"The child who tastes salty will soon die" -- German folklore

An 8 month old child presents with a history of poor growth and a chronic cough. He was the product of a 21 year old Gravida 2 Para 1, Ab 0 mother and was born at 41 weeks of gestational age. Soon after birth, he developed respiratory distress and was admitted to the neonatal intensive care unit where he was mechanically ventilated for 1 day and discharged after 5 days. He was initially breast-fed, but due to frequent vomiting and loose bowel movements, he was changed to formula feeding. Despite trials of different types of formulas (soy, hypoallergenic, etc.), his clinical course was remarkable for bloating, diarrhea and failure to thrive. He developed a daily cough and some respiratory difficulty. At the age of 5 months he was hospitalized for respiratory distress and was diagnosed as having asthma. He continued to have loose, large, greasy, foul-smelling stools and failure to thrive. An iontophoresis of pilocarpine sweat test is now being obtained.

Family history: Mother (age 21), racially mixed Japanese, Chinese, English and Irish. Father (age 23), racially mixed, Portuguese. Hawaiian and Chinese. He has a sister (age 2). All three family members are alive and well.

Exam: VS T. 37.0 C. P120, R45, BP 80/60, oxygen saturation 97% in room air, weight 6.7 kg (<5th percentile). He is alert and active in no distress. He is small for his age. HEENT exam is significant for bilateral otitis media and mild nasal congestion. Neck supple without adenopathy. Heart regular. Lungs with good aeration and mild wheezing and rales. Abdomen soft, non-tender, active bowel sounds. Color and perfusion are good.

Chest radiographs: Some hyperexpansion with increased peribronchial markings.

Laboratory Results: Sweat test: Weight 120 micrograms; 105 mmol/L (normal <60). Deep throat culture after coughing induced by respiratory therapy using a suction trap collection unit (specimen treated by laboratory as a sputum culture): Klebsiella pneumoniae. AST 44 H (normal 0-37), ALT 49 H, (normal l0-40), Alk Phos 324 (normal 104-345). Cystic fibrosis mutation analysis (genetic testing): Positive for one copy of Delta F508 and one copy of R1066C.

A series of events that took place during the very hot summer of 1938 in New York City led to the recognition of a new disease, cystic fibrosis. Dr. Dorothea Anderson (1) noted that a number of children presented to Columbia Hospital with severe dehydration, but without diarrhea or vomiting. Several of these children had been followed in the GI clinic for failure to thrive and greasy stools. Many also coughed. Thus began the recognition of cystic fibrosis of the pancreas (CF). By 1946, the genetic nature of this autosomal recessive disease was described. In 1953, Dr. Paul di Sant'Agnese recognized that CF patients lost excessive salt in their sweat (2), forming the basis for use of the sweat chloride test as a cornerstone of the diagnosis of this disease. The chloride values for patients with cystic fibrosis were elevated and a clear separation from normal volumes was found to exist. Similar elevations for sodium as well as potassium exist but there is greater overlap with the normal population. Historically, obtaining a sweat test involved bundling the child to induce sweating. Sometimes children were even placed near furnaces to make them sweat more profusely. This resulted in some deaths. Informed consent for testing was not obtained in those days. Currently, the iontophoresis of pilocarpine (a cholinergic agent) is used to induce sweating (3). This is a safer and standardized method of obtaining a sweat sample for the sweat chloride test. Some causes of a false positive sweat test include conditions associated with serum electrolyte abnormalities or conditions associated with abnormal skin and sweating. These include adrenal insufficiency, anorexia nervosa, atopic dermatitis, ectodermal dysplasia, fucosidosis, mucopolysaccharidosis type 1, and nephrogenic diabetes insipidus among others. A positive sweat test in association with pancreatic exocrine dysfunction (maldigestion as opposed to malabsorption) and lung disease is the diagnostic triad of CF.

