Perspectives in Cystic Fibrosis

Symposium on The Chest

Perspectives in Cystic Fibrosis Dennis Gurwitz, MB., B.Ch.,':' Mary Corey, M.8c.,t Paul W. J. Francis, MB., B.8., FR.A.CP.,! Douglas Crozier, M.D.,§ and Henry Levison, M.D.fl

Cystic fibrosis is the most common lethal genetic abnormality in North America today. In 1950 the average life expectancy for a child with cystic fibrosis was four years. By 1976 the median survival age had risen to 19 years. 7 This improvement has been ascribed to a clearer understanding of the pathogenesis of the disease, a more accurate means of diagnosis, greater efficacy of treating bacterial infections, improved nutrition, and the appreciation of the existence of mild or asymptomatic patients. In our clinic of 535 patients at the Hospital for Sick Children in Toronto, many children now survive into adulthood and indeed are able to live useful productive lives for increasing periods of time. It would seem that early diagnosis and the institution of an aggressive treatment program before widespread irreversible lung damage has occurred may greatly prolong survival. 27 • 33 Diagnosis, complications, and treatment have been reviewed previously.6. 9. 25. 32. 38 Individual prediction at the time of diagnosis is impossible, but there are a number of factors which, when considered together, enable the clinician to place patients in a number of broadly defined risk groups. It is the definition and characteristics of these groups which would help the physician in assessment, counseling, and follow-up of patients with cystic fibrosis which are addressed in this article. "Clinical Fellow, Division of Chest Diseases, Department of Pediatrics and the Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada t Senior Research Assistant, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada !Research Fellow, Respiratory Physiology, The Hospital for Sick Children, Toronto, Ontario, Canada §Assistant Professor, University of Toronto; Division of Chest Diseases, The Hospital for Sick Children, Toronto, Ontario, Canada flProfessor of Pediatrics, University of Toronto; Medical Coordinator, Cystic Fibrosis Clinic, and Director, Pulmonary Function Laboratory, The Hospital for Sick Children, Toronto, Ontario, Canada

Pediatric Clinics of North America - Vol. 26, No.3, August 1979

603

604

DENNIS GURWITZ ET AL.

HETEROGENEITY OF CYSTIC FIBROSIS Cystic fibrosis is assumed to be inherited by single autosomal transmission. However, some investigators have questioned whether cystic fibrosis is not just one disease but a disease of different genetic types, indicating more than one gene locus. Danes and Beam were able to distinguish three classes of firoblasts derived from the skin of patients with cystic fibrosis. 8 However, other workers were unable to confirm these findings. Epidemiologic evidence to support the existence of genetic variants has been unrewarding. Although there are striking variations in racial incidence, cystic fibrosis being most common in white races,38 the main clinical and pathologic features do not differ in children from different racial groups or from different countries. This disorder occurs in both sexes and all socioeconomic groups with equal frequency.31 Interestingly, an advantage for heterozygotes has not been documented. Clinical observation has shown the disease to vary greatly from patient to patient. At one end of the spectrum is the child who dies in heart failure secondary to severe lung involvement by four years of age. At the other end is the individual who lives a normal life until the mid-thirties. For obvious reasons, the latter is often not diagnosed as having cystic fibrosis until relatively late. Meconium ileus accounts for the initial presentation in 10 per cent of patients in our clinic. Shwachman has observed that in families who had one child with meconium ileus, there was an increased likelihood that a subsequent child with cystic fibrosis would present with meconium ileus. 31 Other gastrointestinal manifestations of cystic fibrosis such as cirrhosis and liver failure have a tendency to occur in the same family. 31 In addition, we have found the course of pulmonary function to be less variable within familes having more than one patient with cystic fibrosis than between such families. 5 Quantitative studies indicate that exocrine acinar cell development in infants who have died with cystic fibrosis regresses at or before birth from the normal pattern of development usually seen. 16 This pattern is similar for most infants with and without a history of meconium ileus. However, there are notable exceptions which may represent those infants who have normal pancreatic function. Approximately 15 per cent of patients when first seen have no clinical or laboratory evidence of pancreatic insufficiency, 19, 23 but with time there may be a progressive loss of pancreatic function. We have noted in our clinic that these patients tend to have a mild form of cystic fibrosis with relatively less lung involvement,12 Stern et al. have described seven patients who they believe constitute a genetic variant. 35 These patients had sweat chloride levels consistently between 40 and 60 mEq per liter and chronic staphylococcal and Pseudomonas bronchitis but no overt steatorrhea or laboratory evidence of pancreatic dysfunction. The clinical manifestations of cystic fibrosis result from a basic metabolic defect as yet undefined. As cystic fibrosis has a wide variation in presentation and progression, attempts to define different genetic types on the basis of clinical variations may be unproductive.

