Pulmonary Function and Morbidity in 40 Adult Patients with Cystic Fibrosis" Robert I. Fink, M.D.;oO Carl F. Doershuk; M.D.; Arthur S. Tucker, M.D.; Robert C. Stern, M.D.; Thomas F. Boat, M.D.; and LeRoy W. Matthews, M.D.
Pulmonary function and cardiopulmonary compUcatioDS were studied in a group of 40 patients with cystic fibrosis who reached the age of 2S years. Mean values for vital capacity (VC), functional residual capacity, residual volume (RV), the ratio of RV over total lung capacity (RV / TLC), conductance, and the ratio of the forced expiratory volume in one second over VC were abnormal. There was a variable pattern of progression from patient to patient. The men differed from the women only in that they had
a significandy larger TLC and inspiratory capacity than the women. The resultant preservation of VC may have an advantage for survival in those patients In whom it is observed. Pseudomonas tJeTUginosa was encountered with increasing frequency with age. Massive hemoptysis did not result in early death. The occurrence of rightsided heart failure secondary to cor pulmonale, with or without respiratory failure, was a poor prognostic sign.
Development of the sweat test and improved approaches to therapy during the past 20 years have contributed to increasing the national cumulative rate of survival for patients with cystic fibrosis to 17.0 years;' however, there is great variability in the course of the disease, and not all patients have their condition deteriorate clinically at the same rate. Reports of adults with cystic fibrosis have recently been reviewed," and the clinical aspects have been described for 70 patients who reached the age of 25 years," but there have been no detailed reports of pulmonary function. This communication relates our clinical experience and data on pulmonary function from 40 patients who have survived into their 25th year of life. Variability was observed in the progression of pulmonary involvement. Our analysis of longitudinal studies of pulmonary function suggests that some patients with cystic fibrosis have a period of relative stability of pulmonary function after the age of 18 years.
in the sweat and either typical pulmonary or gastrointestinal disease or a history of cystic fibrosis in the family. Patients were seen as outpatients at intervals of four to six weeks. The program of treatment- included pancreatic replacement therapy and supplemental vitamins, intermittent aerosol therapy with 0.125 percent phenylephrine in a 10 percent solution of propylene glycol, segmental postural drainage, and administration of antimicrobial agents as indicated by in vitro studies of susceptibility and by the clinical status. Patients have used nightly mist therapy for varying lengths of time. Bivalent influenza virus vaccine was administered yearly. Longitudinal tests of pulmonary function were analyzed in the nine patients for whom results were available from the age of 18 years to greater than 28 years. For patients who had more than one test of pulmonary function during an analyzed year, the single best test during that year is reported. All tests of pulmonary function were performed in our laboratory using a 9-L spirometer (Collins) 5 and a totalbody pressure plethysmograph,6 and the results are reported as a percentage of the predicted value for that height. T Bacteriologic results at the ages of 18, 25, and 28 years or older are based on three successive cultures of sputum or deep throat cultures at intervals of four to six weeks. All gramnegative organisms, as well as Staphylococcus aureus, were reported even if they were present on only one culture. A clinical score, utilizing our modificationS of the system of Shwachman and Kulczyeki," was assigned to each patient at six-month intervals. In this system a maximum of 25 points (highest possible score, 100 points) is given to each of the following four categories: (1) case history; (2) pulmonary physical findings and history of cough; (3) growth, nutrition, and stool history; and (4) evaluation of the chest by roentgenograms. Roentgenograms of the chest were scored by ODe of us without knowledge of the patient's clinical status.
MATERIALS AND METHODS
Records of all patients who survived to the age of 25 years as of January 1977 were reviewed. The diagnosis of cystic fibrosis was established by elevated concentrations of chloride °From the Deparbnent of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children s Hospital, Cleveland. Supported in part by grants AM 08305, HL 13885, and HL 06009 from the Public Health Service and by grants from the Cleveland Cystic Fibrosis Foundation and the United Torch Services of Greater Cleveland. oONational Institutes of Health and Cystic Fibrosis Foundation Pediatric Pulmonary Disease Fellow. Manuscript received March 20; revision accepted May 10. Reprint requests: Dr. Doershuk, 2106 Adelbert Road, Cleveland 44106
CHEST, 74: 6, DECEMBER, 1978
REsULTS
We reviewed the records of the 70 patients seen at our center whose date of birth was before Jan 1, 1952. Forty (57 percent) of the 70 patients survived to the age of 25 years. These 40 patients have been ob-
PULMONARY FUNCTION AND MORBIDITY IN ADULTS WITH CF 843
Table
I--Clini~al
Patient, Height, Sex
em
1, F 2, F 3, F 4, F 5, F 6, Ft 7, F 8, Ft 9, F 10, F 11, F 12, F 13, Ft 14, M 15, M 16, M 17, M 18, M 19, M 20, M 21, M 22, M 23, M 24, M 25, M 26, Mt 27, M 28, Mt 29, M 30, M 31, M 32, Mt 33, Mt 34, Mt 35, M 36, M 37, M 38, M 39, M 40, M
161 161 172 151 154 173 162 166 159 162 166 165 169 171 178 177 178 164 170 175 176 174 175 166 162 177 181 160 177 181 166 167 164 176 180 169 170 180 176 178
Mean
Data and Data on Pulmonary Funelion from 40 Patienh .,ith Cy.ti~
Percent of Predicted Value for Height
Age at Diagnosis
VC
FRC
RV
TLC
Gaw
RV/TLC
1 yr 11 yr 3 yr 17 yr 6 rno 1 rno 19 yr 4 yr 9 yr 7 yr 15 yr 2 yr 10 yr 10 yr 5 yr 1 yr 17 yr 23 yr 10 yr 9 yr 14 yr 10 yr 7 yr 13 yr 16 yr 14 yr 16 yr 2 rno 6 rno 9 yr 2 yr 5 mo 11 yr 1 rno 2 yr 9 mo 7 mo 9 yr 5 mo 25 yr
77 61 97 60 56 64 79 29 98 27 105 81 38 52 105 115 84 83 93 34 100 59 63 65 87 82 84 47 101 65 56 36 31 61 69 109 120 89 88 124
115 173 161 196 82 133 147 127 105 171 118 138 207 143 279 104 79 142 108 156 158 130 225 290 124 174 162 235 114 138 201 131 220 211 197 150 143 118 174 124
220 318 298 400 127 272 229 255 1·9 382 134 235 457 304 544 131 105 253 167 347 273 276 477 582 224 358 317 486 170 271 420 275 520 422 403 276 173 182 365 125
III
41 39 62 36 44 41 27 30 135 12 126 53 21 39 30 66 147 71 76 20 34 58 16 30 73
0.44 0.58 0.45 0.66 0.41
8 yr
74
160
288
125
A.
124 141 142 72 111 115 78 103 106 112 115 128 109 205 121 94 126 111 103 135 110 151 183 119 144 131 151 121 107 143 88 135 150 139 146 136 107 145 126
40 22 104 63 25 31 43 16 18 62 107 60 57 50
0~52,
0.45 0.71 0.26 0.81 0.26 0.45 0.77 0.60 0.57 0.33 0.23 0.44 0.32 0.71 0.42 0.54 0.66 0.70 0.42 0.52 0.50 0.72 0.30 0.51 0.64 0.69 0.82 0.60 0.60 0.41 0.27 0.35 0.53 0.21 0.52
Fibro.i. at Age 25 Year.
Score for Chest X-ray FEV!, L FEV1/VC% Film*
1.54 0.98 1.61 0.98 0.21 1.32 1.03 0.57 2.48 0.44 2.84 1.21 0.21 0.98 1.94 3.07 2.72 1.86 2.48 0.55 1.65 1.37 0.95 0.94 1.60 2.27 1.58 0.60 3.24 1.45 1.16 0.60 0.50 0.95 0.99 1.44 3.75 1.75 1.94 4.90
Total Clinical Score**
52 65 39 56 12 48 37 51 75 46 69 40 40 45 40 58 69 61 65 36 36 53 34 37 52 66 38 37 70 46 52 43 43 34 30 33 76 41 49 84
15 12 19 10 10 7 4 10 15 7 15 10 9 9 9 22 18 13 15 5 14 5 9 7 7 4 8 9 8 14 6 6 7 9 13 15 16 7 7 25
72 56
48
11
61
88
54 61 58 47 46 70 33 78 64 49 66 62 82 81 72 77 46 78 59 60 56 57 29 72 40 69 64 43 32 23 54 63 70 83 68 52 97
"Maximum of 25 points. **Highest possible score, 100 points. [Deceased.
served at our center for periods .ranging from 3 to 29 years, with a mean length of follow-up of 20 years. Age at diagnosis of cystic fibrosis varied from 1 month to 25 years (mean, 8 years). The group of 27 men and 13 women had a mean age at the time of analysis of 27 years (range, 25 to 39 years). The individual data on pulmonary function and clinical findings from all 40 patients at the age of 25 years are presented in Table 1 and are summarized in Figure 1. Many patients showed marked increases in residual volume (RV), functional residual capacity (FRC), and the ratio of RV over total lung
644 FINK ET AL
capacity (RV/TLC); marked decreases in the rates of How and airway conductance (Caw); and a mild decrease in vital capacity (VC ) characteristic of obstructive pulmonary disease. Six patients (patients 9, 11, 17, 29, 37, and 40) had results of pulmonary function tests that were within normal limits or only minimally abnormal. The great variation in individual results was evidenced by the large standard deviation for each mean value (Fig 1) and the heterogeneity of individual subjects (Table 1). Longitudinal results of pulmonary function tests ( Fig 2 to 4) are presented for the nine patients who
CHEST, 74: 6, DECEMBER, 1978
1. Mean values (± 1 SD) for pulmonary function at age of 25 years for all 40 patients. FEV l' forced expiratory volume in one second, expressed as percentage of VC. Ratio of BV/TLC is percentage based on 0.3 as normal value.
FIGURE
VC
FRC
fN
nc
fN
me
GAW
had initial testing by 18 years of age and follow-up to at least three years beyond the age of 25 years. Major respiratory complications have occurred in these 40 adults to the present time. Nine had episodes of massive hemoptysis, with 300 ml or more of expectorated blood per episode. Spontaneous pneumothorax greater than 10 to 15 percent occurred in seven patients, three of whom later had a contralateral pneumothorax. Patients were hospitalized for each occurrence and were treated by one of several methods (drainage via a chest tube, such drainage plus therapy with intrapleural sclerosing agents, or surgical pleural abrasion and plication of blebs'"). Respiratory failure (as defined by an arterial oxygen pressure of less than 50 mm Hg and an arterial carbon dioxide tension of greater than 50 mm Hg) occurred in 13 patients, all after the age of
FEY 1
18 years, and 12 of these 13 developed cor pulmonale with right ventricular failure. Eight deaths have occurred in five men and three women (mean age, 28 years). The prevalence of mucoid Pseudomonas aeruginosa, a major pathogen in cystic fibrosis, increased with age, while the incidence of recoverable S aureus (50 percent [13/26 patients] at the age of 18 years and less than 20 percent [8/40 patients] at the age of 25 years) and Hemophilus influenzae decreased. At the age of 18 years, 17 (65 percent) of 26 patients had P aeruginosa; at the age of 25 years, this incidence was 26 (65 percent) of 40 patients; and at ages greater than 28 years, 15 out of 15 subjects (100 percent) had P aeruginosa. Thirty-nine patients completed high school, 25 completed college, and 11 hold advanced degrees.
125
i §~ ~o
~§ s-'I
>z
g
100
75
50-
~ 25
/1
10
18
25
30
AGE IN YEARS 2. Vital capacity vs age for nine patients with cystic fibrosis. Each line presents trend of VC for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open oval, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hextJgOR, patient 31; and solid circle, patient 39. FIGURE
CHEST, 74: 6, DECEMBER, 1978
PULMONARY FUNCTION AND MORBIDI" IN ADULTS WITH CF 645
1.0
.75
.25
II
10
18
30
25
AGE IN YEARS FIGURE 3. Ratio of RV/TLC vs age for nine patients with cystic fibrosis. Each line presents trend of RV/TLC for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open oval, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hexagon, patient 31; and solid circle, patient 39.
heterogeneous, and presentation of only mean data on pulmonary function for patients with cystic fibrosis obscures the variability of the pulmonary involvement, as seen in Table 1. Figures 2 to 4 illustrate the marked variability that occurs in data on pulmonary function for nine patients studied from adolescence through early adulthood. There is marked variability within each patient and between patients in the trend of an individual test of pulmonary function with age. Some data on an individual pulmonary function test exhibit improvement or
All were full-time students or were employed fulltime during their 25th year of life. Nineteen have married, with four subsequent divorces. Of 32 current survivors, 26 are employed full-time, two are unemployed but not disabled, and four are disabled. DISCUSSION
The mean values for the results of tests of pulmonary function (Fig 1) at the age of 25 years are characteristic of moderate to severe obstructive pulmonary disease; however, these results are markedly Q
Z
o U
4.0
w en
3.0
2.0
1.0
2S
18
30
AGE IN YEARS
FIGURE 4. Forced expired volume in first second vs age for nine patients with cystic fibrosis. Each line presents trend of FEV 1 for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open ooal, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hexagon, patient 31; and solid circle, patient 39.
