment with Tocotrienol given 2 times/6 soft gel capsules (total 600 mg) /day (BID) in the morning and in the evening with food followed by a 14 day wash out period without drug.
EGCG + Tocotrienol
Combination of both arms
Dietary Supplement: EGCG + Tocotrienol
combination of both arms 375 mg EGCG + 600mg/day Tocotrienol

Detailed Description:

Background: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF trans-membrane conductance regulator protein. Despite substantial progress achieved in the understanding of the molecular basis and physiopathology of CF, a cure is not available. Mutation specific therapy is a novel approach to overcome the molecular defect in CF. We have previously shown that gentamicin and PTC 124 can induce read-through of nonsense CFTR mutations, and lead to functional CFTR. In addition we have shown that in vitro treatment with (-)epigallocatechin gallate (EGCG) and or Tocotrienol of cells harboring splicing mutations can augment production of full-length transcripts of affected proteins.

Working hypothesis and aims: EGCG and tocotrienol can act as genetic modifiers and increase the level of correctly spliced CFTR transcripts. Aim: To determine in CF patients if oral administration of EGCG and/or Tocotrienol, will modify CFTR splicing, as assessed by (1) Transepithelial Potential Difference (TEPD) as a measurement of ion channel activity, (2) levels of correctly spliced CFTR mRNA in nasal mucosa, (3) cytokine levels in sputum and (4) pulmonary function (FEV1). Methods: Patients with CF carrying splicing mutations will be treated with EGCG 200 mg/day, Tocotrienol 600mg/day or both for 28 day cycles. Clinical parameters (TEPD, FEV1 and cytokine levels in sputum) and molecular parameters (mRNA levels,) will be analyzed to determine the effectiveness of the treatment. Expected results: In vitro studies with cell cultures derived from CF patients have shown positive results; therefore an improvement in TEPD will be an indication for CFTR expression. An increase in mRNA levels and changes in FEV1, and cytokine levels will confirm the results.

Importance: Genetic therapy has encountered many technical difficulties. It is therefore of importance to develop alternative molecular strategies that will lead to an improvement or to a cure of genetic diseases. Probable implications to Medicine: Alternative splicing mechanisms are a common cause of genetic disease as ~15% of all known human mutations result in defective pre-mRNA splicing. Therapies based on augmenting the levels of full length or fully functioning proteins may have a substantial impact on the treatment of patients with genetic diseases.


Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Inclusion Criteria:

  1. Confirmed diagnosis of CF.
  2. Abnormal chloride secretion as measured by TEPD (a less than -5 mV TEPD assessment of chloride secretion with chloride-free amiloride and isoproterenol).
  3. Presence of a splicing mutation in at least one allele of the CFTR gene.
  4. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures (including TEPD measurements, clinical laboratory tests,), and study restrictions.
  5. Ability to provide written informed consent.
  6. Evidence of personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.

Exclusion Criteria:

  1. Prior or ongoing medical condition (e.g., concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
  2. Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
  3. History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
  4. Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF.
  5. Abnormal liver function (serum ALT, AST, GGT, alkaline phosphatase, LDH, or total bilirubin > 2 times upper limit of normal). Abnormal renal function (serum creatinine >1.5 times upper limit of normal).
  6. Pregnancy or breast-feeding.
  7. History of solid organ or hematological transplantation.
  8. Ongoing participation in any other therapeutic clinical trial or exposure to another investigational drug within 14 days prior to start of study treatment.
  9. Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
  10. Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00889434

Contact: Eitan Kerem, MD 972-2-5844430/1 kerem@hadassah.org.il
Contact: Hadas Lemberg,, PhD 972 2 6777572 lhadas@hadassah.org.il

Hadassah Medical Organization, Mount Scopus
Jerusalem, Israel, 91240
Sponsors and Collaborators
Hadassah Medical Organization
Principal Investigator: Eitan Kerem, MD Hadassah Medical Organization, Jerusalem, Israel
More Information
No publications provided

Responsible Party: Hadassah Medical Organization, Jerusalem, Israel ( Arik Tzukert, DMD )
Study First Received: April 20, 2009
Last Updated: April 27, 2009
ClinicalTrials.gov Identifier: NCT00889434 History of Changes
Health Authority: Israel: Israeli Health Ministry Pharmaceutical Administration

Keywords provided by Hadassah Medical Organization:
Cystic fibrosis
splicing mutations
molecular therapy
Splicing-mutation-mediated Cystic Fibrosis

Study placed in the following topic categories:
Tocopherol acetate
Trace Elements
Vitamin E
Digestive System Diseases
Cystic Fibrosis
Respiratory Tract Diseases
Genetic Diseases, Inborn
Lung Diseases
Pancreatic Diseases
Infant, Newborn, Diseases

Additional relevant MeSH terms:
Cystic Fibrosis
Molecular Mechanisms of Pharmacological Action
Growth Substances
Physiological Effects of Drugs
Protective Agents
Pharmacologic Actions
Vitamin E
Digestive System Diseases
Pathologic Processes
Respiratory Tract Diseases
Genetic Diseases, Inborn
Lung Diseases
Pancreatic Diseases
Infant, Newborn, Diseases

ClinicalTrials.gov processed this record on April 28, 2009


What CFer's need to know about swin flu

From the CFF:

Swine Flu and Cystic Fibrosis

What is influenza?