Cystic fibrosis is said to be the most common, lethal inherited disease of white people. Cystic fibrosis occurs in 1:2,500 whites in North America, 1:8,000 Latinos (4), 1:17,000 African-Americans (5) and 1:32,000 Asian-Americans (6). Since the life expectancy of patients with CF has increased to more than 30 years, some have called it a semi-lethal disease. A better term would be a disease associated with a dramatically decreased life expectancy.

The CF mutation (7) has been localized to chromosome 7, band q31 (8). This locus codes for a transport protein named the cystic fibrosis transmembrane conductance regulator (CFTR) (9). More than 800 mutations are now known. The Caucasian associated delta F508 defect is the most common mutation found. The R1066C identified in this child is one of the rarer CF genes. It is found in people of Portuguese decent. The CFTR protein functions as a chloride channel regulated by a cAMP dependent protein kinase phosphorylation. The genetic variations and molecular implications are becoming clearer (10). The clinical features associated with cystic fibrosis are listed in the table below:

Phenotypic Features Consistent With The Diagnosis of Cystic Fibrosis (11)

1. Chronic sinopulmonary disease manifested by:
. . . . . a. Persistent colonization/infection with typical CF pathogens including: Staphylococcus aureus, non-typable Haemophilus influenza, Pseudomonas aeruginosa, mucoid and non-mucoid, Burkholderia cepacia, E. coli mucoid type (12), other gram negative organisms.
. . . . . b. Chronic cough and sputum production.
. . . . . c. Persistent chest radiograph abnormalities (e.g. bronchiectasis, atelectasis, infiltrates, hyperinflation, peribronchial cuffing).
. . . . . d. Airway obstruction manifested by wheezing and air trapping.
. . . . . e. Nasal polyps: radiograph or CT abnormalities of the paranasal sinuses.
. . . . . f. Digital clubbing.

2. Gastrointestinal and nutritional abnormalities including
. . . . . a. Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal prolapse.
. . . . . b. Pancreatic: pancreatic insufficiency; recurrent pancreatitis, diabetes mellitus.
. . . . . c. Hepatic: chronic hepatic disease manifested by clinical, biochemical or histologic evidence of focal biliary cirrhosis or multilobar cirrhosis.
. . . . . d. Nutritional: failure to thrive (protein-calorie malnutrition), hypoproteinemia and edema; complications secondary to fat soluble vitamin deficiency.

3. Salt loss syndromes (acute salt depletion; hypochloremic metabolic alkalosis).

4. Male urogenital abnormalities resulting in obstructive azoospermia.

In a review of cystic fibrosis patients, the frequency of presenting signs and symptoms were: acute and persistent respiratory illnesses (51%), failure to thrive or malnutrition (43%), abnormal stool or steatorrhea (35%), meconium ileus or intestinal obstruction (19%), family history of CF (17%), electrolyte imbalance (5%), rectal prolapse (3%), nasal polyps/sinus disease (2%), hepatobiliary disease (1%), and prenatal diagnosis by chorionic villus sampling or amniocentesis (1%) (13). Almost all male CF male patients have azoospermia due to occlusion of the tubules in the testes. Adult men have been diagnosed with cystic fibrosis after being evaluated for infertility (no sperm found in their semen sample).

Gastrointestinal complications are the most obvious early presenting symptoms. Approximately 19% of babies with CF present with meconium ileus, an intestinal occlusion in neonates which results from thick, viscid meconium obstructing the small bowel. This frequently results in a distal microcolon that requires surgical intervention. Others present with rectal prolapse in association with failure to thrive. As in the case presented above, fat maldigestion, steatorrhea and failure to thrive are presenting features. Some degree of pancreatic enzyme deficiency is found in 80-90% of CF patients. It is important to note that 10-20% of CF patients do not have this component of the disease and its absence does not preclude the diagnosis of CF. Pancreatic replacement enzymes, dietary regulation and the replacement of the fat-soluble vitamins (ADEK) play a major role in treating these GI complications. Since better enzymatic preparations are now available, fat restrictive diets are rarely needed. Once this therapy begins, patients grow rapidly, with catch up growth and normal subsequent growth percentiles. Further growth failure is usually related to pulmonary disease and its complications, listed below. Hepatic involvement is usually limited to hepatic enzyme elevations as was seen in our case. This can progress over time to frank hepatic disease and cirrhosis. Blood flow can be diverted from the liver which results in esophageal varices which can present with bloody vomiting (hematemesis).