605

PERSPECTIVES IN CYSTIC FIBROSIS

SEX DIFFERENCES The median age of survival has improved from 12 years in 1966 to 19 years in 1976 according to data collected annually by the American Cystic Fibrosis Foundation. 7 However, females have had consistently poorer survival from birth than males. The reported median survival for Unite States males in 1976 was 21 years and for females 17 years. 7 This is particularly surprising when one considers that in most diseases males have an increased mortality rate. In our clinic, twice as many boys as girls survive to adulthood and similar proportions have been reported from other populations of adults with cystic fibrosis. 7 , 13,30,37.36 The sex difference is even more pronounced in the Canadian survival data (Fig. 1). The age-sex distribution in our clinic shows a striking difference after 15 years of age in the numbers of surviving males and females (Fig. 2). Because the survival of patients with cystic fibrosis is largely determined by the severity of lung involvement, it is not surprising that this sex difference is also reflected in our pulmonary function data. Table 1 gives mean values of selected measurements of pulmonary performance and demonstrates the more pronounced fall with age in females. Females have persistently lower values than males in all age groups with the exception of the five to nine year age group, where they are comparable. The smaller number of females surviving after age 15 indicates that the sex differences in pulmonary function are in fact understated since in general those who died had poor pulmonary function. In trying to explain the faster deterioration in females after age 10, we found that CF SURVIVAL CURVE FOR CANADA 1972-76

lexcluding meconium ileus} % Surviving

100 \

90

\-',

Male

Fema Ie . ___ .

80

70

Figure 1. Male and female survival curves for cystic fibrosis in Canadian children 1972 to 1976.

60

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20 10

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606

DENNIS GURWITZ ET AL.

Frequency

222 FEMALES

70 ,--

60

,--

50

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293 MALES

70-

Figure 2. Age-sex distribution of patients with cystic fibrosis attending the Toronto Cystic Fibrosis Clinic in 1978.

605040-f-3020

10-

o

5

10

15

20

25

30 35 40

Age (yrs)

age and centile weight groups were the only variables that correlated strongly with pulmonary (unction. Age at diagnosis and severity and duration of symptoms before diagnosis were much less clearly related to pulmonary course. Figure 3 shows the distributions of height and weight of males and females over two years of age in our clinic. One is struck by the near normal distribution of height for males and females, whereas although the males have near normal distribution for weight, female weights are skewed into the lower percentile area. Sixty-seven per cent of females fall below the 50th percentile compared with 57 per cent of males. When the patients are further classified into five year groups, the difference is even more obvious (Table 2). Thus, the striking drop in weight after age 10 parallels the deterioration in pulmonary function described above. We were unable to determine which occurred first, the decrease in weight or the deterioration in pulmonary function. With our present knowledge, one can only speculate as to the causes of this deterioration. It may be that changes associated with the onset of puberty render the female more susceptible to ongoing lung disease. Tracheal mucous secretory function has been reported to be influenced by female sex hormones. 2 , 14,39 Social and cultural factors may also playa part. At adolescence, young girls tend to reduce their amount of physical activity whereas boys generally continue to play sports and usually remain active. Social and peer group pressure may play an important part in adolescence with the normal changes in psyche occurring in boy-girl relationships. Girls tend to eat less and

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Table 1.

Mean (± SD) Age, FVC, FEV\> and FEF 25 ,75% of Currently Surviving Patients in Five Year Groups"

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....

