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(Received February 5; accepted for publication April 10, 1970.) -Supported in part by a research grant (A-6339) from the Division of Arthritis and Metabolic Dis-eases, National Institutes of Health, U. S. Public Health Service, and by the National Cystic Fibrosis Research Foundation.

ADDRESS: (H.S.) Children’s Hospital Medical Center, 300 Longwood Avenue, Boston, Massachusetts 02115.

PEnwrlucs, Vol. 46, No. 3, September 1970

335

STUDIES

IN CYSTIC FIBROSIS

Repor±

of

130

Patients

Diagnosed

Under

3 Months

of

Age

Over

a 20-Year

Period

Harry Shwachman, M.D., Aileen Redmond, M.D., and

Kon-Taik Khaw, M.D.

From the Division of Clinical Laboratories and the Department of Medicine, Children’s Hospital Medical

Center, the Department of Pediatrics, Harvard Medical School, and the

Children’s Cancer Research Foundation, Boston

ABSTRACT. Early diagnosis and treatment can a!-ter the morbidity and mortality of patients with

cystic fibrosis (CF). This conclusion is based on a study of 130 patients in whom the diagnosis was made under the age of 3 months during the 20-year period from 1949 to 1969. These patients were observed for a total of 912 patient-years.

The patients were segregated into three groups as follows: Group A (63) were diagnosed prior to the development of symptoms; Group B (13) had mild symptoms; Group C (54) were diagnosed during hospitalization. Immediately following the

diagnosis all patients were started on a therapeutic program and followed at regular intervals. There were 29 deaths, 11 in Groups A and B, and 18 in Group C, 8 of which occurred under 1 year of age.

The present clinical status of the 101 surviving children is an follows: 14 are in excellent condi-tion, 71 have mild disease or are in good health, and 12 are moderately or severely ill and have a poor prognosis. For all the 130 patients the calcu-lated survival rate at age 20 is 77%. Pediatrics, 46:

335, 1970, CYSTIC FIBROSIS, EARLY DIAGNOSIS AND SURVIVAL.

D

ESPITE our failure to comprehend the

nature of the basic defect in cystic fibrosis (CF), a better understanding of the natural history of the disease and its complications and the application of

em-piric therapeutic measures can modify the

hopeless prognosis of the past.

Early diagnosis, prior to the appearance of irreversible pulmonary lesions, consider-ably increases the life span and improves the health and comfort of children with CF. Conversely, when a child is initially

diagnosed with advanced pulmonary

involvement, the delay in establishing a

therapeutic program frequently results in progression of disease and early death. Prior to 1939 more than 85% of the patients were

dead by the end of the second year of life.1

From 1940 through 1948 the mean age of the 57 patients who died in our hospital

was 12.8 months. During the next 5-year

period, 1949 to 1954, the mean age at death of the 42 fatal cases had risen to 45.2 months.2 But, in contrast to these figures, the mean age of the 53 patients in our clinic who died during 1968 and 1969 was 15 years.

DIAGNOSIS

The rapid evolution of diagnostic tests for cystic fibrosis2,313 began as soon as

this condition was recognized as a distinct entity. At present the most widely used test is based on the determination of sodium and/or chloride in sweat collected follow-ing stimulation with piocarpine. A recent simplification of this technique, using a chloride ion electrode, indicates that this method could be used in a mass screening

program for the detection of CF in the

newborn infant.’0 Prior to the availability of

(2)

es-336

TABLE I

130 PATIENTS WITH CYSTIC FIBROSIS DIAGNOSED

UNDER 3 MONTHS OF AGE LISTED ACCORDING TO YEAR AND AGE OF DIAGNOSIS

Year Number

of Patient,

0-1

Week

1

Week-1 if onth 1-2 Month. -3 Month. 1949 1950 1951 1952 1953 4 3 5 3 4 1 1 2 1 2 1 1 2 1 2 2 1 2 1954 1955 1956 1957 1958 5 3 7 8 8 1 1 2 1 2 3 3 2 1 1 2 2 1 1 3 3 2 1959 1960 1961 1982 1963 10 12 12 3 12 2 2 2 1 2 3 5 8 2 3 2 2 4 4 3 1 3 1964 1965 1966 1967 1968 9 10 4 4 4 3 1 2 1 2 2 1 1 3 4 3 2 1 3 2