As CF patients get older, pancreatic complications include pancreatitis as well as the insulin deficient form of diabetes mellitus. This diabetes mellitus is rarely associated with ketoacidosis. In spite of this, insulin therapy is required to treat the caloric losses associated with this complication.

It soon becomes apparent, however, that the pulmonary aspects of this disease are the major, life-limiting process. It progresses from a bronchiolitic process with chronic bacterial colonization of the airway, to bronchiectasis and obstructive pulmonary disease. In infancy, the organisms are most frequently Staphylococcus aureus, non-typable Haemophilus influenza, and other gram negative organisms (14). These are often replaced by Pseudomonas aeruginosa (both mucoid and non-mucoid colony type). Once established in the airways, mucoid pseudomonas is almost impossible to eradicate. There seems to be a local environment in the CF airways that promotes the growth of pseudomonas. Whether this is due to the abnormally viscid mucus or the local calcium or chloride concentrations is uncertain. Colonization, which may not actually mean infection, with pseudomonas (mucoid colony type) leads to a state of chronic airway inflammation. This has been labeled frustrated phagocytosis. The inflammatory process directed against the pathologic organisms is incapable of eradicating the organisms and causes nonspecific damage to the airways that are "innocent" bystanders. Over time, this results in irreversible airway damage. This hyperimmune process is now known to be a major factor in the progressive lung disease that characterizes CF. Indeed, early studies showed that patients with hypogammaglobulinemia had less lung disease, fewer hospitalizations, and better oxygenation than those with normal or elevated levels of IgG (15). Indeed, those cystic fibrosis patients with the highest IgG levels had the worst prognosis and the shortest life expectancy (16). A study aimed at decreasing this hyperimmune process with prednisone therapy showed less progression of lung disease to controls (17). Unfortunately, the complications of steroid therapy were unacceptable. These include growth failure, development of cataracts and glucose intolerance. Further anti-inflammatory studies are underway.

The pulmonary disease is progressive, essentially unremitting and fatal. Therapy aimed at slowing this process includes mechanical mobilization of the thick secretions by chest physical therapy and postural drainage. This can be done by hand, mechanical percussors or by a vest percussion device. The use of nebulized rhDNase (Pulmozyme) (18) has been effective in decreasing the viscosity of CF mucus by aiding in the removal of the excessive DNA from the inflammatory cells destroyed in the airways. All of this is aimed at mobilizing secretions and encouraging expectoration.

Sputum cultures are used to define the organisms present. It is important to remember, however, that Staphylococcus aureus is frequently present in concentrations 100 to 1000 times less than that of the pseudomonas (19), such that Staph aureus is frequently undetected in routine (qualitative) sputum cultures. Quantitative culture, which would detect both organisms, remains a research tool unavailable to most clinicians. This could explain why CF patients with pseudomonas positive sputum cultures, improve on anti-staphylococcal antibiotics even after determining pseudomonas resistance to these antibiotics (20). In spite of this, antibiotic therapy aimed at specific organisms is a mainstay of therapy. Oral antibiotics are used when possible but hospitalization and intravenous antibiotics are frequently required. The timing of such intensive therapy in this chronic disease is best governed by symptoms as well as by objective pulmonary function data. Bacterial sensitivities are used to help select the best antibacterial agents. Usually, two antibiotics are used, an aminoglycoside and a anti-pseudomonal penicillin. Trials of single agents such as anti-pseudomonas cephalosporins (e.g. ceftazidime) continue. The aim is minimization of the yearly decrement in pulmonary function tests associated with the pulmonary deterioration. Nebulized therapy has offered an additional route for delivery of antibiotics (21). Twice daily aerosolized tobramycin (Tobi) has been used in a 28 day on, 28 day off pattern.