846 FINK ET AL
CHEST, 74: 6, DECEMBER, 1978
stability for periods of seven to ten years. Men outnumbered women by a 2:1 ratio at the age of 25 years, which may reflect increased male survival, chance, or other variables; however, male survival up to the age of 20 years in 355 patients who are presently being observed at our center is similar to that for female patients. Analysis of the data on pulmonary function for the 27 men and 13 women at the age of 25 years revealed significant differences only in the mean TLC being larger in men (P < 0.01) and the mean inspiratory capacity being larger in men (P < 0.05). The ability to expand TLC and thus preserve VC may have an advantage for survival in adult patients with cystic fibrosis. Of the nine patients who had at least one episode of massive hemoptysis, one patient died 2.8 years after the initial hemoptysis, and eight still survive at a mean of 10.5 years after the initial hemoptysis, which is consistent with our overall experience with hemoptysis!' and contrasts markedly with the data of Holsclaw et al l 2 showing 13 of 19 patients dying within six months of the initial episode. Respiratory failure occurred in 13 patients, and some have remained in chronic respiratory failure. Echocardiographic measurements of right and left ventricular systolic time intervals'" have been useful in assessing the degree of cor pulmonale and the response to therapy. The occurrence of right ventricular failure secondary to cor pulmonale is a poor prognostic sign. Seven of 12 such patients died within three years of the onset of right-sided heart failure. Our data from cultures showing increasing frequency of recovery of P aeruginosa and decreasing recovery of S aureus diHer from the report that 25 out of 63 patients at ages greater than 25 years had no P aeruginosa, while 56 out of 63 had S aureus. 13 Differences in the technique of culture, therapy, or unknown variables may be responsible. Continued collection and analysis of data from longitudinal pulmonary function tests will allow further evaluation of the pulmonary effects of cystic
CHEST, 74: 6, DECEMBER, 1978
fibrosis, of changes in therapy (such as new antimicrobial agents), and of changes in the patient's status as a result of spontaneous pneumothorax, cor pulmonale, and massive hemoptysis. Such tests will also permit further delineation of the course of pulmonary function into adulthood in patients with cystic fibrosis. ACKNOWLEDGMENT: We thank Mr. Marvin D. Lough, A.R.R.T., and the technicians of the pediatric pulmonary laborato-!)' for their testing of the patients and Ms. Barbara L. SchiHhauer for her assistance in compiling and analyzing the data. REFERENCES
1 Cystic Fibrosis Foundation 1976 report on survival studies of patients with cystic fibrosis. Atlanta, Cystic Fibrosis Foundation, 1978 2 Stem RC, Boat TF, Doershuk CF, et al: Cystic fibrosis diagnosed after age 13. Ann Intern Med 87: 188, 1977 3 Shwachman H, Kowalski M, Khaw KT: Cystic fibrosis: A new outlook. Medicine 56:129,1977 4 Matthews, LW, Doershuk, CF, Wise M, et al: A therapeutic regimen for patients with cystic fibrosis. J Pediatr 65:558, 1964 5 Comroe JH, Jr, Forster RE II, Dubois AB, et al: The lung volumes. In the Lung: Clinical Physiology and Pulmonary Function Tests. Chicago, Year Book Medical Publishers, 1962, pp 7-13 6 Dubois AB, Botelho SY, Bedell GN, et a1: A rapid plethysmographic method for measuring thoracic gas volume: A comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J Clin Invest 35:322, 1956 7 Helliesen PJ, Cook CD, Friedlander L, et al: Studies of respiratory physiology in children. Pediatrics 22:80, 1958 8 Doershuk CF, Matthews LW, Tucker AS, et al: A fiveyear clinical evaluation of a therapeutic program for patients with cystic fibrosis. J Pediatr 65: 677, 1964 9 Shwachman H, Kulczycki LL: Long-term study of 105 patients with cystic fibrosis. Am J Dis Child 96:615,1958 10 Stowe SM, Boat TF, Mendelsohn H, et al: Open thoracotomy for pneumothorax in cystic fibrosis. Am Rev Respir Dis 111:611, 1975 11 Stern RC, Wood RE, Boat TF, et al: Treatment and prognosis of massive hemoptysis in cystic fibrosis. Am Rev Respir Dis 117:825, 1978 12 Holsclaw DW, Grand RJ, Shwachman H: Massive hemoptysis in cystic fibrosis. J Pediatr 76:829, 1970 13 Shwachman H, Kowalski M, Khaw KT: Cystic fibrosis: a new outlook. Medicine 56: 129, 1977
PULMONARY FUNCTION AND MORBIDITY IN ADULTS WITH CF 647
Pulmonary function and cardiopulmonary compUcatioDS were studied in a group of 40 patients with cystic fibrosis who reached the age of 2S years. Mean values for vital capacity (VC), functional residual capacity, residual volume (RV), the ratio of RV over total lung capacity (RV / TLC), conductance, and the ratio of the forced expiratory volume in one second over VC were abnormal. There was a variable pattern of progression from patient to patient. The men differed from the women only in that they had
a significandy larger TLC and inspiratory capacity than the women. The resultant preservation of VC may have an advantage for survival in those patients In whom it is observed. Pseudomonas tJeTUginosa was encountered with increasing frequency with age. Massive hemoptysis did not result in early death. The occurrence of rightsided heart failure secondary to cor pulmonale, with or without respiratory failure, was a poor prognostic sign.
