Pulmonary
- Critical Care Associates
of East Texas
Jeffrey M.
Shea, M.D., F.C.C.P.
Catherine M. Martinez, M.D.
|
Jeffrey M.
Shea, M.D., F.C.C.P. |
|
About
Our Practice
Patient
Information
Critical Care
Procedure Photos
Advanced Directives
BET
Program
What's New
|
Introduction Every year, 1,000 children with cystic fibrosis (CF) are born in the United States. One in 3,000 Caucasian babies have the disorder, making CF one of the most common lethal genetic diseases in Caucasians. Overall, there are 30,000 Americans with CF, and an estimated 8 million people carry one copy of the defective gene that causes the disease. These carriers do not have symptoms of CF, because a person must inherit two defective gene copies, one from each parent, to develop the disease. However, each child of two CF carriers has a one in four chance of being born with CF. Genetic testing is now available to identify couples at risk for having children with CF. Improved therapy has transformed CF from a disease characterized by death in early childhood to a chronic illness, with most patients living to adulthood. But despite this progress, there still is no cure for the disease and most patients eventually succumb to infections of the airways and lung failure. Since the 1989 identification of the gene, which is altered in CF, the pace of basic research has increased rapidly, and scientists hope to translate new knowledge about the molecular basis of the disease to new therapies to improve the lives of patients with this genetic disease. Symptoms of Cystic Fibrosis CF affects tissues that produce mucus secretions, such as the airway, the gastrointestinal tract, and the ducts of the pancreas, the bile ducts of the liver and the male urogenital tract. Normal mucus forms a gel-like barrier that plays an important role in protecting the cells lining the inside surfaces of these tissues. In the lung, mucus also transports dust and other particles out of the airway and helps to prevent infection. CF alters the chemical properties of mucus; instead of protecting tissues from harm, the abnormal mucus obstructs the ducts and airways, causing tissue damage. The most characteristic symptom of CF is the excessive production of thick, sticky mucus in the airways. Several factors may contribute to this mucus abnormality. In CF, the cells lining the airway do not transport salt and water normally, so mucus and other airway secretions may be depleted of water. There are also chemical changes in the mucus proteins. The mucus becomes so thick that it clogs the airways and provides an environment in which bacteria thrive. In response, white blood cells are recruited into the lung to fight the infection. These white blood cells die and release their genetic material, sticky DNA, into the mucus. This DNA aggravates the already excessive stickiness of the mucus, setting up a vicious cycle of further airway obstruction, inflammation and infection. To dislodge the mucus, CF patients cough frequently and require time-consuming daily chest and back clapping and body positioning to drain lung secretions. Because the mucus provides an ideal breeding ground for many microorganisms, CF patients have frequent airway infections. Among the most common germs causing infections in CF patients are Staphalococcus and Pseudomonas bacteria. The Pseudomonas bacteria is difficult to clear in CF patients, even after treatment with antibiotics. Typically, CF patients have a pattern of low-grade, persistent infection with periodic worsening, sometimes requiring hospitalization. Recurring Pseudomonas infection and the inflammation that accompanies it gradually damage the lungs, causing respiratory failure, which is the leading cause of death among CF patients. As in the lung, thick secretions clog the pancreatic ducts and damage the pancreas. In some CF patients, this damage occurs even before birth, while in others it develops more gradually. The pancreas supplies digestive enzymes and bicarbonate to neutralize stomach acid so the enzymes can work properly in the intestine. Most CF patients have insufficient amounts of digestive enzymes for normal digestion. Pancreatic insufficiency causes foul-smelling, bulky bowel movements, malnutrition and slowed growth and development. Replacement of pancreatic enzymes can alleviate these symptoms. Attention to diet and supplements of fat-soluble vitamins are also required. As the disease progresses, the cells in the pancreas that make insulin may also be damaged and patients may develop diabetes. In addition to the pancreas, abnormalities are seen in other parts of the gastrointestinal tract in CF. The bile ducts in the liver may be affected, causing biliary cirrhosis in a small percentage of patients. Newborns with CF may develop a condition called meconium ileus, in which the small intestine is obstructed by a plug of meconium, the material in the newborn gastrointestinal tract. CF also affects the reproductive organs, causing infertility in nearly all men and some women with the disease. Men with CF are generally infertile because the tubules called the vas deferens, that transport sperm from the testes are absent or undeveloped. Fertility may be reduced in women due to abnormal cervical mucus or to menstrual irregularity. Although pregnancy can be risky, many women with CF with relatively good pulmonary function have borne healthy children. However, the incidence of CF in their offspring