Influenza (the flu) is an illness caused by a virus. It usually happens in the fall and winter but people can get the flu at other times of the year. The flu is easily spread by direct contact, coughing, sneezing, and when an infected person touches a surface that others then use, like doorknobs and railings. Read this fact sheet to learn more about the flu and ways to avoid getting it.

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What is swine flu?

Swine Influenza (swine flu) is a respiratory disease of pigs caused by type A influenza viruses, which can cause regular outbreaks in pigs. People do not normally get swine flu, but human infections can and do happen. Like seasonal flu, swine flu may cause a worsening of chronic medical conditions, like CF.

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What are the signs and symptoms of swine flu in people?

The symptoms of swine flu in people are similar to the symptoms of regular human flu and include:

  • fever and chills,
  • cough,
  • sore throat,
  • body aches, headache and
  • fatigue.

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How does swine flu spread?

Spread of the swine influenza A (H1N1) virus is thought to be happening in the same way that seasonal flu spreads. Flu viruses are spread mainly from person to person when someone with influenza coughs or sneezes. Sometimes a person may become infected with the flu by touching something that has flu viruses on it and then touching their mouth or nose.

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How can I avoid swine flu and other germs?

There are everyday actions people can take to stay healthy.

  • Clean your hands with alcohol-based hand gel or soap and water.
  • Use a tissue when coughing or sneezing, throw it away, then clean your hands.
  • Keep at least three feet away from others who appear ill or are coughing.
  • Avoid touching your eyes, nose or mouth since germs spread that way.

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What should I do if I think I or my child has the flu?

If you or your child has CF and you think you or they may also have the flu, call your doctor. If you get sick, Centers for Disease Control and Prevention (CDC) recommends that you stay home from work or school and limit contact with others to keep from infecting them. If you have swine flu your doctor may prescribe an antiviral drug like Tamiflu® that can modify the severity of your illness.

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My doctor has prescribed Tamiflu®, but I can’t get it locally. What can I do?

CF Services Pharmacy, Inc. has Tamiflu® available for people with CF. You can contact CF Services at (800) 541-4959.

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Is the CF Foundation monitoring the swine flu outbreak?

The Foundation is closely monitoring the evolving swine flu outbreak and will update this site with more information and recommendations as needed.

You can learn more about the swine flu and how to avoid germs from:


Monday, April 27, 2009

Quest Diagnostics Discovers New Genetic Mutations Affecting Cystic Fibrosis Screening

MADISON, N.J., April 27 NJ-QuestDiagnostics

Company's Scientists also Enhance Industry Standards for Quality Screening in Three Articles Published in The Journal of Molecular Diagnostics

MADISON, N.J., April 27 /PRNewswire-FirstCall/ -- Quest Diagnostics scientists provide new insights into genetic factors affecting the accuracy and quality of Cystic Fibrosis (CF) carrier and newborn screening in three separate articles published in the May 2009 issue of The Journal of Molecular Diagnostics. Quest Diagnostics Incorporated (NYSE: DGX) is the world's leading provider of diagnostic testing, information and services.

The research may enhance the accuracy of carrier and newborn screening for CF, a genetically inherited disease that damages the respiratory and gastrointestinal systems. One in 29 Americans of Northern European Caucasian or Ashkenazi Jewish descent are symptomless carriers of the defective, or mutated, cystic fibrosis transmembrane regulator (CFTR) gene. A child whose parents are both carriers has a one in four chance of developing the disease.

"Taken together, these three papers demonstrate how the widespread and thoughtful experience with [cystic fibrosis] mutation testing and screening continues to reveal new insights about the mutational alleles of the CFTR gene and further refinements in how best to detect them and assure appropriate quality control while doing so," said Wayne W. Grody, M.D., Ph.D., professor in the Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics at the UCLA School of Medicine. Dr. Grody, who wrote the commentary "Cystic Fibrosis Testing Comes of Age(1)" in the journal's May issue, is not affiliated with the studies.

"Since the CFTR gene was discovered two decades ago this year, scientists have acquired significant insights into the genetics of CF, one of the most common autosomal recessive genetic disorders," said Charles (Buck) Strom, M.D., Ph.D., medical director of the genetic testing center of Quest Diagnostics Nichols Institute, the esoteric research, development and testing services operation of Quest Diagnostics. "As the world's leading provider of genetic testing for cystic fibrosis, Quest Diagnostics has been at the forefront of efforts to advance scientific understanding of the disease and promote testing quality across the laboratory industry. These efforts are noteworthy because insights into the more than 1,500 mutations affecting the CFTR gene are enhancing the medical understanding of cystic fibrosis as well as the mechanisms of other genetic diseases."

In "Apparent homozygosity of a novel frame shift mutation in the CFTR gene because of a large deletion,(2)" Strom and his colleagues at Quest Diagnostics present a patient with classic cystic fibrosis who exhibits previously undescribed (novel) mutations that include deletions, or the absence, of large parts of the CFTR gene. The investigators demonstrate that conventional screening techniques may not accurately identify both defective CFTR genes in patients who have inherited CFTR genes with large deletions. "The failure to identify these CFTR mutations in carriers could increase the potential that their family members are falsely identified as non-carriers," said Dr. Strom, lead investigator of the study. "Comprehensive mutation analysis using DNA sequencing and exon deletions/duplications is therefore important to resolve apparent homozygosity (the false appearance that the patient inherited the same mutations from each parent) for novel and rare mutations, some of which are currently found in recommended testing panels."

In "Identification of cystic fibrosis (CF) variants by PCR/oligonucleotide ligation (OLA) assay,(3)" Quest Diagnostics' scientists analyzed one million specimens in the Quest Diagnostics database in order to identify rare genetic variants that are potential sources of testing error. The investigators, led by Victoria Pratt, Ph.D., FACMG, chief director, Molecular Genetics, Quest Diagnostics Nichols Institute, identified eleven instances of "allele drop-out," or failure to detect a targeted mutation, for an aberrancy rate of less than 0.01%. "We concluded that the recognition and enumeration of such variants along with clinical information in CF testing is valuable in avoiding false-positive and false-negative results," Dr. Pratt said.

In addition, Quest Diagnostics, participated in a study coordinated by the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination (GeT-RM) to develop a set of genomic DNA reference materials for CF mutations not currently included in a 23-mutation test panel recommended for carrier screening by the American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG). These additional mutations are currently offered in half of the nearly dozen commercially available test panels on the CF testing market, which has grown significantly since ACMG/ACOG made their first CFTR mutation screening recommendation in 2001.

"Accurate characterization of CF mutations is essential to promoting uniform standards and quality screening. Yet, the surge in CF testing demand caused by ACMG/ACOG's promotion of broader population screening has outpaced scientific efforts to characterize several mutations commonly found on test panels used in clinical practice and research," said Dr. Pratt, investigator of "Development of genomic reference materials for cystic fibrosis testing.(4)" "The establishment of genomic DNA reference materials will promote CF testing accuracy across the U.S. lab industry and may be expected to advance CF research and development."

Quest Diagnostics and Genetic Screening

Quest Diagnostics is one of the leading providers of pre- and post-natal and carrier genetic screening. In March 2009, the company announced that it operates one of only three laboratories approved by the state of New York to perform microarray-based comparative genomic hybridization (aCGH) postnatal testing, using its ClariSure aCGH postnatal test, for copy-number chromosomal abnormalities implicated in mental retardation, birth defects, and autism spectrum and developmental disorders. The company also provides a broad-based population screening technology designed to help determine whether parents are carriers of the genetic mutation that causes Fragile X syndrome, the most common form of inherited mental retardation. In 2002, the company launched its CF Complete test, which enables physicians to identify rare mutations that cause CF by sequencing the complete coding sequence of the cystic fibrosis gene.

About Quest Diagnostics

Quest Diagnostics is the world's leading provider of diagnostic testing, information and services that patients and doctors need to make better healthcare decisions. The company offers the broadest access to diagnostic testing services through its network of laboratories and patient service centers, and provides interpretive consultation through its extensive medical and scientific staff. Quest Diagnostics is a pioneer in developing innovative diagnostic tests and advanced healthcare information technology solutions that help improve patient care. Additional company information is available at www.questdiagnostics.com.

(1) Grody W: Cystic fibrosis testing comes of age. J Mol Diagn 2009, 173-175

(2) Hanta FM, Reburying A, Pang M, Redman JOB, Sun W, Strom CM: Apparent homozygosity of a novel frame shift mutation in the CFTR gene because of a large deletion. J Mol Diagn 2009, 253-256

(3) Schwartz KM, Pike-Buchanan LL, Muralidharan K, Redman JB, Wilson JA, Jarvis M, Cura MG, Pratt VM: Identification of cystic fibrosis (CF) variants by PCR/oligonucleotide ligation (OLA) assay. J Mol Diagn 2009, 211-215

(4) Pratt VM, Caggana M, Bridges C, Buller AM, DiAntonio L, Highsmith WE, Holtegaard LM, Muralidharan K, Rohlfs EM, Tarleton J, Toji L, Barker SD, Kalman LV: Development of genomic reference materials for cystic fibrosis testing. J Mol Diagn 2009, 186-193

SOURCE Quest Diagnostics


New Yorker Vertex Article

There is no text version of the entire article, but you can register for the New Yorker (free) to see the full text of the article.

Here is a summary of what the article talks about:

ABSTRACT: ANNALS OF MEDICINE about the development of new treatments for cystic fibrosis and how those treatments might be applied to other diseases. Cystic fibrosis is the most common fatal genetic disorder in North America among Caucasians; some thirty thousand Americans have the disease, and about ten million Americans are silent carriers. Describes the symptoms of those who suffer from cystic fibrosis, including the blockage of the gastrointestinal tract and reduction of lung function.

Tells about Chrissy Falletti, who has cystic fibrosis and participated in a trial of an experimental oral drug produced by Vertex Pharmaceuticals. After twenty-eight days on the medication, her lung function had increased by eighteen per cent over all. Her lung function began to decline within a week of the trial's end.

Vertex is launching a long-term, placebo-controlled trial that could lead to F.D.A. approval this year. And while the drug targets a form of cystic fibrosis that occurs only in four per cent of patients, the fact that similar drugs are being developed by Vertex and other companies seems to signal a new treatment paradigm.

Briefly gives the history of cystic-fibrosis treatment from its identification by Dr. Dorothy Hansine Andersen in 1935, to the discovery in 1985 that the cystic-fibrosis gene was situated on the seventh chromosome. In 1989, researchers identified the gene and determined its function. The discovery set off a wave of euphoria, with many people convinced that cystic fibrosis would soon be cured.

Yet, despite successes in the laboratory, patients had an immune reaction to the procedure, rejecting the delivery system that held the normal gene. Discusses the work of the Cystic Fibrosis Foundation, which is headed by Dr. Robert Beall, and its funding of research for the disease, including the use of automated systems to help produce a drug that could be taken orally and would work throughout the body to restore the functioning of diseased organs.

Discusses the different categories of mutations in the cystic-fibrosis gene and the "molecular origami" undertaken by scientists in their attempt to address these categories. Tells about the development of other cystic fibrosis drugs, including one by PTC Therapeutics, which reduced the rate of coughing in patients in a study in Israel. These drugs may have ramifications beyond cystic fibrosis. The drug produced by PTC Therapeutics could be applied to a wide number of genetic diseases.

Although the treatment of genetic disorders has long been considered too small a market for most pharmaceutical companies, an increasing number of biotech firms have found that genetic research can be used in broader ways than anticipated. All of the physicians and scientists the writer spoke with emphasized the many unknown variables, but for the first time, there is convincing evidence that the underlying defect in cystic fibrosis can be corrected.


Saturday, April 25, 2009

Lung Transplant in Children With Cystic Fibrosis

Lung Transplant in Children With Cystic Fibrosis

Lung transplant is the standard treatment for children with end-stage lung disease as a result of CF. But do the benefits of transplant outweigh the risks of early rejection-related mortality in these children?

Ingrid M. Pitts, PA-C

Vol. 16 • Issue 12 • Page 41
Cystic fibrosis (CF) is an autosomal recessive monogenic disorder that affects multiple organ systems.1 The gene responsible for CF is located on chromosome 7, and in 1989 it was discovered that it encodes the molecular mutations in the CF transmembrane conductance regulator (CFTR) protein.1,2 CFTR regulates epithelial cell transport of sodium ions and chloride ions in the respiratory tract, the gastrointestinal tract, the sweat glands and the genitourinary system.1

Upper respiratory tract disease is common in most CF patients. Chronic cough and repeated infections lead to bronchiectasis, bronchiolectasis and, ultimately, respiratory failure.1 Most patients with CF die prematurely because of repeated lung infections with Gram-negative bacteria, which leads to respiratory insufficiency.3


About 30,000 people in the United States have CF.4 About 1,000 new cases are diagnosed each year in the United States, and more than 70% of CF patients are diagnosed by age 2.5 CF can affect people of any race but is most common in Caucasians.4

CF once was considered exclusively a pediatric disease; however, it can be diagnosed in adults.4 Until the mid-20th century, patients diagnosed with CF had short survival expectancies; however, as the disease has become better understood and as treatment has improved, survival expectancies have increased.1 Now, more than 40% of the CF patient population is 18 or older.5 The Cystic Fibrosis Foundation reports the predicted median age of survival of a person with CF to be now more than 37 years.5

