A 5 year clinical evaluation of a therapeutic program for patients with cystic fibrosis

T h e Journal o[ P E D I A T R I C S

677

A 5 year clinical evaluation of a therapeutic program for patients Mth cysticfibrosis A clinical evaluation of a comprehensive prophylactic therapeutic program for patients with cystic fibrosis is presented. Ninety-six consecutive patients were followed for 18 to 60 months (average 37 months) and evaluated with the use of a modification of the Shwachman scoring system. Eighty-two per cent of these patients showed improvement, 11% remained the same, 4% showed progression beyond their initial status, and only 3% died. None of the deaths occurred before 5 years of age. Evidence is presented supporting the desirability of early diagnosis and the early institution of an intensive prophylactic and therapeutic regimen.

Carl F. Doershuk, M.D,, ~ LeRoy W. Matthews, M.D., ~ Arthur S. Tucker, M.D., Harry Nudelman, M.D., George Eddy, M.D., Melvin Wise, M.D., ~nd Samuel Spector, M.D. CLEVELAND~

OHIO

I • T H E first paper of this series, 1 a therapeutic program for children with cystic fibrosis was presented in detail. It is the purpose of this paper to give the results of a 5 year clinical evaluation of this program. Although the availability of antibiotic therapy has resulted in a significant proFrom the Department of Pediatrics, Western Reserve University School of Medicine. Supported by grants from the Cystic Fibrosis Foundation, Cleveland Chapter, the National Cystic Fibrosis Research Foundation, and United States Public Health Service Grants No. AM-06748 and AM-03485. ~'United States Public Health Service Post Doctoral Fellow. ~'~Address, Department o] Pediatrics, Western Reserve University School o] Medicine, Cleveland, Ohio.

longation of life, cystic fibrosis remains a progressive disease. The treatment recommended in the past has been aimed chiefly at management of the pancreatic lesion and of the frequent exacerbations of chronic pulmonary infection. Intensive treatment of the pulmonary lesion has been carried out mainly during hospitalization. Therapy to prevent progression of the disease has been largely concerned with the secondary infection rather than the primary pulmonary obstructive lesion. The therapeutic program evaluated in this study differs in that it is aimed primarily at the obstructive pulmonary lesion. Every effort is made to assist the normal mechanisms of pulmonary hy-

678

November 1964

Doershuk et al.

Table I. Clinical evaluation and grading criteria for patients with cystic fibrosis Pzdmor~ary physical findines and cough

Points

Case histories

25

Full activity Normal exercise tolerance and endurance Normal motor deveIopment Normal personality and disposition Normal school attendance

No cough Normal pulse and respiration No evidence of emphysema Lungs clear to auscultation Good posture No cIubbing

Maintains weight and No evidence of eraheight above twenty-fifth physema percentile or compatible No increase in with familial pattern markings Good muscle mass and No infiltration or tone atelectasis Normal subcutaneous fat Normal sexual maturation Good appetfte Well formed almost normal stools

20

Slight limitation of strenuous activity Tires at end of day or after prolonged exertion Less energetic Low normal range of motor development Occasionally irritable or passive Good school attendance.

Occasional hacking cough Clearing of throat Resting pulse and respiration normal Mild emphysema Occasional, usuaIIy localized harsh breath sounds, rhonchi or prolonged expiratory phase Good posture + clubbing or residual nonprogressive clubbing

Maintains weight and height above t e n t h percentile or slightly below familial pattern Go,od muscle mass and tone Slightly decreased subcutaneous fat Slightly retarded sexual maturation Appetite normai Stools. more frequent and slightly abnormal

15

Moderate emphysema May rest voluntarily Mild chronic nonrepeti- Maintains weight and Increased anteroposTires after exertion tive cough in the morn- height above third perterior diameter ing on arising, after centile or moderately Fair school attendexertion or crying, or below familial pattern Lung fields .nore ance radiolucent occasionally during the Weight usually deficient Moderately inactive Slight motor retarda- dam for height Diaphragms modertion No night cough Fair muscle mass and tone ately depressed Lacking spontaneity Respiration and pulse Deficient in subcutaneous Increased bronchoPassive or irritable slightly elevated fat vascular markings Increased anteroposterAbdomen slightly disLocalized or patchy ior diameter and detended atelectasis pressed diaphragms Maturation definitely re- Occasional transient tarded infiltration Coarse breath sounds Appetite fair Occasional localized rales, rfionchi, or Stools usually abnornlaI, wheezing large, floating, occasionally foul but formed Moderate rounding of shoulders 1-2+ clubbing

10

Limited physical activity and exercise tolerance Dyspneic after exertion Moderate motor retardation Fussy or irritable Sluggish, listless Poor school attendance, may require home tutor

Chronic cough, frequent, repetitive, productive, and rarely paroxysmal Respiration and pulse moderately elevated Moderate to severe emphysema often with chest deformity Rales, rhonchi, or wheezing usually present and often widespread Rounded shoulders and forward head Clubbing 2-3+

Growth and nutritior~

Weight and height below third percentile Weight deficient for height Poor muscle mass and tone Marked deficiency of subcutaneous fat Moderate abdominal distention Failure of sexual maturation and no adolescent growth spurt Poor appetite

X-ray

Minimal evidence of emphysema Mild accentuation of bronchovascular markings No infiltration or atelectasis

