abstract: There is increasing evidence that close monitoring and early intervention lead to better outcomes in patients with cystic fibrosis. At each office visit, spirometry should be performed and sputum culture specimens should be obtained; if the patient cannot produce sputum, a throat culture can be done instead. New respiratory symptoms or other evidence of worsening lung disease should prompt antibiotic therapy, increased airway clearance, and adjunctive anti-inflammatory medication as appropriate. Close attention should be paid to the patient's diet, appetite, stooling pattern, and growth measurements. Adolescents should be given additional information about their medications and adjunctive therapies to encourage them to take on a larger role in their own care. (J Respir Dis.2006;27(7):298-305)
Cystic fibrosis (CF) is an autosomal recessive disease that was first described in the English literature by Andersen1 in 1938. Since then, understanding of CF has evolved from a description of disease progression to knowledge of cellular and molecular pathogenesis.
Numerous factors have improved median survival from less than 2 years to more than 32 years.2 These include better recognition of CF; better health care delivery; and comprehensive treatment programs modeled after those introduced in the 1950s by Matthews and Doershuk,3 including pancreatic enzyme supplements and aggressive use of antibiotics and methods of airway clearance. Despite improvements in survival, CF continues to be the most common profoundly life-shortening genetic disease in whites.
It has long been believed, and was recently demonstrated, that close monitoring and early intervention by a multidisciplinary CF team result in better patient outcomes.4 Several overviews of the management of CF have been published.5-7 In this article, we will focus on the monitoring of adolescents with CF.
CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The cloning of the CFTR gene was announced in 1989,8 and there are now more than 1300 known mutations.9 Disease-causing mutations in the CFTR gene result in reduced or absent protein function in the apical membrane of epithelial cells. Abnormal CFTR function causes abnormal salt and water transport across epithelial surfaces and stimulates the production of thick, tenacious secretions.10
In the sweat glands, CFTR abnormalities stimulate the production of sweat with higher sodium and chloride concentrations, forming the basis for the diagnostic sweat test.11 In the lungs, accumulation of mucus in the bronchi and bronchioles--and perhaps other as-yet-undefined consequences of the epithelial defect--cause inflammation and chronic infection that lead to damage of the lung parenchyma. This progressive damage is responsible for most of the morbidity and mortality in patients with CF.
Because of the predominance of lung-related morbidity and mortality, many persons think of CF as a lung disease. However, CF affects nearly every organ system (Table). Although respiratory disease is the primary cause of morbidity and mortality in patients with CF, GI and endocrine dysfunction cause mortality and morbidity as well.
THE CF TEAM
The CF care team comprises physicians, nurses, social workers, clinical nutritionists, respiratory therapists, and others, all working closely with patients and their families. Each team member plays a unique role in monitoring and treating the adolescent with CF. Communication between families and medical personnel, as well as that among various members of the medical team, is essential for improving or maintaining a patient's health.
Successful communication begins with frequent clinic visits. The Cystic Fibrosis Foundation (CFF) recommends that children with CF be seen at a CFF-accredited cen- ter at least every 3 months, in addition to their regularly scheduled pediatrician visits. Recommendations for monitoring are somewhat flexible; more frequent monitoring may be necessary when a patient's health is worsening or unexpected results are encountered. Recent data point to the association between more frequent visits and better outcomes, even--and perhaps especially--for patients who are relatively healthy. In these pa-tients, early detection of declining health can prompt lung-preserving intervention.
Respiratory involvement results in most of the morbidity and mortality in patients with CF. The history should include the patient's ease of breathing; exercise tolerance; cough; sputum production; wheeze; and sinus symptoms, such as pain, pressure, headache, and nasal congestion.
The patient's physical examination focuses on nasal obstruction (with or without readily observed nasal polyps), chest overinflation, prolonged exhalation, crackles, and wheezes. The laboratory evaluation includes pulmonary function testing and either throat or sputum cultures.
Pulmonary function testing
Spirometry, the simplest pulmonary function test, is performed at each visit. The results are initially interpreted by the physician, who should pay particular attention to expiratory flow rates. It is useful to review the results of spirometry with the patient and parents, both to educate them about CF and to motivate them to play a more active role in maintaining or improving lung health.