is about one in 50. Salt absorption in the sweat ducts is also impaired, and CF patients produce extremely salty sweat. Based on this observation, a scientist developed a sweat test forty years ago to diagnose CF. This test is still the standard for diagnosis. With the discovery of the gene defective in CF, the sweat test can be supplemented by genetic tests when the results are ambiguous. The symptoms and severity of CF vary from patient to patient. For example, not all CF patients suffer from impaired pancreatic function. The degree of lung disease also varies. Some of this variation can be attributed to differences in the specific genetic defects in different patients, but even patients with identical mutations may have very different severity of disease. Even siblings with the same genetic defect who share other genetic traits can have different CF manifestations. Therefore, although the specific mutation in the CF gene contributes to the course of the disease, other differences in the individual genetic makeup, and perhaps in the environment, also play a role. Treatment of Cystic Fibrosis Improvements in antibiotic therapy, clearance of lung secretions, and nutritional support have increased the mean survival of patients with CF from under 5 years to approximately 30 years. Since the identification of the CF gene in 1989, there has been a rapid increase in our understanding of CF and the challenge now is to translate this improved understanding into new approaches to therapy. While the discovery of the CF gene has stimulated research to find a cure for the disease, until this is achieved, the pulmonary infection and inflammation that ultimately leads to respiratory failure and premature death remain prime targets for therapy. Continued improvement in therapy directed at removing airway mucus and reducing infection and inflammation can preserve lung function until more definitive therapy is developed. In recent years researchers have made further progress in developing new treatment approaches to improve CF patients length and quality of life. Some of the devices and drugs that are available for therapy are described below.
Flutter Valve The "flutter," a small, hand-held device that looks like a pipe, allows a patient to loosen the mucus that clogs their airways without having to endure conventional chest and back clapping therapy. When patients exhale through the flutter, a special valve causes rapid air pressure fluctuations in the patients airways. The resulting vibrations dislodge the mucus from the airway walls and promote mucus movement. DNase One factor contributing to mucus stickiness is the DNA released from white blood cells that die while fighting bacterial infections. A naturally occurring enzyme called DNase can cut long DNA molecules into shorter pieces and reduce their stickiness. In 1993 the Food and Drug Administration approved the use of DNase for CF treatment. The enzyme is administered as an aerosol spray and is generally well tolerated, although patients may experience transient throat irritation or hoarseness. Treatment with DNase reduced the frequency of severe episodes of lung infection and slightly improved lung function after 24 weeks of therapy. Longer studies are needed to determine whether the small improvement in lung function at 24 weeks persists and whether this therapy will retard progressive loss of lung function.
Antibiotic Therapy Pseudomonas bacteria are a leading cause of lung infection and death among CF patients. Until recently, Pseudomonas infections were treated by intravenous administration of antibiotics that were not available in oral form. This treatment required high antibiotic dose so that enough of the drug would reach the lung. Besides being expensive, the high doses could damage hearing and kidney function in patients. An aerosol form of the antibiotic Tobramycin significantly reduced Pseudomonas infections in CF patients. The inhaled drug directly reaches the infected lung tissue, reducing the dose required and the potential for side effects. Tobramycin by aerosol form is easier and less expensive to administer than by intravenous injection. In addition, there are now oral anti-Pseudomonas antibiotics. For some patients, these oral antibiotics can effectively substitute for a course of intravenous antibiotic, if the patient’s germs are sensitive and the illness is mild. Ibuprofen A clinical trial conducted at a supported CF research center recently showed that the anti-inflammatory dug ibuprofen, an ingredient in many over-the-counter pain killers, can preserve lung function in CF. To reduce the inflammation that contributes to progressive lung damage, CF patients received high, twice-daily doses of ibuprofen for four years. Patients who took the drug consistently maintained their lung function and body weight significantly better than control patients who received a placebo did. The treatment was most effective in younger patients under 13 years of age. Researchers warn that ibuprofen treatment should be performed only under medical supervision because the high drug doses required must be determined individually for each patient. Nutrition Malnutrition contributes significantly to the deterioration of CF patient’s health. Although the vast majority of CF patients now take supplements of pancreatic enzymes to compensate for pancreatic insufficiency, these supplements do not fully corrected the malabsorption, and