Development of the sweat test and improved approaches to therapy during the past 20 years have contributed to increasing the national cumulative rate of survival for patients with cystic fibrosis to 17.0 years;' however, there is great variability in the course of the disease, and not all patients have their condition deteriorate clinically at the same rate. Reports of adults with cystic fibrosis have recently been reviewed," and the clinical aspects have been described for 70 patients who reached the age of 25 years," but there have been no detailed reports of pulmonary function. This communication relates our clinical experience and data on pulmonary function from 40 patients who have survived into their 25th year of life. Variability was observed in the progression of pulmonary involvement. Our analysis of longitudinal studies of pulmonary function suggests that some patients with cystic fibrosis have a period of relative stability of pulmonary function after the age of 18 years.
in the sweat and either typical pulmonary or gastrointestinal disease or a history of cystic fibrosis in the family. Patients were seen as outpatients at intervals of four to six weeks. The program of treatment- included pancreatic replacement therapy and supplemental vitamins, intermittent aerosol therapy with 0.125 percent phenylephrine in a 10 percent solution of propylene glycol, segmental postural drainage, and administration of antimicrobial agents as indicated by in vitro studies of susceptibility and by the clinical status. Patients have used nightly mist therapy for varying lengths of time. Bivalent influenza virus vaccine was administered yearly. Longitudinal tests of pulmonary function were analyzed in the nine patients for whom results were available from the age of 18 years to greater than 28 years. For patients who had more than one test of pulmonary function during an analyzed year, the single best test during that year is reported. All tests of pulmonary function were performed in our laboratory using a 9-L spirometer (Collins) 5 and a totalbody pressure plethysmograph,6 and the results are reported as a percentage of the predicted value for that height. T Bacteriologic results at the ages of 18, 25, and 28 years or older are based on three successive cultures of sputum or deep throat cultures at intervals of four to six weeks. All gramnegative organisms, as well as Staphylococcus aureus, were reported even if they were present on only one culture. A clinical score, utilizing our modificationS of the system of Shwachman and Kulczyeki," was assigned to each patient at six-month intervals. In this system a maximum of 25 points (highest possible score, 100 points) is given to each of the following four categories: (1) case history; (2) pulmonary physical findings and history of cough; (3) growth, nutrition, and stool history; and (4) evaluation of the chest by roentgenograms. Roentgenograms of the chest were scored by ODe of us without knowledge of the patient's clinical status.
