Progression of lung disease is the most prominent cause of morbidity and death in patients with cystic fibrosis (CF), but the severity of lung disease and the rate of lung function decline are highly variable. An attempt was made to define accurate estimates of disease progression in these patients early diagnosed and prospectively evaluated until 10 years of age. The primary question to ask was whether functional abnormalities detected already in infancy are associated with functional derangements later on in life, and may be useful as parameters of prognostic value. Early diagnosis of CF can best be achieved by screening of mutation by new techniques (buccal cell brushing) in infants, even when the sweat test or accurate blood sampling is not available. Moreover, in infants lung function can be assessed by infant whole-body plethysmography enabling the study of the interrelationship with delayed weight gain and growth retardation, as well as the associations with the most common disease-causing mutations. Out of a cohort of 80 infants (39 males, 41 females) with CF a follow-up study was started with 50 CF infants diagnosed during infancy (mean age 4.6 ± 4.0 months; range 0.1–12.7 months) and prospectively evaluated at 6-month intervals during the first 2 years of life. Moreover, in 32 CF children out of this cohort, follow-up was continued until 10 years of age. Differences were encountered with respect to the different events occurring during the first years of life, especially the onset of chronic colonization with Pseudomonas aeruginosa. The association between infant lung function and specific mutations (ΔF508 homozygotes, frameshift ΔF508/3905insT compound heterozygotes and nonsense ΔF508/R553X compound heterozygotes) furthermore revealed that differences in lung function within the genetic groups are mainly related to the degree of pulmonary hyperinflation. Pulmonary hyperinflation was also associated with the degree of impaired nutritional status. An association between impaired gas exchange characteristics at 10 years of age and the degree of pulmonary hyperinflation during infancy finally demonstrates that by early mutation screening, lung function testing and assessment of the nutritional status predictors of disease progression later on in life can be defined. Therefore, preventive therapeutic measures should primarily be based on such prognostic factors.

Keywords:
Cystic fibrosis, Early assessment and follow-up, Infant whole-body plethysmography, Mutation screening, Genotype-phenotype association, Nutritional status, z-score for weight, z-score for height, Pseudomonas aeruginosa colonization, Multibreath nitrogen washout
1.
Fanconi G, Uehlinger F, Knauer C: Das Coeliakie-Syndrom bei angeborener zystischer Pankreasfibrose and Bronchiektasien. Wien Med Wochenschr 1936;86:753–756.
2.
Andersen DH: Cystic fibrosis of the pancreas and its relation to coeliac disease: A clinical and pathological study. Am J Dis Childh 1938;56:344–399.
3.
FitzSimmons SC: The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1–9.
4.
Kraemer R, Stoll E, Moser H, Rossi E: Morbidity and mortality in cystic fibrosis. Results of 20 years of experience (in German). Schweiz Med Wochenschr 1977;107:271–275.
5.
Davis PB, Drumm M, Konstan MW: Cystic fibrosis: State of the art. Am J Respir Crit Care Med 1996;154:1229–1256.
6.
Riordan JR: The cystic fibrosis transmembrane conductance regulator. Annu Rev Physiol 1993;55:609–630.
7.
Collins FS: Cystic fibrosis: Molecular biology and therapeutic implications. Science 1992;256:774–779.
8.
Welsh MJ, Tsui LC, Boat TF, Beaudet AL: Cystic fibrosis; in Sciver CR, Beaudet AL, Sly WS, Valle D (eds): The metabolic and molecular bases of inherited disease, ed 7. New York, McGraw-Hill, 1995, pp 3799–3876.
9.
Konstan MW, Berger M: Infection and inflammation of the lung in cystic fibrosis. Lung Biol Health Dis 1993;64:219–276.
10.
Littlewood JM: Cystic fibrosis: Gastrointestinal complications. Br Med Bull 1992;48:847–859.
11.
Kraemer R, Hadorn B, Rossi E: Classification at time of diagnosis and subsequent survival in children with cystic fibrosis. Helv Paediatr Acta 1977;32:107–114.
12.
Kraemer R, Rüdeberg A, Hadorn B, Rossi E: Relative underweight in cystic fibrosis and its prognostic value. Acta Paediatr Scand 1978;67:33–37.