NUMBER

AGE

FVC

FEV,

FEF:!.-,.7.i%

(YEARS)

(% PRE D)

(% PRED)

(% PRED)

to ~

o

~

AGE GROUP

5-9 10-14 15-19 20-24 25-38

[Jl

Females

Males

43 70 51 20 9

42 62 77 34 23

Females 8,0 12,9 17,3 22,3 28,9

± ± ± ± ±

1.2 1.5 1.3 1.4 3,6

Males 8.2 12,5 17,3 21.8 29,5

± ± ± ± ±

1.1 1.4 1.5 1.4 3,6

Females 89 78 73 59 49

± 19 ± 23 ± 25 ±27 ± 23

Males 87 83 78 78 64

± 18 ± 19 ±25 ± 24 ±22

Females 86 70 64 49 38

± ± ± ± ±

20 24 26 27 18

Males 86± 77 ± 68 ± 66 ± 47 ±

22 23 29 28 19

Females

Male

91 62 55 41 23

92 71 58 55 26

± 38 ± 34 ± 34 ±40 ± 12

± 35 ± 34 ± 36 ±39 ± 15

':'Abbreviations: FVC, forced vital capacity; FEV" one-second forced expiratory volume; FEF25 ,75%, forced expiratory flow during the middle half of forced vital capacity; and % Pred, percentage of predicted volume,

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DENNIS GURWITZ ET AL.

608 % Frequency 215 FEMALES

30 20

10

o 284 MALES

30 20

10

o

o

3 10 25 50 75 90 97 100

o

3

10 25 50 75 90 97 100

Percentile Weight

Percentile Height

Figure 3. Percentage frequency distributions of percentile height and weight of patients over two years of age attending the Toronto Cystic Fibrosis Clinic in 1978.

hope for a more feminine appearance; consequently their diets may suffer.

PRESENTATION AND AGE AT DIAGNOSIS The age at diagnosis and the type and severity of symptoms in the presentation of cystic fibrosis reflect its clinical heterogeneity. Age at diagnosis has not been useful in delineating groups with a different prognosis except that those diagnosed at a later age often have milder disease and have a greater median survival age by virtue of elimination of early deaths from the referenced population. 7. 9 Age at diagnosis depends on the severity of the disease, the diagnostic ability of the individual physician, and many other factors which make it unreliable Table 2.

Percentage of Patients Below the 50th Percentile for Weight in Different Age-Sex Groups

AGE IN YEARS

MALES

FEMALES

2-4 5-9 10-14 15-19 20-24 25-38

56 45 58 58 66 64

57 48 74 76 81 86

609

PERSPECTIVES IN CYSTIC FIBROSIS

to determine specific subgroups. However, strong subjective evidence suggests that earlier diagnosis with an intensive therapeutic program may result in a better prognosis. 27 , 33 The correlation between prognosis and symptoms at presentation is described in Table 3. The highest mortality in our institution has occurred in patients diagnosed as having meconium ileus. However, the operative mortality has decreased over the past eight years with improvement in operative techniques, life support, and management. Those patients who survived the neonatal period had a good prognosis. This concurs with studies of the Cystic Fibrosis Foundation in which the median survival of this group is approximately the same as the group without meconium ileus. 7 This catch-up survival may partially reflect the benefits of early treatment. Patients who present with pulmonary and gastrointestinal symptoms (the symptoms typical of cystic fibrosis) exhibit the next highest mortality. This group, which was the largest group studied (53 per' cent of the total group), showed the male-female difference, with twice as many females dying as males. Those presenting with gastrointestinal symptoms only (17 per cent), and those presenting with pulmonary symptoms only (18 per cent), have survival rates half those of the combined pulmonary and gastrointestinal group. Patients diagnosed without symptoms because of a family history of cystic fibrosis (siblings of _ patients with cystic fibrosis) have the best prognosis. However, this is a small group and has been followed for the shortest period of time. It is surprising that a patient who presents with gastrointestinal symptoms has the same prognosis as a patient who presents with pulmonary symptoms because pulmonary disease usually determines the eventual outcome. This would suggest that nutritional factors may be as important as lung disease in ultimate prognosis. However, the group with pulmonary symptoms alone also includes many patients without complete pancreatic insufficiency who tend to have milder lung disease. 7 Table 3. Classification (Male, Female, Total) of Diagnoses of Cystic Fibrosis and Deaths by Different Types of Presentation at The Hospital for Sick Children, Toronto,from 1952 to 1978 DEATHS/DIAGNOSED NUMBER DIAGNOSED SYMPTOMS AT PRESENTATION