MATERIALS AND METHODS
Records of all patients who survived to the age of 25 years as of January 1977 were reviewed. The diagnosis of cystic fibrosis was established by elevated concentrations of chloride °From the Deparbnent of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children s Hospital, Cleveland. Supported in part by grants AM 08305, HL 13885, and HL 06009 from the Public Health Service and by grants from the Cleveland Cystic Fibrosis Foundation and the United Torch Services of Greater Cleveland. oONational Institutes of Health and Cystic Fibrosis Foundation Pediatric Pulmonary Disease Fellow. Manuscript received March 20; revision accepted May 10. Reprint requests: Dr. Doershuk, 2106 Adelbert Road, Cleveland 44106
CHEST, 74: 6, DECEMBER, 1978
REsULTS
We reviewed the records of the 70 patients seen at our center whose date of birth was before Jan 1, 1952. Forty (57 percent) of the 70 patients survived to the age of 25 years. These 40 patients have been ob-
PULMONARY FUNCTION AND MORBIDITY IN ADULTS WITH CF 843
Table
I--Clini~al
Patient, Height, Sex
em
1, F 2, F 3, F 4, F 5, F 6, Ft 7, F 8, Ft 9, F 10, F 11, F 12, F 13, Ft 14, M 15, M 16, M 17, M 18, M 19, M 20, M 21, M 22, M 23, M 24, M 25, M 26, Mt 27, M 28, Mt 29, M 30, M 31, M 32, Mt 33, Mt 34, Mt 35, M 36, M 37, M 38, M 39, M 40, M
161 161 172 151 154 173 162 166 159 162 166 165 169 171 178 177 178 164 170 175 176 174 175 166 162 177 181 160 177 181 166 167 164 176 180 169 170 180 176 178
Mean
Data and Data on Pulmonary Funelion from 40 Patienh .,ith Cy.ti~
Percent of Predicted Value for Height
Age at Diagnosis
VC
FRC
RV
TLC
Gaw
RV/TLC
1 yr 11 yr 3 yr 17 yr 6 rno 1 rno 19 yr 4 yr 9 yr 7 yr 15 yr 2 yr 10 yr 10 yr 5 yr 1 yr 17 yr 23 yr 10 yr 9 yr 14 yr 10 yr 7 yr 13 yr 16 yr 14 yr 16 yr 2 rno 6 rno 9 yr 2 yr 5 mo 11 yr 1 rno 2 yr 9 mo 7 mo 9 yr 5 mo 25 yr
77 61 97 60 56 64 79 29 98 27 105 81 38 52 105 115 84 83 93 34 100 59 63 65 87 82 84 47 101 65 56 36 31 61 69 109 120 89 88 124
115 173 161 196 82 133 147 127 105 171 118 138 207 143 279 104 79 142 108 156 158 130 225 290 124 174 162 235 114 138 201 131 220 211 197 150 143 118 174 124
220 318 298 400 127 272 229 255 1·9 382 134 235 457 304 544 131 105 253 167 347 273 276 477 582 224 358 317 486 170 271 420 275 520 422 403 276 173 182 365 125
III
41 39 62 36 44 41 27 30 135 12 126 53 21 39 30 66 147 71 76 20 34 58 16 30 73
0.44 0.58 0.45 0.66 0.41
8 yr
74
160
288
125
A.
124 141 142 72 111 115 78 103 106 112 115 128 109 205 121 94 126 111 103 135 110 151 183 119 144 131 151 121 107 143 88 135 150 139 146 136 107 145 126
40 22 104 63 25 31 43 16 18 62 107 60 57 50
0~52,
0.45 0.71 0.26 0.81 0.26 0.45 0.77 0.60 0.57 0.33 0.23 0.44 0.32 0.71 0.42 0.54 0.66 0.70 0.42 0.52 0.50 0.72 0.30 0.51 0.64 0.69 0.82 0.60 0.60 0.41 0.27 0.35 0.53 0.21 0.52
Fibro.i. at Age 25 Year.
Score for Chest X-ray FEV!, L FEV1/VC% Film*
1.54 0.98 1.61 0.98 0.21 1.32 1.03 0.57 2.48 0.44 2.84 1.21 0.21 0.98 1.94 3.07 2.72 1.86 2.48 0.55 1.65 1.37 0.95 0.94 1.60 2.27 1.58 0.60 3.24 1.45 1.16 0.60 0.50 0.95 0.99 1.44 3.75 1.75 1.94 4.90
Total Clinical Score**
52 65 39 56 12 48 37 51 75 46 69 40 40 45 40 58 69 61 65 36 36 53 34 37 52 66 38 37 70 46 52 43 43 34 30 33 76 41 49 84
15 12 19 10 10 7 4 10 15 7 15 10 9 9 9 22 18 13 15 5 14 5 9 7 7 4 8 9 8 14 6 6 7 9 13 15 16 7 7 25
72 56
48
11
61
88
54 61 58 47 46 70 33 78 64 49 66 62 82 81 72 77 46 78 59 60 56 57 29 72 40 69 64 43 32 23 54 63 70 83 68 52 97
"Maximum of 25 points. **Highest possible score, 100 points. [Deceased.
