Cystic fibrosis

Author : Dr Jerry Nick National Jewish Medical and Research Center, Denver

2008-08-20

Cystic Fibrosis : History, clinical manifestations, and treatment

Introduction

Cystic fibrosis is a genetic disease that primarily affects the lungs and digestive system of about 30,000 children and adults in the United States (over 60,000 worldwide). The underlying abnormality is the secretion of unusually thick, dehydrated, and sticky mucus in many tissues of the body, including the airways, pancreatic ducts, sweat ducts, sinuses, and bowels. Obstruction of the pancreatic ducts severely damages the pancreas, and results in reduced capacity to make enzymes required to digest proteins and fat. Patients with CF are typically diagnosed in infancy due to symptoms of diarrhea and malnutrition. Later in childhood, obstruction of the small airways of the lung results in the permanent dilation of these bronchi (bronchiectasis), and provides a site where certain infections can take hold. The thick and dehydrated mucous prevents the normal clearance of bacteria and other microbes from the lungs, and patients acquire chronic infections with specific pathogens. The most important complication of CF is progressive destruction of the lungs, which results in respiratory failure and death in approximately 80% of CF patients. Fortunately, steady advances in medical treatments have provided a range of therapies to slow or prevent the complications of CF, resulting in extended lifespan and improved quality of life for children and adults with CF.

What Causes Cystic Fibrosis?

CF is a genetic disease caused by a mutation in a gene named the cystic fibrosis transmembrane conductance regulator (CFTR). The inheritance pattern is autosomal recessive. Thus, to have symptoms of CF, an individual must have two defective CFTR genes, by inheriting a mutant copy of the CFTR gene from both mother and father (right). People with a single CFTR mutation are termed “carriers”, and do not have symptoms of CF. There are approximately 1500 different CFTR mutations which can cause CF. The most common mutation is named ΔF508, and approximately two-thirds of all CFTR mutations worldwide are ΔF508. While having 2 copies (homozygote) of ΔF508 is associated with severe disease, many of the less common mutations are associated with less severe clinical symptoms. Detailed information about all known CFTR mutations is available by scientists at the Hospital for Sick Children in Toronto, Canada

The CFTR gene is responsible for the production of the CFTR protein, which is a channel for the passage of salt (sodium and chloride ions) onto the surface of a variety of tissues. The CFTR protein contributes to the normal secretions produced in the airways, pancreatic ducts, sweat ducts, sinuses, and bowels. When the CFTR protein is not present, the result is mucous that is unusually thick, dehydrated, and sticky. Most of the complications of CF arise from damage caused by this abnormal mucus to the pancreas and lungs. Later in life, the most significant complications are due to infections that have taken advantage of the damaged lungs, and are often impossible to eradicate.

How common is Cystic Fibrosis?

There are approximately 30,000 people with CF in the United States, and over 60,000 people worldwide. Moreover, the prevalence of the disease is increasing, with over 1200 new cases in 2006 from the United States alone (1 out of every 3500 newborns) [1].

The CFTR mutation is extraordinarily common in the general population, with approximately 10-12 million carriers in the United States. Worldwide, prevalence of the CFTR mutation varies greatly between ethnic groups, with the greatest frequency in European-derived populations and Ashkenazi Jews. Estimates of carrier rates and disease prevalence in the United States are listed in Table 1. In some regions of Europe, an even greater carrier rate has been reported.  

 Table 1: Estimated Prevalence of CFTR mutations and new cases of
Cystic Fibrosis in the United States 

Ethnicity                                       Carrier rate                 Newborns with CF
    Caucasian Americans                    1 in 29                                1 in 3200
    Hispanic Americans                      1 in 46                                1 in 8500
    African Americans                         1 in 65                                1 in 17,000
    Asian Americans                            1 in 90                                1 in 31,000
    Overall US population                   1 in 31                                1 in 3500

Many scientists have questioned why the CFTR mutation is so common in select ethnic groups. Genetists have determined that the important ΔF508 mutation has been present in the human gene pool for over 50,000 years. As the condition has historically been lethal, it is widely assumed that the carrier state (a single CFTR mutation) must have afforded a survival advantage to certain populations. One clue is that ethnic groups with the highest prevalence of the CFTR mutation are indigenous to cooler climates, such as Ireland, parts of Scandinavia, and other European regions. It is known that carriers of CF are predisposed to greater salt loss in their sweat then individuals without the gene. In these climates, salt loss in hot weather would be less relevant, compared to regions of Africa and Asia where the CFTR mutation is very rare. Proposed diseases that the CF carrier state may protect against include diarrhea from cholera or lactose intolerance, typhoid fever, high blood pressure and tuberculosis. While these theories have not yet been confirmed in man, it seems likely that one (or more) of these mechanisms are responsible for keeping the CFTR mutation in the gene pool.