Marked emphysema Marked increase in anteroposterior diameter Marked depression of diaphragms Narrow cardiac silhouette Widespread areas of atelectasis Occasional localized segmental or lobar atelectasis--often transient

Volume 65

Number 5

Therapeutic program for cystic fibrosis 6 7 9

Table I. Cont'd Points

Case histories

Severe limitation of activity Dyspnea and orthopnea Inactive or confined to bed or chair Marked motor retardation Apathetic or irritable Cannot attend school

Pulmonary physical findings and cough

Severe, paroxysmal, frequent, and productive cough often associated with vomiting and hemoptysis Night cough Tachypnea and tachycardia Severe emphysema-fixed chest Generalized fine and coarse tales, rhonchi, musical wheezes and audible expiration Poor posture 3-4+ clubbing Often cyanosis

giene, to prevent the accumulation of secretions in the tracheobronchial tree, and to prevent the development of or to facilitate treatment of the secondary pulmonary infection. Our over-all goal was to prevent progression of the disease and to provide comprehensive care for the patient. The mortality rate has been and continues to be reported as relatively high, especially during early infancy. Although very few data have been published recently, it is obvious from the figures presented by Shwachman, 2 Huang, 3 Kramm and associates, 4 and Sirken and co-workers5 that between 5 and 15 per cent of the children with cystic fibrosis die annually. Sirken a n d co-workers 5 found, in

hospitals with approved pediatric residencies, that the mortality rate for patients admitted at least once during the year under study did not change from 1952 through 1957. For the year 1957, K r a m m and associates 4 found that "almost 15 per cent of the 2,500 hospitalized patients with cystic fibrosis were discharged by death." Forty per cent of these deaths occurred during infancy and another 25 per cent before the age of 5 years.

Growth and nutrition X-ray

Stools poorly formed, bulky, fatty and foul smelling

Persistent foci of infiltration Localized cysts Marked increase in markings

Malnourished and stunted Weak, flabby, small muscles Absence of subcutaneous fat Large, flabby, protuberant abdomen Failure to grow or gain Often weight loss Bulky, frequent, foul, fatty stools Often rectal prolapse

Extensive changes Severe emphysema Widespread atelectasis and infiltration Widespread cyst formation Bronchiectasis and abscess formation Lobar atelectasis-persistent

O u r m o r t a l i t y figures p r i o r to 1957 v a r i e d m a r k e d l y from y e a r to year; however, over the 5 y e a r p e r i o d from July, 1952, t h r o u g h July, 1957, 19 of the 76 patients a d m i t t e d to Babies a n d C h i l d r e n ' s H o s p i t a l with cystic fibrosis died. T h e t h e r a p e u t i c prog r a m described in the p r e c e d i n g p a p e r was initiated in July, 1957, a n d has resulted in a m a r k e d alteration in both the m o r b i d i t y a n d the m o r t a l i t y rates of the 167 patients studied over the last 5 years. METHOD

Patients. On July 1, 1957, a special clinic for patients with cystic fibrosis was established at Babies and Children's Hospital with 11 patients. Between July 1, 1957, and July 1, 1962, 156 patients with cystic fibrosis have been added to this group bringing the total to 167 patients. Of this number, 96 have been followed for 18 months or longer. The latter group provided the clinical material for most of the data reported here and includes every patient with cystic fibrosis referred to us for care. Only 3 patients have left the Cleveland area but they have continued with the therapeutic program

D o e r s h u k et at.

680

November 1964

T a b l e I I . T h e r e s u l t s o f c l i n i c a l e v a l u a t i o n o f t h e f o u r p a t i e n t s w h o d i e d of cystic fibrosis d u r i n g t h e p a s t five y e a r s

Age at Follow-up death period .... (year(months) month)

Patient

Case histories

.. Pulmonary findings

I* I L t [ D ~ .

I f L [D

IILID

7 8 9 8

10 10 12 14

'2~4 15 - 2 J.B. 10' ,18 23 T1-4 S.T. I1 11 A.E. ,2'0 6-2 10 20 0 5-9 S.C. 9 ~I, initial score. ~'L, last score 1 to 6 monflrs before death. +D, difference.

8 0 10

8 10 12

Growth and nutrition

1 2 3

12 12 18

X-ray

Total score

r!LID

2 2 6

5 1 1 5

2

-3

1 6

0 5

32 30 32 36

40 34 56

8

4 24

T a b l e I I I . A v e r a g e clinical e v a l u a t i o n scores o f 93 p a t i e n t s w i t h cystic fibrosis

Scores I

Categ~ ~

I Initial

Case histories Pulmonary physical findings Growth and nutrition X-ray (chest) Total score

year

16 14 14 12 56

Differences between initial and 1 year

23 19 18 15 75

7 5 4 3

Last

Differences between 1 year and last

Differences between initial and last

0 -1

7 4 5 3

23 18 19 15 75

19

l

0 0

19

*See Table I.

T a b l e I V . C l i n i c a l e v a l u a t i o n results f o r 24 p a t i e n t s w i t h cystic fibrosis f o l l o w e d f o r 48 to 60 m o n t h s

Patient

Present age

No.

(year-month)

5 10- 9 8' 9- 2 9 4- 8 10 14- 3 11 13- 0 13 6- 8 15 11- 1 19 4- 9 24 4- 3 29 4- 8 30 14- 8 31 8- 3 40 8- 1 41 8- 1 52 17- 2 55 ll- 9 56 10- 0 61 15-10 66 5- 0 68 10- 0 77 4- 9 83 7-10 87 12-10 88 4- 4 Average ~I, initial score. 1 year, one year score. L, last score.