Total 130 17 44 32 37

tablish the diagnosis of

CF

in early life

ex-cept in patients with meconiun ieus. A rel-atively small number of patients with CF have sufficient symptoms in the first few months of life to suggest diagnostic testing

for this disease. To obtain an adequate pa-tient population for this study we examined the newborn offspring in families in which the disease occurred. In these infants an at-tempt was made to determine whether or

not they had CF as soon after birth as pos-sible. In 1949, when this study was first

un-dertaken, the diagnosis was based on an

assay of duodenal fluid for viscosity and

pan-creatic enzyme activity, as well as on stool trypsin tests. The “bag” sweat test first ap-plied to the 2- to 3-month-old infant group in 1955, was followed in 1959 by the piocar-pine stimulation test,#{176}which could be

per-formed as early as the first or second day of life. All infants diagnosed prior to 1955

have subsequently had positive quantitative sweat tests. The group provided an oppor-tunity for observing the effect of a

com-bined preventive and therapeutic approach to the management of this disease from its

onset. Patients with meconium ileus,

ex-cluded in this study, constituted about 18%

of our total CF population, and were

de-scribed in a previous report.”

THE PATIENTS

The patients, all diagnosed at less than 3

months, are listed in Table I according to

the year and age at diagnosis. Seventeen

pa-tients were diagnosed under 1 week of age; all but one were siblings of known cases. Eight in this group were hospitalized

because of meconium impaction. They

re-sponded to conservative medical manage-ment and did pot require surgery. The

absence of symptoms and difficulty in carry-ing out the early diagnostic procedure is il-lustrated by the fact that in the first decade of this study only 3 of the above 17 patients

were diagnosed under 1 week of age. In the

44 patients diagnosed between 1 week and 1 month, 36 were asymptomatic siblings of known cases. Of the 32 patients diagnosed

between 1 and 2 months, 16 had no

symp-toms, whereas only 11 out of 37 diagnosed between the ages of 2 and 3 months were symptom free.

Table II lists the patients according to the circumstance attending the diagnosis. The patients are divided into three groups: In Group A 63 patients were diagnosed prior to the onset of symptoms. All were

siblings of patients known to have cystic fibrosis. In Group B

13

infants were

diag-nosed as mild cases because their present-ing symptoms and general condition did

not suggest the need for hospitalization.

Seven

in

this group were siblings of known cases. The 54 patients comprising Group C were diagnosed during the initial hospital investigation. These infants were hospital-ized because they were acutely ill with either respiratory or gastrointestinal symptoms or a combination of both. Only seven patients in this group had a family history of cystic fibrosis.

(3)

TABLE II

PATIENTS LISTED ACCORDING TO YEAR OF ENTRY INTO STUDY AND CLINICAL STATUS AT TIME OF DIAGNOSIS

FROM JANUARY 1, 1949, TO JANUARY 1, 1969

patients diagnosed under 3 months of age, because they were followed for short pen-ods of time and were referred to other

din-ics for further care.

EARLY CLINICAL COURSE

All infants in whom the sweat test was

positive or pancreatic enzymes were absent

from the duodenal fluid when first seen, subsequently developed clinical features of

the disease. There were no exceptions. The

initial clinical symptoms were gastrointesti-nal or respiratory or a combination of both. Pancreatic insufficiency was manifest by hunger, slow weight gain, and abnormal

bowel movements. As soon as evidence of

pancreatic insufficiency was noted clinically

or by laboratory tests, treatment to be de-scribed was instituted. Early or mild

respi-ratory symptoms were more difficult to

recognize. Many infants appeared with an elevated respiratory rate. A slight cough was first noted at the time of the initial exami-nation in a number of infants. These

symp-toms persisted and in general, if left

untreated, became progressively more no-ticeable over a period of weeks or months. In some untreated cases the cough became

par-oxysmal, resembling that of pertussis, and often was associated with vomiting. Sticky

mucous secretions were brought up with

these episodes. Fever was not a symptom.

In Group A (Table II), 25 of the 63

pa-tients had a slight or infrequent cough by 3 months. Twelve more patients developed cough between 3 and 6 months. In many in-stances the development of a “cold” or up-per respiratory infection would initiate the

cough, which might persist for weeks or

even longer. The earliest changes in the

lungs, detected by chest films, consisted of hyperinfiation or irregular aeration and were present in approximately 25% of the

patients in Group A by 1 year of age. The 13 patients in Group B were diag-nosed in the outpatient clinic or office and none had been hospitalized elsewhere

previ-ously. They had symptoms suggesting CF

and the initial visit established the

diagno-Mild Severe

Number Symptom Symptoms Symptom.