History of Cystic Fibrosis

While humans have certainly died of CF for thousands of years, the first clear references to the disease extend back only a few centuries. European folklore from the Middle Ages warned “woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die”. References have been found in medical texts as early as 1595 that linked salty skin and damage to the pancreas with death in childhood by infants who were “hexed” or “bewitched” [2]. Scholars have proposed that the Polish composer Frederic Chopin (1810-1849), who died of respiratory failure after a lifetime of malabsorption and lung infection, likely had a mild form of CF. In 1938, the American Pathologist Dr. Dorothy Andersen provided the first description of the disorder in the medical literature, calling the disease “cystic fibrosis of the pancreas” based on her autopsy findings of children that died of malnutrition. Other physicians of the era referred to the disease as “mucoviscidosis”, which called attention to the presence of thickened mucous.

The modern history of CF is dominated by the definition of the underlying genetic defect, and the rapid increase in survival following the introduction of improved therapies. During a heat wave in the summer of 1948, Dr. Paul di Sant’Agnese observed infants presenting with dehydration to a New York City emergency room. This lead to his discovery that the sweat of children with CF had abnormally high concentrations of salt, and validated the ancient folklore of the disease. In the 1980’s, the protein defect was described, and in 1989 the responsible gene (CFTR) was identified and its genetic code was sequenced. With each decade, new therapies have been introduced, leading to a dramatic increase in survival.

In recent years, public awareness of CF has risen dramatically. In the 1950s and 1960s, a variety of organizations were formed worldwide, in part to educate patients, families and the public about CF. In particular, the CF Foundation (United States) has played a significant role in developing the current model of CF care, as well as providing financial support for much of the current CF-related research and drug discovery. More recently, public attention has been drawn to individuals with CF who are the children (or close relatives) of celebrities, or who have achieved fame in their own right (Table 2). 

 Table 2: Notable people with CF
        Frankie Abernathy (1981–2007)            Television personality (U.S.)
        Lisa Bentley (1968-)                                Ironman triathlete (Canada)
        Ricky Briggs (1981-)                               Actor and comedian (U.S.)
        Christopher Davies (1978-)                    Cricketer (Australia)
        Oliver Dillion (1998-)                              Actor (U.K.)
        Bob Flanagan (1952–1996)                    Writer, performance artist, and comidian (U.S.)
        Chris Fowler (1975-)                               Race Car Driver (U.S.)
        Nolan Gottlieb (1982-)                           Basketball player and coach (U.S.)
        Grégory Lemarchal (1983-2007)           Singer (France)
        Alice Martineau (1972–2003)                Singer-songwriter and model (U.K.)
        Kimberly Myers (1970-97)                      Race Car Driver (U.S.)
        Elizabeth Nash, Ph.D.                             Scientist and CF Researcher (U.S.)
        Laura Rothenberg (1981–2003)             Author (U.S.)
        Andrew Simmons (1984-)                      Professional wrestler (U.K.)
        Bill Williams (1960–1998)                      Author and software developer (U.S.)
    

Notable people with family members that have CF
        Gordon Brown, Prime Minister (U.K.)                   Son Fraser
        Tammy Cochran, Singer (U.S.)                              Brothers Shawn and Alan
        Frank Deford, Author and Journalist (U.S.)         Daughter Alexandra
        Celine Dion, Singer (Canada)                                Niece Karine
        Boomer Esiason, Football Player (U.S.)                 Son Gunnar  
        Brian Hill, Basketball Coach (U.S.)                        Daughter Kim
        Rosie O’Donnell, Comidian (U.S.)                          Nephew Joey
        Ken Read, Skier (Canada)                                      Nephew Andrew

Many high quality websites and weblogs are written by people with CF, or by members of their family, and this work has done much to document the wide variety of perspectives and experiences encountered by individuals of varying ages and backgrounds with the disease worldwide.

What are the Signs and Symptoms of Cystic Fibrosis?

CF is a progressive disease that involves a number of different organs. Therefore, people with CF can have a variety of symptoms, depending on their age, and the severity of their disease. The severity of disease is largely determined by the specific CFTR mutations. But severity of disease is also related to the type of infections that are present in the airway, as well as several “modifier” genes, which in some cases appears to alter the expected clinical features [19]. More then 70% of patients are diagnosed by age 2, but in patients with less severe symptoms, the diagnosis may be delayed for decades. Some of the more prominent age-related features of CF are listed in Table 3.