Meconium ileus Pulmonary and gastrointestinal symptoms Gastrointestinal symptoms only Pulmonary symptoms only No symptoms TOTAL

NUMBER OF DEATHS

(PER CENT)

M

F

T

M

F

T

M

F

T

44

39

83

17

17

34

39

44

41

19.6

191

387

37

76

113

19

40

29

63

58

121

6

12

18

10

21

15

74 6 383

54 9 351

128 15 734

10 0 70

7 0 112

17 0 182

14 0 18

13 0 32

13 0 25

610

DENNIS GURWITZ ET AL.

PULMONARY FUNCTION Pulmonary dysfunction represents the most significant clinical component of cystic fibrosis and is the main cause of death in older patients. Postmortem studies of infants dying with meconium ileus suggest that the lungs in cystic fibrosis are morphologically normal at birth 28 or may show hyperplasia and obstruction of the submucosal glands in the trachea and major bronchi even in the absence of pulmonary infection. 26 Bedrossian et al. examined the lungs of children dying of cystic fibrosis at various age groups.1 The commonest changes were seen in the airways, the most striking change being noted in the epithelium and the submucosa. Parenchymal changes were less common. All the changes were present in more than half the patients less than four months of age, indicating early appearance. For example, bronchiectasis was found in 20 per cent of patients less than four months of age but in 100 per cent of patients greater than two years of age. Mucopurulent plugging increased from 67 per cent in patients under four months of age to 96 per cent in patients over two years of age. Thus there is a progression of lung disease as the child grows older, with bronchiolitis, bronchiolectasis, mucous plugging, bronchitis, and bronchiectasis, and a vicious cycle of obstruction and chronic infection resulting in further lung damage, eventual respiratory failure, cor pulmonale, and death. The initial pulmonary lesion is caused by obstruction of the small airways.20 The earliest manifestation is ventilation-perfusion inequality owing to unequal distribution of small airway resistance and lung compliance. Ventilation-perfusion inequality is manifest by changes in the alveolar-arterial difference in O 2 and CO 2 which occur before detectable changes in flow rates or lung volumes. 2o With progression of the disease, peripheral airway obstruction may be demonstrated by other sensitive techniques such as the helium flow volume curve. Lapierre at al. 21 and others l l • 15 have shown this to be a very sensitive index of pulmonary dysfunction. Closing volume has not proved to be helpful,3 which is not surprising, as elastic recoil is a primary determinant of closing volume and only becomes abnormal late in the disease. 24 As the disease progresses, more standard pulmonary function measurements become abnormal. In Figure 4 the sensitivity of the various pulmonary parameters in 26 patients is shown. 22 The helium flow volume curve (VisoV /VC) and arterial oxygen tension (Pa02 ) have the highest percentage of abnormal results. Featherby et al. 10 found a good correlation between declining arterial oxygen tension and clinical and radiologic score (Fig. 5). There is also a good correlation between findings on clinical examination and chest x-rays, respiratory flow rates, and lung volumes in assessing the severity of the disease. 29 To assess the progression of lung disease, we studied the longitudinal pulmonary function records of children with cystic fibrosis followed for more than five years. 4 We found that spirometric measurements were most useful in determining long-term trends. The greatest

611

PERSPECTIVES IN CYSTIC FIBROSIS

CYSTIC FIBROSIS

Figure 4. Percentage of abnormal results of pulmonary function tests in 26 patients with cystic fibrosis (abnormal .,;2 SD from normal) (From Levison, H., and Godfrey, S.: Pulmonary aspects of cystic fibrosis. In Mangos, J. A., and Talamo, R. C. (eds.): Cystic Fibrosis: Projections into the Future. New York, Stratton Intercontinental Medical Book Corporation, 1976, with permission.)