Year of

Patients Free

Group A

not

Hospildized GrovpB

Requiring

Hospitalization Group C

1949 4 1 3

1950 3 2 1

1951 5 4 1

1952 3 1 2

1953 4 3 1

1954 5 1 1 3

1955 3 1 2

1956 7 3 1 3

1957 8 5 1 2

1958 8 6 2

1959 10 4 2 4

1960

12

3 1 8

1961

12

6

2

4

1962

3

3

1963

12

8

4

1964 9 4 5

1965 10 7 1 2

1966 4 2 1 1

1967 4 1 3

19684

Total 130 3

63 13

1

54

sis. A treatment program was initiated im-mediately. Four had respiratory symptoms, three had gastrointestinal symptoms, and six had a combination of both. Three patients

were hospitalized during the first year be-cause of pulmonary infection.

Of the 54 infants composing Group C, only 13 were referred with the diagnosis suspected. Eight patients were transferred

from other hospitals without recognition

that the illness was CF. The initial com-plaints varied, although respiratory

(4)

TABLE III

SOME COMPLICATIONS NOTED IN TILE COURSE OF

FOLLOWING

126

PATIENTS DIAGNOSED UNDER

3 MONTHS OF AGE FROM JANUARY 1, 1949,

TO JANUARY 1, 1969

18

#{149}#{149}

6

4

AGEAT 12

:

DEATH

to

8

6 #{149}.

U

4

.

2 U

T Y . T1 . .

//-,-949 51 53 55 57 59 61 63 65 69

YEAR OF BIRTH

GROUP A-U -DIAGNOSED BEFORE ONSET OF SYMPTOMS

GROUP B- A- MILD SYMPTOMS -NOT HOSPITALIZED

GROUP C- -SEVERE SYMPTOMS REQUIRING HOSPITALIZATION

Fic. 1. Age at death of 29 patients. .

Complications Number. of Patients

Hypoproteinemia and Anemia 3

Intestinal

delay in passing meconium 8

intussusception 3

volvulus I

mairotation I

fecal impaction 5

rectal prolapse 2

Pulmonary

hemoptysis 4

pneumothorax 5

empyeina 2

atelectasis and bronchiectasis

with pulmonary resection 3

Diabetes Mellitus 2

meconium was the main symptom in eight

patients and edema and anemia were the main symptoms in three patients. The

diag-nosis of CF was established soon after ad-mission, and therapy was started at once. In 46 instances these were the index cases of CF in their respective families.

The weight gain during the first year of life is used as one means of assessing both

the severity of disease and the initial

re-sponse to therapy. Although at birth the weight of all infants in Groups A, B, and C was equally distributed, with an abnormal

fraction below the 50th percentile,14 by 3 months of age, more of Group C (the

sick-est infants

)

were below the 3rd and 10th percentile than of Groups A and B. How-ever, those infants in Group C who

sun-vived to 1 year weighed nearly as much as

the infants in Groups A and B, at that age.

TREATMENT

Our current therapy, outlined in

Shir-key’s Pediatric Therapy15 and in Current

Pediatric Therapy by Gellis and Kagan,’6

has largely developed since 1948. Prior to

1940 effective therapeutic measures were practically nonexistent. In 1948 the first ma-jor dramatic advance in therapy occurred

with the introduction of

chlortetracy-cline.17’9

All

patients with evidence of pul-monary infection receive antibiotics, though 14 with predominantly intestinal manifesta-tions (11 in Group A, 3 in B, and 1 in C) were not given antibiotics until the advent

of their pulmonary symptoms. Those with

moderate or severe pulmonary infection generally received a combination of antibi-otics. The most commonly used antibiotics at present are: prostaphlin, gantrisin, linco-ci chloromycetin, erythromycin, rondo-mycin, and oxytetracycline. Colymycin and

gentamycin are used intravenously in com-bating pulmonary infection with

pseudo-monas in our hospitalized patients.

We have used pancreatin (Viokase) in

powder or tablet form as an effective prod-uct since

1951.

The diet is modified by

re-ducing total fat, increasing protein intake and total calories, and adding supplemental vitamins.