Table 3: Typical age-related signs and symptoms of Cystic Fibrosis
    Newborns and Infants
            Obstruction of the bowel at birth (meconium ilius)
            Poor growth and weight gain, despite a good appetite
            Frequent greasy, bulky stools, or difficulty in bowel movements.
            Very salty-tasting skin
            Cough and other respiratory symptoms
    Children
            Persistent coughing, at times productive with sputum
            Frequent respiratory infections
            Wheezing or shortness of breath
            Poor growth and difficulty with weight gain
            Malnutrition and vitamin deficiency 

   Adolescents and Young Adults
            Recurrent or persistent lung infections with Staphylococcus aureus or  Pseudomonas aeruginosa
            Chronic sinusitis, sinus infections and nasal polyps
            Clubbing of the fingers and toes
            Male infertility with an absence of sperm
            Malnutrition and vitamin deficiency

Older Adults
   Progressive decline in lung function
   Recurrent exacerbations of lung                     infections
   CF-related diabetes
   Infection with non-tuberculous mycobacterium species
  Osteoporosis or osteopenia
  Malnutrition and vitamin deficiency

  

"Clubbing" of the fingers is a classic features of Cystic Fibrosis, although not present in many patients. 

What is the life expectancy for people with CF?

Historically, children with CF died as infants, and as recently as 1980 the median survival was less then 20 years. However, over the past 3 decades the lifespan of CF patients has risen dramatically, and in 2006 the median survival in the United States was 37.5 years (shown by red line, figure on right). Many factors influence the health of CF patients. Older adults with CF had fewer treatment options during their childhood when compared to children born more recently. 

Improving survival in CF. The red line represents the median survival (in years) for the CF registry population in the United States. Important scientific milestones and advances in treatment are depicted. (Adapted From 2005 Annual Data Report to the Center Directors. Cystic Fibrosis Patient Registry, Bethesda, MD; used with permission).

Statistics from the CF Foundation registry show that patients born in the 1990’s will have a longer lifespan then patients born in the 1980s [1]. For reasons that are not completely understood, in the past, women with CF had a significantly shorter lifespan then men. However, for women born since 1990 this “gender gap” appears to no longer be present [1]. Thus, children born now with CF can be expected to greatly exceed today’s current average lifespan for CF patients. In addition, it is evident that individuals with less common CFTR mutations and milder forms of the disease will have a much greater life expectancy then the majority of the CF population that has the classic form of the disease.

How do doctors test for Cystic Fibrosis?

The availability of reliable testing is one of the most significant advances in our understanding and treatment of CF. Testing is important not only for children and adults suspected of having the disease, but for individuals without symptoms that are concerned about the risk of being a CF carrier, with the potential to pass the gene to their children. Several different tests are currently available:

Newborn Screening: While long available, newborn screening for cystic fibrosis is now required in 36 States. Many studies have proven that CF diagnosed early in life results in healthier children, and even increased survival, when compared to children with a delayed diagnosis [3]. Thus, newborn screening is recommended by the United States Centers for Disease Control (CDC) and the CF Foundation. The test detects elevated quantities of trypsinogen in a drop of blood collected from the heel. This procedure is already widely performed to test for other congenital disorders. Newborn screening is not a definitive diagnostic test for cystic fibrosis, but if positive, indicates the need for additional testing to rule out or confirm a CF diagnosis.

Sweat Test: The sweat chloride test is the classic method to diagnose CF in children and adults suspected of having the disease. The test is based on the principal that the sweat of CF patients is dramatically more “salty” then the general population, thus a high chloride level indicates CF. While the test is painless, the procedure is somewhat complicated, and reliable results depend on very careful administration of the test. Sweat tests must be performed by trained technicians, and evaluated in an experienced, reliable laboratory, or at a Cystic Fibrosis Foundation-accredited Care Center where strict guidelines help ensure accurate results. Sweat chloride concentrations less than 40 mmol/L are normal, but sweat chloride concentrations greater than 60 mmol/L are consistent with the diagnosis of CF. All positive results need to be confirmed with a repeat test on a separate day. Detailed information about the sweat test for patients and families is available from the United States CF Foundation.

Genetic Testing: Several tests are available that can identify the presence of defective CFTR genes in newborns with positive screening results, as well as children and adults with symptoms of CF. In addition, these tests are useful in identifying symptomless carriers of an abnormal CF gene, including an estimated 10-12 million Americans. The American College of Obstetricians and Gynecologists now recommend that all pregnant women and their partners, as well as couples planning to have children, have genetic testing to screen for carriers of CF [4]. Even CF patients confirmed to have the disease by the sweat test can benefit from genetic testing, as identifying the specific CFTR mutations can help predict the future severity of the condition. In addition, identification of which mutations each patient has may someday have therapeutic importance, as experimental therapies are in clinical trials to improve defective CFTR function for specific classes of mutations.

Genetic testing analyzes a person’s DNA (genetic material), which can be obtained from a blood sample, or from cells that are gently scraped from inside the mouth. Currently, most genetic testing looks for the presence of between 30 and 90 of the most common CFTR mutations, which accounts for up to 90% of all cases in specific ethnic groups. However, as there are approximately 1500 known CFTR mutations, these screening panels have the potential to miss rare mutations that often produce more mild forms of the disease. In cases where CF is strongly suspected, despite the presence of only one mutation from previous testing, the entire CFTR gene can be sequenced to definitively determine the presence or absence of two disease-causing mutations.

