The International Association of Cystic Fibrosis Adults (IACFA) held its Seventh Annual Conference in Paris, France from May 29 to June 3, 1994 in conjunction with the Nineteenth Annual Conference of the European Working Group for CF (EWGCF). Almost 1300 physicians, researchers and laypersons from many countries attended the meetings and medical sessions. Here are some highlights:
The use of liposomes in CF gene therapy was presented by Dr. Chris Higgins from the University of Oxford. Evidence was shown that liposome DNA complexes can deliver CFTR DNA to the airways of CF transgenic mice and that this procedure corrected the ion transport defects of the airway epithelia. A Phase I clinical trial is underway. The study is open to male and females over age 16, having at least one delta F508 allele and no severe lung disease. Researchers also reported that a 10% transfer rate is all that would be required to correct the defect.
Progress towards gene therapy for cystic fibrosis using adenovirus-mediated CFTR transfer was presented by Dr. Ron Crystal, CEO of Genvec, Inc. (USA). He dosed the noses of six people. Then he dosed the same six patients through a bronchoscope. There was no toxicity in five of the patients. He noted that the bronchoscope itself can cause a mild fever whether or not it is used in gene therapy. All patients remained in pretest lung function state. He reported evidence that gene transfer occurred and is feasible in humans. Continued treatment and immune response to the virus may be potential problems.
The United States is the only country in the world that uses postural drainage as the primary means of chest physiotherapy. Europeans, Canadians and Australians use Autogenic Drainage (AD), Positive Expiration by Pressure Mask (PEP), the Flutter, and exercise in different combinations, and their CF populations do quite well. The three techniques are taught to patients to allow choices of the most effective therapy in accordance with their lung conditions.
The Flutter, recently approved by the FDA, was proven to be more than three times as effective as postural drainage as indicated in a study completed at Rainbow Babies and Children's Hospital at Cleveland, Ohio and published in the May 1994 Journal of Pediatrics. In France the Flutter cost 400 Francs or about $80 US dollars. Additional information on the Flutter study appears in this newsletter.
Nebulizer performance was surveyed by the AFLM, the French Cystic Fibrosis Association. Aerosol therapy is effective and is the best route of administration for new treatments such as amiloride, Pulmozyme and gene therapy. Unfortunately, determination of aerosol dosages is difficult. The amount of drug deposited in the lungs is only a fraction of the prescribed drug, and that fluctuation depends on drug solution, device, and breathing pattern. In this study, the performances of nebulizers, five jet and six ultrasonic, were tested with tobramycin, colistin, and amiloride. Results show a great variability among nebulizers, with efficient output ranging from 35% to less than 2% of the prescribed dosage. Ultrasonic nebulizers were better than jet nebulizers for tobramycin and amiloride. Thus, the choice of nebulizer is an important part of aerosol therapy.
Liver involvement in CF patients was presented by Dr. C. Colombo of Italy.
Liver dysfunction varies greatly among CF patients:
The onset of liver disease most often occurs in CF patients at age eight or nine years of age, peaks at adolescence and slows at age 20. It is usually diagnosed by clinical examination. Liver biochemistry is tested with liver function tests (blood tests) and imaging (ultrasound evaluation). It was reported that patients with the delta F508 allele are at the highest risk for liver disease. At least risk are patients with the G542X allele. Thirty-five percent of meconium ileus patients are likely to develop liver disease, and pancreatic- insufficient patients who have mild lung disease are also at risk.
Treatment includes the use of ursodeoxycholic acid and transplantation. Gene therapy treatment for liver disease is under study and showing great promise. Since CF patients are at risk for liver damage and organ failure, consumption of alcohol is not advised. If CF patients must drink, they should drink only small amounts of wine or beer with food.
Gastrointestinal and pancreatic problems were discussed by Dr. J. Navarro of France, who stated that 80-90% of all CF patients have exocrine pancreatic dysfunction.
The most severe alleles at risk for this problem are:
Progress in the quality of enzymes was noted. The percentage of fecal fat excretion in CF patients who are:
During 1993 five CF patients in Liverpool developed colonic strictures after taking high doses of lipase. Since then, about 30 cases have been reported from other countries including the USA. Scientists question whether the strictures were actually related to lipase or trypsin. Other environmental factors, such as viruses, bacteria, dehydration and other drugs must be considered and studied.
Up to 70% of all CF patients have gastro/esophageal reflux and excessive acid stomach problems during their lifetimes. Primary therapy is Propulsid (cisapride), an oral medication that is now available in the USA. Prilosec and Pepcid are also prescribed for this condition. It is important to treat excessive acid conditions in the stomach that can interfere with digestion, cause vomiting, weight loss, and scarring, and can lead to esophagitis, general deterioration, and precancerous conditions.
Nutritional aspects of cystic fibrosis were presented by Dr. Brigitta Strandvik of Sweden. Good nutrition is most important because it increases survival and gives CF patients a boost in fighting bacterial infections. Patients having at least one delta F508 allele usually have more severe nutrition problems. Also, these patients often have lower linoleic acid levels and essential fatty acids present in their bodies. It has been proven that poor weight gain and low body weight is caused by malabsorption and chronic infection. It was shown that CF patients can increase their essential fatty acids by eating protein, a diet of 40-50% fat and supplementary foods containing corn oil and saffola oil. Essential fatty acids may also be given in I.V. form.
During the past few years, physicians have become aware of the problems involving cross-infection with Pseudomonas aeruginosa (P. aeruginosa) and Pseudomonas cepacia (P. cepacia). These problems continue to be controversial and the subject of much discussion. Those people having P. cepacia and MRSA (Methicillin resistant staph aureus) were asked not to attend the conference. Participants having cystic fibrosis were asked to follow an hygienic protocol that is detailed in this newsletter [see box].
As a result of clinical experiences involving the spread of P. cepacia, many clinics are segregating patients into four groups - non P. aeruginosa, P. aeruginosa, "classic" P. cepacia and P. cepacia RIV. Vigorous hygiene measures have been adopted. This includes: seeing the non P. aeruginosa patients first in the morning, then each group in the above order with seeing P. cepacia RVI last in the afternoon. Between patients everything is scrubbed down with alcohol, and vigorous handwashing is required. In one case, P. cepacia patients stay on a different floor of the hospital than non P. cepacia patients. Until mechanisms of P. cepacia survival are understood, it is necessary to be most prudent.
Every industrialized country except the USA provides government health care for all their citizens who have cystic fibrosis. France even provides heart-lung transplants for its CF patients; two conference participants from France demonstrated their new heart-lung lung endurance by dancing for four continuous hours during the farewell party. Even though it is an exciting time in the history of CF research, there remains a great deal more research to be done. The IACFA/EWGCF Conference offered a unique opportunity to experience CF research presentations by outstanding scientists from throughout the world who are hopeful about controlling this disease.
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