In 1954 we instituted the use of night

mist tents in the home in some of our pa-tients with moderate pulmonary

involve-ment. As of January 1969, 91 of the

101

pa-tients were sleeping in mist tents. Although this form of therapy has been viewed with

(5)

the basis of pulmonary function tests in a

controlled study. Our experience indicates that this form of therapy is beneficial.

Physical therapy, as currently practiced, was introduced in our clinic in 1955 and is recommended to all of our patients.2’ This

form of therapy includes breathing exercises, general physical fitness activities, and post-ural drainage for specified involved areas using clapping and vibration motions. The regularity with which parents and patients carry out our recommendations in this re-gard is dependent on their attitude and un-derstanding of the disease.

COMPLICATIONS

Table III lists some complications noted in the course of following these

130

pa-tients. In general, the frequency and num-ber of complications increase with age as the disease process progresses and as clini-cal experience has accumulated. For exam-ple, when the majority of patients suc-cumbed in early infancy, diabetes, nasal

poi-yposis, sinusitis, pneumothorax, hemotysis,

scoliosis, cirrhosis, portal hypertension, in-fertility in the male, intestinal obstruction, and some other complications were un-known. In 1956 we were aware of only two

patients with diabetes mellitus, yet cur-rently 26 patients from our clinic have devel-oped this complication. The complications that occur predominantly in early life in-clude delay

in

passing meconium at birth

(noted in eight patients) and malrotation, volvulus, and peritonitis, usually associated

with meconium ileus. Hypoproteinemia and

edema has been noted in infancy.

Em-pyema, usually staphylococcal, may occur at any time but more commonly in infancy. Rectal prolapse has a high incidence be-tween 1 and 3 years. Diabetes is more

com-mon after age 10. Hemoptysis and pneumo-thorax are more frequently noted after 15

years of age.22 In 1961 we first noted steril-ity

in

one adult male patient with CF. We now know that this condition exists in nearly all adult males with CF.23

Many of the so-called symptoms of the disease are indeed complications and are

TABLE IV

CLINICAL STATUS OF

97

PATIENTS

AS OF JANUARY 1, 1969

Group

Rating Total

A B C

Excellent 9 2 3 14

Good 28 4 24 56

Mild 7 4 4 15

Moderate 6 1 3 10

Severe

1

1

2

Total patients

50

12

35

97

preventable. An illustration is “rectal pro-lapse,” which we noted in 22.6% of un-treated infants and children with CF. By contrast, in the present series of patients di-agnosed early, only two developed rectal prolapse, and in both instances the parents did not follow dietary instructions. Other

preventable complaints are

hypoproteine-mia and anemia25 or hemorrhage secondary to vitamin K deficiency. Failure to thrive as a feature of CF may become an infrequent complaint if the disease is recognized and appropriate therapy is begun early.

During this 20-year study period a num-ber of complications led to hospital admis-sion. Of 63 patients in Group A, 28 were admitted to the hospital for a total of 50 hos-pitalizations with an average stay of 10.6 days. Of the 13 patients in Group B, 6 en-tered the hospital for a total of 10 admis-sions with an average stay of 8.7 days. In Group C, 35 of the original 53 patients were subsequently readmitted to the hospital, and the average stay was 8.7 days. Most of the hospital admissions were to treat the advancing pulmonary disease; some pa-tients had diffuse infiltrates, others had lob-ular or segmental atelectasis, and a large number had bronchiectasis.

A few iatrogenic complications occurred. The most common was dental staining26

secondary to the administration of

tetracy-dines during the first 4% years of life. All

69 patients treated initially with

chlortetra-cycline showed staining of deciduous teeth

(6)

denti-CLINICAL SCORE

NUMBER OF YEARS SINCE DIAGNOSIS

I 2. 3 4 5 6 7 8 9 10 II 12 13 14 15 16 I? 18 9 20

luc

EXCELLENT

8#{128}

0

AD 00

8

0

0 0 A

GOOD

-71

MILD

0 0

0

Ao 0 0 00 000 o 0 0 0

0 OQoOo 8A.oo 0

000 0 A 0

p

#{241}

DO 0 o AA o

A 00 00

0 5#{128}

MODERATE

41

U 0 A 0 0 0

0

SEVERE

0 A

DEATHS Us. #{149} U #{149} #{149}Us U . #{149}.

