(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 thenature 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
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 lifeex-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 werediag-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.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 81961
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
TABLE III
SOME COMPLICATIONS NOTED IN TILE COURSE OF
FOLLOWING
126
PATIENTS DIAGNOSED UNDER3 MONTHS OF AGE FROM JANUARY 1, 1949,
TO JANUARY 1, 1969
18
#{149}#{149}
6
4
AGEAT 12
:
DEATHto
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 whosun-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 adventof 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 byre-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 withthe 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, nasalpoi-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.23Many of the so-called symptoms of the disease are indeed complications and are
TABLE IV
CLINICAL STATUS OF
97
PATIENTSAS 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
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
00 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,
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 thatmany 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
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 incystic 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.
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: