Adult Cystic Fibrosis

DR BOYLE: Thank you for coming today, sir. Can you tell us about yourself?

MR Y: Thank you for having me. I am 52 years old and grew up in North Carolina. I am now married and live in Virginia where I have worked as an engineer for the last 23 years. And I have cystic fibrosis.

DR BOYLE: Tell us about how you were diagnosed.

MR Y: Well, I think my parents suspected something was wrong shortly after I was born because I was constantly having large greasy bowel movements. But it wasn't until I developed pneumonia at age 3 that I underwent a sweat test and was diagnosed with cystic fibrosis.

DR BOYLE: Do you know what your parents were told to expect from your health?

MR Y: They were told not to get too attached to me because I was unlikely to live past the age of 7.

DR BOYLE: And when you reached the age of 7?

MR Y: They were told that I might make it to 10.

DR BOYLE: Tell us about your childhood. Were you sick often?

MR Y: No, other than taking pancreatic enzymes and having to do airway clearance I felt like a normal child. I did have recurrent sinus infections, which required antibiotics, but I was able to keep up with all the other kids and was actually fairly athletic. As a matter of fact, in college I ran a 5-minute mile.

DR BOYLE: What type of health problems did you have as you got older?

MR Y: Later in college I developed pneumonia and after that had a productive cough on a regular basis. But I never needed treatment with intravenous antibiotics and did not feel limited by my disease. In my 20s and 30s, I acted in many ways as if I did not have cystic fibrosis. My health care consisted of occasionally seeing my local internist, taking pancreatic enzymes, and inhaling albuterol as needed. This changed however when I reached my 40s. I began to have worsening shortness of breath and more frequent lung infections. I also developed severe sinusitis, which required surgery. It was because of the worsening shortness of breath and frequent infections that I decided to find a center that specialized in the care of adults with cystic fibrosis.

DR BOYLE: I believe that when you first came to see us at the Johns Hopkins Adult Cystic Fibrosis Program you had never had a prolonged course of intravenous antibiotics, or taken advantage of any of the newer cystic fibrosis medications that are now available. How did you feel after you began more aggressive treatment?

MR Y: Prior to treatment, I was experiencing severe shortness of breath, even at rest, for the first time in my life. This caused a significant amount of anxiety. After the first course of intravenous antibiotics, I felt like a different person. I was able to take the stairs again and not spend most of my day focused on breathing and coughing. Best of all, this improvement has lasted. Shortly after completing the intravenous antibiotics, I started regularly using azithromycin, inhaled dornase alfa, tobramycin, and hypertonic saline, along with aggressive daily airway clearance. And I have felt amazingly well. The regimen does take a significant investment of time each day, but is has been well worth it.

DR BOYLE: That is great to hear. I think this graph of your lung function over the last 7 years clearly demonstrates the benefit of all your hard work (Figure 1).

The case of Mr Y is instructive because it highlights several important aspects of cystic fibrosis: the growing importance of adult care, the variability in severity of disease, and the effectiveness of newer therapies.

Cystic fibrosis is a multisystem disease that leads to significant chronic sinopulmonary disease, pancreatic exocrine impairment, elevated sweat chloride, and male infertility. All of these phenotypic abnormalities are caused by dysfunction of the protein cystic fibrosis transmembrane conductance regulator (CFTR).² The CFTR protein is a chloride channel present in the epithelia of most of the lumens of the body and is a significant contributor to sodium and water balance. The CFTR gene is located on chromosome 7 and cystic fibrosis is caused by mutations in the gene that lead to dysfunction of the protein channel.² More than 1500 mutations have been identified that can lead to dysfunction of the CFTR protein and result in a cystic fibrosis phenotype.³ The precise mechanism by which CFTR dysfunction leads to the cystic fibrosis phenotype is unknown, although it is clear that effect of CFTR protein dysfunction on airway epithelial and glandular cells results in a decrease in the depth of the airway surface liquid layer in the lungs, an increase in the viscosity of airway secretions, and decreased ability to clear bacterial infection.⁴

