Course of cystic fibrosis in 95 patients

September 1976

406

The Journal o f P E D I A T R I C S

Course of cystic fibrosis in 95 patients The course of 95 patients with cystic fibrosis is presented Survivors have a mean/bllow-up period of over 14 years (minimum: 13 years). Of 45 patients diagnosed prior to extensive irreversible pulmonary involvement, only one has died and none is disabled. In contrast, o f the other 50 patients diagnosed after substantial irreversible pulmonary disease was present, 26 have died. Mortality and morbidity has been greater in females. Possible factors contributing to the improving prognosis" include early diagnosis, aggressive management with comprehensive care, easy access' to specialized care, and improved antimicrobial therapy.

Robert C. Stern, M.D.,* Thomas F. Boat, M.D., Carl F. Doershuk, M.D., Arthur S. Tucker, M.D., Frank P. Primiano, Jr., Ph.D., and LeRoy W. Matthews, M . D . , C l e v e l a n d , O h i o

IN 1 964, we presented a five-year clinical evaluation 1 of a comprehensive therapeutic program for patients with cystic fibrosis.'-' The goal was to prevent or delay the progression of the pulmonary lesion while providing optimal treatment for the other manifestations of the disease. Survival was improved and evidence was presented suggesting the desirability of instituting therapy prior to the advent of irreversible pulmonary changes. Many workers have speculated on the factors contributing to the improving prognosis for patients with CF" .... There has been considerable debate regarding the importance of instituting pulmonary therapy prior to the onset of oVert pulmonary disease and about the efficacy of many, if not all, of the therapeutic measures. Concomitant with advances in antimicrobial therapy and aggressive and comprehensive management, however, there has been an extension of mean survival which reached 16 years in 1974. TM We report here our extended experience with 95 patients who were originally described in 1964. The 67 From the Departments' of Pediatrics and Radiology, Case Western Reserve University. Supported in part by grants AM08305 and H L 13885 fkom the United States Public Health Service and by grants from the Cystic Fibrosis Foundation and They Health Fund of Greater Cleveland. *Reprint address: 2103 Adelbert Road, Cleveland, Ohio 44106.

Vol. 89, No. 3, pp. 406-411

surviving patients have a minimum follow-up of 13 years. This long-term experience documents the survival and quality of life achieved by patients with CF under comprehensive medical supervision. Abbreviation used CF: cystic fibrosis METHOD

Patients. In 1957, a CF clinic was started at Babies and Childrens Hospital (Cleveland). Within four years, 102 patients had been referred and constituted the patient material for our initial report? Three patients who were not treated here after 1961 and three others who died prior to March, 1960, were reported previously and are not included in the present study. One of the remaining 96 patients now receives medical care elsewhere and is also omitted from this series. Of the remaining 95 patients, 28 have died and 67 continue to receive medical care at this center as of September 1, 1974. Cystic fibrosis was diagnosed by a positive sweat test in addition to typical pancreatic or pulmonary disease or a family history of CF. Most patients were hospitalized for initiation of treatment and family a n d / o r patient education. The treatment program-' included intermittent aerosols with l/8% phenylephrine in 10% propylene glycol, segmental postural drainage, antimicrobials as

Volume 89 "Number 3

Cystic fibrosis follow-up

oo-

407

................

90

t0,o 6050--

'*"%,%~.~ "~,,,.,,,~.

40t

%%,.

%%%

30-

GROUP 2

20I00

I

I

2

I

I

4

!