Pulse oximetry, performed while the patient breathes ambient air, may be the single most important pulmonary function test and should be assessed at each visit. Each year, patients undergo full pulmonary function testing, which includes measurement of static lung volumes.
Oropharyngeal and sputum cultures
At each visit, throat or sputum specimens are obtained for culture. If the patient can produce sputum, a sputum culture is preferred, because the findings correlate well with cultures obtained directly from the lower respiratory tract via bronchoscopy or even from the cut surface of the lung.12,13 If the patient is unable to produce sputum, then a post-cough posterior pharyngeal swab may be used. However, this method probably does not reflect tracheobronchial flora as accurately as a sputum sample does.14
In either case, the specimen should be sent only to a microbiology laboratory that can comply with the CFF recommendations for the processing of respiratory specimens.15 The results of these cultures are used to help determine antibiotic choices during pulmonary exacerbations. New respiratory symptoms or physical or laboratory findings suggestive of worsening lung disease should be addressed with an appropriate combination of antibiotics, increased airway clearance, and anti-inflammatory medication.
The choice of an antibiotic regimen is usually based on the results of the most recent respiratory specimen. However, several studies have demonstrated that the presence of in vitro resistance does not correlate with clinical response. This may result from alterations in antibiotic sensitivity in bacteria growing planktonically (in the laboratory) versus in biofilm (as in patients with CF). Therefore, a patient's previous clinical response influences the decision regarding the regimen.
Adjunctive therapy for new respiratory symptoms or worsening lung disease often includes anti- inflammatory medications. The 2 most commonly used anti-inflammatory agents are oral corticosteroids (prednisone or prednisolone) and inhaled corticosteroids (such as budesonide or fluticasone). In some centers, NSAIDs, such as ibuprofen, are used as long-term treatment. The benefits of corticosteroids and ibuprofen have been prospectively demonstrated in patients with CF.16,17
Anteroposterior and lateral chest radiographs are taken annually and during acute changes in respiratory status, especially if there is sudden onset of chest pain or of symptoms that are severe enough to warrant hospitalization. Chest radiographs are interpreted for increased linear and cystic markings, consolidation, air trapping, pneumothorax, and bronchiectasis. Unexpected findings or rapid worsening of radiographic appearance should prompt further evaluation and therapy.
Cardiopulmonary exercise testing
Children older than 6 years may be able to perform cardiopulmonary exercise testing. Any child who can reliably perform such testing should be tested annually. Exercise testing is particularly important because of the proven correlation between exercise test results and survival in patients with CF.18 Furthermore, children and adults with CF are able to improve exercise tolerance and cardiopulmonary fitness when they have an appropriate exercise regimen.19
Much like the infant and young child with CF, the adolescent with CF needs to be monitored closely for GI problems. Primary monitoring of the GI system is performed by taking a history of diet; appetite; and stooling patterns, including number of stools per day, size and form of stools, and whether oil is present in the stool. A large number of stools, bulky malodorous stools, or stools that leave an oily sheen on water are indicators of fat malabsorption. At each visit, historical data are combined with measurements of height, weight, and body mass index.
A patient who fails to grow according to the CDC growth curves should be treated appropriately. If the stooling pattern indicates malabsorption, the patient's pancreatic supplementation should be increased or an acid blocker added to increase its efficacy.
A voracious appetite may be another sign of increased malabsorption. Failure to grow in the absence of signs of malabsorption may be attributable to inadequate calories in the diet and can be managed with dietary supplementation. Attention to growth is critical because good nutritional status has been correlated with better pulmonary health.20
While pancreatic exocrine dysfunction is a hallmark of CF, pancreatic endocrine dysfunction develops in only about 20% of patients, most frequently arising after the first decade of life. CF-related diabetes mellitus (CFRDM) is not completely understood. However, it probably results from fibrotic damage to the pancreas and loss of beta cells in the pancreatic islets, which interferes with adequate insulin production.
Management of CFRDM results in better nutritional and pulmonary health.21 Therefore, it is recommended that patients older than 16 years have an annual oral glucose tolerance test (OGTT) in or-der to uncover unsuspected glucose intolerance.