What establishes the diagnosis of Cystic Fibrosis?

Despite the availability of testing for the disorder, results can at times be subject to interpretation, and many physicians have differing opinions as to the exact criteria required to diagnose CF. In 1997, the CF Foundation sponsored a Consensus Conference of experts to establish guidelines for diagnosis, and their recommendation remain widely used [5]. Patients suspected of having CF must demonstrate at least one clinical feature of the disease (see below), or have a sibling with CF, or have a positive newborn screening test. In addition, they must have laboratory evidence of a CFTR abnormality. This can be either a positive sweat test on two separate occasions, or the presence of two disease causing CFTR mutations by genetic testing.

What are the major clinical features of Cystic Fibrosis?

The CFTR protein is expressed in many organs and tissues of the body, thus when the CFTR gene is defective, many organ systems are affected. While damage to the lungs and pancreas is the most clinically important manifestation of CF, involvement of other organ systems can also greatly impact the lives of people with CF.

Lung Disease

CF lung disease primarily involves the small and medium sized airways of the lungs. Very early in life, increased inflammation and mucous production starts to obstruct the smallest bronchi, leading to abnormal dilation and damage. This dilation of the bronchi (termed bronchiectasis) causes permanent damage to the lungs. Bronchiectatic airways can become plugged with mucous (shown above) and contributes to an environment where specific bacteria can take hold an avoid eradication by either antibiotics or the immune system. One of the classic features of CF is that the upper lobes of the lungs are typically the sites of greatest damage. Bronchiectasis can easily be detected by a CT scan of the chest. It is now recognized that bronchiectasis can be present in children prior to a reduction in pulmonary function [6]. The presence of bacteria further increases the inflammation and mucous production, accelerating the damage to the airways.

Ultimately, as many as 80% of CF patients die of respiratory failure. Thus preservation of lung function is a principal goal of treatment. The extent of lung disease is measured by a pulmonary function measurement called the FEV1, which represents the volume of air an individual can forcibly exhale in 1 second. In addition to being the primary marker of disease severity, FEV1 is often the principal measure used to judge the success of new treatments.

Infection of the Lungs

The first lung infections in children with CF are typically Hemaphillus influenza and Staphylococcus aureus. Later in childhood or adolescence, Pseudomonas aeruginosa is commonly recovered from the sputum. Burkholderia cepacia is a rare (3% of CF patients) but serious infection that is somewhat similar to Pseudomonas, but usually more resistant to antibiotics, and occasionally associated with an extremely rapid decline in lung function. By adulthood, P. aeruginosa is the most common and most important infection in CF. Over 80% of CF patients will become chronically infected with P. aeruginosa, and infection with this bacteria clearly accelerates the rate of lung damage and clinical decline. 

The prevalence of lung infections changes as CF patients become older. Ultimately, Pseudomonas aeruginosa is the most common and most important infection. (Adapted from 2005 Annual Data Report to the Center Directors. Cystic Fibrosis Patient Registry, Bethesda, MD; used with permission).

Prompt and aggressive treatment of Pseudomonas when it first appears can sometimes clear the bacteria from the lungs, and prevent (or at least postpone) permanent infection. Intense efforts are underway to define the best treatment strategies to eradicate Pseudomonas when it first appears in the sputum. Once established in the CF airway, Pseudomonas undergoes many adaptations that reduce the potential for the immune system or antibiotics to successfully fight the infection. However, even when chronic Pseudomonas infection is present, antibiotic therapies can significantly reduce the quantity of live bacteria in the airway. Reduction in the amount of bacteria in the airway has been linked to decreased inflammation, reduced symptoms, and preservation of lung function [6]. Thus, even though antibiotics rarely “cure” an infection in the CF lungs, they are still effective and essential in treating the disease.

Other Respiratory complications

Many people with CF have a degree of airway bronchospasm that resembles asthma. In these individuals, respiratory symptoms and FEV1 are improved through the use of bronchodilators. Patients with more advanced lung disease are at risk for complications such a bleeding into the airways (hemoptysis). Coughing-up blood is a common feature of increased infection, and usually is resolved with antibiotics. More severe complications include collapse of lobes, or leaking of air outside of the lungs (pneumothorax). These complications are associated with advanced lung disease and can be a cause of sudden worsening of respiratory symptoms. Urgent medical evaluation and treatment is required.

Pulmonary Exacerbation of CF

Like other lung diseases, such as asthma and emphysema, one of the most important features of cystic fibrosis is episodic exacerbation in disease severity. Most people with CF will have fewer then one exacerbation per year, but with advancing lung disease the frequency typically increases [1]. Clinical features are listed in Table 4. No definitive diagnostic criteria exists, although usually several of these signs and symptoms will be present [7].
 

