AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Cystic fibrosis (CF) is the most common lethal inherited disease in white persons. CF is an autosomal recessive disorder, and most carriers of the gene are asymptomatic. CF is a disease of exocrine gland function, involving multiple organ systems and chiefly resulting in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

Pathophysiology

CF is caused by defects in the gene for cystic fibrosis transmembrane conductance regulator (CFTR), which encodes for a protein that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the gene for CFTR (CFTR) result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. Resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which results in infection and inflammation. These abnormalities result in viscid secretions in the respiratory tract, pancreas, gastrointestinal tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

Lung

Most fatalities associated with CF result from progressive lung disease. For individuals with CF, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation (except possibly for the presence of dilated submucosal gland ducts in the airways). Shortly after birth, many patients with CF acquire a lung infection, which incites an inflammatory response. Infection becomes established with a distinctive bacterial flora. A repeating cycle of infection and neutrophilic inflammation develops.

Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis, leading to bacterial persistence. NE also causes production of the neutrophil chemoattractant interleukin (IL)–8 from epithelial cells and elastin degradation, and it acts as secretogogue, thereby contributing to persistence of inflammation and infection, structural damage, impaired gas exchange, and, ultimately, end-stage lung disease and early death.

Intestine

Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life. In addition, other pathologic disorders complicate the simple relationship between the apical chloride and water secretion and the disease. The pancreatic insufficiency (PI) decreases the absorption of intestinal contents. Mechanical problems associated with inflammation, scarring, and strictures may predispose the patient to sludging of intestinal contents, leading to intestinal obstruction by fecal impaction or to intussusception. Adhesions may form, leading to complete obstruction. A complete obstruction may require resection, leading to loss of absorptive epithelium of the distal ileum.

Pancreas

As a part of normal digestion, stomach acid is neutralized by pancreatic bicarbonate, leading to the optimal pH for pancreatic enzyme action. Reduced bicarbonate secretion in response to secretin stimulation has been demonstrated in patients with CF with both PI and pancreatic sufficiency (PS). Reduced bicarbonate secretion affects the digestion so that neither endogenous nor exogenous pancreatic enzymes can work at their optimal pH.

Other factors, such as reduction of water content of secretions, precipitation of proteins, and plugging of ductules and acini, prevent the pancreatic enzymes from reaching the gut. Autodigestion of the pancreas occasionally leads to pancreatitis. Most patients with CF (90-95%) have pancreatic enzyme insufficiency and present with digestive symptoms and/or failure to thrive early in life. However, onset of PI varies and may occur in patients older than 6 months.

Some patients never develop PI. Patients with PI typically present with poor weight gain in association with frequent stools that are malodorous, greasy, and associated with flatulence and colicky pain after feeding. The combination of increased energy intake demand at baseline, the added energy intake demand of chronic disease, difficulty sustaining energy uptake because of malabsorption, and anorexia associated with ongoing lung inflammation leads to poor weight gain. PI predisposes patients to poor absorption of fat-soluble vitamins A, D, E, and K. Symptomatic deficiency of any of these vitamins can occur before diagnosis or as a later complication of the disease.

Liver

Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. The biliary ductules may be plugged with secretions. If this process is extensive, obstructive cirrhosis complicated by esophageal varices, splenomegaly, and hypersplenism may occur. Secondary involvement of the liver may also occur because of involvement of other organs; for example, malnutrition may be associated with hepatic steatosis, and right heart failure caused by chronic hypoxia may result in passive congestion of the liver.

Gallstones are more prevalent in patients with CF than in age-matched control subjects. As many as 15% of young adults with CF have gallstones, irrespective of the status of the pancreatic function. Abnormal mucin in the gallbladder and malabsorption of bile acids in a patient with PI result in a higher frequency of gallstones.

Frequency

United States

CF is the most common lethal disease inherited by the white population. CF is inherited as an autosomal recessive trait. In the United States white population of Northern European origin, prevalence is 1 case per 3,200. In African Americans, prevalence is 1 case per 15,000. In Hispanics, prevalence is 1 case per 9,200. In Asian Americans, prevalence is 1 case per 31,000.

International

Prevalence ranges from 1 case per 620 in a confined population with Dutch ancestry to 1 case per 90,000 in Asians.