Cystic fibrosis demonstrates the classic recessive inheritance pattern of genetics, requiring 2 mutations to be present for the disease to be manifested. Carriers of a single cystic fibrosis mutation do not generally demonstrate any phenotypic abnormalities. This is fortunate because approximately 4% of all whites carry a single cystic fibrosis mutation, making cystic fibrosis the most common life-shortening autosomal recessive disease in the white population (1 in 3200 live births).^{5 - 6} Cystic fibrosis is less common in nonwhites, with an incidence of approximately 1 in 15 000 live births in blacks, 1 in 9200 in Hispanics, and 1 in 10 000 in Asians.^{6 - 7} Currently there are more than 30 000 individuals with cystic fibrosis in the United States, and it is estimated that there are 100 000 cases worldwide.^{8 - 9}

Making the diagnosis of cystic fibrosis requires a clinical picture consistent with the cystic fibrosis phenotype and laboratory evidence of CFTR dysfunction.¹⁰ A consensus statement on the diagnosis of cystic fibrosis has summarized the key aspects of the phenotype.¹⁰ These include (1) chronic sinopulmonary disease as manifested by chronic cough and sputum production, persistent infection with typical cystic fibrosis pathogens including Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia cepacia, radiographic evidence of bronchiectasis, and chronic sinusitis, often with nasal polyposis; (2) gastrointestinal tract and nutritional abnormalities as manifested by pancreatic insufficiency or recurrent pancreatitis, meconium ileus or distal intestinal obstruction syndrome, failure to thrive or chronic malnutrition, and evidence of focal biliary cirrhosis; and (3) male urogenital problems as manifested by congenital bilateral absence of the vas deferens and obstructive azoospermia. Individuals who demonstrate any 1 or more of these features fulfill the criteria for a cystic fibrosis phenotype.

But because many of these features are not specific, it is essential that laboratory evidence of CFTR dysfunction is also established before making a diagnosis of cystic fibrosis. Dysfunction in CFTR can be demonstrated in 1 of 3 ways: (1) a sweat chloride level greater than 60 mEq/L (to convert to mmol/L, multiply by 1.0); (2) CFTR genotyping demonstrating the presence of 2 known cystic fibrosis mutations; or (3) characteristic bioelectric abnormalities by direct measurement of CFTR function in nasal epithelium. Because of its combination of sensitivity (98%), specificity (95%), and low cost ($150-$300), the sweat test remains the recommended initial screening test for cystic fibrosis in patients suspected of having disease.^{11 - 12} On the other hand, 2% of individuals with cystic fibrosis will not have a positive sweat chloride test of 60 mEq/L or above, making other ways of demonstrating CFTR dysfunction essential in patients for whom there is a high clinical suspicion of the diagnosis and who have a negative sweat test.

Genotyping to look for the presence of 2 cystic fibrosis mutations is the usual second option; however, sensitivity of genotyping for cystic fibrosis depends entirely on the number of mutations tested for and the ethnic background of the individual being tested.¹¹ Because approximately 1500 different mutations have been identified that cause cystic fibrosis, the sensitivity of sweat testing exceeds genotyping unless an extremely thorough mutation screening is performed. These thorough mutation screenings are now commercially available and include sequencing of all CFTR exons and key intron sequences. Cost considerations limit genotyping from being the first line of screening for individuals with a suggestive phenotype. However, thorough genotyping can be extremely valuable in individuals with inconclusive sweat test results.¹³ In addition, direct in vivo measurement of CFTR function in nasal epithelium of individuals (nasal potential difference) is available at some cystic fibrosis centers to aid in the diagnosis of challenging cases.¹⁰

In the last 4 decades, median survival in cystic fibrosis has increased dramatically. Parents of children with cystic fibrosis born in the 1950s or 1960s, like Mr Y's parents, were told that it was unlikely their children would live into their teenage years. With the development of antipseudomonal antibiotics and pancreatic enzyme replacement, survival began to significantly increase. Continued developments in therapy have resulted in almost yearly improvements in survival, leading to the current median survival in cystic fibrosis of 36.9 years (Figure 2).⁸