13.
Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med 1993;32:1308–1313.
14.
Moullier P, Jéhanne M, Audrézet MP, Mercier B, Verlingue C, Quéré I, Guillermit H, Raguénès O, Storni V, Rault G, Férec C: Association of 1078delT cystic fibrosis mutation with severe disease. J Med Genet 1994;31:159–161.
15.
Chillon M, Dork T, Casals T, Gimenez J, Fonknechten N, Will K, Ramos D, Nunes V, Estivill X: A novel donor splice site in intron 11 of the CFTR gene, created by mutation 1811+1.6kbA→G, produces a new exon: High frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype. Am J Hum Genet 1995;56:623–629.
16.
Highsmith WE, Burch LH, Zhou Z, Olsen JC, Boat TE, Spock A, Gorvoy JD, Quittel L, Friedman KJ, Silverman LM, et al: A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994;331:974–980.
17.
Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui L, Durie P: Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992;50:1178–1184.
18.
Rozmahel R, Wilschanski M, Matin A, Plyte S, Oliver M, Auerbach W, Moore A, Forstner J, Durie P, Nadeau J, Bear C, Tsui LC: Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet 1996;12:280–287.
19.
Ramsey BW: Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 1996;335:179–188.
20.
Stern RC: The diagnosis of cystic fibrosis. N Engl J Med 1997;336:487–491.
21.
Boat TF, Cantin AM, Cutting GR, et al: The diagnosis of cystic fibrosis. Bethesda, Cystic Fibrosis Foundation, 1998.
22.
Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: A consensus statement. J Pediatr 1998;132:589–595.
23.
Schöni MH, Kraemer R, Bähler P, Rossi E: Early diagnosis of cystic fibrosis by means of sweat microosmometry. J Pediatr 1984;104:691–694.
24.
Liechti-Gallati S, Schneider V, Neeser D, Kraemer R: Two-buffer PAGE system based SSCP/HD analysis: A general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet 1999;7:590–598.
25.
Bennett LC, Kraemer R, Liechti-Gallati S: Buccal cell DNA analysis in premature and term neonates: Screening for mutations of the complete coding region for the cystic fibrosis transmembrane conductance regulators. Eur J Pediatr 2000;159:99–102.
26.
Reid L, de Haller R: The bronchial mucus glands – their hypertrophy and changes in intracellular mucus. Bibl Pediatr 1967;86:195–200.
27.
Chow CW, Landau LI, Taussig LM: Bronchial mucous glands in the newborn with cystic fibrosis. Eur J Pediatr 1982;139:240–243.
28.
Sturgess J, Imrie J: Quantitative evaluation of the development of tracheal submucosal glands in infants with cystic fibrosis and control infants. Am J Pathol 1982;1:303–311.
29.
Nikolaizik WH, Moser M, Crameri R, Little S, Warner JO, Blaser K, Schöni MH: Identification of allergic bronchopulmonary aspergillosis in cystic fibrosis patients by recombinant Aspergillus fumigatus I/a-specific serology. AM J Respir Crit Care Med 1995;152:634–639.
30.
Kraemer R, Birrer P, Liechti-Gallati S: Genotype-phenotype association in infants with cystic fibrosis at the time of diagnosis. Pediatr Res 1998;44:920–926.
31.
McElvaney NG, Nakamura H, Birrer P, Hebert CA, Wong WL, Alphonso M, Baker JB, Catalano MA, Crystal RG: Modulation of airway inflammation in cystic fibrosis. In vivo suppression of interleukin-8 levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor. J Clin Invest 1992;90:1296–1301.
32.
Birrer P, McElvaney NG, Rüdeberg A, Sommer CW, Liechti-Gallati S, Kraemer R, Hubbard R, Crystal RG: Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 1994;150:207–213.
33.
Armstrong DS, Grimwood K, Carlin JB, Carzino R, Gutierrez JP, Hull J, Olinsky A, Phelan EM, Robertson CF, Phelan PD: Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 1997;156:1197–1204.
34.
Balough K, McCubbin M, Weinberger M, Smits W, Ahrens R, Fick R: The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis. Pediatr Pulmonol 1995;20:63–70.
35.
Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DWH: Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995;151:1075–1082.
36.