GROUP A- 60- 0 DIAGNOSED BEFORE ONSET OF SYMPTOMS

GROUP B- I3- MILD SYMPTOMS NOT HOSPITALIZED INITIALLY

GROUP C 53- 0 SEVERE SYMPTOMS REQUIRING HOSPITALIZATION INITIALLY

U DEATHS 9) GROUPA- GROUP B-I GROUP C-lB

FIG. 2. Status as of January 1, 1969, of 126 patients diagnosed before 3 months.

tion. For this reason we have avoided using

tetracyclines during the first 43 years of life. We noted that oxytetracycline produces less dental staining than the other tetra-cyclines.

A total of 59 patients received chloram-phenicol daily for varying and prolonged

periods (up to 3 years). The dose varied from 15 mg to 50 mg/kilo/24 hours. Com-plications attributable to chloramphenicol did not occur in these 59 patients.27 How-ever, our total experience with this drug in

treating patients with cystic fibrosis in-cludes two patients with hematologic com-plications and 15 patients with optic

neu-ritis and three patients with peripheral

neuritis.

Prophylactic measures have included the

vaccination of all patients against measles

and the use of influenza vaccines before ex-pected outbreaks.

DEATHS

There were 29 deaths among the 130

pa-tients in this study, 10 were from Group A;

1 from Group B, and 18 from Group C. The

age and year of death is shown in Figure 1.

The average age of the 13 males at death

was 7M2 years as compared to Th2 years for

the 16 females.

In reviewing the course of the disease in the 10 patients in Group A who succumbed,

we noted the following contributing factors

in four cases: poor and inadequate home

care, lack of educational opportunities or emotional immaturity of parents, failure to

appreciate the nature of the disease and hence disregard of the instructions, irregu-lar clinic attendance, economic hardships,

parental discord, and religious beliefs

which interfered with our medical advice.

Of the 13 patients in Group B, only one died. This boy was 8’9’12 years of age and had three short hospital admissions because of recurrent pulmonary infection. Postmor-tem examination revealed extensive

bron-chiectasis and con pulmonale.

Eighteen patients succumbed from Group C; four died during the initial hospi-talization. Four other infants died under the age of 5 months with the following di-agnoses: pseudomonas pneumonia,

(7)

I’,

A’ B

0 z > >

U)

Lu

0

z Lu (-3 Lu 0.

GROUP MB --76 PATIENTS GROUP A’B+CI3OPATIENTS

20 GROUP C -53 PATIENTS

10

ARTICLES

341

of death in the majority of patients were at-tnibutable to pulmonary disease.

Bron-chiectasis was present in nearly all cases.

There were more survivors in Groups A

and B (62, or 84%) than in Group C (35,

on 66%) . As expected, patients who were initially hospitalized because of severe

ill-ness due to CF have a much poorer

progno-sis than those in whom the disease is recog-nized in the asymptomatic on early stage. In our sickest patients, i.e., those in Group C, the correct diagnosis of CF had been suggested in only 14 out of the 53 patients prior to referral to this hospital. There is no

doubt that the mortality would have been

higher had the condition of these patients

remained undiagnosed and appropriate

therapy withheld.

PRESENT STATUS

In 195628 we proposed a scoring system

for assessing the severity of cystic fibrosis, based on a physical examination, chest

x-nay, and complete history. Accordingly, pa-tients with a score of 86 or above are con-sidered in excellent health, those with a

score of 71 to 85 are in a good status, those with a score of 56 to 70 are rated as mild, those with a score between 41 and 55 have

moderate disease, while patients with a

score of 40 or below represent instances of

severe disease. In assessing the severity of

disease in the survivors among these 136

children,

it

is gratifying to observe that

many patients are still in the “good” and

“mild” categories. The scores of the

survi-vors in all groups are summarized in Table

IV. The prognosis in these 12 patients is

poor. It is noteworthy that 27 of the pa-tients in Group C are in the “excellent” to “good” category. Figure 2 shows the status of all patients as of January 1, 1969. Each pa-tient is recorded on the chart according to age and severity of disease. This figure also

indicates that 31 of the 97 patients are now

over 10 years of age. The survival curves of

the 130 patients followed for the period of

the study are presented in Figure 3. These curves were made from data prepared

ad-O 2 4 6 8 10 $2 14 (6 8 20

YEARS OF OBSERVATION

FIG.