This increased survival has resulted in a dramatic increase in the number of adults with cystic fibrosis (Figure 3).^{8 ,14} The number of individuals with cystic fibrosis aged 18 years or older has increased by more than 400% since the early 1970s, and currently 43% of all individuals with cystic fibrosis are aged 18 years or older. In the next decade, 50% of all individuals with cystic fibrosis will be older than 18 years, and cystic fibrosis will become a condition seen more commonly in adult medicine than in pediatrics. While the majority of the adults with cystic fibrosis are between the ages of 18 and 30 years, there are a growing number of older adults with cystic fibrosis, with 25% being between the ages of 30 and 39 years, and 10% being older than 40 years.⁸ Last year there were 10 individuals older than 70 years in the US Cystic Fibrosis Foundation National Data Registry.⁸

While the most important reason for adult caregivers to know about cystic fibrosis is the growing number of adults with cystic fibrosis, there is also potential diagnostic importance. The majority of individuals with cystic fibrosis are diagnosed before the age of 3 years. However, approximately 5% of individuals with cystic fibrosis are diagnosed after the age of 16 years.⁸ A good number of these do not demonstrate all the classic symptoms of cystic fibrosis, potentially causing diagnostic dilemmas for internists who do not keep cystic fibrosis in mind when considering the differential diagnosis of adults with isolated bronchiectasis, chronic sinusitis, recurrent pancreatitis, or male infertility. The recent advent of newborn screening for cystic fibrosis in many states will likely decrease the frequency of late cystic fibrosis diagnoses in the distant future.¹⁵

The hallmark pulmonary pathology observed in cystic fibrosis is bronchial mucous plugging, inflammation, and eventually bronchiectasis. Most commonly, the bronchiectasis initially presents in the upper lobes and then progresses to involve all lobes over time. In assessing pulmonary disease, numerous studies have demonstrated that the forced expiratory volume in the first second of expiration (FEV₁) is a good general predictor of mortality in individuals with cystic fibrosis.^{16 - 17} While older studies have suggested that an FEV₁ below 30% of predicted function is associated with a 2-year mortality rate of 50%, recent data suggest outcomes in this group have improved and wide variability exists in individual patient experience depending on the frequency of infectious exacerbations and associated comorbidities.^{17 - 20} Unfortunately there is a characteristic progressive loss of lung function in cystic fibrosis beginning in the teenage years and averaging between 1% and 4% per year. However, different rates of decline in lung function results in a wide spectrum of severity of lung disease in adults with cystic fibrosis, with approximately 25% having severe lung disease, 40% with more moderate disease, and 35% having mild lung disease or normal lung function (based on FEV₁ criteria).⁸ Individuals with cystic fibrosis often demonstrate characteristic bacterial flora in their sputum, with chronic infection with S aureus and H influenzae as children and P aeruginosa as adults. Approximately 80% of individuals with cystic fibrosis are chronically infected with P aeruginosa by the age of 18 years.⁸ The clinical course of lung disease in cystic fibrosis is marked by periodic exacerbations, which are characterized by increased sputum, dyspnea, cough, fatigue, weight loss, and a decrease in spirometry measurements.¹⁴ These exacerbations can be contrasted with classic pneumonias in that they are not usually accompanied by fever, dramatic infiltrates on chest x-ray, or positive blood cultures.

Therapy for cystic fibrosis pulmonary disease involves both acute and chronic management. Individuals with acute pulmonary exacerbations are treated with aggressive airway clearance and antibiotics based on sputum bacterial cultures. Because the vast majority of adults with cystic fibrosis are infected with P aeruginosa, 2 intravenous antipseudomonal antibiotics are typically given for 14 to 21 days.^{14 ,21} These antibiotics are combined with airway clearance techniques 3 to 4 times per day to aid in clearance of infected secretions. The goal of therapy is to both improve symptoms and return the individual's FEV₁ to its baseline value.