An OGTT may be appropriate for patients younger than 16 years who experience unexpected weight loss, polyuria, polydipsia, glycosuria, or a random blood glucose level of more than 180 mg/dL. An OGTT is performed by measuring fasting blood glucose, then administering 1.75 g/kg (to a maximum of 75 g) of glucose. Blood glucose is measured again 2 hours after the glucose load. A fasting blood glucose level of greater than 140 mg/dL is diagnostic of CFRDM.
Any patient found to have CFRDM should be treated with insulin to maintain normal serum glucose levels. A fasting blood glucose value of less than 140 mg/dL and a 2-hour glucose level of greater than 200 mg/dL indicate glucose intolerance without overt diabetes. A patient with these values should be monitored closely. The administration of insulin should be considered, depending on the patient's clinical and nutritional status.22
In addition to pancreatic endocrine dysfunction, young adults with CF may have endocrine dysfunction related to a relative growth hormone deficiency. One randomized, double-blind, controlled clinical trial demonstrated that daily injections of growth hormone resulted in improvement in height, lean body mass, and overall clinical status in prepubertal patients with CF.23
Acute pancreatitis sometimes occurs in the small percentage of adolescents and adults with CF who have pancreatic sufficiency. Pancreatitis develops in as many as 15% of those who do not require supplemental pancreatic enzymes for adequate food digestion. The treatment of pancreatitis in these patients is similar to that of patients with pancreatitis who do not have CF.
CF-related liver disease develops in a small percentage of patients. This may range from asymptomatic multifocal biliary fibrosis to multilobular biliary cirrhosis with portal hypertension, hypersplenism, and the risk of bleeding from esophageal varices. Patients are monitored for liver disease by a physical examination to check for liver enlargement and by the annual measurement of liver enzyme levels, albumin levels, bilirubin concentration, and complete blood cell count.
Elevations of liver enzyme levels or bilirubin concentration should be followed up with an abdominal sonogram to look for intrahepatic bile duct dilatation and gallstones. Treatment of biliary stasis with ursodeoxycholic acid should be begun early because of its relative safety and its potential for slowing disease progression.24
MONITORING PSYCHOSOCIAL HEALTH
Medical monitoring and intervention are incomplete without attention to the psychosocial impact of life-shortening, chronic illness. Adolescents engage in many behaviors aimed at establishing independence from their parents. This sometimes includes the avoidance of therapy as well as parent-adolescent conflict. One strategy for addressing this is to empower the patients: Tell them that if they demonstrate knowledge of their medical regimen and consistent adherence to daily therapy, their parents will have no reason to be constantly "on their case."
Other adolescents may become passive and relinquish their care and knowledge of their disease to their parents. Because patients with CF are living longer than ever, it is critical that adolescents be knowledgeable about their therapy and participate actively in treatment. At each visit, the patient should be addressed as the primary source of the history and current therapy; parents should be allowed to give their "version" as well. The adolescent should be provided with the opportunity to speak confidentially with one or more members of the CF care team.
Patients also should be monitored for signs and symptoms of depression. If depression is identified, appropriate steps should be taken to provide necessary treatment. A private conversation may also be an opportunity to discuss puberty and fertility with adolescents. The reduced fertility associated with CF (especially in males) should be discussed in an age- appropriate manner.
TRANSITIONING TO ADULTHOOD
Adolescents may inquire about career choices. While many patients with CF can pursue the career of their choice, some guiding principles are helpful. First, patients with CF probably should avoid jobs that involve significant exposure to airborne pollution. Second, jobs that require rigorous or sustained physical activity may be difficult to perform over a long period.
Finally, choosing a career in patient care, such as that of a physician, nurse, or medical assistant, requires particular forethought. Frequent exposure to respiratory pathogens may be harmful to persons with CF. Conversely, a medical professional with CF may, through coughing, transmit harmful pathogens to an immunocompromised patient.
Maintaining good health requires significant energy and attention to detail from the patient and his or her family. The adolescent with CF should begin to play a major role in monitoring his own care. To that end, the patient should be familiar with the names, dosages, and timing of medications and adjunctive therapy. The effort invested by the patient and his fam-ily will be well rewarded, with a feeling of greater control and bet-ter overall emotional and physical health.
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