Mortality/Morbidity

Currently, the median age of survival is 36.8 years; the median age of survival is significantly higher in males than in females. Pulmonary involvement is progressive. Beginning as bronchitis, bronchiolitis, and, then, bronchiectasis, pulmonary involvement leads to cor pulmonale and end-stage lung disease. Hemoptysis and pneumothorax are complications. Sweat abnormalities may result in heat stroke and salt depletion, especially in infants. Mucocele and mucopyocele associated with chronic sinusitis and nasal polyps can cause erosion of the sinus wall, resulting in central nervous system complications from the space-occupying effect of mucopyocele or from associated complications. Portal hypertension occasionally causes death through esophageal varices.

The clinical presentation, age at diagnosis, severity of symptoms, and rate of disease progression in the organs involved vary widely. Gastrointestinal tract complications result from pancreatic involvement (leading to insufficient pancreatic enzymes), pancreatic tissue damage (leading to diabetes mellitus in 8-12% of patients >25 y), and excessive administration of exogenous pancreatic enzymes (resulting in fibrosing colonopathy). Intestinal complications range from meconium ileus with associated complications during the neonatal period (12% of neonates with CF) to distal intestinal obstruction syndrome, rectal prolapse, peptic ulcer, and gastroesophageal reflux. Liver involvement may result in a fatty liver (30-60% of patients), focal biliary cirrhosis, multinodular biliary cirrhosis, and associated portal hypertension.

The prevalence of cholecystitis and gallstones is higher in patients with CF than in other individuals. Delayed puberty and reduced fertility are other complications; most males are azoospermic because of agenesis of the vas deferens. Female fertility is probably only mildly impaired, and many successful pregnancies have been reported in women with CF.

Race

Distribution of CFTR mutations varies according to the background of patients; for example, 508delF is the most common mutation found in the white population of Northern European origin. Variability in clinical features between people of different races with same genotype has not been reported. Clinical manifestations are similar in black and white populations, except that a poorer nutritional status exists in black patients. Black patients with CF currently are younger and were younger at diagnosis, and they have poorer nutritional status and pulmonary function than white patients with CF. Whether this is genetic or due to socioeconomic factors is unclear; low socioeconomic status is associated with significantly worse pulmonary outcomes in patients with CF.

Sex

Male patients with CF appear to be less affected than female patients with CF. Females have greater deterioration of pulmonary function with increasing age and younger mean age at death. Although the idea has been suggested that the increase in hormone secretion related to menarche may interfere with the defense mechanisms of the immune system, thereby promoting progressive pulmonary involvement, the immune system in patients with CF is fundamentally intact.

Age

Clinical manifestations vary with the patient's age at presentation; for example, neonates may present with meconium ileus or, rarely, with other features such as anasarca. In patients younger than 1 year, patients can present with wheezing, coughing, and/or recurring respiratory infections and pneumonia. Gastrointestinal tract presentation in early infancy may be in the form of steatorrhea, failure to thrive, or both. Patients diagnosed later in childhood or in adulthood have PS more frequently and often present with chronic cough and sputum production.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

A correlation is emerging between the specific mutation and the patient's clinical condition. Based on current knowledge of the association between genotype and phenotype, the clinical characteristics of patients with cystic fibrosis (CF) are divided into severe, milder than severe, and variable phenotypes.

• Gastrointestinal tract manifestations (intestinal)
• • Neonates: Infants may present with intestinal obstruction at birth and a variety of surgical findings, for example, meconium ileus (7-10% of patients with CF), volvulus, intestinal atresia, perforation, and meconium peritonitis. Less commonly, passage of meconium may be delayed (>24-48 h after birth) or cholestatic jaundice may be prolonged.
  • Infants and children: Patients present with increased frequency of stools, which suggests malabsorption (ie, fat in stools, oil drops in stools), failure to thrive, intussusception (ileocecal), or rectal prolapse.
• Gastrointestinal tract manifestations (pancreatic)
• • Patients with PI have fat-soluble vitamin deficiency and malabsorption of fats, proteins, and carbohydrates (however, malabsorption of carbohydrates is not as severe as that of fats and proteins). Steatorrhea is characterized by frequent, poorly formed, large, bulky, foul-smelling, greasy stools that float in water. Cloth diapers, if used, are difficult to clean.
  • Patients present with failure to thrive (despite an adequate appetite), flatulence or foul-smelling flatus, recurrent abdominal pain, and abdominal distention. Alternatively, some patients have anorexia without obvious steatorrhea. Many infants have symptoms of gastroesophageal reflux.
• Gastrointestinal tract manifestations (hepatobiliary): Patients may present with a history of jaundice or gastrointestinal tract bleeding.
• Respiratory tract manifestations
• • Patients present with a chronic or recurrent cough, which can be dry and hacking at the beginning and can produce mucoid (early) and purulent (later) sputum. Prolonged symptoms of bronchiolitis occur in infants.
  • Paroxysmal cough followed by vomiting may occur.
  • Recurrent wheezing, recurrent pneumonia, atypical asthma, pneumothorax, hemoptysis, and digital clubbing are all complications and may be the initial manifestation.
  • Dyspnea on exertion, history of chest pain, recurrent sinusitis, nasal polyps, and hemoptysis may occur.
• Urogenital tract manifestations
• • Males are frequently sterile because of the absence of the vas deferens. Undescended testicles or hydrocele may exist.
  • Fertility is maintained, although possibly decreased, in females. Secondary sexual development is often delayed.
  • Amenorrhea may occur in patients with severe nutritional or pulmonary involvement.