It is in the chronic therapy of pulmonary disease in cystic fibrosis that there have been the most significant developments ( Article ).²¹ These therapies target the chronic obstruction, infection, and inflammation present in cystic fibrosis airways. Obstruction is treated first by mechanical airway clearance techniques, which aid in loosening and clearing the viscous secretions characteristic of cystic fibrosis. Some of these methods are high-frequency chest wall oscillation with a vest, oral airway oscillation with a flutter valve, and manual chest percussion.²² All of these serve to loosen secretions and are followed by episodes of “huffing” designed to clear the airways. Because much of the increased viscosity of pulmonary secretions in patients with cystic fibrosis is due to DNA from neutrophils involved in chronic lung infection, recombinant human DNase (dornase alfa) is often inhaled to decrease sputum viscosity. Daily use of inhaled dornase alfa has been shown in several studies to improve FEV₁ and reduce the frequency of acute pulmonary exacerbations.²³ Recently, inhalation of 7% hypertonic saline has also been shown to aid in airway clearance in cystic fibrosis.^{24 - 25} When inhaled 2 to 4 times per day, hypertonic saline results in FEV₁ improvement and in decreased frequency of exacerbations.

For the treatment of chronic pulmonary infection in cystic fibrosis, inhaled antibiotics are used. Chronic oral antipseudomonal antibiotics are rarely used because of the concern of development of resistance to the only oral antipseudomonal class of antibiotics, the fluoroquinolones. Inhaled antibiotics, however, offer a greater number of antibiotic options along with the advantage of high intrapulmonary drug concentrations and minimal systemic absorption. When chronically inhaled twice per day in an every-other-month regimen, inhaled tobramycin has been demonstrated to significantly improve FEV₁ and decrease the frequency of cystic fibrosis exacerbations.²⁶ While it does occur, the development of resistance has been less frequent than initially feared. Other inhaled antibiotics that have been demonstrated to be potentially beneficial with chronic use include colistimethate and aztreonam.²¹ Finally, there is increasing interest in therapies that may reduce the inflammation that is intrinsic to cystic fibrosis airways. Chronic daily use of oral azithromycin has been demonstrated in 4 separate studies to reduce the frequency of exacerbations in cystic fibrosis.²⁷ Whether the mechanism of this effect is due to reduction of inflammation or antimicrobial effects is still under investigation. Numerous other trials investigating anti-inflammatory therapies in cystic fibrosis are currently under way.

These therapies are combined with regular monitoring of spirometry and quick intervention for pulmonary decline in an effort to minimize loss of lung function. Adult care guidelines also suggest the use of intermittent radiological imaging to aid in monitoring progression of lung disease, while attempting to balance the need for detailed imaging and exposure to radiation.¹⁴ While available therapies can make a significant impact on both pulmonary symptoms and pulmonary function, they may require 1 to 2 hours each day, which is a considerable challenge for adults in school, on the job, or with a family. Current research is focusing on strategies that improve speed and efficacy in the delivery of cystic fibrosis medications.²⁸

If the chronic decline in lung function results in an FEV₁ consistently below 30% of predicted function, individuals often begin to experience both significant limitation in their daily activities and more frequent need for hospitalization and intravenous antibiotics. It is usually a combination of decreased FEV₁ and increasing symptoms that leads to individuals being referred for initial evaluation for double lung transplantation.¹⁹ Exact timing for the lung transplantation surgery depends on subsequent severity of symptoms and the rate of clinical decline because studies have demonstrated that only the sickest patients have a 5-year survival advantage after transplantation.²⁹ Individuals with cystic fibrosis undergoing lung transplantation do as well or better than individuals with any other disease that leads to lung transplantation.¹⁹ About 150 individuals with cystic fibrosis undergo lung transplantation each year, approximately 1.5% of the adult cystic fibrosis population annually. However there is still only a 5-year survival rate of 50% after this procedure and little evidence that the advent of lung transplantation has affected overall median predicted survival in cystic fibrosis.^{19 ,29}