SGaw RV/TLC

Visa 'it IVC

o

20

40

60

80

Percentage Abnormal Tests

decline was in forced expiratory flow during the middle half of forced vital capacity (FEF 25-75%)- Patients were classified into three groups on the basis of the initial mean FEF 25 - 75%. The initial FEF 25- 75 % in patients in group 1 exceeded 80 per cent of predicted normal (within normal limits), in patients in group 2 it was between 40 and 80 per cent (mild to moderate disease), and in group 3 less than 40 per cent (severe disease). For the three groups combined, the average per cent predicted FEF 25-75% was 92 per cent of its value in the previous year, an exponential decline of 8 per cent per year. Group 1 had an 8 per cent decline, group 2 an 8.5 per cent decline and group 3 a 6 per cent decline. When analyzed according to sex, males and females in group 1 y= -12.2 + 1.00 x , , , r=.738 ,, , , n=59 ,

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Figure 5. Relationship between arterial oxygen tension and combined clinical and chest x-ray scores, with regression line and 95 per cent confidence limits. (From Featherby, E. A., Weng, T. R., Crozier, D. N., et al.: Dynamic and static lung volumes, blood gas tensions and diffusing capacity in patients with cystic fibrosis. Am. Rev. Resp. Dis., 102: 737, 1970, with permission.)

DENNIS GURWITZ ET AL.

612 FEf25-75% (% of predicted)

120 100

80

60 40

20

9%/Y80r

lI%/year

"=70

25

6%/yeor

Figure 6. Average linear slopes of patients grouped by sex and initial FEF 25-750/0' Corresponding average exponential rate is shown below each slope.

17

120 MALES

100

80

60 40

20

n=79

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70;0/yeor

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90

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9

YEARS Of fOLLOW-UP

had similar average rates, but the decline in females in groups 2 and 3 was markedly steeper than in males. In our clinic, there are now 258 patients with longitudinal pulmonary function measurements over a 5 to 12 year period. (average 9 years). The average linear slopes of FEF 25 - 75 % are shown in Figure 6 for these 258 patients grouped by initial FEF 25-75'k and sex. The corresponding average exponential rates of decline are noted under each slope. With longer follow-up, the sex difference has become apparent even in the patients in group 1. The low average rate of decline in males in group 3 reflects the fact that many males survive for long periods with markedly compromised but stable lung function. We believe that this is probably the result of better nutrition and activity in the male as well as better specific ventilatory muscle endurance and upper body strength. 17 Although there was a great variation among individual rates of deterioration in both sexes, 25 per cent of all patients (18 per cent of females and 30 per cent of males) remained stable or have improved over a 5 to 12 year period. A large number of these stable patients are in group 1 and demonstrate that some individuals (both male and female) with cystic fibrosis maintain remarkably good health.

613

PERSPECTIVES IN CYSTIC FIBROSIS

RADIOLOGIC ASSESSMENT The radiologic changes in cystic fibrosis have been well described. 29 There is an excellent correlation between radiologic scores and pulmonary function studies. Reilly et aL showed that FEV! and Pa0 2 have the highest correlation with radiologic assessment. 29 Wood et al. have used chest x-ray films to define patient groups and to predict survivaP8 They divided their patients into two groups according to the highest radiologic score achieved during the first year of treatment. The group whose degree of pulmonary involvement was sufficiently reversible to result in a near normal chest x-ray film (284 patients) had 13 deaths during an 18 year period, whereas the group with poor x-ray films (251 patients) had 106 deaths during the same period.