I

6

I

I

I

I

I

I

8 I0 12 Years of treatment

I

I

14

I

I

16

I

I

18

Fig. 1. Life table analysis of 95 patients with cystic fibrosis comparing patients with mild pulmonary disease at diagnosis (group 1), patients with more severe puhnonary disease at diagnosis (group 2), and the total patient population. These calculations and those shown in Fig. 2 are based on 1,248 treatment years. indicated by in vitro susceptibility studies and clinical status, nightly mist therapy, pancreatic replacement, and supplemental vitamins. Patients were seen at four to sixweek intervals. Bivalent influenza vaccine was administered yearly. Evaluation. A clinical score, utilizing our modification 1 of the system devised by Shwachman and Kulczycki :~was assigned to each patient initially and at six-month intervals. In this system a m a x i m u m of 25 points is given to each of four categories with a best possible total score of 100 points, Chest roentgenograms were scored by one of us (A. S. T.) without knowledge of the patient's clinical status. The initial, one-year, and most recent scores are presented. For patients who died the scores three months prior to death were used as the most recent score. The difference between the initial and one-year score reflects the improvement achieved during the initial hospital treatment a n d / o r the subsequent therapy at home. The difference between the one-year and last score reflects the course of the disease under treatment. The patients were divided into two groups after the first treatment year on the basis of the chest roentgenogram score. The 45 patients who attained a roentgenogram score of 19 or more points at any time during the first year of follow-up were arbitrarily assigned to group 1 (minimal pulmonary involvement). The remaining 50 patients did not achieve'a roentgenogram score of 19 or more points and were arbitrarily assigned to group 2 (moderate-tosevere pulmonary involvement). The two patient groups were subsequently compared

with respect to clinical and roentgenographic scores as well as mortality, frequency of hospitalization, and complications. The combined patient population was considered in assessing overall mortality, complications, academic success, social adaptation, and vocational achievement. The life table method 14 was applied to the combined patient population as well as to groups 1 and 2 individually. Height and weight data were analyzed using the Boston Childrens Hospital growth grids~ RESULTS Of the 95 patients, 28 have died and 67 continue to receive care at this center. All patients who died had clinically severe pulmonary and pancreatic disease. All but one had respiratory failure prior to death. Mean age at death was 14 years, eight months (range: six years to 24 years). Four of the 16 females and five of the 12 males had overt right heart failure. Clinical cirrhosis, present in three patients, and insulin dependent diabetes, present in two patients, were not important factors terminally. Autopsy permission was obtained on 13 of 16 females and eight of 12 males. Four patients not examined post mortem died elsewhere. All postmortem examinations showed typical pulmonary and pancreatic findings a n d 18 revealed right ventricular hypertrophy. Other major findings included: duodenal ulcer (4/21), cirrhosis ( 10/21), hypoplastic gallbladder (3/21), and cholelithiasis (1/21). There was no sex difference noted for these findings. The mean ages at initiation of the treatment program

408

Stern et al.

The Journal of Pediatrics September 1976

I0090-

~ "'~.~.,

80-

/Male

70.~

\

60-

Female~-~.,

5040B020I00

I

I 2

I

I 4

I

I 6

I

I I I I I I 8 I0 12 Years of treatment

I I 14

I 16

I "1 18

Fig. 2. Life table analysis of 95 patients with cystic fibrosis comparing male and female survival.

were as follows: Group I females: 3 years, 2 months; group 1 males: 2 years 6 months; group 2 females: 5 years, 0 months; group 2 males: 8 years 6 months. The results of the life table analyses are shown in Figs. 1 and 2. Mean cumulative survival after initiation of treatment was 0.64 for the entire patient population 0.98 for group 1 and 0.40 for group 2. Male survival was considerably better than female in group 2 after 14 treatment years. Group 2 females had the poorest survival (0.25). Clinical and roentgenographic grading results for various subgroups of the total patient population are summarized in Table I. The 28 patients who died had a mean age of 14 years, seven months, with a mean followup of eight years. Survivors have a mean age of 18 years, 10 months, after a mean follow-up of 14 years, 11 months. In group 1, males have a better last score for every category although their mean follow-up period is only five months less than for females. In group 2, this sex difference is not present. Only one patient in group 1 has died and she is included with the remainder of the patients who died for calculations of mean values (Table I). Mean age at death is somewhat higher for males. Males seem able to survive with worse pulmonary Status as reflected by generally lower roentgenogram scores shortly prior to death. Fourteen patients from group 1 and 19 from group 2 have reached 18 years of age. Sixteen are students. Five have graduated from college and two are enrolled,in graduate school. Careers pursued by the 16 patients who are presently employed full-time include: teacher (3), clerk (3), professional entertainer (2), factory worker (2),