One unusual bacterium that is worth being aware of because it can significantly influence the pulmonary course in cystic fibrosis is B cenocepacia, a specific genomic species in the B cepacia complex that is feared in the cystic fibrosis community because it can lead to a rapid decline in pulmonary status and is able to be transmitted between individuals with cystic fibrosis.³⁰ Outbreaks of B cenocepacia leading to significant morbidity and mortality have resulted in strict infection control guidelines for cystic fibrosis centers and for gatherings involving individuals with cystic fibrosis.³¹ Burkholderia cenocepacia is often resistant to standard antipseudomonal antibiotics and may require treatment with multidrug regimens including meropenem and trimethoprim/sulfamethoxazole.²¹

Other common complications that can make management of pulmonary disease in adults with cystic fibrosis more challenging include infection with multiple antibiotic-resistant P aeruginosa (17%-25%),³² infection with nontuberculous mycobacteria (7%-13%),³³ and development of allergic bronchopulmonary aspergillosis (2%-7%).³⁴

Although the strongest determinant of length and quality of life in cystic fibrosis is pulmonary health, nutritional and gastrointestinal issues also play a significant role. Approximately 90% of individuals with cystic fibrosis demonstrate pancreatic exocrine insufficiency and require the use of oral pancreatic enzyme supplementation with meals to prevent chronic malabsorption.⁸ This pancreatic pathology is often noted on computed tomography scans as “fatty replacement of the pancreas.” Most patients with cystic fibrosis take pancreatic supplements containing a mixture of amylase, lipase, and protease before each meal. Even with the use of pancreatic enzyme supplements however, individuals with cystic fibrosis still demonstrate a degree of fat malabsorption. The combination of fat malabsorption and chronic pulmonary disease can result in extremely high caloric requirements, requiring individuals with cystic fibrosis to concentrate on eating high-caloric meals (as well as high-salt content meals to counterbalance excess sweat sodium loss).^{14 ,35} Extra amounts of the fat-soluble vitamins A, D, E, and K are also required. Often, despite efforts to maximize caloric intake, malnutrition results in failure to reach maximum growth and weight potential.³⁵ Therapeutic options in this setting include the use of appetite stimulants or placement of a gastrostomy tube to allow nighttime feeding. The Cystic Fibrosis Foundation has set a goal body mass index of 22 for women with cystic fibrosis and 23 for men (calculated as weight in kilograms divided by height in meters squared).³⁶ Studies have suggested a strong association between nutritional status and outcomes, so recent management guidelines have stressed the importance of close attention to nutritional status.^{14 ,20 ,36}

One other common manifestation of gastrointestinal tract pathology in adults with cystic fibrosis is distal intestinal obstruction syndrome. This is classically caused by thickened stool and mucus in the terminal ileum and presents with a clinical picture consistent with small bowel obstruction.¹⁴ Distal intestinal obstruction syndrome often develops in the setting of chronic malabsorption, nonadherence to enzyme supplementation, swallowing of mucus, dehydration, or use of narcotics. The obstruction usually responds to treatment with oral polyethylene glycol solution and water-soluble contrast enemas. Other potential gastrointestinal issues in adults with cystic fibrosis include chronic elevation of serum liver enzyme levels, cirrhosis with portal hypertension, and increased risk of cholelithiasis and nephrolithiasis.¹⁴ Although the exact mechanisms are unknown, the increased viscosity of secretions and gastrointestinal tract malabsorption characteristic of cystic fibrosis are thought to be major contributors to all of these complications.

By the time they reach adulthood, 20% to 30% of individuals with cystic fibrosis develop pancreatic endocrine insufficiency in addition to their exocrine insufficiency, with the typical onset of this complication between the ages of 18 and 24 years.³⁷ Cystic fibrosis–related diabetes (CFRD) is a unique type of diabetes mellitus that has characteristics different from both insulin-dependent and non–insulin-dependent diabetes. Cystic fibrosis–related diabetes is caused by the cystic fibrosis pancreas being able to produce a small amount of insulin, but insufficient amounts to fully respond to intake of carbohydrates. This results in CFRD almost never being complicated by ketoacidosis but frequently characterized by significant hyperglycemia after meals. To avoid weight loss, CFRD is rarely managed by diet restrictions. Instead, treatment usually involves short-acting insulin at the time of meals.