Lung Transplant and CF

The focus of this article is limited to CF characteristics pertaining to the lungs, and treatment with lung transplantation. Treatments for pulmonary manifestations are aimed at clearing mucus secretions and controlling infections. Lung transplant is an option for patients with CF that results in end-stage disease.6 The first lung transplant was performed in 1963 at the University of Mississippi,7 and the first lung transplant in a CF patient was performed in 1983 at the University of Pittsburgh.2

Posttransplantation complications include infections; the side effects of immunosuppressants; other underlying diseases, such as sarcoidosis and cancer; and acute and chronic rejection, which ultimately lead to bronchiolitis obliterans (BO). Rejection occurs because the body recognizes the donor lung as foreign, and the immune system fights to rid the body of it. Alloreactive cytotoxic T-lymphocyte-mediated endothelial damage or bronchiolar epithelial damage results in rejection.8

Half or more of patients experience at least one episode of acute rejection in the first year after transplantation.6,9 As many as 54% of lung transplant recipients eventually develop progressive chronic rejection-continuous breakdown of the graft lung and associated scarring-leading to BO.10

Scarring develops when airway submucosal mononuclear cells infiltrate the basement membrane and enter the epithelium. The epithelial cells then break down and cause fibroblasts and myofibroblasts to migrate to the submucosa of the bronchioles. Granulation develops and ultimately renders the donor lung nonfunctional.

Immunosuppressants, in conjunction with antibiotics, are used for induction and as a maintenance regimen for the rest of the recipient's life. Most transplant recipients are managed with a three-drug regimen of a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a purine antagonist (i.e., azathioprine or mycophenolate mofetil) and prednisone.6

In a child with CF, the decision about lung transplantation for end-stage disease can be daunting. Rejection and other transplantation complications can increase the already higher risk of early mortality in CF patients. The benefits of lung transplant in children with CF and the increased risk of early mortality must be carefully assessed.

Survival Rates and Transplant

In one study, Geertsma and colleagues assessed the effects of lung transplantation on survival of patients with end-stage lung disease.11 From November 1990 to January 1996, the lung transplant program at a hospital in the Netherlands prospectively analyzed 157 patients on the transplantation waiting list, 76 of whom underwent transplantation. All of the subjects had a predicted life expectancy of less than 12 to 18 months without transplantation.

By Jan. 31, 1996, 17 patients had died posttransplantation, most of whom died as a result of BO. The 47 patients still on the waiting list at that time served as control subjects. Ultimately, 33 of these patients died. The mean age of all 157 patients was 41 years.

The authors note that the study's limitations include conservative estimates resulting from differences in the two groups. Additionally, the sample size of 157 patients is small. Nevertheless, the authors found that the one-, three- and five-year survival rates were 85%, 73% and 70%, respectively, for patients who received a lung transplant. The one- and two-year survival rates for subjects on the waiting list who died or who waited until a lung was available were 78% and 58%, respectively. They also noted that transplantation reduced the risk of death by 55%.

The results suggest that the predicted life expectancy would have been less than 12 to 18 months without transplantation. In comparison, 73% of patients undergoing transplantation were still alive at three years, suggesting that transplantation extends life expectancy.

In another study, Huddleston and colleagues evaluated the practicality of lung transplantation in children.12 They analyzed 207 lung transplants in 190 children younger than 18 from 1990 to 2002 at the St. Louis Children's Hospital transplant program in Missouri. The patients were followed on average for 3.5 years posttransplantation and had a life expectancy of less than two years prior to transplantation. Eighty-nine of the patients had CF.

The 166 recipients who were followed for more than six months experienced an average of 1.95 rejections. Of these 166 subjects, 84 had BO, which was the leading cause of death in the long term. A smaller percentage of recipients of lungs with ischemic times of less than two hours went on to BO than did recipients of lungs with ischemic times of more than two hours. Posttransplantation survival rates at one, three and five years were 77%, 63% and 54%, respectively.

The results suggest that the predicted life expectancy of these patients would have been two years hadthey not received a transplant. In comparison, 63% of the posttransplantation patients were still alive at three years, implying an increased life expectancy with transplantation.

The sample size of 190 patients is small and creates limitations of the study; nevertheless, at that time, this was the largest series of pediatric lung transplants in the world.

Transplant Extends Life

Aurora and colleagues evaluated the effects of lung or lung-heart transplantation on the survival of children from ages 4 to 19 years with CF and other severe lung diseases.13 Between May 1988 and May 1998, 124 children, all with a life expectancy less than two years, were accepted for lung transplant at the Great Ormond Street Hospital transplant program for children in London. Of the 124 children, 47 received transplants, 68 died waiting and nine remained on the list after the study period ended.