Table 4: Signs and Symptoms of a Pulmonary Exacerbation of CF
        Symptoms
                Increased cough
                Increased sputum production
                Change in sputum appearance (darker or blood streaked)
                Coughing up blood (hemoptysis)
                Increased shortness of breath
                Decreased appetite
                Weight loss
                Unable to attend school or work
                Weakness and fatigue
        Signs on physical exam
                Increased respiratory rate
                Increased heart rate
                Fever
                Weight loss
                Retraction of intercostal muscles
                Increased chest crackles
        Laboratory Tests
                Decreased FEV1
                Decreased oxygen saturation
                Increased white blood cell count
                New changes on chest X-ray
 

The causes of CF exacerbations are not clearly understood. Likely, exacerbations are triggered in part by increased growth of the bacteria that chronically infect the airways, especially P. aeruginosa. Often, people with CF will report that exacerbations began following symptoms of a viral upper respiratory tract infection. But in some cases, symptoms will come on gradually over the course of weeks or months.

Pancreas

Like the bronchi, the small ducts of the pancreas are also obstructed by thick secretions. Nearly 90% of people with CF lack the capacity to excrete sufficient pancreatic enzymes or bicarbonate into the duodenum (pancreatic insufficiency). The duodenum is the first portion of the small intestine. This condition greatly reduces the capacity to metabolize and absorb dietary fats and proteins. Carbohydrate absorption can also be impaired. Symptoms include greasy and foul-smelling diarrhea, abdominal pain, failure to gain weight and malnutrition. Historically, children with CF died in early childhood as a result of pancreatic insufficiency, before the lung manifestation of the disease became severe. Development of pancreatic replacement enzymes, and other nutritional supplements have significantly reduced the complications associated with pancreatic insufficiency.

CF-related diabetes

Insulin is produced by cells of the islets of Langerhan, located within the pancreas. Even with pancreatic insufficiency, most children with CF are still capable of producing sufficient insulin. However, in adulthood, increasing numbers of men and women with CF will require supplemental insulin, as the residual islet cell function declines [8]. This CF-related diabetes (CFRD) is distinct from the Type I or Type II diabetes that are encountered in the general population. Often the symptoms of CFRD are quite subtle, and can include weight loss or inability to regain weight after an exacerbation, as well as unexpectedly rapid decline in lung function. Administration of insulin is nearly always associated with improved weight gain and lung function.

Bowel

As with the lungs and pancreatic ducts, the mucous of the bowel is abnormal in CF patients. At birth, up to 20% of CF patients will have an obstruction of the bowel, termed “meconium ileus” [1]. Many individuals with CF experience difficulty with constipation throughout life. In its most extreme form, CF patients can become severely obstructed with stool. This condition is termed the Distal Intestinal Obstruction Syndrome (DIOS), and requires prompt and aggressive treatment by physicians familiar with the condition [9].

Sinus disease

Inflammation and infection of the upper airways and sinuses is extremely common in people with CF. Symptoms include runny nose, recurrent or chronic sinusitis, post-nasal drip, or nasal polyps. Aggressive medical treatment of CF sinus disease is very important, as poorly controlled sinusitis can greatly worsen the severity of CF lung disease and impact quality of life. Although sinus surgery is sometimes needed, this should only be performed by an Ear Nose and Throat (ENT) specialist experienced in the treatment of CF-related sinus disease.

Fertility

In over 98% of men with CF, semen analysis demonstrates the absence of sperm (azoospermia). Infertility in men with CF is due to obstruction of the reproductive tract. In particular, damage to the vas deferens duct, which occurs prior to birth, results in a condition termed congenital bilateral absence of the vas deferens (CBAVD). However, when the obstruction is bypassed by directly aspirating the sperm from the epididymis, the sperm is generally found to be normal. Thus, for men with CF who wish to father children, various techniques are available to harvest sperm, which can then be used for assisted reproduction [10]. 

The first report of a successful pregnancy by a women with CF appeared in 1960. Historically, women with CF were considered to have decreased fertility, usually attributed to dehydrated and thickened cervical mucus. However, women with CF generally have normal reproductive anatomy, and pregnancies followed by uncomplicated deliveries are no longer unusual. While a number of aspects of the female reproductive system can be altered by CF, decreased fertility previously observed in women probably related more to malnutrition, delayed menarche (the first menstrual period), overall poor health, and a shortened life span. All women with CF should be considered capable of childbirth, and appropriate birth control should be considered to prevent unplanned pregnancies. Many CF-related treatments, including certain classes of antibiotics, are not recommended during pregnancy, or have unknown consequence. Thus pregnancy testing should be considered before initiating treatment with such medications.

With the steady increase in the life expectancy of individuals with CF, many women with CF are considering planned pregnancies. Each situation is different, and sweeping recommendations are not possible. The non-CF partner should undergo genetic testing to determine if he is a CF carrier [4]. Typically, CF pregnancies are considered “high risk.” Common issues include difficulty in achieving recommended weight gain (especially with women undernourished prior to pregnancy), high rates of gestational diabetes, pulmonary exacerbations, high rates of C-sections, and low birth weights [11].