In spite of the large number of organisms present in the airways and sputum, CF patients rarely become septic and blood cultures are not helpful. It is an airway colonization process and not a pneumonic one.

One specific organism is known to be particularly worrisome. The acquisition Burkholderia cepacia is associated with rapid deterioration in pulmonary status and earlier death (22).

Other pulmonary complications include allergic bronchopulmonary aspergillosis (ABPA) (23) (another disease with airway colonization rather than tissue invasion), which requires corticosteroid treatment. Antifungal agents are not needed. Sinusitis is universally present in CF patients (24). Bronchospasm symptoms are treated with the usual medications outlined under asthma therapy. Pneumothoraces occur later in the disease and usually require chest tube drainage. Sclerosing agents, although effective in terminating persistent pneumothoraces (25), are relatively contraindicated since it may preclude lung transplantation (26). Hemoptysis is treated expectantly. Bronchial artery embolization has proven to be effective but has significant risks (27). Cor pulmonale is treated with oxygen therapy, diuretics and digoxin. Its presence is a sign of severe pulmonary disease and a poor prognosis sign (28).

Questions

1. The percentage of CF patients with pancreatic exocrine dysfunction (decreased lipase, amylase, etc.) is:
. . . . . a. 10%
. . . . . b. 25%
. . . . . c. 50%
. . . . . d. 85%

2. The carrier rate for the CF gene in the white population is:
. . . . . a. 1 in 10
. . . . . b. 1 in 15
. . . . . c. 1 in 25
. . . . . d. 1 in 50

3. The frequency of cystic fibrosis is:
. . . . . a. whites>blacks>latinos>asians
. . . . . b. whites>latinos>blacks>asians
. . . . . c. whites>asians>latinos>blacks
. . . . . d. latinos>whites>blacks>asians

4. An abnormal sweat test is:
. . . . . a. diagnostic of cystic fibrosis
. . . . . b. supportive of the diagnosis of cystic fibrosis
. . . . . c. has been replaced by genetic testing
. . . . . d. an abnormal sodium value

5. The most common CF gene is:
. . . . . a. R1066C
. . . . . b. Delta F508
. . . . . c. Not detected by genetic screening
. . . . . d. Present in less than 40% of patients

6. The percentage of CF patients with sinus opacification and/or infection is:
. . . . . a. 10%
. . . . . b. 25%
. . . . . c. 50%
. . . . . d. 75%
. . . . . e. 95%

7. What percentage of CF male patients have azoospermia
. . . . . a. 10%
. . . . . b. 25%
. . . . . c. 50%
. . . . . d. 75%
. . . . . e. 95%

8. The CFTR gene is located on chromosome:
. . . . . a. 5
. . . . . b. 7
. . . . . c. 9
. . . . . d. 11
. . . . . e. 13

9. The life expectancy of newly diagnosed patients with cystic fibrosis is:
. . . . . a. 5 years
. . . . . b. 10 years
. . . . . c. 15 years
. . . . . d. 20 years
. . . . . e. 30 years

10. Organisms characteristically isolated from the sputum of patients with cystic fibrosis includes all the following except:
. . . . . a. Staphylococcus aureus
. . . . . b. Streptococcus pneumoniae
. . . . . c. Klebsiella pneumoniae
. . . . . d. Pseudomonas aeruginosa
. . . . . e. Burkholderia cepacia

References

1. Andersen, DH. Cystic fibrosis of the pancreas and its relation to celiac disease, a clinical and pathological study. Am J Dis Child 1938;56:344.

2. Di Sant'Anese PA, Darling RC, Perera GA, et al. Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas. Pediatrics 1953;12:549.

3. Gibson LE, Cooke RE. A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. Pediatrics 1959;23:545.

4. Grebe TA, Seltzer WK, DeMarchi J, et al. Genetic Analysis of Hispanic individuals with cystic fibrosis. Am J Hum Genet 1994;54:443.