Physical

Physical signs depend on the degree of involvement of various organs and the progression of disease.

• Nose
• • Rhinitis
  • Nasal polyps
• Pulmonary system
• • Tachypnea
  • Respiratory distress with retractions
  • Wheeze or crackles
  • Cough (dry or productive of mucoid or purulent sputum)
  • Increased anteroposterior diameter of chest
  • Clubbing
  • Cyanosis
  • Hyperresonant chest on percussion may be noted; crackles are heard acutely in associated pneumonitis or bronchitis and chronically with bronchiectasis.
• Gastrointestinal tract
• • Abdominal distention
  • Hepatosplenomegaly (fatty liver and portal hypertension)
  • Rectal prolapse
  • Dry skin (vitamin A deficiency)
  • Cheilosis (vitamin B complex deficiency)
• Other systems
• • Scoliosis
  • Kyphosis
  • Swelling of submandibular gland or parotid gland

Causes

CF is an autosomal recessive disease caused by defects in the CFTR gene, which encodes for a protein that functions as a chloride channel and is regulated by cAMP. CFTR mutations result in abnormalities of cAMP-regulated chloride transport across epithelial cells on the mucosal surfaces.

The failure of chloride conductance by epithelial cells and associated water transport abnormalities result in viscid secretions in the respiratory tract, pancreas, gastrointestinal tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Allergic bronchopulmonary aspergillosis (ABPA)
Immunodeficiency (presenting as recurrent respiratory infections)
Celiac disease

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The diagnosis of cystic fibrosis (CF) is based on typical pulmonary and/or gastrointestinal tract manifestations, a family history, and positive results on sweat test.
• Sweat test: Several methods are used to conduct a sweat test. Performed properly, the quantitative pilocarpine iontophoresis test (QPIT) to collect sweat and perform a chemical analysis of its chloride content is currently considered to be the only adequately sensitive and specific type of sweat test (see Cystic Fibrosis Foundation).
• • For reliable results, collect at least 50 mg or, preferably, 100 mg of sweat. Current macroduct collection methods allow adequate analysis with smaller volumes of sweat. The sweat chloride reference value is less than 40 mEq/L, and a value of more than 60 mEq/L of chloride in the sweat is consistent with a diagnosis of CF. The sweat test must be performed at least twice in each patient, preferably several weeks apart. Values of 40-60 mEq/L are considered borderline, and the test must be repeated because these values have been found to be consistent with the diagnosis in some patients with typical features.
  • Repeat a sweat test to confirm positive results. Repeat a sweat test with negative results if clinical features suggestive of CF are present. Some patients with genetically documented CF and typical symptoms have consistently negative results on sweat tests.
  • Other causes of elevated levels of sweat chloride include the following:
    • Untreated adrenal insufficiency
    • Glycogen storage disease
    • Type I fucosidosis
    • Hypothyroidism
    • Vasopressin-resistant diabetes insipidus
    • Ectodermal dysplasia
    • Malnutrition
    • Mucopolysaccharidosis
    • Panhypopituitarism
    • Familial cholestasis
    • Familial hypoparathyroidism
    • Atopic dermatitis
    • Iatrogenic causes (ie, infusion of prostaglandin E₁, improper technique)