Poorly controlled diabetes, which can result in neutrophil dysfunction and malnutrition, is associated with accelerated loss of lung function and increased mortality risk in individuals with cystic fibrosis.^{37 - 38} Aggressive management of CFRD has therefore become an important part of cystic fibrosis care.³⁷ Other common endocrine complications of adult cystic fibrosis include osteopenia and osteoporosis, with approximately two-thirds of adults with cystic fibrosis demonstrating decreased bone mineral content.³⁹ While vitamin D deficiency is extremely common in adults with cystic fibrosis and often contributes to decreased bone density, the decreased bone mineral content seen in cystic fibrosis is likely the result of multiple factors including chronic inflammatory cytokines, inadequate testosterone levels, malnutrition, and direct effect of CFTR mutations on bone development.³⁹

Approximately 99% of men with cystic fibrosis have congenital bilateral absence of the vas deferens (CBAVD), which has effects akin to a healthy male who has undergone a vasectomy.¹⁴ Although the vas deferens is abnormal, men with cystic fibrosis make sperm normally and are thus able to father children through assisted reproduction techniques involving microepididymal sperm aspiration and in vitro fertilization. On the other hand, women with cystic fibrosis do not appear to have a significant decrease in their ability to become pregnant. Studies have demonstrated that women with cystic fibrosis who have adequate pulmonary and nutritional status can do quite well with pregnancy.^{40 - 41} Because of the recessive inheritance genetics, offspring of individuals with cystic fibrosis will not be affected by cystic fibrosis unless their partner is a cystic fibrosis mutation carrier (or also has cystic fibrosis).

Both the increasing number of adults with cystic fibrosis and the fact that 5% of individuals with cystic fibrosis are diagnosed after the age of 16 years make it important for adult medicine clinicians to be familiar with cystic fibrosis. One pearl to remember is that bronchiectasis plus any 1 of 3 things should make a clinician think of cystic fibrosis: (1) male infertility (5% of male infertility is caused by CBAVD and approximately 80% of CBAVD is associated with CFTR mutations⁴² ); (2) recurrent idiopathic pancreatitis (10%-20% of individuals with chronic idiopathic pancreatitis carry cystic fibrosis mutations⁴³ ); or (3) recurrent nasal polyposis (recurrent bacterial sinusitis with nasal polyps can be a classic presentation of mild forms of cystic fibrosis).

Therefore, any combination of male infertility, unexplained pancreatitis, or recurrent nasal polyps, particularly in the setting of bilateral bronchiectasis, should immediately lead to further evaluation for cystic fibrosis. Additional diagnoses that should be considered in individuals with cystic fibrosis–like lung disease include primary ciliary dyskinesia, immunoglobulin deficiency, and allergic bronchopulmonary aspergillosis. Initial evaluation for these would include electron microscopy of ciliary structure and serum IgG and IgE levels.

Because of the unique care needs of adults with cystic fibrosis, the Cystic Fibrosis Foundation has established guidelines for a facility to become a certified adult cystic fibrosis care center. An adult cystic fibrosis care center has 1 or more lead physicians with expertise in adult cystic fibrosis care and a dedicated multidisciplinary team including a nurse coordinator, dietitian, respiratory therapist, and social worker focused on supporting the adult with cystic fibrosis. Lists of certified cystic fibrosis adult centers are available at http://www.cff.org.

Mr Y has continued to be devoted to his daily care regimen and has continued to use his engineering background by tracking his progress using a spreadsheet. During the past 3 years, he has not needed to be hospitalized and has not required intravenous antibiotics. He says that the regular use of airway clearance, inhaled antibiotics, and mucolytics has “given him his life back.”