Ramsey BW, Wentz KR, Smith AL, Richardson M, Williams-Warren J, Hedges DL, Gibson R, Redding GJ, Lent K, Harris K: Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. Am Rev Respir Dis 1991;144:331–337.
37.
Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan PD: Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996;21:267–275.
38.
Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, Wagener J: Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999;28:321–328.
39.
Johansen HK, Høiby N: Seasonal onset of initial colonisation and chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis in Denmark. Thorax 1992;47:109–111.
40.
Aebi C, Bracher R, Liechti-Gallati S, Tschappeler H, Rüdeberg A, Kraemer R: The age at onset of chronic Pseudomonas aeruginosa colonization in cystic fibrosis – prognostic significance. Eur J Pediatr 1995;154:S69–S73.
41.
Kraemer R: Early detection of lung function abnormalities in infants with cystic fibrosis. J R Soc Med 1989;82(suppl 16):21–25.
42.
Kraemer R: Whole-body plethysmography in the clinical assessment of infants with bronchopulmonary diseases. Respiration 1993;60:1–8.
43.
Kraemer R: Models for prediction of whole-body plethysmographic measurements in infants. Am Rev Respir Dis 1993;174:A221.
44.
Kraemer R, Casaulta Aebischer C, Liechti-Gallati S, Schöni MH: Pulmonary hyperinflation: A beneficial or harmful factor for lung function in infants with cystic fibrosis (CF)? Am J Respir Crit Care Med 1999;159:A674.
45.
Malmberg LP, Pelkonen A, Hakulinen A, Hero M, Pohjavuori M, Skyttä J, Turpeinen M: Intraindividual variability of infant whole-body plethysmography measurements: Effects of age and disease. Pediatr Pulmonol 1999;28:356–362.
46.
Agrawal KP, Kumar A: Fall in specific airway conductance at residual volume in small airway obstruction. Respir Physiol 1980;40:65–78.
47.
Hampton F, Beardsmore CS, Morgan W, Williams A, Taussig L, Thompson JR: A scoring system for lung function tests in infants. Pediatr Pulmonol 1992;14:149–155.
48.
Tepper RS, Hiatt P, Eigen H, Scott P, Grosfeld J, Cohen M: Infants with cystic fibrosis: Pulmonary function at diagnosis. Pediatr Pulmonol 1988;5:15–18.
49.
Tepper RS: Assessment of the respiratory status of infants and toddlers with cystic fibrosis (editorial; comment). J Pediatr 1998;132:380–381.
50.
Tepper RS, Montgomery GL, Ackermann V, Eigen H: Longitudinal evaluation of pulmonary function in infants and very young children with cystic fibrosis. Pediatr Pulmonol 1993;16:96–100.
51.
Liechti-Gallati S, Bonsall I, Malik N, Schneider V, Kraemer LG, Rüdeberg A, Moser H, Kraemer R: Genotype/phenotype association in cystic fibrosis: Analyses of the delta F508, R553X, and 3905insT mutations. Pediatr Res 1992;32:175–178.
52.
Prader A, Largo RH, Molinari L, Issler C: Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Acta Suppl 1989;62:1–125.
53.
Rolland-Cachera MF, Sempé M, Guilloud M, Patois E, Péquinot-Guggenbühl F, Fautrad V: Adiposity indices in children. Am J Clin Nutr 1982;36:178–184.
54.
Levison H, Godfrey S, Talamo R: Pulmonary aspects of cystic fibrosis; in Mangos JA (ed): Cystic Fibrosis: Projection into the Future. New York, Stratton Intercontinental Medical Book Corporation, 1976.
55.
Lamarre A, Reilly BJ, Bryan AC: Early detection of pulmonary functional abnormalities in cystic fibrosis. Pediatrics 1972;50:291–298.
56.
Kraemer R, Meister B: Fast real-time moment-ratio analysis of multibreath nitrogen washout in children. J Appl Physiol 1985;59:1137–1144.
57.
Kraemer R, Schöni MH: Ventilatory inequalities, pulmonary function and blood oxygenation in advanced states of cystic fibrosis. Respiration 1990;57:318–324.
58.
Corey M, Edwards L, Levison H, Knowles M: Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis (see comments). J Pediatr 1997;131:809–814.
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