Despite these risks, women with CF generally have done well during the actual pregnancy and childbirth [12]. The greatest concern often lies with the capacity of the mother to keep up with the progressive severity of her conditions in the setting of the demands of raising a child [10]. Clearly, the severity of the mother’s lung disease, the presence of other CF-related conditions such as diabetes, and the amount of support present from spouse and family are important factors in this decision. Couples need to have a realistic understanding that the progression of CF is difficult to predict, and a mother may not survive to see her child reach adulthood. These considerations are also present when men with CF consider having children, or when men or women with CF consider adoption. Finally, each child conceived from a parent with CF will be a CF carrier, and has a 50% chance of having CF if the other parent is a carrier. Some individuals with CF choose not to have children to avoid passing the gene onto future generations.

Nonclassic forms of CF

With over 1500 different CFTR mutations described, it is now recognized that many of the less common mutations allow for partial function of the gene and protein, and a less severe form of disease. Increasingly, it is evident that “mild” forms of CF remain undiagnosed until adulthood. Interestingly, the adult diagnosis of CF is more common in women, suggesting that the historic survival advantage for men in classic CF is not present in nonclassic disease [13]. Usually, cases of CF diagnosed in adulthood will have normal pancreatic function. In the most extreme form, nonclassic CF can appear to present with involvement of a single organ, such as recurrent pancreatitis or male infertility due to CBAVD. However, physicians should be cautioned against assuming that patients with mild CF mutations and limited organ involvement will never face the respiratory difficulties common to classic CF. Careful analysis of these individuals has demonstrated signs of early CF lung disease. In many cases, typical and severe CF lung disease can develop, abet decades later in life then in patients with the classic form of CF. Little is known about the clinical course of patients diagnosed as adults with nonclassic CF. However, it is apparent that life expectancy is significantly longer then patients diagnosed in childhood.

Treatment of Cystic Fibrosis

Although there is not yet a cure for CF, significant advances in the treatment of the disease has occurred. With new therapies there has been a remarkable increase in the expected survival of CF patients (see above). Early discoveries of the ability of pancreatic enzyme replacement to permit digestion of proteins and fats allowed CF patients to survive childhood. More recently, advances in techniques to clear the airways of mucous, as well as improved antibiotics, have propelled median survival to over 37 years. Many of the therapies available or under development for the treatment of CF are medications that are administered by inhalation of an aerosol or mist (nebulization), as shown above. However, with each new medication and therapy, the complexity of the treatment plan increases. Perhaps more then any chronic disease, successful management of CF requires an enormous commitment by the patient. Especially in the setting of advanced disease, individuals with CF may be required to spend hours each days to keep up with airway clearance and a variety of inhaled, injected and orally administered medications to combat airway infections, chronic sinusitis, diabetes, and pancreatic insufficiency.  

Sputum mobilization and clearance from the airways

The presence of very thick and sticky mucous in the airways of CF patients has clearly been shown to accelerate lung damage and promote infection. Thus, a critical component of CF treatment is to perform effective airway clearance to loosen and get rid of the mucus from the lungs. A wide variety of methods and devices are available to assist with airway clearance. The classic technique commonly used with children is called “postural drainage and percussion.” The person with CF sits, stands or lies in a position that will help free up mucus as their chest and back are pounded or clapped by family members or respiratory therapists. Adults with cystic fibrosis usually prefer an airway clearance technique (ACT) that can be done without assistance. A mechanical “vest” has been developed that reproduce the effect of handclapping to the chest. A fitted vest is coupled to a pneumatic compressor capable of high frequency oscillation and compression of the chest wall (shown above). Many other devices are available that combines the action of blowing against pressure, combined with vibration, to open the airways and help mobilize the thick mucous. No method or technique has been shown to be clearly superior. However, individuals with CF can usually identify the mode of ACT that works best for them, with the goal of facilitating sputum expectoration. As patients get older, they should be given the opportunity to try, and retry, different forms of ACT. Nearly always, aerobic exercise is helpful as an addition to other forms of airway clearance. More then any other CF treatment, airway clearance requires a strong commitment by the patient and their families, as it is time consuming and physically demanding.

Medications to assist with airway clearance

The first agent ever approved by the FDA for the treatment of CF lung disease was the enzyme DNase (Pulmozyme®). DNase is a medication that serves to thin the mucus, and is delivered by inhalation of an aerosol. DNase works by degrading the long strands of DNA that are mixed within the sputum, thus resulting in decreased viscosity and improved ability to clear organisms from the bronchi. The DNA in the CF sputum originates from the massive number of white blood cells (neutrophils) that are trapped and eventually die within the mucous layer. A number of studies have demonstrated small but significant improvements in FEV1, as well as general trends towards decreased infection and/or fewer pulmonary exacerbations [9, 14].