Of the 47 recipients, 28 died. While the reasons for death-whether infection, rejection or BO-were not provided, the survival rates at one, two and five years were 74%, 66% and 33%, respectively. The authors also noted a 69% reduction in overall risk of death. Predicted life expectancy of two years without transplantation compared with a two-year posttransplantation survival rate of 66% suggests that transplantation extends life.

Among the authors' identified study limitations are the incomparable groups (because random selection was not possible) and prioritization (the sickest patients received transplants first). Furthermore, the sample size of 124 is small.

Egan and colleagues tried to identify factors influencing long-term survival of 123 patients with CF in the lung transplantation program at the University of North Carolina at Chapel Hill.14 All 123 patients received transplantation during the 10 years between 1990 and 2001. Nine recipients had living donors, while the rest had double lung transplant from cadavers.

The authors evaluated the impact of age on survival and found no difference in survival estimates between patients younger than 20 years old and patients older than 20. BO caused 50% of deaths after the first year of transplant. By the end of the follow-up period, 53 posttransplantation CF patients had died as a result of multiple complications, including BO.

Bacterial infection was the most dominant cause of death within the first posttransplantation year. Recipients who were not colonized with Burkholderia cepacia prior to transplant were found to have an 86% survival rate. Although BO-related deaths were significant, the authors reported one-, five- and 10-year survival rates of 81%, 58% and 36%, respectively. They also noted that more patients died on the waiting list than who received transplants.

Further Studies Concur

To examine the long-term outcome of lung transplantation, de Perrot and colleagues reviewed 521 lung transplants in 501 patients between the ages of 8 and 71 with end-stage lung disease.7 Patients had estimated life expectancies before transplant of less than 2 years and received transplants at Toronto General Hospital between 1983 and 2003. Children younger than 18 comprised 22% of the total cohort. Of the 501 patients, 124 had CF and received bilateral lung transplantation.

The five-, 10- and 15-year survival rates were 55.1%, 35.3% and 26.5%, respectively, with better survival outcomes for CF patients without B. cepacia infection than CF patients with it. Negative B. cepacia CF patients' five- and 10-year survival was 76% and 52%, respectively. BO was the third cause of mortality, with sepsis and graft failure predominantly responsible for most deaths (36% and 29%, respectively).

The results imply that BO was not as significant mortality concern as were other complications, implying that lung transplantation increases life expectancy.

Bech and colleagues id a retrospective study of 47 patients with CF accepted for transplant at a hospital in Copenhagen, Denmark, from 1992 to 2003.3 The patients' ages ranged from 11 to 50, and all had an estimated life expectancy of less than two years. Twenty-nine received transplantation, and 18 died while awaiting organs.

The authors found that the survival of transplant at one, three, five and eight years was 89%, 80%, 80% and 70%, respectively. Only two patients died of BO. Posttransplantation survival rates for patients without BO at one, three and five years were 90%, 77% and 60%, respectively. Those still awaiting lung transplants survived an average of 189 days, and the one- and two-year survival rates were 28% and 11%, respectively.

The 47-patient sample size cannot provide a strong representation of the population; nevertheless, a three-year survival rate of 77% is quite significant.

A team led by Venuta reviewed 102 patients who received lung transplants at a transplant program in Rome, Italy.15 They evaluated the effects of bilateral sequential lung transplant for patients with CF from 1996 to 2002. Patients' ages ranged from 7 to 51 years. Fifty-six patients received transplants, and 34 died while on the waiting list. By the end of the reviewed period, 12 were still on the waiting list.

In the first year posttransplantation, acute rejection occurred an average of 1.6 times per patient, and BO occurred in only 15 patients. The overall two-year survival rate was 79%. This relatively high percentage likely relates to a very small sample size; regardless of this limitation, the authors concluded that lung transplant does improve survival.

A team led by Quattrucci evaluated 114 patients with CF who had been referred to their lung transplant program in Rome, Italy.16 Between October 1996 and October 2002, they evaluated posttransplantation survival and incidence of rejection and BO. Of the 114 referrals, 99 were placed on the waiting list. Thirty-five died while waiting for an organ, and 55 (six of whom were children) received bilateral sequential transplants.

Survival rates at one month, three years and six years were 80%, 70% and 58%, respectively. All told, 95% of patients stayed free of BO at one year, 82.5% at two years, 70% at three years and 65% at four, five and six years posttransplantation.

Not All Research Agrees

Liou and colleagues used a retrospective observational cohort study of 11,630 CF patients whose information was gathered from the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 1992 to 1998.17 They sought to identify the impact of bilateral lung transplant on survival of patients with CF. These patients did not receive transplants but were used as a control group against 468 transplanted patients from centers across the United States.

Based on a five-year survivorship predictor model that the authors developed and described elsewhere,18 patients in the transplantation and control groups were placed into one of five subgroups: subjects with survival predicted at less than 30% were placed in group 1; 30% to 49% in group 2; 50% to 69% in group 3; 70% to 89% in group 4; and 90% to 100% in group 5.