Imaging Studies

• Chest radiography: Initial changes are hyperinflation and peribronchial thickening. Progressive airtrapping with bronchiectasis may be apparent in the upper lobes. With advancing pulmonary disease (see Image 1), pulmonary nodules resulting from abscesses, infiltrates with or without lobar atelectasis, marked hyperinflation with flattened domes of the diaphragm, thoracic kyphosis, and bowing of the sternum develop. Pulmonary artery dilatation and right ventricular hypertrophy associated with cor pulmonale is usually masked by marked hyperinflation. Several radiologic scoring systems exist.
• Sinus radiography: Panopacification of the sinuses is present in almost all patients with CF, and its presence is strongly suggestive of the diagnosis. Conversely, absence of panopacification strongly suggests that CF is not present.

Other Tests

• Genotyping
• • More than 1300 CF mutations have been identified. In the commercially available CF gene sequencing method, the entire coding region, splice junction sites, and promoter region of the CFTR gene are amplified from genomic DNA by polymerase chain reaction (PCR) and the subjected to nucleotide sequence analysis on an automated capillary DNA sequencer. This test can detect more than 98% of disease-causing mutations. The detection rate is lower in African American, Hispanic, and Asian populations; therefore, failure to find 2 abnormal genes does not exclude the disease.
  • A finding of 2 CFTR mutations in association with clinical symptoms is diagnostic, but negative results on genotype analysis do not exclude the diagnosis.
• Semen analysis: Obstructive azoospermia, in the absence of any other obvious cause (eg, vasectomy), provides additional corroborative evidence for the diagnosis of CF. Confirm results from semen analysis by obtaining a testicular biopsy.
• Nasal potential difference measurement
• • Potential difference (PD) (voltage) measured from nasal mucosa and the reading obtained by a reference electrode inserted into the forearm correlates with the movement of sodium across cell membranes, which is a physiologic function rendered abnormal by a CFTR mutation. The nasal potential difference (NPD) is a sensitive test of electrolyte transport that can be used to support or refute a diagnosis of CF. A normal mean value standard error (SE) is 0.9-24.7 mV; an abnormal value is 1.8-53 mV. When measurements are repeated after mucosal perfusion with amiloride to block an epithelial sodium channel, the drop in PD is greater in patients with CF (73%) than in control subjects (53%). Normally, subsequent perfusion with chloride-free solution and isoproterenol produces a sharp increase in the PD but has little effect when CFTR function is abnormal.
  • As a result of the lack of commercially available equipment and the practical difficulties with NPD measurement, this test is performed in only a few research centers to diagnose CF in patients in whom making a diagnosis is difficult or a sweat test is not technically possible because of skin problems.

Procedures

• Pulmonary function testing (PFT)
• • Standard spirometry may not be reliable until patients are aged 5-6 years; however, some younger patients can be taught to do reproducible maneuvers. Partial flow-volume curves may show abnormalities, in addition to an elevated airway resistance, and hyperinflation.
  • The recently described forced oscillation technique (FOT), which uses the impulse oscillometry system (IOS), can be used successfully in younger children. Airway resistance measured by IOS has been found to be similar to the airway resistance measured by body plethysmography, and this technique has been successfully used to measure lung function in young patients with CF unable to perform spirometry.
  • Typically, peripheral airway involvement resulting from CF manifests as an obstructive defect with airtrapping and hyperinflation; oxyhemoglobin desaturation may occur because of a ventilation-perfusion mismatch. In the early stages, forced expiratory volume in 1 second (FEV₁) may be normal and forced expiratory flow (FEF) after 25-75% of vital capacity has been expelled (FEF 25-75) is reduced, suggesting small airway involvement. As the disease progresses, FEV₁ is also reduced.
  • The associated airtrapping results in an elevated ratio of residual volume to total lung capacity (RV/TLC). With hyperinflation, TLC is also increased. In patients with advanced disease, extensive lung changes with fibrosis are reflected as restrictive changes characterized by declining TLC and vital capacity.
• Bronchoalveolar lavage: Airway inflammation is the hallmark of CF lung disease. Studies suggest airway inflammation even in the absence of infection. Bronchoalveolar lavage fluid usually shows a high percentage of neutrophils, and recovery of Pseudomonas aeruginosa from bronchoalveolar lavage fluid supports the diagnosis of CF in a clinically atypical case.
• Sputum microbiology: The most common bacterial pathogens in the sputum of patients with CF are Haemophilus influenzae, Staphylococcus aureus, P aeruginosa, Burkholderia cepacia, Escherichia coli, and Klebsiella pneumoniae. Findings of P aeruginosa, especially the mucoid form, support the diagnosis of CF in children.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