More recently, small studies have demonstrated benefits from inhaling concentrated salt water (hypertonic saline) [15]. This therapy appears to rehydrate the very concentrated mucous, and thus improves the ability of cilia to clear mucous from the airways. Although much less studied than DNase, it appears that hypertonic saline may also reduce the frequency of pulmonary exacerbations, and in some cases improve lung function [14].

Other respiratory therapies

Many people with CF have some degree of bronchospasm or wheezing, which is sometime referred to “CF asthma”. In addition, some people experience chest tightness or wheezing after using inhaled DNase, hypertonic saline and/or tobramycin. Thus, many individuals with CF use one or more bronchodilators. Specific, evidence-based recommendations for bronchodilator use in CF are not available, thus Physicians often utilize treatment strategies similar to those recommended for patients with asthma. In people with advanced CF lung disease, oxygen may be required. Assisted ventilation by mask with positive airway pressure may be useful for patients with even more severe lung damage.

Maintenance antibiotics

Many different antibiotics have been used to try to keep the “burden” of bacteria at the lowest possible level. Two antibiotics have now been shown to be effective for this purpose [14]. Tobramycin solution for inhalation (TOBI® ) when prescribed in one-month intervals (followed by one month off treatment), has been shown to improve lung function and reduce the frequency of exacerbations in the setting of chronic P. aeruginosa infections [16]. A second antibiotic, azithromycin (taken orally), has been shown to have similar benefits. The two antibiotics are often used together. Interestingly, azithromycin is not an antibiotic known to kill P. aeruginosa in the laboratory, and many scientists believe that it instead acts as an anti-inflammatory drug in the CF airway. While P. aeruginosa has the ability to develop resistance to many antibiotics, this has not emerged as a significant problems as a result of the use of either inhaled tobramycin or azithromycin, and most CF experts believe that the preservation of lung function outweighs the potential risks of developing antibiotic resistance. Although S. aureus is also a common chronic infection of the CF airway, there are no currently recommended antibiotics to suppress it growth.

Anti-inflammatory agents

The non-steroidal anti-inflammatory medication ibuprofen has been shown to slow the rate of lung function decline in children and adolescents with mild CF lung disease. However, to be effective in CF, ibuprofen needs to be administered in extremely high doses. Patients on this therapy need to be closely monitored by their CF physician to ensure therapeutic blood levels of ibuprofen have been achieved, and that side effects are avoided [9]. For these reasons, this therapy is not widely used, but has helped to establish the principal that anti-inflammatory strategies are important targets for future drug development. Systemic steroids, such as prednisone, also have a poor side effect profile, but may have a role when used in short bursts with some individuals [9].

 

Pancreatic enzyme replacement

Pancreatic enzymes are primarily derived from the pancreas of pigs, and contain lipases, proteases, and amylases. Enzymes are taken orally with each meal and snack. As the proteins are combined with the acid of the stomach, enzyme activity rapidly diminishes, and thus large doses are often required. Most products are provided as enteric coated microbeads to reduce inactivation in the stomach. Co-administration with various acid reducing medications usually improves efficiency of the enzyme products.

A wide variety of enzymes are available, some with varying ratios of lipases, proteases, and amylases. Many people with CF will have a clear preference for a particular product. Of interest, no pancreatic enzyme currently in use in the United States has undergone FDA approval. In April 2004, the FDA mandated that all pancreatic enzymes undergo the clinical testing required for FDA approval. This difficult process is currently underway.

Other nutritional considerations

Good nutrition is an essential component of the treatment of CF. Even with pancreatic enzyme replacement, absorption of fat-soluble vitamins (A, D, E, and K) is impaired, and supplementation of these vitamins is required. In addition to difficulties with nutrient absorption, people with CF have an increased caloric requirement as a result of the demands imposed by increased work of breathing, chronic inflammation and infection. Thus, recommended diets are high in protein and fat, with approximately 30-50% more calories then a typical diet. Occasionally, patients benefit from supplemental calories at night through a tube entering directly into the stomach ("tube-feeding"). Also, in adulthood, many people with CF will require supplemental insulin (see CF Related Diabetes). The excessive loss of salt in the sweat of individuals with CF can predispose them to dehydration. Care should be taken by children and adults with CF to avoid dehydration through liberal intake of salt and fluids when faced with hot conditions.

Lung Transplant

Lung transplantation has long been an option for people with CF who are approaching respiratory failure. Due to the multiple infections and high volume of sputum production that is characteristic of advanced CF lung disease, double-lung transplants are required. While transplantation can correct the respiratory component of the disease, other organs remain severely effected. The average survival following transplant is approximately 5 years. Surprisingly, recent analysis of children receiving lung transplants from 1992-2002 did not show an overall improvement in survival [17]. While the overall role of lung transplant in the treatment of CF continues to be evaluated, at this point, lung transplant should be considered as an option for patients with advanced CF lung disease.