In contrast to other studies described here, the Liou and colleagues study indicates that only a minority of CF patients benefit from lung transplantation. Patients with a predicted five-year survival less than 30% were the only group to demonstrate improved outcomes. In fact, the remaining groups had equivocal or reduced five-year survival rates.

Limiting the study is that most of the survival estimates were based on data from the CFFPR. Patients on the registry were used as the control group, but those who died while waiting for transplant were not included in the data. This approach could have skewed the data to the disadvantage of positive survival effects.

Analysis of the Literature

Some of the most significant studies of lung transplantation and rejection have been performed in the United States and Europe. All the studies reviewed here are a compilation of retrospective or prospective observational cohorts reviewing patient progress to evaluate the benefits of lung transplant in adults and children with CF. After 1970, the trend in the literature has been to use patients on waiting lists as control groups.11

Similar statistical measures are used in all the cited studies. While relatively few studies offer 10- and 20-year outcomes for transplanted patients, most studies reveal a decreased percentage of survival as the years progressed; nevertheless, these percentages were better than those of the estimated survival before transplantation.

One of the most significant observations reported in a number of studies is that if CF were better understood, outcome results could be influenced positively. If CF were categorized in progressive stages, patients in need of transplantation would be more easily identified. Another observation was that lung donation is limited, negatively impacting life expectancy data. If more donors were available, high-risk patients would have more opportunities to receive transplants.

A number of vital considerations were lacking in the literature reviewed. First, although the literature did not provide documentation of any direct harm resulting from lung transplantation, there was a lack of analysis of the potential risk of lung transplantation. Second, there was a lack of analysis of potential untoward effects of the donor organ itself. A few studies considered the influence on survival from using single, double or lobar transplants. Some reported the influence of the donor lung size, but few evaluated the effects of the mode of organ transportation. Only one mentioned the concern for preservation or ischemic time between donor and recipient. Third, there is much room for more analysis of quality of life posttransplantation.

Furthermore, one population has been unexplored throughout the literature: End-stage lung disease patients who do not want transplantation are not on waiting lists and therefore are not included in the data. The literature does not explain the impact of this unaccounted for population on outcomes.

Other limitations of the cited studies include small sample size, conservative estimates, prioritizing patient selections for transplantation and the inability to quantify quality of life after transplantation. Despite these limitations, the articles conclude that lung transplantation does extend life expectancy. Rejection resulting in BO is most concerning after lung transplantation; however, the literature implies that infections are far more responsible for mortality. With the exception of one report from Liou and colleagues,17 of which data for the conclusion were not provided, all studies reported a benefit of lung transplant in CF patients.


The Registry of the International Society for Heart and Lung Transplantation includes data from more than two dozen pediatric lung transplant centers.19 These data reveal that more than 60% of pediatric lung transplants are performed in teenagers, with most recipients ranging in age from 12 to 17 years. CF is most diagnosed during childhood and adolescence and is the underlying diagnosis of 56% of all pediatric lung transplants.19

The data further show that survival in the pediatric population is the same as that of the adult population, and that pediatric survival was better from 2000 to 2004 compared with 1988 to 1994. Infants have a better survival rate than recipients aged 12 to 17, and concern is increasing about the complication of BO. Rejection was not the leading cause of mortality within the first year posttransplantation; however, BO was the leading cause of death after one year (40%) and after seven years (32%).

According to the United Network for Organ Sharing, more than 100,000 patients are on U.S. waiting lists for organ transplantation.20 More than 2,000 patients await lungs, of whom more than 300 are waiting as a result of CF.21 More than 17,000 lung transplants have been performed in the United States since 1988.20 More than 800 of these transplants have been in patients 17 and younger.21

Transplant Eligibility

Prior criteria for referral timing and lung allocation have influenced the outcome of transplanted and nontransplanted CF patients. It is difficult for primary care providers to know when to refer patients for transplantation, because CF is a multisystem disease without a categorized staging system to identify progression.

Historically, patients' eligibility to undergo lung transplantation was determined solely by the forced expiratory volume in one second (FEV1.17 If FEV1 as 30% or less for a CF patient, then the two-year mortality rate was considered 50% or greater.17 The patient then would be considered for lung transplantation. However, this method may not identify the sickest patients in order to facilitate referral and transplantation.

The same problem existed when allocation was predicted by length of time spent on a waiting list. Retrospective observational cohort studies that assessed survivorship and effectiveness of lung transplantation used data collected from the Cystic Fibrosis Foundation Patient Registry to determine that more clinical features are necessary to identify gravely ill patients.17,18

The following clinical features of CF wereanalyzed and determined to aid in the process of gravely ill patient identification: age, FEV1 sex, weight-for-age Z score, pancreatic sufficiency, diabetes, Staphylococcus aureus infection, B. cepacia infection and the annual number of acute pulmonary exacerbations.18 The Organ Procurement Network and the United Network for Organ Sharing observed these considerations, and the method for referral and allocation has been modified since 2005.