manage family business (2), social worker (1), restaurant worker (1), accountant (1), and bank teller (1). Only one patient is disabled. Seven patients have married. No pregnancies have occurred. Complications are shown in Table II. Pneumothorax occurred exclusively in patients from group 2 and was more common in males. No other sex difference was noted for these complications. Hemoptysis was more common in group 2 but did occur in five patients in group 1. Rectal prolapse was more common in group 2. Nasal polyps were more common in group 1. Six females and four males have had sufficient psychologic problems to warrant consuhation. In general, weight was deficient for height and frequently was below the third percentile. In survivors, height is also below average, with boys growing less well than girls. This sex difference was particularly noticeable in the group 1 males less than 18 years of age in whom 11 of 17 are below the fiftieth percentile including four at the third percentile. Only four of the 12 younger girls in group 1 were below the fiftieth percentile including two at or below the third percentile. As expected, linear growth was very retarded in the patients who died and weight was even more abnormal. The mean age at menarche was 14 years, 4 months, in group 1 and 14 years, 1 month, in group 2. Menarche did not occur by age 16 in one patient in group 1 and four patients in group 2. in group 1, only five of the 18 females and five of the 27 males had more than one admission for treatment of pulmonary disease. Two males had one admission each for allergic aspergillosis and eight other patients had one

Volume 89 Number 3

Cystic fibrosis follow-up

409

T a b l e I. S u m m a r y o f clinical a n d r o e n t g e n o g r a p h i c s c o r i n g d a t a *

Mean scores

Patient subgroup'~

Mean age~

Mean follow -upS,

All patients Girls Boys All surviving Girls Boys All died Girls Boys All group 1 Girls Boys All group 2 Girls Boys

17-7 17-3 17-it 18-10 19-2 18-8 14-'7 13-10 15-8 17-6 18-3 17-0 17-8 16-7 19-0

12-11 13-1 12-9 14-11 14-11 14-11 8-0 9-10 5-8 14-9 15-0 14-7 11-3 11-10 10-6

I

History 1 1

16.3 16.3 16.3 17.0 17.5 16.6 14.6 14.1 15.2 17.9 19.~, 1"7~1 14.8 14.4 15.3

22.9 23~1 22.7 23.8 23.9 23.6 20.8 21.3 19.8 24.3 24.5 24.1 21.6 22.0 21.1

Pulmonary findings L

I

1 8 . 7 13.3 17.3 13.4 19.9 13.2 21.5 14.4 20.9 14.7 21.9 14.2 12.0 1 0 . 5 1~.8 ll.1 13.7 9.8 23.0 1 5 . 5 22.5 16.7 23.3 14.7 14.8 11.3 1 3 . 8 11.2 16.0 11.3

Nutrition I I 1 L

1

L

18.8 19.3 18.4 20.4 20.8 20.2 15.0 16.5 12.9 21.5 21.9 21.3 16.4 10.5 15.1

14.9 13.8 15.8 17.5 16.8 18.1 8.5 8.4 8.6 19.5 18.8 19.9 10.7 10.4 11.0

13.9 13.8 13,9 14.5 14.7 14.3 12.6 12.3 12.9 14.8 15.3 14.5 13.1 12.9 13.3

1 8 . 5 16.2 1 8 . 2 15.6 1 8 . 8 16.7 1 9 . 7 18.0 1 9 . 2 17.7 20.1 18.1 15.5 11.9 16.2 11.6 14.6 12.2 20.7 19.8 20.3 19.4 21.0 20.0 16.5 12.9 1 6 . 7 13.0 16.1 12.8

Roentgenogram I

1

12.4 15.4 11.9 15.3 12,9 15.4 14,5 17.8 13.6 17.4 15,2 18.2 7.5 9.6 8.8 11.7 5.8 6.7 1 7 . 1 20.6 1 6 . 1 19.6 17.8 21.3 8.2 10.7 9.1 12.5 7.2 8.5

