II.
Observations
on
Incidence
and
Symptoms
of
Allergy
to
Milk
in
Allergic
Infants
By Kay D. Bachman, M.D., and Susan C. Dees, M.D.
Department of Pediatrics, Duke Unieersity School of Medicine
(Submitted November 8, 1956, accepted March 5, 1957.)
This study was aided by a research grant from the Prescription Products Division, Borden Company,
New York, New York.
I)r. Bachunan was Borden Fellow in Pediatric Allergy.
ADDRESS: (S.C.D.) Durham, North Carolina.
400
T
HE INCIDENCE of allergy to cow’s milkamong the general population, and among infants in particular, is a frequently disputed point. In a series of observations made during a 2-year period on a group of well babies, a total of 4 infants among 403
had an allergy to milk which was
responsi-ble for colic, diarrhea, rash, rhinitis and
wheezing either alone or in combination.’ Concurrently with this study of “well babies” information was gathered on the incidence and symptoms presumably due to allergy to milk which were encountered in the 109 allergic infants who were referred to us specifically for allergy consultations during the same 2-year period. The pres-ent report concerns itself with allergy to cow’s milk in allergic infants, and is not an attempt to present the over-all aspects of
allergy, nor its treatment in this age group.
PLAN OF STUDY
Clinical Material
A total of 172 children under 2 ears of age
were referred to us for allergy studies during
this time (1954-1956). In 63 of these children
no allergy could be established by careful
his-tory, ph\sical examinations, appropriate
labo-ratory studies and tests, or subsequent
obser-vations. The principal nonallergic conditions,
which had simulated or suggested allergy to
the referring physicians, were respiratory in-fections, pneumonia, atelectasis, foreign bodies,
cystic fibrosis of the pancreas, tuberculosis,
flaccid epiglottis, vascular ring around the
trachea, thrush, diaper rash, contact
derma-titis, moniliasis of the skin, acrodermatitis
enteropathica, sweat retention syndrome,
seb-orrheic dermatitis, urticaria pigmentosa,
ich-thyosis, feeding problems, intestinal polyps,
and starch intolerance.
Excluding those babies with nonallergic
dis-orders, there remained 109 allergic infants
whose age range is shown in Table I. Infants
with allergic disorders were separated
accord-ing to their age at the initial visit. The
differen-tiation between allergic and nonallergic
disor-ders is based upon the final diagnosis, since this
frequently could not be made at the first visit.
Forty-five were less than 9 months of age
when first seen; among these we found onl’
22 infants whom we considered allergic. Even
between the ages of 9 and 12 months, only 33
of 57 were definitel’ allergic. Among the 70
babies seen during the second year of life, 54
were allergic, indicating that b this age the
diagnosis of allergy becomes relativel\ clear-cut
for both pediatrician and allergist.
The 4 infants listed as unclassified merit
brief comment. These children had clinical
‘FABLE I
CLAssIFIcATIoN OF INFANTS IN ALLERGY
Pu ACTICE, 1954-19.56
;lge (no)
6-i 3-6 6-9 9-13 12-3’ Total
Allergic 5* 8 9 33 .54 109
Questionably allergic 5 7 1 t
Nonallergic 7 5 11 18 6 47
Unclassified 1 3 4
12 13 057 70 17t
* Allergic infants are classified by age at initial visit,
vitl,out regard to length of time under observation,
since diagnostic tests were made at these ages. The
number of patients in each column represents (lifferent
TABLE II
INCIDENCE OF MILK ALLERGY-FIRST 2 YEARS
Symptoms 5111k-allergic Infants (33 patients) JJI,oie .i!Iergic (;rouj (109 jatents) Gastrointestinal Skin Respiratory Rhinitis Asthma 10* 21 13 8 11 11 47 71 39 59
* Figures refer to occurrence of symptoms. Many ifl’-
-tients had symptoms related to more than one system or had more than one respiratory conuphuint.
ARTICLES
and skin test evidence of sensitivity to milk,
which was presumably responsible for
intrac-table diarrhea, controlled only on a milk-free diet. In addition, all had strongly positive
tuberculin tests without demonstrable lesions
in any system. Since the picture they presented
is strikingl\T uniform, but not entirely
charac-teristic of either childhood tuberculosis or milk
allergy, we feel that these patients should be
kept as a separate group until time determines the true nature of their illness.
Criteria for Milk Allergy
From the foregoing it is apparent that
svmp-toms after feeding cow’s milk may be
mislead-ing and due to nonallergic causes. As in the
previous study on well babies, we have
consid-ered a child to be allergic to cow’s milk only
when ingestion of small amounts is regularly
followed by one of the recognized allergic
manifestations, or by gastrointestinal or
be-haviour patterns which are definitely abnormal
in the setting in which they occur. These
symptoms must be reproducible on repeated
exposure, absent when milk is withdrawn, and
with no detectable organic or functional cause.
A positive skin test to milk was not considered
obligatory to the diagnosis of milk allergy, and
no diagnosis rested on this finding alone.
Since there were no babies among this
par-ticular series who appeared to have a
danger-ouslv high degree of milk sensitivity, we
re-quired a clinical trial of milk under our
super-vision before definitely assigning that diagnosis
to a child. The re-introduction of cow’s milk for
a minimum of 2 days on a least three occasions
at 2 or more week intervals with the
produc-tion of the same definite symptoms and
remis-sion of symptoms in milk-free period were our
specific standards for accepting milk as the
re-sponsible allergen. Obviously while such trials
were bemg made no other changes were made
in an infant’s therapeutic program or diet.