As a result of the complex and multisystemic involvement of cystic fibrosis (CF) and the need for care by specialists, treatment and follow-up care at specialty centers with multidisciplinary care teams (ie, CF centers) is recommended. At the time of initial confirmation of the diagnosis, baseline assessment, investigations, and initiation of therapy are recommended. In addition, patient/parent education, including counseling and instructions regarding airway clearance techniques and the use of equipment (eg, nebulizer, spacer for metered-dose inhaler), is recommended. When a patient presents with complications necessitating hospital admission, these objectives can be obtained during hospitalization. Follow-up outpatient visits are scheduled at 2-3 monthly intervals. Hospital admission is required for treatment of acute pulmonary exacerbation and severe complications.

Surgical Care

Surgical therapy may be required for the treatment of respiratory complications such as pneumothorax, massive recurrent or persistent hemoptysis, nasal polyps, or persistent and chronic sinusitis. Gastrointestinal tract complications, such as meconium ileus, intussusception, gastrostomy tube placement for supplemental feeding, and rectal prolapse, also require surgical therapy. Lung transplant is indicated for the treatment of end-stage lung disease.

Consultations

In addition to the specialists available at CF centers (usually pulmonologists and/or gastroenterologists), other specialists may need to be consulted when other systems are involved or complications involve other organs.

• Surgeon
• Otolaryngologist
• Endocrinologist
• Cardiologist
• Transplant surgeon

Diet

In general, a normal diet with additional energy and unrestricted fat intake is recommended. A high-energy and high-fat diet, in addition to vitamin (especially fat soluble) and mineral supplementation, is recommended to compensate for malabsorption and the increased energy demand of chronic inflammation. In children, because of a variety of physical activities and eating habits, base assessment and modification of energy requirements on growth and weight gain. Special consideration is given to female patients with a potential for delayed puberty because of malnutrition, patients with diabetes mellitus, and patients with liver disease. Nutritional supplements in the form of either high-energy oral preparations (eg, Scandishake) or enteral feeds (eg, elemental formulas, high-fat mixtures) via nasogastric tube or gastrostomy may be indicated in some patients.

Activity

Regular exercise increases physical fitness in patients with CF. Upper body exercises, such as canoe paddling, may increase respiratory muscle endurance.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The primary goals of cystic fibrosis (CF) treatment include maintaining lung function as near to normal as possible by controlling respiratory infection, clearing airways of mucous, administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth, and managing complications.

Mild acute pulmonary exacerbations of CF can be treated successfully at home by increasing the frequency of airway clearance; by inhaled bronchodilator treatment, chest physical therapy, and postural drainage; by increasing the dose of dornase alfa (Pulmozyme); and by use of oral antibiotics such as oral fluoroquinolones.

Drug Category: Enzymes, pancreatic

These agents aid digestion when the pancreas is malfunctioning. Current pancreatic enzyme preparations are derived from porcine extracts and contain various proportions of lipase, amylase, and protease. Most of the preparations are available in multiple strengths. A particular dose is prescribed based on clinical symptoms and age and weight and then modified according to the clinical response. Usually, the dose of pancreatic enzymes should not exceed 2000 U/kg/meal of lipase. The novel preparation TheraCLEC-Total, a highly purified microbiologically-derived enzyme preparation, is under investigation in clinical trials.

Drug Category: Vitamins

Vitamins are organic substances required by the body in small amounts for various metabolic processes. They may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are classified as fat or water soluble. Vitamins A, D, E, and K are fat soluble while biotin, folic acid, niacin, pantothenic acid, B vitamins (ie, B-1, B-2, B-6, B-12), and vitamin C are generally water soluble.

Vitamin deficiency may result from an inadequate diet, increased requirements (eg, pregnancy, lactation), or secondary to disease or drug use. They are used clinically for the prevention and treatment of specific vitamin deficiency states.

Supplementation of fat-soluble vitamins is routine in CF because of chronic malabsorption.