L

I

11.4 10.3 12.4 13.8 12.2 15.0 5.7 6.9 4.2 16.3 13.9 17.9 7.0 7.9 6.0

55.9 55.4 56.3 60.4 60.4 60.4 45.2 46.4 43.6 65.3 67.1 64.2 47.4 47.7 47.1

Total I 1 75.5 75.8 75.3 81.7 81.3 82.0 60.8 65.9 54.0 87.1 86.2" 87.7 65.2 68.9 60.8

L 61.1 57.0 64.8 70.7 67.6 73.0 38.1 37.7 38.7 78.5 74.7 81.0 45.4 45.2 45.8

*I = Initial score; 1 = score at one (1) year; L = most recent score (July 1, 1974, or 3 months before death). tData on individual patients may be obtained from the authors. SMean ages and follow-ups given in years and months. T a b l e II. I n c i d e n c e o f c o m p l i c a t i o n s * in 95 p a t i e n t s w i t h cystic fibrosis

Complications Meconium ileus Meconium ileus equivalent Intussusception Rectal prolapse Pneumothorax Hemoptysist Clinical cirrhosis$ Diabetes Nasal polyps

Group 1 (45) 4 1 1 4 0 5 1 2 12

(9%) (2%) (2%) (9%) (0%) (11%) (2%) (4%) (37%)

Group 2 (50) 3 1 0 12 7 14 3 3 7

(6%) (2%) (0%) (24%) (14%) (28%) (6%) (6%) (14%)

Males (50) 3 1 0 9 6 10 3 2 11

(6%) (2%) (0%) (18%) (12%) (20%) (6%) (4%) (22%)

Females (45) 4 1 1 7 1 9 1 3 8

(9%) (2%) (2%) (16%) (2%) (20%) (2%) (7%) (18%)

]

Total (95) 7 2 1 16 7 19 4 5 19

(7%) (2%) (1%) (I7%) (7%) (20%) (4%) (5%) (20%)

*These data refer to the number of patients experiencing a given complication. Some patients had more than one episode of a complication, e.g., nasal polyps. tHemoptysis of more than 250 ml within one 24-hour period on at least one occasion. :~Clinical cirrhosis as reflected by bleeding esophageal varices, ascites, hypersplenism, or hepatocellular failure. Hepatomegaly alone is not included.

a d m i s s i o n for i n t e n s i v e antibiotic t r e a t m e n t . I n g r o u p 2, all b u t o n e o f the survivors h a v e h a d

at least o n e

than their p r e d e c e s s o r s w h o usually died in early childh o o d . A d v a n c e s in a n t i m i c r o b i a l t h e r a p y have b e e n

a v e r a g e d o n e p u l m o n a r y h o s p i t a l i z a t i o n for e v e r y 12.5

p r o p o s e d as the m o s t i m p o r t a n t , if n o t the only, '2 factor r e s p o n s i b l e for the e x t e n d e d survival. R e c e n t l y d e v e l o p e d antibiotics, p a r t i c u l a r l y those effective a g a i n s t Pseudo-

t r e a t m e n t years as o p p o s e d to o n e p u l m o n a r y h o s p i t a l i z a -

monas, have u n q u e s t i o n a b l y

admission and

12 o f the 21 h a v e h a d

two o r m o r e

a d m i s s i o n s for p u l m o n a r y i n d i c a t i o n s . G r o u p 1 p a t i e n t s

tion every 2.1 t r e a t m e n t years for g r o u p 2. DISCUSSION

b e e n i m p o r t a n t in the i m p r o v e d survival o f p a t i e n t s in g r o u p 2 in w h i c h 21 o f 22 patients r e q u i r e d h o s p i t a l i z a t i o n for t r e a t m e n t o f p u l m o -