FoHow-up

r 60 54 55 59 59 60 58 54 49 57 60 51 52 52 60 54 57 53 52 53 52 49 52 49 54

Pulmonary physical findings and cough

Case histories

I*

t l yearnj

L~

I

] Z year I

15 15 15 15 22 22 15 15 5 25 25 15 25 8 15 20 20 20 5 20 15 13 15 23 17

22 22 22 20 22 25 15 23 25 25 25 25 25 25 18 23 20 23 25 25 25 20 20 25 23

25 25 22 23 17 25 20 25 20 25 25 22 25 25 15 25 20 20 25 25 25 22 10 25 22

12 13 12 15 13 17 6 5 5 25 23 15 24 8 15 18 13 11 5 18 i0 10 10 14 13

18 20 20 15 13 23 10 20 20 25 23 21 25 20 15 20 13 15 25 23 23 15 15 22 19

L 20 20 15 15 11 17 9 20 t2

22 20 12 22 17 11 20 14 t5 23 22 22 15 5 23 17

Volume 65 Number 5

Therapeutic program lot cystic fibrosis

68 1

given either the complete therapeutic regim e n 1 or all except the mist tent therapy. This was omitted in 31 cases to permit evaluation of the effect of adding it once the patient's condition had stabilized on the r e m a i n d e r of the therapeutic regimen. D u r i n g the follow-up period, m a n y of the individual therapeutic measures were excluded for a period of one to two months or were altered to permit evaluation. No effort has been made to correct for these omissions or alterations i n this over-all clinic a l appraisal. Evaluation. All of the cases have been reviewed clinically at 6 m o n t h intervals with the use of a modification a n d expansion of the clinical criteria a n d a grading system published by S h w a c h m a n and associates. 2 T h e criteria were slightly modified to permit application to patients of any age. Each p a t i e n t was given from 0 to 25 points for each of the four categories: (1) ease history; (2) p u l m o n a r y physical findings a n d cough history; (3) growth, nutrition, a n d stool

a n d have been seen at yearly intervals for evaluation. T w o patients have been lost to m o n t h l y follow-up b u t they are k n o w n to be alive a n d are included in the d a t a only for the periods of actual follow-up. T h e average age of the 93 surviving patients is 8 years a n d 2 m o n t h s (range 2 years a n d 2 months to 29 years a n d 8 m o n t h s ) . T h e y have been followed for a period r a n g i n g from 18 to 60 m o n t h s a n d averaging 37 months. T h e diagnosis of cystic fibrosis was established in all cases by the history, physical examination, sweat tests (patch test 6 or iontophoresis t e c h n i q u e J 1la~ fat absorption studies, s a n d p u l m o n a r y evaluations (clinical a n d roentgenologic). I n all cases, evidence of a positive sweat test plus involvem e n t of either the pancreas or the lungs, or both was required before the diagnosis was made. All except 13 patients were originally hospitalized. After a thorough clinical a n d laboratory examination, the patients were

Total score Growth and nutrition

z 15 15 15 13 20 17 7 14 5 20 18 18 20 13 I0 13 15 10 8 20 10 12 10 15 14

Ilye~r] 22 20 20 15 20 23 8 25 13 24 18 25 22 20 12 15 15 12 25 23 23 15 15 18 19

L 22 22 t8 15 15 20 9 22 20 22 17 19 23 23 t2 16 15 12 23 22 22 13 8 19 18

X-ray

Z 6 8 13 13 4 17 12 7 5 20 8 12 17 4 13 11 8 6 6 13 14 6 5 20 10

]lye~r] 20 17 18 12 5 18 12 17 16 20 19 14 18 9 13 ii 8 8 25 15 25 9 7 20 15

L 22 18 17 10 3 12 9 20 10 20 21 12 19 9 6 12 7 10 21 22 25 9 3 19 14

I

I 48 51 55 56 59 73 40 41 20 90 74 60 86 33 53 62 56 47 24 71 49 41 4O 72 54.

Difference

I Difference 1 year (I-I year) 82 79 80 62 60 89 45 85 74 94 85 85 90 74 58 69 56 58 100 86 96 59 57 85 75

34 28 25 6 1 16 5 44 54 4 11 25 4 41 5 7 0 11 76 15 47 18 17 13 21

89 85 72 63 46 74 47 87 62 89 83 65 89 74 44 73 56 57 92 91 94 59 26 86 71

7 6 -8 1 -14 -15 2 2 -12 -5 -2 -20 -t 0 -14 4 0 -1 -8 5 -2 0 -3I 1 -4

41 34 17 7 -13 1 7 46 42 -1 9 5 3 41 -9 11 0 10 68 20 45 18 -14 14 17

68 2

November 1964

Doershuk e t a [ .

Fig. 1A. Posteroanterior film of the chest of Patient No. 66 (Table IV) at the age of 9 months. It shows irregular aeration and extensive bilateral pulmonary infiltrate. Clinically, she had severe pulmonary obstructive disease, marked cyanosis, and presented a severe feeding probiem.

Fig. lB. Posteroanterior film of the chest of the same patient at 5 years of age (52 months' followup). It shows slight residual fibrosis but no active infiltration. Pulmonary function tests and the physical examination were normal; however, throat and sputum cultures usually revealed

history; (4) evaluation of the chest by roentgenograms (Table I ) . Each patient was thoroughly evaluated when originally seen or just prior to the initiation of the therapeutic regimen and, subsequently, at 6 month intervals. I n an effort to make the evaluation as objective as possible, the appraisali of the first 3 categories were made independently by two of the authors. These usually agreed within _+5 points for the total score; an average score was used in most cases. Where there were differences of more than 5 points, a compromise score was assigned after a discussion of the two scores. Since all of the patients were seen monthly, each assessment took into consideration the patient's general condition for the previous 3 month period. T h e roentgenograms were appraised independently at 6 m o n t h intervals by one of us (A. S. T.) who had no knowledge of the patient's clinical status or of the scores for the other 3 categories. I t is recognized that

some aspects of this evaluation are subjective; however, such factors as school attendance, the record of growth and weight gain, and the number of deaths are, indeed, objective. The differences between the initial and the one year scores on these patients reflect the improvement achieved during the initial period of intensive hospital treatment and the subsequent therapy received at home. T h e differences between the one year and the last available records reflect the effect of the therapeutic regimen on the course of the disease. O t h e r data. The data on morbidity, the mortality rate, specific complications, and the financial cost of the treatment were obtained by a review of the patient's hospital and outpatient charts and from a questionnaire completed by the parents. Bacteriologic data were acquired from the results of the monthly tests performed as a

Pseudomonas aeruginosa.

Volume 65 Number 5

Fig. 2A. Lateral film of the chest showing marked increase in anteroposterior diameter, anterior bowing of the sternum, increased radiolucency, irregular aeration, scattered linear densities, fluffy infiltration, flat depressed diaphragm, and blunting of the costophrenic angle.

routine part of the therapeutic regimen. Sputum cultures or, if no sputum was available, throat cultures 3 were obtained on all patients at monthly intervals. Each culture was planted on a blood agar plate and, if indicated, on chocolate agar and phenylethyl alcohol plates." T h e chocolate agar plates were incubated in a CO2 jar. All staphylococci were classified according to the color of the colony, the type of hemolysis produced, and the coagulase production. Phage typing was obtained frequently on antibiotic-resistant strains of staphylococci,* Other organisms were identified by routine methods. Antibiotic sensitivities of all potential pathogens were determined on para-aminobenzoic acid-free media by the disc method by use of 2 concentrations of each drug.

~Performed at the Ohio State Department of I-Iealth Laboratorles, Columbus, Ohio.

Therapeutic program for cystic fibrosis

683

Fig. 2B. Lateral film of the chest of the same patient after 23 months of treatment. It shows a marked return in shape of the chest toward normal configuration, decreased bowing of the sternum, decreased radiolucency, and decreased fluffy infiltration. There is an increase in anteroposterior diameter and scattered linear densities persist.

RESULTS T h e mortality rate. During the period from July 1, 1957, to July 1, 1962, 167 patients were placed on the therapeutic program and followed for an average of 23 months. During this time, only 4 patients succumbed to the disease; so the mortality rate was approximately 1 per cent per year. T h e results of evaluations of the 4 patients who died are shown in Table II. All four of the patients who died had faradvanced chronic pulmonary disease and total evaluation scores of less than 40 points before they were admitted to the study. T h e youngest was 5 ~ years old at time of death. It is interesting that 3 of the 4 patients received prolonged intermittent positive pressure breathing therapy. None of the infants in the study have died during the 5 year follow-up period, despite the fact that m a n y of them had pulmonary involvement severe enough to produce severe respiratory acidosis.

684

Doershuk

et al.

CLINICAL EVALUATION Table I I I shows the average initial, one year, and last evaluation scores, and the differences between them, for each of the 4 evaluation categories and for total scores of the 93 patients who were followed from 18 to 60 months or for an average of 37 months. T h e 3 patients referred to us during this period who succumbed to the disease are not included in this table. I n the category of "case histories" (Table I ) , the 93 patients had an average improvement of 7 points during the first year of treatment (Table I I I ) . Seventy patients were improved by 5 points or more and 23 patients by less than 5 points, but 17 of the latter group had initial scores of more than 20 out of a possible 25 points. None of them had one year scores lower than their initial ratings. T h e subsequent follow-up from the one year to the last evaluation revealed no statistically significant change in the average scores for the group; however, 4 patients' scores dropped 5 points or more, two patients improved by 5 points, and the rest remained unchanged (• points). Three of the four patients whose scores dropped had initial scores below 15 points. The last evaluation was 5 points or more lower than the initial score for only 2 patients, both of whom were followed for over 52 months. T h e differences between the initial and one year evaluations for the category "pulmonary physical findings" averaged plus 5 points for the group. Fifty-five patients had 5 points or more improvement, 37 less than 5 points improvement and only one showed slight deterioration. Of the 37 patients with little improvement, 11 had initial scores of more than 20 points and 10 initial scores of 10 points or less. T h e subsequent follow-up from the one year to the last evaluation again showed no significant change for the group; however, 3 patients had an improvement of 5 or more points, 81 remained unchanged (_+4 points), and 9 had a decrease of 5 or more points. Four of the latter patients had initial scores of 10 points or less. Between the initial and last evaluations, the scores of

November 1964

46 patients increased over 5 points, there was no change in 45 (• points), and only 2 scores decreased 5 points or more. T h e evaluations of "growth and nutrition" revealed an average improvement of 4 points during the first year of treatment. Forty-one of the patients had 5 points or more improvement, 52 had no change (_+4 points), and in no case was there a significant decrease in the evaluation rating. The follow-up from the one year to the last assessment again disclosed no significant change for the group, however, there was 5 or more points improvement in 7 cases and a decrease of 5 points or more in only 4. Between the initial and last appraisals, 52

Fig. 3A. Infant C. F. three weeks after admission at the age of 5 months, weighing 6 pounds, 13 ounces. Note thin extremities, protuberant abdomen, and overinflated chest. The infant was cyanotic and showed evidence of air hunger in room atmosphere. The capillary pCO~ ranged between 90 and 102 mm. Hg for the first 30 days of treatment. Weight gain was not achieved until the obstructive lesion responded to therapy; pCO2 returned to normal on the fortieth day.