Drug Category: Bronchodilators

Albuterol provides selective agonistic action on beta2-adrenoceptors. Stimulate adenyl cyclase resulting in smooth muscle relaxation of the bronchi, uterus, and skeletal muscle. Inhaled beta2-agonists are often administered before chest physical therapy for airway clearance. They also are indicated when clinical evidence of bronchial hyperresponsiveness exists. In children with CF, use of bronchodilators must be evaluated. Children with bronchiectasis may have a paradoxic bronchodilatation in response to beta-adrenergic agents. Pulmonary function testing before and after bronchodilators is suggested to avoid these counterproductive effects.

Drug Category: Mucolytic agents

Large amounts of neutrophil-derived DNA released from the dead neutrophils increase sputum viscosity. Mucolytics, such as dornase alfa, an enzyme that hydrolyses the DNA, are used in patients with CF to improve airway clearance.

A recent comparative trial of patients receiving 7% hypertonic NaCl (4 mL via nebulizer bid) versus patients receiving normal saline in similar fashion, were shown to have improved lung function and fewer pulmonary exacerbations. At this time, 7% hypertonic saline is not commercially available.

Drug Category: Antibiotics

Antibiotic treatment may vary from a short course of one antibiotic agent to a continuous course with multiple antibiotics administered via various routes, including PO, IV, or inhalation. Since patients with CF have a larger lean body mass, they often have a higher clearance rate for many antibiotics. Achieving effective levels in respiratory secretions is difficult; higher doses of antibiotics and monitoring of aminoglycoside levels are required.

Administer aerosolized antibiotics when the airway pathogens are resistant to oral antibiotics or when the infection is difficult to control at home. Aerosolized antibiotics may reduce symptoms by reducing the organism density in the airways. Other advantages include prevention of infection or delay of chronic colonization, treatment of acute infection, and treatment of bacterial colonization in patients following transplantation to prevent infection in the transplanted lungs.

Of all the agents used in the aerosolized form (eg, gentamicin, colistin, tobramycin), preservative-free high-dose tobramycin is especially formulated for inhalation (ie, TOBI) and has been used in 2 large controlled studies and been reported to be safe and effective in patients older than 6 months. Usual dose is 300 mg bid given during alternate months. Currently clinical trials using a powder form of tobramycin and colistin are underway. These preparations will use novel delivery devices and result in shortening the time required for dosage administration.

Cephalosporins are effective against staphylococci and H influenzae. A small subset of third-generation cephalosporins is effective against P aeruginosa. Generally speaking, moving from first-generation to third-generation cephalosporins gives increasing gram-negative coverage and less gram-positive coverage.

Fluoroquinolones are effective against most gram-positive and gram-negative organisms. They are the only class of oral antibiotics effective against P aeruginosa. The most commonly used medication in this class is ciprofloxacin. None are approved for children because of concern regarding their effects on deposition in the cartilage. However, studies from Europe have reported substantial evidence of their safety in patients with CF.

In patients with colonization with P aeruginosa, azithromycin administered PO 3 times/wk on a long-term basis has been shown to improve lung function, nutritional status, and reduce acute pulmonary exacerbations.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Patients are monitored in the cystic fibrosis (CF) clinic every 2-3 months to achieve the following goals:
• • Maintenance of growth and development
  • Maintenance of as nearly normal lung function as possible using clinical assessment, pulmonary function testing, and oxyhemoglobin saturation
  • Intervention and retardation of the progression of lung disease via appropriate use of antibiotics, bronchodilators, and airway clearance techniques
  • Clinical assessment to monitor gastrointestinal tract involvement and presence of malabsorption and to provide enzyme and nutrition supplementation
  • Monitoring for complications and their treatment
  • Addressing psychosocial issues
• Airway clearance techniques: Various techniques used to clear airways may include chest physical therapy by hands, forced expiratory technique and autogenic drainage, positive expiratory pressure (PEP) using a PEP mask, high-frequency oscillation using a Flutter device, and high-frequency chest compression using a ThAIRapy Vest. These can be combined with bronchodilator therapy via a nebulizer.