T h e data c o n f i r m the widely r e p o r t e d i m p r o v i n g p r o g -

n a r y infection. O n the o t h e r h a n d , 27 o f t h e 45 p a t i e n t s w h o were assigned to g r o u p 1 o n the basis o f their initial

nosis for p a t i e n t s with C F . :'-~' It s e e m s unlikely that patients d i a g n o s e d f r o m 1957 to 1960 h a d m i l d e r d i s e a s e

status or early r e s p o n s e to t h e r a p y h a v e n e v e r r e c e i v e d a n y a n t i m i c r o b i a l a g e n t that was n o t a v a i l a b l e in 1964. Six

4 !0

Stern et al.

patients have received just one course of the newer antimicrobials. For these 33 patients (33% of the combined population and 75% of group 1), recent advances in antimicrobial therapy have had little or no impact. If their prognosis has been improved, it appears to be due to changes in other aspects of the therapeutic regimen. Another factor proposed to partially explain the,apparently improved prognosis is that better diagnostic facilities and increased physician awareness hiive resulted in the "early diagnosis" of patients with inti;insically mild pulmonary disease who previously would have escaped altogether?~ 12 This argument does not apply to the patients in group 1. Five of these patients had meconium ileus allowing diagnosis at birth regardless of physician awareness or availability of diagnostic facilities. An additional 33 patients had readily apparent p~almonary a n d / o r digestive symptoms at diagnosis. Only five patients were diagnosed solely on the basis of family history. The remaining three patients had unequivocal digestive symptoms but had not yet developed failure to thrive. Even in group 2 where all of the patients came to diagnosis and treatment after irreversible puhnonary involvement had occurred, the observed survival is better than that presently reported for unselected large populations of CF patients. TM Furthermore, the patients in group 1 began treatment at an earlier age than the patients in group 2 (one year, 10 months, in females and six years in males). If treatment had been delayed by this amount of time, the patients in group 1 might have deteriorated to a considerable degree. Earlier institution of therapy may account for their better pulmonary status rather than their having had intrinsically milder disease. Decreasing morbidity is more difficult to document than improved survival. Only five of the 45 group 1 survivors and nine of the 22 group 2 survivors have general activity scores of less than 19 points. In group 1 females there has been gradual worsening of the chest roentgenogram at a somewhat faster rate than in males. This also appears to be true for pulmonary function which will be reported separately. Work and school attendance has been good in the young adults. Only one of the 67 survivors has been completely disabled. The high proportion of males (six of seven) among the patients developing pneumothorax is different from our total experience with pneumothorax 1~ where the ratio was 14 females to 15 males. Similarly, the incidence of clinical cirrhosis (four of 95) is higher than in the total population seen at this center. '~ Among patients who die, the incidence of terminal overt right heart failure has been increasing. Nasal polyps were more common in group 1 but the possibility that allergy is protective in CF 17was not

The Journal of Pediatrics September 1976

investigated in these patients. Menarche is noticeably delayed in both groups 1 and 2. Despite the trend at this center to admit patients early for treatment of exacerbations of pulmonary infection, only 20 of the 67 surviving patients required hospitalization for pulmonary indications during the two years preceding this report. Only seven required more than one such admission. Many subtleties may play an important part in the success of a treatment program. Success may hinge in part on early inpatient treatment of pulmonary infection. There is no "quota system" limiting admissions or length of stay and no age limit for admission to the pediatric service provided the patient has been followed for pediatric illness. Many patients are allowed daily leaves of absence to attend college if this does not interfere with antibiotic therapy, chest physiotherapy, or other treatment. Some patients have continued to work full-time during hospitalization. Routine outpatient appointments are available throughout the week including Saturday and all patients have 24 hours access to a center physician. Patients are followed exclusively by center ' physicians and usualIy by the same physician at each visit. Residents may follow newly diagnosed patients (under supervision) but as each resident leaves, the care of his patients is taken over by a center physician. Psychologic problems are discussed openly and consultation obtained if indicated. Virtually all decisions concerning cystic fibrosis involve a center physician. An independently operating pharmacy cooperating with the center provides delivery of drugs and some therapy equip~ment at minimal cost. Many questions remain unanswered; many obstacles to good health~ The reasons that females do more poorly than ~ales, particularly during adolescence, are largely unknown. Social inhibition of cough, inactivity, use of spray cosmetics, and hormonal differences may be involved but are still uninvestigated. The possible role of diabetes in aggravating bacterial infection must be assessed to determine if this complication will assume increasing importance as more patients reach the third and fourth decades. The effect of liver disease on general health or the progress of the pulmonary lesion remains unclear? '~ The data suggest that, with diagnosis and institution of aggressive therapy before substantial irreversible puhnonary disease, conscientious follow-up by knowledgeable physicians, 24-hour access to specialized care and optimal inpatient facilities, cystic fibrosis usually can be well, albeit not easily, controlled throughout childhood. Cystic fibrosis, however, even if diagnosed early and treated