Volume 65 Number 5

Fig. 3B. The same infant six mouths later after continued intensive care, weighing 1389 pounds. Note decreased prominence of chest and return of subcutaneous fat. The chest was clinically clear and roentgenologically normal. There was no recent history of cough and her respiratory rate was normal.

patients had 5 or more points improvement, there was no change in 40 (_+4 points), and only one patient showed over 5 points deterioration. T h e "evaluation of roentgenograms" revealed an average improvement of 3 points during the first year of treatment. T h e scores of 23 patients showed 5 or more points improvement, 69 revealed no change (_+4 points), and only one showed a decrease of over 5 points. Subsequent follow-up from the one year to the last evaluation again revealed no significant change for the group; however, 7 patients had 5 points or more improvement, and 4 had 5 or more points deterioration. Between the initial and last evaluation, 30 patients showed 5 or more points improvement, 59 no change (_+4 points),

Therapeutic program for cystic fibrosis

685

and only 4 had 5 or more points deterioration. Typical roentgenologic changes are presented in Figs. 1 and 2. T h e average initial totM evaluation score was 56 points, the average one year was 75 points, and the average last evaluation score remained unchanged at 75 points. Only one patient had a one year total score below his initial one and only 9 patients showed less than 5 points improvement. Although no difference was found between the average one year and last total evaluation scores, 23 patients had continued improvement of 5 or more points, and only 15 had 5 or more points deterioration. Thirteen of the latter group had initial scores below 60 points. Comparisons of the individual initial and last evaluation scores revealed deterioration of 5 points or more in only 4 of the surviving patients, no change (_+4 points) in 10 of them, and improvement (5 points or more) in the remaining 79 patients. Forty-five patients had an over-all improvement of 20 points or more. Table I V shows the scores for each category and total scores of the 24 patients in our series who have been followed for 48 to 60 months (average follow-up 54 months) are also shown. T h e average results do not differ from those previously summarized for the entire group. As can be seen, from the initial to last evaluations, only 3 of these patients had a decrease in the total score of 5 or more points, 4 remained the same (_+4 points), and 17 had improvement of 5 or more points. I n 9 patients, the disease has progressed over the last 3I,/2 years, i.e., one year to last evaluation scores. Twelve patients are holding their own, and 3 have shown further improvement. T h e improvement of two of the patients who manifested severe disease when first seen is presented in Fig. 3, A and B, and Fig. 4, A and B. OTHER CLINICAL DATA T h e clinical evaluation results for "case histories" (category one, Tables I and I I I ) are further supported by the data collected on school attendance of the 67 patients of school age during the 1960-1961 school year.

686

November 1964

D o e r s h u k et al,

Fig. 4A. K. R., 6 years of age on the eleventh hospital day weighing 3189 pounds. On admission she was cyanotic, in severe respiratory distress, and too weak to walk. Note apathy, wasting, increased A-P diameter of the chest, and poor posture. Clinical evaIuation revealed severe obstructive and pneumonic pulmonary disease,

Fig. 4B. K. R. one year after the initial 3 week hospitalization and subsequent continued care at home. She now weighed 44 pounds. She was active and attended school regularly. She had minimal pulmonary symptoms and minimal clinical evidence of ohstruction. Irreversible pulmonary damage and mild chronic infection persist.

T h e number of days absent due to illness were determined for the patients with cystic fibrosis and for their 96 normal siblings. T h e patients with this disease missed an average of 7.4 days of school per year, as compared to an average of 9.6 days missed by their normal siblings. Only two of the 96 patients followed for more than 18 months have not attended school regularly. T h e evaluation of data on the growth of the 96 patients revealed a marked upward shift. T h e initial average height percentile for the group was the sixteenth; this increased to the twenty-seventh percentile. T h e initial average weight percentile was the, twelfth and this rose to the twenty-eighth. Typical

growth and weight changes are shown in Figs. 5 and 6. During the 18 to 60 m o n t h follow-up period (average 37 months), only 20 of the 96 patients required re-admission to the hospital after their initial hospitalization; 3 of them died. An average of approximately 7 per cent were re-admitted to the hospital each year. Five of these patients had inadequate home care because of social, marital or financial problems of the parents which necessitated readmission to the hospital. BACTERIOLOGIC

EVALUATION

Monthly sputum or throat cultures were obtained on all of the 96 patients included