served at our center for periods .ranging from 3 to 29 years, with a mean length of follow-up of 20 years. Age at diagnosis of cystic fibrosis varied from 1 month to 25 years (mean, 8 years). The group of 27 men and 13 women had a mean age at the time of analysis of 27 years (range, 25 to 39 years). The individual data on pulmonary function and clinical findings from all 40 patients at the age of 25 years are presented in Table 1 and are summarized in Figure 1. Many patients showed marked increases in residual volume (RV), functional residual capacity (FRC), and the ratio of RV over total lung
644 FINK ET AL
capacity (RV/TLC); marked decreases in the rates of How and airway conductance (Caw); and a mild decrease in vital capacity (VC ) characteristic of obstructive pulmonary disease. Six patients (patients 9, 11, 17, 29, 37, and 40) had results of pulmonary function tests that were within normal limits or only minimally abnormal. The great variation in individual results was evidenced by the large standard deviation for each mean value (Fig 1) and the heterogeneity of individual subjects (Table 1). Longitudinal results of pulmonary function tests ( Fig 2 to 4) are presented for the nine patients who
CHEST, 74: 6, DECEMBER, 1978
1. Mean values (± 1 SD) for pulmonary function at age of 25 years for all 40 patients. FEV l' forced expiratory volume in one second, expressed as percentage of VC. Ratio of BV/TLC is percentage based on 0.3 as normal value.
FIGURE
VC
FRC
fN
nc
fN
me
GAW
had initial testing by 18 years of age and follow-up to at least three years beyond the age of 25 years. Major respiratory complications have occurred in these 40 adults to the present time. Nine had episodes of massive hemoptysis, with 300 ml or more of expectorated blood per episode. Spontaneous pneumothorax greater than 10 to 15 percent occurred in seven patients, three of whom later had a contralateral pneumothorax. Patients were hospitalized for each occurrence and were treated by one of several methods (drainage via a chest tube, such drainage plus therapy with intrapleural sclerosing agents, or surgical pleural abrasion and plication of blebs'"). Respiratory failure (as defined by an arterial oxygen pressure of less than 50 mm Hg and an arterial carbon dioxide tension of greater than 50 mm Hg) occurred in 13 patients, all after the age of
FEY 1
18 years, and 12 of these 13 developed cor pulmonale with right ventricular failure. Eight deaths have occurred in five men and three women (mean age, 28 years). The prevalence of mucoid Pseudomonas aeruginosa, a major pathogen in cystic fibrosis, increased with age, while the incidence of recoverable S aureus (50 percent [13/26 patients] at the age of 18 years and less than 20 percent [8/40 patients] at the age of 25 years) and Hemophilus influenzae decreased. At the age of 18 years, 17 (65 percent) of 26 patients had P aeruginosa; at the age of 25 years, this incidence was 26 (65 percent) of 40 patients; and at ages greater than 28 years, 15 out of 15 subjects (100 percent) had P aeruginosa. Thirty-nine patients completed high school, 25 completed college, and 11 hold advanced degrees.
125
i §~ ~o
~§ s-'I
>z
g
100
75
50-
~ 25
/1
10
18
25
30
AGE IN YEARS 2. Vital capacity vs age for nine patients with cystic fibrosis. Each line presents trend of VC for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open oval, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hextJgOR, patient 31; and solid circle, patient 39. FIGURE
CHEST, 74: 6, DECEMBER, 1978
PULMONARY FUNCTION AND MORBIDI" IN ADULTS WITH CF 645
1.0
.75
.25
II
10
18
30
25
AGE IN YEARS FIGURE 3. Ratio of RV/TLC vs age for nine patients with cystic fibrosis. Each line presents trend of RV/TLC for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open oval, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hexagon, patient 31; and solid circle, patient 39.
heterogeneous, and presentation of only mean data on pulmonary function for patients with cystic fibrosis obscures the variability of the pulmonary involvement, as seen in Table 1. Figures 2 to 4 illustrate the marked variability that occurs in data on pulmonary function for nine patients studied from adolescence through early adulthood. There is marked variability within each patient and between patients in the trend of an individual test of pulmonary function with age. Some data on an individual pulmonary function test exhibit improvement or
All were full-time students or were employed fulltime during their 25th year of life. Nineteen have married, with four subsequent divorces. Of 32 current survivors, 26 are employed full-time, two are unemployed but not disabled, and four are disabled. DISCUSSION
The mean values for the results of tests of pulmonary function (Fig 1) at the age of 25 years are characteristic of moderate to severe obstructive pulmonary disease; however, these results are markedly Q
Z
o U
4.0
w en
3.0
2.0
1.0
2S
18
30
AGE IN YEARS
FIGURE 4. Forced expired volume in first second vs age for nine patients with cystic fibrosis. Each line presents trend of FEV 1 for one patient. Symbols for patients are as follows: solid hexagon, patient 5; open circle, patient 11; open square, patient 19; open ooal, patient 20; open triangle, patient 23; solid square, patient 25; solid triangle, patient 29; open hexagon, patient 31; and solid circle, patient 39.