5. Phillips OP, Bishop C, Woods D, et al. Cystic fibrosis mutations among African Americans in the southeastern United States. J Natl Med Assoc 1995;87:433.

6. Wang W, Okayama H, Shirato K. Genotypes of cystic fibrosis (CF) in the world and polymorphism of cystic fibrosis transmembrane regulator (CFTR) gene in Japan. Nippon Risho 1996;54:525.

7. Tsui L-C, Buchwald M, Barker D, et al. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science 1985;230:1054.

8. Riordan JR, Rommen JM, Buchanan D, et al. Identification of the cystic fibrosis gene: Cloning and characterization of complimentary DNA. Science 1989;245:1066.

9. Hasagawa HW, Skach W., Baker O, et al. A multifunctional aqueous channel formed by CFTR. Science 1992;258:1477.

10. Tsui L-C. The spectrum of cystic fibrosis mutations. Trends Genet 1992;8:392.

11. Rosenstein BJ, Cutting GR. Diagnosis of cystic fibrosis: A consensus statement. J Pediatr 1998;132:589.

12. Macone AB, Pier, GB, Pennington JE, Matthews WJ, et al. Mucoid Escherichia coli in cystic fibrosis. N Engl J Med 1981;304:1445.

13. Rosenstein BJ. What is a cystic fibrosis diagnosis? Clin Chest Med 1998;19(3):423-41.

14. Ramsey, BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996;335:179.

15. Matthews WJ, Williams M, Oliphint B, et al. Hypogammaglobulinemia in patients with cystic fibrosis. N Engl J Med 1980;302:245.

16. Wheeler WB, Williams M, Matthews WJ, Colten HR. Progression of cystic fibrosis lung disease as a function of serum immunoglobulin G levels: a 5-year longitudinal study. J Peds 1984;104:695.

17. Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985;2(8457):686.

18. Christopher F, Chase D, Stein K, Milne R. rhDNase therapy for the treatment of cystic fibrosis patients with mild to moderate lung disease. J Clin Pharm Ther 1999;24:415.

19. McLaughlin FJ, Matthews WJ, Strieder DJ, et al. Randomized, double-blind evaluation of azlocillin for the treatment of pulmonary exacerbations of cystic fibrosis. J Antimicro Chem 1983;11(Suppl B):195.

20. McLaughlin FJ, Matthews WJ, Streider DJ, et al. Clinical and bacteriological responses to three antibiotic regimes for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo. J Inf Dis 1983;147:559.

21. Konstan MW, Butler SM, Schidlow, et al. Patterns of medical practice in cystic fibrosis: part II. Use of therapies. Investigators and Coordinators of the Epidemiological Study of Cystic Fibrosis. Pediatr Pulmonol 1999;28:248.

22. McClosky M, McCaughan J, Redmond AO, Elborn JS. Clinical outcome after acquisition of Burkholderia cepacia in patients with cystic fibrosis. Irish J Med Sci 2001;170:28.

23. Geller DE, Kaplowitz H, Light MJ, Colin AA. Allergic bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Chest 1999;116:639.

24. April MM. Management of chronic sinusitis in children with cystic fibrosis. Pediatr Pulmonol 1999;18:76.

25. Schuster SR, McLaughlin FJ, Matthews WJ, et al. Management of pneumothorax in cystic fibrosis. J Ped Surg 1983;18:492.

26. Meyers BF, Lynch J, Guthrie TJ, et al. Lung transplantation: a decade of experience. Ann Surg 1999;230:362.

27. Chapman SA, Holmes, MD, Taylor DJ. Unilateral diaphragmatic paralysis following bronchial artery embolization for hemoptysis. Chest 2000;118:269.

28. Fraser KL, Tullis DE, Sasson Z, et al. Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of hypoxemia. Chest 1999;115:1321.

Answers to questions

1.d, 2.c, 3.b, 4.b, 5.b, 6.e, 7.e, 8.b, 9.e, 10.b