Volume 65 Number 5

Therapeutic program /or cystic fibrosis 68 7

cluding Klebsiella, Proteus vulgaris, Escherichia coli and Haemophilus influenzae, and for normal flora (N.F.) is shown in Fig. 7 for a representative summer and winter month. Normal flora included only Neisseria catarrhalis, alpha streptococcus, and Staphylococcus albus. As can be seen, Staphylcoccus aureus was isolated from 40 to 50 per cent of the patients, Pseudomonas aeruginosa

in this study. The program of intermittent, specific, intensive antibiotic therapy used is presented in the previous paper? A detailed evaluation of these results will be the subject of another paper. However, certain pertinent data are summarized here. The incidence of positive cultures for Staphylo-

coccus

aureus,

Pseudomonas

aeruginosa,

both of these organisms, other organisms in-

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Fig. 5. Typical growth chart of infant with cystic fibrosis who showed poor weight gain at the age of 4 months. Treatment resulted in a dramatic growth and weight gain. Weight loss or failure to gain (see arrows) is often the earliest sign of pulmonary flare-up in the well-managed case. D. H. is Patient No. 19 in Table IV. At 5 years of age, he remains in the seventyfifth percentile for height and weight 9 Treatment is directed toward the primary obstructive lesion since he usually has no pulmonary infection.

688

Doershuk et al.

November 1964

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*PERCENTILES

40

i!?!:':~,U~T:r- ,,, 5 ~i~,:='!!;!:5:! o:i!~'7Cr ';.tIo:'.J'L~Y?'.~T.2 t:;:: ";, %%%?;~ ,"~

~o

Fig. 6. Growth chart for Di. K. who is Patient No. 41 in Table IV. This child has shown a typical growth and weight gain response to therapy. However, she has chronic irreversible pulmonary changes and the prognosis does not compare with her identical twin's, Patient No. 40 (Table I V ) .

from 45 to 50 per cent, other organisms from 6 to 8 per cent, and normal flora alone from 20 per cent. N o seasonal difference was found. Pseudomonas aeruginosa was consistently isolated from a relatively large group of patients who showed no other clinical evidence of active infection. Only 53 of the 93 patients required antibiotic therapy during the winter month analyzed, and only 58 required it during the summer month analyzed. Analyses of other months

confirm the fact that, on the average, 40 per cent of the patients in this study were receiving no antibiotic therapy in any one month. Table V shows the relationship between the x-ray rating and the incidence of positive cultures for these organisms. One hundred per cent of the patients with x-ray scores below 18 points manifested either Staph. aureus, Ps. aeruginosa, or both. Normal flora and organisms such as H. influ-

Volume 65 Number 5

enzae, P. vulgaris, and E. coli were found only in patients with mild or earIy pulmonary involvement. Staph. aureus was isolated from only 40 of the 93 patients at the time their last chest film was taken. When the antibiotic sensitivities of the first and last Staph. aureus, isolated from 83 of the 93 patients, were reviewed, the results shown in Table V I were obtained. I t is evident that no increase in the incidence of antibiotic-resistant staphylococci has occurred. Phage typing revealed type 80/81 for only 2 of the patients from whom staphylococci were isolated.

Therapeutic program [or cystic fibrosis

initial scores over 86 points improved or remained essentially unchanged during the follow-up period. Over-all, 3 of the 96 patients died, 15 showed progression of the disease process, 55 remained unchanged, and 23 showed further improvement after the first year of treatment. In general, the disease progressed in the children who had advanced irreversible pulmonary disease when first seen. These children had low initial scores and usually were

No, of P a t i e n t s I Percent

REPRESENTATIVE SUMMER STAPH. MONTH

COMPLICATIONS T h e incidence of complications of cystic fibrosis observed in the 96 patients is shown in Table V I I . FOLLOW-UP RESULTS Most patients showed significant improvement when they were first placed on the therapeutic program. This usually occurred within the first month but some patients showed steady improvement for up to one year. When the evaluation scores obtained one year after initiation of the therapeutic program are compared with the last available ones, the effect of therapy on the course of the disease is seen. In Table V I I I , the patients were divided into groups according to the initial evaluation score~ and according to the age when therapy was initiated. As can be seen, 86 per cent of the patients, started on therapy before 2r~ years of age, remained the same or improved during the period of follow-up as compared to 84 per cent of the patients between 2 89 and 6 years of age, and 74 per cent of those over 6 years old. The correlation between the initial score and the effectiveness of the therapeutic program is more apparent. Fifty-eight per cent of the patients with initial scores under 40 points, 80 per cent with initial scores between 41 and 55 points, 92 per cent with initial scores between 56 and 70 points, 95 per cent with initial scores between 71 and 85 points, and 100 per cent of those with

689

. . . . . . .L

25

STAPH & PS.-'Z'+"Y'

30!

N,

r/,~

2S

r 20 ~

2~

!:;:;i ~..'.~.

t 1-

10

I0~ § ,.t

4

t

No. of

!

Puti~'~

I

pe~ent

REPRESENTATIVE WINTER MONTH

25 25,

2O 20,

~0

10~

5

Fig. 7. Culture results on 93 patients with cystic fibrosis.

690

Doershuk et al.

November 1964

older when started on the therapeutic program. It should be noted that all 3 of the patients who died had initial scores below 40 points and were over 5 years of age. No infants have died during the 5 years covered by this treatment study. COST

OF

TREATMENT

Sixty-five families reported accurately their costs for drugs and equipment repair for the year 1961. The average cost of drugs per patient was $345; the range was from $60 to $1.000. All drugs were purchased at cost, plus 10 per cent, through a local druggist. Additional savings were achieved by the druggist through quantity buying and the use of bulk neomycin and polymyxin in aerosol solutions. The initial cost of home equipment averaged $307 per patient. The average cost of equipment repairs and replacement was $29; the range was from $0 to

Table V. Distribution of respiratory flora in 93 patients with cystic fibrosis related to last chest x-ray rating

No.