3. Cumulative survival rate of 130 patients diagnosed under 3 months.

cording to the Life Table Method of Cutler

and Ederer.29

CONCLUSIONS

It is possible to diagnose cystic fibrosis prior to the development of clinical features by appropriate laboratory procedures in the newborn period.

All newborn siblings of patients with cys-tic fibrosis found to have elevated sweat electrolytes eventually developed symptoms

of the disease.

The initiation of dietary and pancreatic replacement therapy prior to or with the ap-pearance of early signs of gastrointestinal

involvement in the absence of pulmonary symptoms permits nearly normal growth and development. It will diminish the usual complaints of frequent, loose, foul move-ments, protuberant abdomen, and excessive appetite; it will markedly reduce the inci-dence of rectal prolapse and possibly secon-dary fecal impaction which may result in intestinal obstruction. Other complications, such as anemia, hypoproteinemia, and

hypo-prothrombinemia are also preventable. The early institution of prophylactic

(8)

physical therapy, and antibiotics orally and

by aerosol, provide effective measures for

either controlling or slowing the

progres-sion of pulmonary involvement. It is sim-pier to institute this program when the di-agnosis is made in the first 3 months of life

than at a much later age. Parents more

readily accept the concept of preventive

measures and the infants adjust more easily.

Better health and prolonged life result from early diagnosis and vigorous therapy. Until more is known about the basic defect

in CF, application of these two concepts constitutes the best available approach to the management of this disease.

REFERENCES

1. Warwick, W. J., and Monson, S.: Life table studies of mortality. In Modem Problems Pediatrics, Vol. 10. New York: S. Karger, pp. 353-367, 1967.

2. Shwachman, H., Leubner, H., and Catzel, P.:

Mucoviscidosis. Adv. Pediat., 7:249, 1955. 3. Shwachman, H., Patterson, P. R., and Laguna,

J.: Studies in pancreatic fibrosis: A simple diagnostic gelatin film test for stool trypsin. PEDIATRICS, 4:222, 1949.

4. Di Sant’Agnese, P. A., Darling, R. C., Perera,

C.

A., and Shea, E.: Sweat electrolyte dis-turbances associated with childhood pancre-atic disease. Amer. J. Med., 15:777, 1953. 5. Shwachman, H., and Gahm, N.: Studies in

cystic fibrosis of the pancreas. A simple test for the detection of excessive chloride on the skin. New Eng. J. Med., 255:999, 1956. 6. Gibson, L. E., and Cooke, R. E.: A test for

concentration of electrolytes in sweat in cys-tic fibrosis of the pancreas utilizing pilocar-pine by iontophoresis. PEDIATRICS,

23:545,

1959.

7. Shwachman, H., Mahmoodian, A., Kopito, L.,

and Khaw, K. T.: A standard procedure for

measuring conductivity of sweat as a diag-nostic test for cystic fibrosis. J. Pediat., 66: 432, 1965.

8. Kopito, L., Mahmoodian, A., Townley, B. R.

W., Khaw, K. T., and Shwachman, H.:

Studies in cystic fibrosis: Analysis of nail clippings for sodium and potassium. New Eng. J. Med., 272:504, 1965.

9. Kopito, L., and Shwachman, H.: Unpublished observations.

10. Kopito, L., and Shwachman, H.: Studies in cystic fibrosis. Determination of sweat

elec-trolytes in situ with direct reading electrode. PEDIATRICS,

43:794,

1969.

11. Elian, E., Shwachman, H., and Hendren, W. H. : Intestinal obstruction of the newborn in-fant. Usefulness of the sweat electrolyte test

in differential diagnosis. New Eng. J. Med.,

264:13, 1961.

12. Green, M. N., Clarke, J. T., and Shwachman, H. : Studies in cystic fibrosis of pancreas: Protein pattern in meconium ileus.

PEDIAT-RICS, 21:635, 1958.

13. Donnison, A. B., Shwachman, H., and Gross, B. E. : A review of 164 children with meco-nium ileus seen at the Children’s Hospital Medical Center. PEDIATRICS, 37:833, 1966. 14. Boyer, P. H. : Low birth weight in fibrocystic

disease of the pancreas. PEDIATRICS, 16:778, 1955.

15. Shirkey, H. C. : Pediatric Therapy. St. Louis:

C.