In/Out Patient Meds

• Pancreatic enzyme supplements
• Multivitamins (including fat-soluble vitamins)
• Mucolytics
• Nebulized, inhaled, oral, or intravenous antibiotics
• Bronchodilators
• Anti-inflammatory agents
• Agents to treat associated conditions or complications (eg, insulin)

Complications

• Possible complications include the following:
• • Nasal polyps
  • Chronic and persistent sinusitis with complications such as mucopyocele formation
  • Bronchiectasis
  • Atelectasis
  • Pneumothorax
  • Hemoptysis
  • Hypertrophic pulmonary osteoarthropathy
  • ABPA
  • Gastroesophageal reflux
  • Pulmonary hypertension
  • Cor pulmonale
  • End-stage lung disease
  • Pancreatitis
  • CF-related diabetes mellitus
  • Meconium ileus
  • Distal intestinal obstruction syndrome
  • Rectal prolapse
  • Vitamin deficiency (especially fat-soluble vitamins)
  • Fatty liver
  • Focal biliary cirrhosis
  • Portal hypertension
  • Liver failure
  • Cholecystitis and cholelithiasis
  • Rickets
  • Osteoporosis

Prognosis

• Prognosis in patients with CF has improved over the last few decades, but CF remains a life-limiting disease, and a cure for the disease remains elusive.
• Median survival age is 36.8 years.
• The median survival age in males is slightly higher than that in females.
• Marked heterogeneity exists in disease severity and progression.
• Severity of pulmonary disease determines prognosis and ultimate outcome.
• With current treatment strategies, 80% of patients should reach adulthood.

Patient Education

• Provide counseling at the time of initial diagnosis, including information regarding inheritance and risk for recurrence in subsequent pregnancies.
• Instruct patients and parents regarding appropriate airway clearance technique and the need for chest physical therapy.
• Instruct patients and parents regarding the use of various drug delivery devices, such as spacers and nebulizers.
• Instruct patients and parents regarding methods for modifying the pancreatic enzyme dosage.
• Discuss when to contact CF center personnel (eg, for acute pulmonary exacerbation or complications) with patients and parents.
• Be prepared to counsel families regarding the impact of the diagnosis on the emotional life of parents, siblings, and members of the extended family.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to suspect and diagnose cystic fibrosis (CF) in a child presenting with atypical symptoms (A child can never look too well to have CF.)
• Failure to counsel families on inheritance and recurrence risk
• Failure to avoid fibrosing colonopathy caused by excessive dosages of pancreatic enzymes

Special Concerns

• Women with CF can have successful pregnancies provided that special care is taken with their nutrition (vitamin and energy supplements), airway clearance, and treatment of respiratory infections. Patients and their partners should attend counseling, including genetic counseling, when planning for pregnancy.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.
	View Full Size Image
Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med. Nov 1996;154(5):1229-56. [Medline].
• Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. Jan 19 2006;354(3):229-40. [Medline].
• Gibson RL, Emerson J, McNamara S, et al. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med. Mar 15 2003;167(6):841-9. [Medline]. [Full Text].
• Johnson CA, Butler SM, Konstan MW, et al. Estimating effectiveness in an observational study: a case study of dornase alfa in cystic fibrosis. The Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. J Pediatr. Jun 1999;134(6):734-9. [Medline].
• Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol. Dec 1996;22(6):387-95. [Medline].
• Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med. Jul 18 1996;335(3):179-88. [Medline].
• Ren CL, Brucker JL, Rovitelli AK, Bordeaux KA. Changes in lung function measured by spirometry and the forced oscillation technique in cystic fibrosis patients undergoing treatment for respiratory tract exacerbation. Pediatr Pulmonol. Apr 2006;41(4):345-9. [Medline].
• Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. May 12 2005;352(19):1992-2001. [Medline].
• Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. Oct 1 2003;290(13):1749-56. [Medline].
• Sharma GD, Tosi MF, Stern RC, Davis PB. Progression of pulmonary disease after disappearance of Pseudomonas in cystic fibrosis. Am J Respir Crit Care Med. Jul 1995;152(1):169-73. [Medline].
• Sharma GD, Doershuk CF, Stern RC. Erosion of the wall of the frontal sinus caused by mucopyocele in cystic fibrosis. J Pediatr. May 1994;124(5 Pt 1):745-7. [Medline].
• Stern RC. The diagnosis of cystic fibrosis. N Engl J Med. Feb 13 1997;336(7):487-91. [Medline].
• Tizzano EF, Buchwald M. Cystic fibrosis: beyond the gene to therapy. J Pediatr. Mar 1992;120(3):337-49. [Medline].
• Yankaskas JR, Mallory GB Jr. Lung transplantation in cystic fibrosis: consensus conference statement. Chest. Jan 1998;113(1):217-26. [Medline].

Article Last Updated: Jun 1, 2006