Staphy-

Last x-ray rating

ti~s pa-

lococcus aureus (%)

0to 8 9 t o 17 18 to 25

22 25 46

63 56 27

Pseudomonas aeruginoga

(%) 63 72 32

NOr-mal Other flora

(%)

(%)

38'

12

Table VI. Antibiotic sensitivities of the initial and last hemolytic Staphylococcus aureus (HSA) isolated from 83 ~' patients with cystic fibrosis

Antibiotic

Initialt HSA (% sensitive)

Last HSA (% sensitive)

Penicillin 51 62 Novobiocin 98 98 Tetracycline 42 46 Erythromycin 88 84 Streptomycin 51 54 Chloramphenicol 91 95 Neomycin 96 95 Kanamycin 95 94 ~'No HSA were ever isolated from 10 of the 93 patients. %Average interval between initial and last evaluations was 35 months.

$183. Where local subsidies are not available, the annual fees for the following laboratory work must be added: 2 chest films, 10 to 12 throat or sputum cultures and antibiotic sensitivity studies, and 3 to 4 blood counts. Locally these costs were so heavily subsidized that the actual cost to the patient never acted as a deterrent. The same applies to professional fees. Although this is a very idealistic therapeutic program, it is evident that the cost is not prohibitive. DISCUSSION I t is r e c o g n i z e d tion

criteria

that

(Table

I)

the

clinical

used

in

evalua-

this

study

are in part subjective although every effort was made to be as objective as possible. Included in each criterion are data which are

Table VII. Incidence of complications in 96 patients with cystic fibrosis

Complication

Incidence be[ore treatment

I

M e c o n i u m ileus Prolapseof rectum Hernia : Epigastric Umbilical Inguinal Cirrhosis of liver Hemorrhage, esophageal varices Ascites Hypersplenism Hypoproteinemia

6~ ll8

Nasal polyps Asthma Eye c h a n g e s ~~ Osteoarthropathy Recent tuberculin conversion Pneumothorax C a r d i a c failure

Incidenc,~ during [ /ollow-up 2

1 (repaired) 1 (repaired) 5 (3 r e p a i r e d ) 4 0

2 4 (same) 1

0 0 0

1 4 0

3 22t 0 35:~ 0

3 8 1 34:~ 1

0 2

1 2 terminal

Discoloration of 11 13 teeth R e n a l calculus 0 1 Diabetes 0 1w Sterility 0 1 ~All of these patients survived operation and are living. +Wheezing respiration. ~Twelve of the patients who showed clubbing when admitted to the study no longer have it and 11 who were initially normal have developed clubbing. w in one patient after July 1, 1962.

Volume 65 Number 5

T h e r a p e u t i c program for cystic fibrosis

quite objective such as school attendance, gross physical findings, pulse and respiratory rate, weight and height measurements, gross roentgenologic findings, and deaths. The data presented are based on every patient referred to our clinic for treatment, and indicate that the therapeutic program described in the preceding paper was effective. A question might be raised as to the magnitude of the improvement achieved. It should be noted that the average over-all improvement of 19 points is fairly evenly distributed between the four evaluation categories ranging from 7 points for case histories to 3 points for roentgenologic criteria. The inclusion of the 24 patients in the group with initial scores under 40 points tends to dilute the magnitude of the changes produced. M a n y of these patients had severe irreversible changes. This particularly affected the roentgenologic evaluation. Inclusion of the 24 patients whose initial scores were over 70 points produces a similar effect in that these patients could not show marked improvement. More important than the degree is the

6 9 1

maintenance of improvement over the average follow-up period of 37 months (range from 18 to 60 months). Eighty-one per cent of the 96 patients continued to improve or maintained their improvement after the first year of rapid recuperation. Only 7 patients including the 3 who died had last evaluation scores below their initial scores. It is interesting to note that in the group of 24 patients who were followed for 48 to 60 months (Table IV) similar results were obtained. Our over-all mortality rate was 3 per cent over an average follow-up period of 37 months, or approximately 1 per cent per year. No comparable data covering the same period have appeared in the literature. Shwachman 2 reported a 17 month followup with similar evaluation in 105 patients who had been observed for over 5 years. In his series, there was improvement in 45 per cent of the patients, no change in 26 per cent, progression of the disease on 20 per cent, and death occurred in 9 per cent. The mortality data reported by K r a m m and associates, 11 from a review of death certificates for 1958 (a year covered in our follow-

Table V I I I . Follow-up study of 96 patients with cystic fibrosis showing change in total score from one Year to last evaluation in relation to initial total score and age Initial age (years) 0 to 2.5

I n i t i a l total e v a l u a t i o n scores -

Condition I Better Same Worse

<40 , ,I 41 to 551 56 to 70 I 71 to 85 I 86 to 100 2 0 3 3 2 7 1 2 5 6 2 2 0 1 0

No. of patients 10 21 5

% 28 58 14

36 2.5 to 6.0

Better Same Worse

l 2 2D

2 2 1

3 3 I

1

0

7

5 0

2 0

14 4

28 56 16 25

>6.0

Better Same Worse

2 4 6 vD

2 6 2

2 6 1

0 3 0

0 1 0

6 20 9

17 57 26 35

No. of patients

24:D~D

25

24

19

4

25 33 42~

28 52 20

29 63 8

16

0

79 5

i00 0

% Better Same Worse D, deaths.