846 FINK ET AL
CHEST, 74: 6, DECEMBER, 1978
stability for periods of seven to ten years. Men outnumbered women by a 2:1 ratio at the age of 25 years, which may reflect increased male survival, chance, or other variables; however, male survival up to the age of 20 years in 355 patients who are presently being observed at our center is similar to that for female patients. Analysis of the data on pulmonary function for the 27 men and 13 women at the age of 25 years revealed significant differences only in the mean TLC being larger in men (P < 0.01) and the mean inspiratory capacity being larger in men (P < 0.05). The ability to expand TLC and thus preserve VC may have an advantage for survival in adult patients with cystic fibrosis. Of the nine patients who had at least one episode of massive hemoptysis, one patient died 2.8 years after the initial hemoptysis, and eight still survive at a mean of 10.5 years after the initial hemoptysis, which is consistent with our overall experience with hemoptysis!' and contrasts markedly with the data of Holsclaw et al l 2 showing 13 of 19 patients dying within six months of the initial episode. Respiratory failure occurred in 13 patients, and some have remained in chronic respiratory failure. Echocardiographic measurements of right and left ventricular systolic time intervals'" have been useful in assessing the degree of cor pulmonale and the response to therapy. The occurrence of right ventricular failure secondary to cor pulmonale is a poor prognostic sign. Seven of 12 such patients died within three years of the onset of right-sided heart failure. Our data from cultures showing increasing frequency of recovery of P aeruginosa and decreasing recovery of S aureus diHer from the report that 25 out of 63 patients at ages greater than 25 years had no P aeruginosa, while 56 out of 63 had S aureus. 13 Differences in the technique of culture, therapy, or unknown variables may be responsible. Continued collection and analysis of data from longitudinal pulmonary function tests will allow further evaluation of the pulmonary effects of cystic
CHEST, 74: 6, DECEMBER, 1978
fibrosis, of changes in therapy (such as new antimicrobial agents), and of changes in the patient's status as a result of spontaneous pneumothorax, cor pulmonale, and massive hemoptysis. Such tests will also permit further delineation of the course of pulmonary function into adulthood in patients with cystic fibrosis. ACKNOWLEDGMENT: We thank Mr. Marvin D. Lough, A.R.R.T., and the technicians of the pediatric pulmonary laborato-!)' for their testing of the patients and Ms. Barbara L. SchiHhauer for her assistance in compiling and analyzing the data. REFERENCES
1 Cystic Fibrosis Foundation 1976 report on survival studies of patients with cystic fibrosis. Atlanta, Cystic Fibrosis Foundation, 1978 2 Stem RC, Boat TF, Doershuk CF, et al: Cystic fibrosis diagnosed after age 13. Ann Intern Med 87: 188, 1977 3 Shwachman H, Kowalski M, Khaw KT: Cystic fibrosis: A new outlook. Medicine 56:129,1977 4 Matthews, LW, Doershuk, CF, Wise M, et al: A therapeutic regimen for patients with cystic fibrosis. J Pediatr 65:558, 1964 5 Comroe JH, Jr, Forster RE II, Dubois AB, et al: The lung volumes. In the Lung: Clinical Physiology and Pulmonary Function Tests. Chicago, Year Book Medical Publishers, 1962, pp 7-13 6 Dubois AB, Botelho SY, Bedell GN, et a1: A rapid plethysmographic method for measuring thoracic gas volume: A comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. J Clin Invest 35:322, 1956 7 Helliesen PJ, Cook CD, Friedlander L, et al: Studies of respiratory physiology in children. Pediatrics 22:80, 1958 8 Doershuk CF, Matthews LW, Tucker AS, et al: A fiveyear clinical evaluation of a therapeutic program for patients with cystic fibrosis. J Pediatr 65: 677, 1964 9 Shwachman H, Kulczycki LL: Long-term study of 105 patients with cystic fibrosis. Am J Dis Child 96:615,1958 10 Stowe SM, Boat TF, Mendelsohn H, et al: Open thoracotomy for pneumothorax in cystic fibrosis. Am Rev Respir Dis 111:611, 1975 11 Stern RC, Wood RE, Boat TF, et al: Treatment and prognosis of massive hemoptysis in cystic fibrosis. Am Rev Respir Dis 117:825, 1978 12 Holsclaw DW, Grand RJ, Shwachman H: Massive hemoptysis in cystic fibrosis. J Pediatr 76:829, 1970 13 Shwachman H, Kowalski M, Khaw KT: Cystic fibrosis: a new outlook. Medicine 56: 129, 1977
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