PROJECTIONS FOR THE FUTURE The general factors that have the greatest effect on prognosis are summarized in Table 4. At present the physiologic basis for these trends is not entirely understood. Intensive research into the sex differences and the interrelationship between pulmonary status and nutrition is of paramount importance. The key to cystic fibrosis will be the development of laboratory methods for determining: an accurate test for the detection of cystic fibrosis in newborn infants; the identification of the heterozygote; and a reliable prenatal test for the homozygote. Although simple screening procedures have been recently introduced which detect the abnormal protein content of meconium in neonates with cystic fibrosis, these methods not infrequently give false postive and false negative results. Neonatal and early diagnosis open the way to initiate preventive care during infancy at a time when such care may be crucial to the long range well being of the patient. However, when it becomes possible to identify the carrier state by a simple method, surveillance of high risk populations and appropriate genetic counseling will be of prime importance. Furthermore, if the homozygote state can be clearly identified,

Table 4.

Prognostic Factors in Cystic Fibrosis

GOOD PROGNOSIS

POOR PROGNOSIS

Ma1e

Fema1e

Maintain appropriate weight

Poor weight gain or loss of weight

Single system involvement at presentation

Multiple system (gastrointestina1 and pulmonary) involvement

Norma1 chest x-ray film within the first year of presentation

Abnormal chest x-ray films in first year of presentation

DENNIS GURWITZ ET AL.

614

prenatal diagnosis with the option of pregnancy intervention will mean that the prevention of cystic fibrosis will become a reality.

REFERENCES 1. Bedrossian, C. W. M., Greenberg, S. D., Singer, D. B., et al.: The lung in cystic fibrosis. Hum. Pathol., 7:195, 1976. 2. Chalon, J., Loew, D. A. Y., and Orkin, L. R.: Tracheobronchial cytologic changes during the menstrual cycle. J.A.M.A., 218:1928, 1971. 3. Cooper, D. M., Down, 1., Mansell, A. L., et al.: The relative sensitivity of closing volume in children with asthma and cystic fibrosis. Am. Rev. Resp. Dis., 109:519, 1974. 4. Corey, M., Levison, H., and Crozier, D.: Five to seven year course of pulmonary nmction in cystic fibrosis. Am. Rev. Resp. Dis., 114:1085,1976. 5. Corey, M., and Levison, H.: Pulmonary function in siblings with cystic fibrosis. Cystic Fibrosis Club Abstracts, 1978, p. 35. 6. Crozier, D. N.: Cystic fibrosis: A not-so-fatal disease. Pediat. Clin. North. Am., 21 :935, 1974. 7. Cystic Fibrosis Foundation: 1976 Report on survival studies of patients with cystic fibrosis. April 1978. 8. Danes, B. S., and Beam, A. G.: Cystic fibrosis of the pancreas. A study in cell culture. J. Exp. Med., 129:775, 1969. 8. di Sant'agnese, P. L., and Davis, P. B.: Cystic fibrosis in adults. Am. J. Med., 66:121, 1979. 10. Featherby, E. A., Weng, T. R., Crozier, D. N., et al.: Dynamic and static lung volumes, blood gas tensions and diffusing capacity in patients with cystic fibrosis. Am. Rev. Resp. Dis., 102:737, 1970. 11. Fox, W. W., Bureau, M. A., Taussig, L. M., et al.: Helium flow curves in the detection of early small airway disease. Pediatrics, 54:293, 1974. 12. Gaskin, K.: Personal communication. 13. Gracey, M., and Anderson, C. M.: Cystic fibrosis of the pancreas in adolesceJ;1ts and adulthood. Aust. Ann. Med., 18:91, 1969. 14. Hayashi, M., and Huber, G. L.: Quantitative differences in goblet cells in the tracheal epithelium of male and female rats. Am. Rev. Resp. Dis., 115:595, 1977. 15. Hutcheon, M., Griffin, P., Levison. H., et al.: Volume of isoflow. A new test in detection of mild abnormalities oflung mechanics. Am. Rev. Resp. Dis., 110:458, 1974. 16. Imrie, J. R., Fagan, D. G., and Sturgess, J. M.: Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants. Am. J. Pathol., in press. 17. Keens, T. G., Krastins, 1. R. B., Wannamaker, E. M., et al.: Ventilatory muscle endurance training in normal subjects and patients with cystic fibrosis. Am. Rev. Resp. Dis., 116:853, 1977. 18. Kollberg, H., and Hellsing, K.: Screening for cystic fibrosis by analysis of albumin in meconium. Acta Paediat. Scand. 64:477, 1975. 19. Kopel, F. B.: Gastrointestinal manifestations of cystic fibrosis. Gastroenterology, 62:483, 1972. 20. Lamarre, A., Reilly, B. J., Bryan, A. C., et al.: Early detection of pulmonary function abnormalities in cystic fibrosis. Pediatrics, 50:291, 1972. 21. Lapierre, J. G., Zamel, N., and Levison, H.: Assessment of small airways disease in cystic fibrosis. Abstracts and Program, Annual Meeting of the Canadian Paediatric Society, 1975, p. 61. 22. Levison, H., and Godfrey, S.: Pulmonary aspects of cystic fibrosis. In Mangos, J. A., and Talamo, R. C. (eds.): Cystic Fibrosis: Projections into the Future. New York, Stratton Intercontinental Medical Book Corp., 1976. 23. Hadom, B., Johansen, P. G., and Anderson, C. M.: Pancreozymin secretin test of exocrine pancreatic function in cystic fibrosis and the significance of the result for the pathogenesis of the disease. Canad. Med. Assoc. J., 98:377, 1968. 24. Mansell, A., Dubrawsky, C., Levison, H., et al.: Lung elastic recoil in cystic fibrosis. Am. Rev. Resp. Dis., 109:190, 1974. 25. Mitchell-Heggs, P., Mearns, M., and Batten, J. C.: Cystic fibrosis in adolescents and adults. Quart. J. Med., 45:479, 1976. 26. Oppenheimer, E. H., and Esterly, J. R.: Pathology of cystic fibrosis and review of the literature, comparison with 146 autopsied cases. Perspect. Pediat. Pathol., 2:241, 1975.