Volume 89 Number 3

well, poses an ongoing and major threat to health and life. Some well-treated patients in group 1 have shown considerable deterioration. Finally, a truly long-term prognosis cannot be m a d e on the basis of a 17-year experience. REFERENCES

1. Doershuk CF, Matthews LW, Tucker AS, Nudelman H, Eddy G, and Wise M: A 5-year clinical evaluation of a therapeutic program for patients with cystic fibrosis, J PEDIATR65:677, 1964. 2. Matthews LW, Doershuk CF, Wise M, Eddy G, Nudelman H, and Spector S: A therapeutic regimen for patients with cystic fibrosis, J PED~A7~65:558, t964. 3. Shwachman H, and Kulczycki LL: Long-term study of one hundred five patients with cystic fibrosis, Am J Dis Child 96:615, 1958. 4. Huang NN, Macri CN, Girone J, and Sproul A: Survival of patients with cystic fibrosis, Am J Dis Child 120:289, 1970. 5. Lawson D: Cystic fibrosis-assessing the effects of treatment, Arch Dis Child 47:l, 1972. 6. Mearns MB: Treatment and prevention of pulmonary complications of cystic fibrosis in infancy and early childhood, Arch Dis Child 47:251, 1972. 7. Matthews LW, Doershuk CF, Stern RC, Tucker AS, and Boat TF: Comprehensive and preventive treatment of cystic fibrosis, in Mangos JA, and Talamo RC, editors: Fundamental problems of cystic fibrosis and related diseases, New

Cystic fibrosis follow-up

4 11

York, 1974, Intercontinental Medical Book Corporation. 8. Warwick WJ, and Pogue RE: Computer studies in cystic fibrosis, in Lawson D, editor: Proceedings of the Fifth International Cystic Fibrosis Conference, Cambridge, London, t969, Cystic Fibrosis Trust, p 320. 9. Crozier DN: Cystic fibrosis a not so fatal disease, Pediatr Clin North Am 21:935, 1974. 10. Gellis S: Editorial comment, Pediatric yearbook, Chicago, 1971, Year Book Medical Publishers, Inc, p 289. 1l. Gellis S: Editorial comment, Pediatric yearbook, Chicago, 1972, Year Book Medical Publishers, Inc, p 176. 12. Gellis S: Editorial comment, Pediatric yearbook, Chicago, 1973, Year Book Medical Publishers, Inc, p 168. 13. Warwick W: Statistical analysis of natior:al cystic fibrosis data, 1974. 14. Cutler SJ, and Ederer F: Maximum utilization of the life table method in analyzing survival, Chronic Dis 8:699, 1958. 15. Stowe SM, Boat TF, Mendelsohn H, Stern RC, Tucker AS, Doershuk CF, and Matthews LW: Open thoracotomy for pneumothorax in cystic fibrosis, Am Rev Resp Dis 111:611, 1975. t6. Stern RC, Stevens DP, Boat TF, Doershuk CF, Izant RJ Jr., and Matthews LW: Symptomatic hepatic disease in cystic fibrosis: incidence, course and outcome of portal systemic shunting, Gastroenterology 70:645, 1976. 17. Rachelefsky GS, Osher A, Dooley RE, Ank B, and Stiehm ER: Coexistent respiratory allergy and cystic fibrosis, Am J Dis Child 128:355, 1974.