V. Mosby Company, 1969.

16. Cellis and Kagan: Current Pediatric Therapy, ed. 4. Philadelphia: W. B. Saunders, 1970. 17. Shwachman, H.: Progress in the study of “mu-coviscidosis” (pancreatic fibrosis) with illus-trative case presentation. PEDIATRICS, 7:153, 1951.

18. Shwachrnan, H., Crocker, A. C., Foley, C. E., and Patterson, P. B.: Aureomycin therapy in the pulmonary involvement of pancreatic fibrosis. New Eng. J. Med., 241:185, 1949. 19. Shwachman, H., Silverman, B. K., Patterson,

P. R., and Zheutlin, L. J.: Antibiotics in the

treatment of pancreatic fibrosis with

em-phasis of terramycin. J.A.M.A., 149:1101,

195Z.

20. Matthews, L. W., Doershuk, C. F., and Spec-tor, S.: Mist tent therapy of the obstructive pulmonary lesions of cystic fibrosis. PaIAT-RICS, 39:176, 1967.

21. Doyle, B.: Physical therapy in the treatment of

cystic fibrosis. Physical Ther. Rev., 39:24, 1959.

22. Shwachman, J., and Hoisciaw, D.: Pulmonary complications of cystic fibrosis. Minnesota Med., 52:1521, 1969.

23. Kaplan, E., Shwachman, H., Perlmutter, A. D., Rule, A., Khaw, K. T., and Holsclaw, D. S.: Reproductive failure in males with cystic fibrosis. New Eng. J. Med., 279:63, 1968. 24. Kulczycki, L. L., and Shwachman, H.: Studies

in cystic fibrosis of pancreas. Occurrence of rectal prolapse. New Eng. J. Med., 295:409, 1958.

25. Shahidi, N. T., Diamond, L. K., and Shwach-man, H.: Anemia associated with protei de-ficiency. J. Pediat., 59:533, 1961.

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343

27. Lloyd, A. V. C., Grimes-C., Khaw, K. T., and Shwachman, H.: Chloramphenicol for long term therapy of cystic fibrosis. J.A.M.A., 184:1001, 1963.

28. Shwachman, H., and Kulczycki, L. L.: Long term study of one hundred and five patients

with cystic fibrosis: Studies made over a five to fourteen year period. J. Dis. Child., 96:6, 1958.

29. Cutler, S. J., and Ederer, F.: Maximum utiliza-tion of the life table method in analyzing survival. J. Chronic Dis., 8:699, 1958.

ON A FIFTEENTH CENTURY TEST FOR STERILITY

Barren marriages until the present century

were usually considered a sign of Divine dis-. pleasure. But as knowledge of the phsyiology

of reproduction was a closed book until

re-cently, many preternatural methods for deter-mining whether sterility was the fault of either husband or wife may be found in the medical literature of the Renaissance. None is more fanciful than the following from an English leechbook of the fifteenth century:

Knowing the default of conception, whether it belong to the man or the woman. Take two new

earthen pots, each by itself; and let the woman make water in the one, and the man in the other; and put in each of them a quantity of wheatbran, and not too much, that it be not thick, but be liq-uid or running; and mark well the pots for identifi-cation, and let them stand ten days and ten nights,

and thou shalt see in the water that is in default small live worms; and if there appear no worms in either water, then they be likely to have children in process of time when Cod will.1

Dawson2 writes that this and similar experi-ments are ancient ones and are described in

Egyptian papyri.

NOTED BY T. E. C., JR., M.D. REFERENCES

1. Dawson, W. B.: A Leechbook or Collection of Medical Recipes of the Fifteenth Century.

London: Macmillan and Company, p. 171,

1934.

2. Dawon, W. B.: Magician and Leech: A Study in the Beginnings of Medicine with special reference to Ancient Egypt. London:

(10)

1970;46;335

Pediatrics

Harry Shwachman, Aileen Redmond and Kon-Taik Khaw

of Age Over a 20-Year Period

STUDIES IN CYSTIC FIBROSIS: Report of 130 Patients Diagnosed Under 3 Months

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(11)

1970;46;335

Pediatrics

Harry Shwachman, Aileen Redmond and Kon-Taik Khaw

of Age Over a 20-Year Period

STUDIES IN CYSTIC FIBROSIS: Report of 130 Patients Diagnosed Under 3 Months

http://pediatrics.aappublications.org/content/46/3/335

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

References

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