I

PERSPECTIVES IN CYSTIC FIBROSIS

615

27. Orenstein, D. M., Boat, T. F., Stern, R. C., et al.: The effect of early diagnosis and treatment in cystic fibrosis: A seven year study of sixteen sibling pairs. Am. J. Dis. Child., 131 :973, 1977. 28. Reid, L., and De Haller, R.: The bronchial mucous glands, their hypertrophy and change in intracellular mucus. Mod. Probl. Pediat., 10: 195, 1967. 29. Reilly, B. J., Featherby, E. A., Weng, T. R., et al.: The correlation of radiological changes with pulmonary function in cystic fibrosis. Radiology, 98:281, 1971. 30. Shwachman, H., Kulczychki, L. L., and Khaw, K. T.: Studies in cystic fibrosis, Pediatrics, 36:689, 1965. 31. Shwachman, H.: The heterogeneity of cystic fibrosis. Birth Defects, 8, 1972. 32. Shwachman, H.: Cystic fibrosis. Curro Prob. Pediat., 8, 1978. 33. Shwachman, H., Redmond, A. and Khaw, K. T.: Studies in cystic fibrosis. Pediatrics, 57:335, 1970. 34. Stephan, U., Busch, E. W., Kollberg, H., et al.: Cystic fibrosis detection by means of a test-strip. Pediatrics, 55 :35, 1975. 35. Stern, R. C., Boat, T. F., Abramowsky, C. R., et al.: Intermediate-range sweat chloride concentration and pseudomonas bronchitis. J.A.M.A., 239:2676, 1978. 36. Stern, R. C., Boat, T. F., Doershuk, C. F., et al.: Course of cystic fibrosis in 95 patients. J. Pediat., 89:406,1976. 37. Warwick, W. J., Pogue, R. E., Gerber, H. U., et al.: Survival patterns in cystic fibrosis. J. Chron. Dis., 28:609, 1975. 38. Wood, R. E., Boat, T. F., and Doershuk, C. F.: Cystic fibrosis. Am. Rev. Resp. Dis., 113 :833, 1976. 39. Yeager, H., Shechter, Y., and Hamosh, M.: Increase in tracheal glycoprotein synthesis with estrogen administration. Proc. Soc. Exp. BioI. Med., 155:115, 1977. Pulmonary Function Laboratory The Hospital for Sick Children 555 University Avenue Toronto, Ontario M5G 1X8 Canada