Aside from FEV1 other variables are included in the equation on determining who is more acutely eligible for transplantation. An allocation score is now given to all lung transplant candidate aged 12 and older, grading them from sick to deathly ill using multiple clinical symptoms. Pediatric and adolescent candidates are prioritized when the donor is the same age.

Referral timing also is important and affects the survival outcome data. A 2006 updated census report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation suggests that guidelines for referral include FEV1below 30% of predicted or a rapid decline in FEV1(particularly in young women), exacerbations of pulmonary disease requiring ICU stay, increasing frequency of exacerbations requiring antibiotic therapy, refractory and/or recurrent pneumothorax and recurrent hemoptysis not controlled by embolization22. They suggest that transplantation in CF patients should occur when the patient has oxygen-dependent respiratory failure, hypercapnia or pulmonary hypertension.22 If the sickest patients are identified, referred and receive lung transplants, the number of deaths of patients on waiting lists would be reduced. This reduction would influence survival outcome data in the comparison between transplanted and nontransplanted patients.

Potential New Therapies

A number of potential treatments to improve CF outcomes are under investigation.23 The discovery of the CFTR protein responsible for CF has propelled multiple scientific investigations in gene therapy. Using gene therapy, the abnormal gene might be replaceable with normal ones, thereby eradicated the disease. The function of the defective CFTR protein could be corrected, which would facilitate proper chloride and sodium ion transport within cells, creating better linings for the lungs and other involved organs.

Other investigations have targeted mucus secretion. Trials evaluating the use of dornase alfa and hypotonic solution are ongoing to evaluate the efficacy of mucus clearing, while others are investigating the use of pharmaceuticals to restore salt transportation-by correcting the amount of salt within the cell surface, the mucus thickness can be hydrated.

Trials of agents that target the body's immune system and inflammation are being conducted, including ones on oral N-acetylcysteine; docosahexaenoic acid; low-dose methotrexate; pioglitazone and hydroxychloroquine; simvastatin, inhaled glutathione; and HE 2000 (16 alpha-bromoepiandrosterone). Inhaled cyclosporine is being evaluated for its efficacy in CF patients.

Other area of potential future improvement for CF patient outcome lies in reducing infections. Studies are ongoing on drugs such as tobramycin inhalation solution and inhaled powder, azithromycin, aztreonam, inhaled ciprofloxacin, sustained-release lipid inhaled targeting (SLIT) amikacin, MP-610.205, KaloBios KB001 and pseudomonas vaccinations.

Nutritional supplements also are being investigated as future treatment. Trials for CF patients are currently under way to test pancreatic enzyme replacements and a specially formulated antioxidant vitamin for CF patients.

Surgical techniques and photopheresis also are being explored. Procedures such as split-lung and reduced-lung techniques now are being implemented.15 ise and colleagues report that extracorporeal photopheresis could be an option for the treatment of rejection in lung transplant patients.24 It has been used with positive effects in 150 transplant centers worldwide for the treatment of rejection in heart and kidney transplant. he therapeutic concept is removing the leukocyte fraction from whole blood and treating it with ultraviolet A light. This treated blood is then reintroduced into the patient. The mechanism of action is unknown, but clinical studies have reported a reduction of lymphocytes active in rejection, suggesting that the procedure may be a new antirejection therapy for CF patients who have undergone lung transplantation.

Transplant Risks and Benefits

The survival outcome of lung transplantation depends on many factors. Age, patient size, transplant waiting list timing, cadaver or living donor, bacterial culture before transplant, immunosuppressant regimen before and after transplant, referral, lung allocation and rejection all play a role in survival. Although chronic rejection can lead to BO, it is responsible for only about one-third of worldwide pediatric deaths after seven years posttransplantation.

The literature implies that lung transplantation remains an acceptable option for the treatment of end-stage lung disease caused by CF in children. Overall, it appears that the benefits of lung transplant for children with CF-related end-stage lung disease outweighs the risk of early mortality related to rejection. Although the risk of rejection and BO are significant, it does not seem to be an overwhelming hindrance to having lung transplantation.

As the disease is better understood, as donors increase and as allocation, treatment and patient identification improve, life expectancy for these patients also will improve. Patients and their families should feel confident using the current data to help in the decision-making process to determine if lung transplantation is suitable for them.


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Ingrid M. Pitts is physician assistant in internal medicine and lung transplantation at the University of Florida Hospital in Gainesville, Fla. She indicates no relationships to disclose related to the contents of this article.