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 recommendations remain widely used . Patients suspected of having CF must demonstrate at least one clinical feature of the disease (see below), 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.
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.
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 and 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 . 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.
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 . 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 as 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 than one exacerbation per year, but with advancing lung disease the frequency typically increases . Clinical features are listed below. No definitive diagnostic criteria exists, although usually several of these signs and symptoms will be present .
Signs and Symptoms of a Pulmonary Exacerbation of CF
- 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
- Weight loss
- Retraction of intercostal muscles
- Increased chest crackles
- 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.
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.
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 . 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.
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” . 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 .
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.
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 .
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 . 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 .
Despite these risks, women with CF generally have done well during the actual pregnancy and childbirth . 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 . 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 . 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.