CF Foundation Care Center Network

Given the complexity of CF care, and with many new therapies emerging, it is recommended that children and adults with CF receive care at CF Care Centers. These Centers utilize a team approach, with doctors and nurses trained and experienced in CF. Also part of the team are respiratory therapists, dietitians, and social workers, and patients typically have access to genetic counselors, mental health professionals, endocrinologists, and other subspecialists familiar with CF. Not surprisingly, patients cared for at CF Centers have been found to have better outcomes then patients cared for by physicians not affiliated with CF Centers. In addition, patients at CF Care Centers may have the opportunity to participate in clinical trials for experimental medications, with the potential to further improve CF care. In the United States, there are presently 115 Care Centers accredited by the CF Foundation, and 95 of these have Adult Programs. A complete listing and contact information is available on the CF Foundation website.

The future of CF care

As discussed above, improving therapies, combined with the availability of better diagnostic testing, has resulted in a steady increase in the average age of CF patients. Very soon, CF will be primarily a disease of adulthood, and increasingly patients with CF are surviving past middle age. While much attention has been focused on the process of adolescents with CF “transitioning” from the pediatric setting to adult programs within Care Centers, a similar process of transition will need to occur within the medical community, as increasingly adult physicians will be required to provide the majority of CF care. Older men and women with CF have unique healthcare needs, with complex infections, malignancies, and unique forms of diabetes and osteoporosis. Thus, the need for CF Centers with experience and commitment to adults care will continue to grow.

Emerging treatment strategies

A wide range of therapeutics are currently undergoing clinical trials for use in the treatment of various aspects of CF. Broad treatment categories and promising examples of each class of medication that are currently being tested include:

Modification of CFTR function

• VX-770: An oral agent that keeps defective CFTR chloride channels open in CF patients with the CFTR mutation G551D. Mutation of this class results in a chloride channel that is present on the cell surface, but doesn’t function properly.
• PTC124: An oral agent that improves protein translation in CF patients whose type of CFTR mutation (nonsense mutations) results in the premature disruption of protein synthesis, producing a shortened, non- functional protein. Approximately 10% of CF patients have these types of mutations. A phase II trial was published in August 2008.

Correction of airway surface liquid abnormalities

• Duramycin (Moli 1901): An aerosolized peptide that activates alternative chloride channels to compensate for the lack of CFTR function.
• Denufusol: A P2Y2 agonist that acts to increase airway surface volume and mucous clearance.
• Mannitol: An aerosolized sugar that may work in a similar fashion as hypertonic saline to rehydrate the mucous in the airways.

  
Antibiotics
•    Tobramycin (TIP): A dry powder form of the inhaled antibiotic, which would significantly reduce the time needed to deliver the drug.
•    Aztreonam (AZLI): An anti-pseudomonas antibiotic for inhalation.
•    SLIT-amikacin: An inhaled anti-pseudomonas antibiotic encased in a liposome.

Anti-inflammatory agents

• N-acetylcysteine: An oral “prodrug” which is converted into the antioxidant glutathione.

Nutritional Supplements
•    ALTU-135: A synthetic pancreatic replacement enzyme, that is not derived from pig pancreas, and would require fewer capsules with each meal.

A complete list of therapies being tested in CF Foundation sponsored studies in the United States are shown (above), and detailed information is available at the website. The promise for an ultimate cure to CF lies with gene therapy. With the identification of the normal genetic sequence of the CFTR gene, the potential exists to replace mutant CFTR genes with normal copies. Early preclinical studies demonstrated the feasibility of this approach, but trials with CF patients have proven that the application of this technology is extremely complicated in the clinical setting. More recently, the use of embryonic or adult stem cells to repair damaged lung tissue has gained attention, and may represent a future therapeutic approach [18].

Further Information

Links to Cystic Fibrosis Organizations and Foundations worldwide:

• Cystic Fibrosis Australia 
• Cystic Fibrosis Trust (UK) 
• European Cystic Fibrosis Society (based in Denmark) 
• Association Gregory Lemarchal (France) 
• Canadian Cystic Fibrosis Foundation 
• Cystic Fibrosis Foundation (United States) 
• Cystic Fibrosis Reaching Out Foundation (United States) 
• Boomer Esiason Foundation (United States) 
• Lungs For Life Foundation (United States) 
• Elizabeth Nash Foundation (United States)
• Cystic Fibrosis Worldwide (International)
• CysticFibrosis.com (International internet hub)

Links to medical sites

• World Health Organization ICD codes for Cystic Fibrosis
• Medline Plus entry for Cystic Fibrosis provided by the U.S. National Library of Medicine and the National Institutes of Health 
• Medical Subject Heading (MeSH) for Cystic Fibrosis by the National Library of Medicine

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