many children are underweight and shorter than would be expected based on parental height. Recently high doses of pancreatic enzyme supplements were found to be associated with the development of colonic strictures in a few patients, causing physicians to be more cautious in dosing. In recent years, increased attention to caloric needs, a balanced diet, and supplements of vitamins and other nutrients have contributed to the increasing longevity and well being of CF patients. Appropriate nutritional therapy improves the patients’ growth and development, strength and exercise tolerance and may improve resistance to bacterial infections. Researchers do not yet know to what extent better nutrition actually can delay progression of lung disease. Researchers are studying the causes and consequences of malnutrition in CF patients, and developing new strategies to prevent and treat malnutrition. Gene Therapy In 1989 researchers identified the genetic defect responsible for CF. Mutations in one gene, called the cystic fibrosis transmembrane conductance regulator (CFTR), cause the body to make nonfunctional CFTR protein, which leads to the disease. About 500 different mutations have since been identified in CF patients all over the world. Scientists are studying the function of the normal and the defective CFTR proteins to understand the biochemical consequences of the defect and to develop new treatment approaches based on that knowledge. CF ultimately could be cured if safe and effective methods could be found to replace the defective CFTR gene with an intact gene in affected tissues. This process is called gene therapy. During such a treatment, shuttle vehicles called vectors deliver a functional copy of the defective gene, CFTR- either to cells throughout the body or to specific affected tissues such as the lungs. These vectors most commonly are derived from viruses that can infect the target cells, although non-virus-based vectors also are available. Once the new CFTR gene has entered the cell, the cell’s biochemical machinery must recognize it and use it as a template for the production of functional protein. Effective gene therapy depends on several conditions. The vector must be able to enter the target cells efficiently and deliver the corrective gene without damaging the target cell. The corrective gene should be expressed in the cells to allow continuous production of functional CFTR protein. Neither the vector nor the CFTR protein produced from it should cause an immune reaction in the patient. Because it is difficult to control the protein amount produced after gene therapy, there should be a wide range of CFTR levels that allow sufficient chloride transport without causing side effects from excess CFTR production. Researchers were encouraged about the feasibility of gene therapy when they found that introducing an intact CFTR gene into cells derived from CF patients restored chloride transport to normal levels. When CF lung cells are grown in thin layers, correction of as few as 6 percent of them restores normal levels of chloride transport to the entire cell layer. In addition, CFTR production at higher than normal levels, or in cells where it is not normally found, does not seem to be harmful, although more experiments are needed. When researchers over produced CFTR protein in mice, the animals suffered no toxic side effects. Correcting the defect in people is much more difficult than achieving correction in cells in the laboratory. Scientists are hopeful that the affected airway cells might be easily accessible to potential gene therapy vectors because patients can inhale vector aerosols. However, the lung cells that express the highest levels of CFTR are not on the airway surface but deeper in the lung. It is not yet known which cells must be corrected to cure CF lung disease: the more easily accessible airway surface cells or the cells in the submucosal glands that express the highest levels of CFTR. Before gene therapy can become a reality, researchers must determine more accurately which cell types in the airways produce CFTR protein, and at what levels, and which are important in the development of disease. Once the CFTR-producing cells have been identified and their role established, appropriate vectors must be developed that can effectively and safely introduce the CFTR gene into these cells. Summary CF researchers from many biological and medical disciplines have made substantial progress in developing new treatments to increase CF patients’ life expectancy and quality of life. Improved treatment of infection, mucus airway clearance and nutritional therapy has already had a dramatic effect on the lives of people with CF. Parents can expect most babies born with CF to survive well into adulthood and to lead productive and fulfilling lives. The combined efforts of all these researchers have two goals: first, to develop new treatments to alleviate the debilitating effects of CF and prolong patients’ lives; and second, to find a cure for this deadly disease. The identification of the genetic defect responsible for CF has opened new avenues to achieve both goals. New treatments based on knowledge of the molecular processes involved in CF are already in the pipeline. Although a cure for CF through gene therapy may not be available in the immediate future, the promise of gene therapy is great and offers hope for thousands of CF patients.
|
|