96

692

November 1964

Doershuk et aI.

u p period), reveals that there were 550 deaths in the entire country attributed to cystic fibrosis of which "33 per cent were among infants and 34 per cent among children in the age group 1-4 years." In a survey of three New England states for the 3 year period from 1956 through 1959, there was an average mortality rate of 5 per cent per year as compared to a rate of 8 per cent per year for the period from 1952 to 1955. During the time from 1956 to 1959, 18 per cent of the deaths occurred before the age of 1 year, 23.5 per cent between 1 and 5 years of age, 29.4 per cent between 5 and 10 years of age, and 28.3 per cent in patients over 10 years of age. The mortality data from Vital Statistics of the United States 12 for the years 1958 and 1959 reveal 1,140 deaths due to cystic fibrosis o f which 30 per cent were among infants, 31 per cent among children 1 through 4 years of age, and 24 per cent among children 5 through 9 years of age. Comparable data *a for the years 1960 and 1961 reveal similar mortality statistics. There were 1,237 deaths reported with 29 per cent among infants, 26 per cent among children 1 through 4 years of age, and 24 per cent among children 5 through 9 years of age. In our series of 167 patients accumulated over a 5 year period, no deaths occurred in patients under 5 years of age. It is also noteworthy that each of the 4 patients who died had had an initial score of less than 40 points. The efficacy of the entire therapeutic program and the specific, intensive, intermittent antibiotic therapy is indicated by the incidence of cultures revealing only normal flora, the number of patients requiring no antibiotic therapy in any given month, and the low incidence of antibiotic-resistant staphylococci. Though our antibiotic sensitivity results, obtained with the use of the disc method are not directly comparable with those of Huang and co-workers a who used the tube dilution technique, it would seem probable that there is a significant difference. The use of specific, intensive antibiotic therapy for 2 weeks to several months has not been associated with an increase in the

incidence of antibiotic-resistant staphylococci in our patients. The good results observed in the patients who had initial scores above 70 points, and the tendency of the disease to be slowly progressive in those whose initial scores were less than 40 points, emphasize the desirability of early diagnosis. The apparent ability to prevent progression of the disease in the first group indicates the importance of early institution of intensive prophylactic therapy. It is our opinion that the over-all results achieved with this therapeutic program are primarily the consequence of intensive therapy, closely and continuously supervised and aimed principally at prevention or treatmerit of the primary pulmonary obstructive lesion. It is apparent that the prognosis of the patients on this therapeutic program has been significantly improved. This is particularly true for those started on the therapeutic program before irreversible puhnonary damage has developed. We wish to thank Mrs. Lee Johnson and Miss Joan Rakoczy for their assistance in the preparation of this manuscript and the personnel of the nursing, dietary, physical therapy, laboratory, and radiology services at Babies and Children's Division of University Hospitals of Cleveland for their diligent and devoted assistance in the care of these patients.

REFERENCES

1. Matthews, L. W., Doershuk, C. Y., Wise, M., Eddy, 0., Nudelman, H., and Spector, S.: A therapeutic regimen for patients with cystic fibrosis, J. PEDIAT. 65: 55g, 1964. 2. Shwachman, H., and Kulczycki, L. L.: Longterm study of one hundred five patients with cystic fibrosis, A. M. A. J. Dis. Child. 96: 6, 1958. 3. Huang, N. N., VanLoon, E. L., and Sheng, K. T.: The flora of the respiratory tract of patients with cystic fibrosis of the pancreas, J. PgmAT. 59: 512, 1961. 4. Kramm, E. R., Crane, M. IV[., Brown, M. L., and Sirken, M. G.: Characteristics of patients with cystic fibrosis discharged from hospitals in 1957: Estimates for the United States~ Pediatrics 28: 128, 1961. 5. Sirken, M. G., Crane, M. M., Brown, M.D.,

Volume 65 Number 5

and Kramm, E. R.: A national hospital survey of cystic fibrosis, Pub. Health Rep. 74: 764, 1959. 6. Chicoine, L.: La conception actuelle de la fibrose kystique du pancrfias, Union m~d. Canada 85: 929, 1956. 7. Gibson, L. E., and Cooke, R. E.: Test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis, Pediatrics 23: 545, 1959. 8. Spector, S., Matthews, L. W., Lemm, F. J., VanErp, Y., and Cline, J.: Study of fat absorption utilizing I T M labeled corn oil in infants and children with and without steatorrhea, Pediatrics 22: 515, 1958.

Therapeutic program for cystic fibrosis

693

9. Schaub, I. G., Foley, M. K., Scott, E. G., and Bailey, W. R.: Diagnostic bacteriology, ed. 5, St. Louis, 1958, The C. V. Mosby Company, pp. 38-40. 10. Bruce, G. M., Denning, C. R., and Spalter, H. F., Ocular findings in cystic fibrosis of the pancreas: A preliminary report, A. M. A. Arch. Ophth. 63: 391, 1960. 11. Kramm, E. R., Crane, M. M., Sirken, M. G., and Brown, M. L.: A cystic fibrosis pilot survey in three New England states, Am. J. Pub. Health 52: 2041, 1962. 12. Vital Statistics of the United States for 1958 and 1959, Volume II. 13. Vital Statistics of the United States for 1960 and 1961, Volume II (to be published).