Feeding
Prior to their inclusion in the series the
allergic infants had received breast feedincz,
raw, pasteurized, dried, evaporated or
modi-fied evaporated cow’s milk, goat’s milk or
non-milk substitute. The frequency with which
formulae had been changed, the brevity of
breast feeding, and the earh use of
homoge-nized cows milk were the only characteristic
features of the former diets in these infants.
5111k
Infants Total
iiuergy Per Cent
Unselected 403 4
Allergic 109 33
1
30
From the past histories it was impossible to
arrive at any accurate tabulation of the ages
when various changes had been made. By the
time they became part of the group under
ob-servation, in many instances, milk sensitivity
had been strongly suspected or quite well
es-tablished by repeated clinical trials. Once we felt that milk allergy was established we used
as substitutes, soybean formulas (Mull-Soy’,
Sobee powder#{174}) for 22 infants, casein
hvdrolv-sate (Nutramigen#{174}) for 7, and strained pork
or lamb for 4 babies.
Incidence
RESULTS
Based on the criteria outlined, we found that 33 of 109 allergic infants were sensitive to cow’s milk. Table II contrasts the inci-dence in the unselected well babies with that found in the allergic infants.
Symptoms
A comparison of the symptoms found in
the 33 infants sensitive to cow’s milk is made with the symptoms encountered in the entire allergic group in Table III. As is usual with allergic and other disorders, multiple symptoms may be present in one
TABLE III
Boldface figures indicate milk allergy.
Figures refer to symptoms at first visit. Some infants had multiple symptoms.
individual, so the total symptoms exceed the number of patients. Eczema was the commonest symptom due to milk sensitivity,
being present in 21 of the 33. Next in fre-quency were gastrointestinal symptoms due to milk, in 10 of the 33 infants. Respiratory symptoms were even less frequently due to milk sensitivity, since in the 13 children sensitive to milk who had either allergic rhinitis or asthma, it was not possible to demonstrate that milk was the sole allergen in those over 1 year of age.
In contrast to this, in the allergic group as a whole, we found 71 of 109 with respira-tory symptoms, and in only the 13 instances just mentioned did the children also have milk allergy. Nearly one-half of the children (27 of 41) with eczema were sensitive to milk, while in almost all of those with gas-trointestinal symptoms (10 of 11), allergy to milk was felt to be responsible.
It must be emphasized at this point that there may be a bias toward respiratory com-plaints in these figures for the allergic group as a whole, since these symptoms are more alarming than the others and therefore more likely to cause referral to a specialist.
It is interesting to consider the age at which various complaints are first noted. Table IV also indicates the number of in-stances in which it could be demonstrated that sensitivity to milk was present. As this study is concerned only with allergy to milk we cannot elaborate on the various other etiologic allergens.
Regardless of the small total number of allergic infants seen under 1 year of age (22
of 104), one is impressed with the variety of gastrointestinal symptoms present in some cases and their persistence through the first 2 years. In all but one infant these
were due to milk allergy. With only 8
in-fants under 6 months of age one cannot
draw any conclusions about the significance of milk allergy as a cause of the colicky crying found in 4 of them. A larger sample of younger allergic babies would be neces-sary in order to compare this most important symptom with colic in well babies, in whom we found 52 with this complaint among the
403 infants studied.
Eczema before 9 months of age was largely due to sensitivity to milk as shown in 9 of 12 infants. After 9 months milk
de-TABLE IV
SYMPTOMS IN ALLERGIC BABIES RELATED TO AGE AT INITIAL \ISIT (109 BABIES)
Age (ma)
0-3 3-C 6-9 9-12 12-24
Total
5 8 9 33 54 109
3 1 4
Patients
Crying
Gastrointestinal Spitting
Vomiting
I)iarrhea Mucus Blood
1 2 1 4
2 1 1 4 4
3 1 1,2 1 8
0
1 1
Skin
Eczema i 1 1,6 2,2 10,5 8,7 42
hives 1 4 5
Respiratory
Rhinitis 1 1, 1 11, 2 19,4 39
Number
_________
________
_________________
Tested 8 9 33
54
--o
0
MONTHS 3 6 9 12 24
creased somewhat in importance as the cause of eczema.
In 13 infants who were sensitive to milk, rhinitis was present in 8 and asthma in 11. It was interesting to find that while these symptoms were present in babies sensitive to milk, the rhinitis and/or asthma were not invariably precipitated by the ingestion of milk, but were frequently due to other allergens to which the child had become sensitive. The incidence of milk sensitivity was lower in the older infants than in those under 6 months.
Skin Tests
The allergic infants were tested by scratch technique with glycerinated extracts,
those reacting negatively to milk or to other allergens suggested by history were tested intradermally. In the data presented, only scratch test results are tabulated. Our ex-perience is in agreement with accepted ideas that many nonspecific reactions of no clini-cal importance are obtained in young chil-dren even by scratch tests. This is shown by positive scratch tests in 24 of 41 of the in-fants under 1 year of age who proved to have no allergy. The 9 to 12-month-old group gave the largest number (12 in 18) of positive reactions. It is important to keep
this trait in mind when interpreting skin tests in infants.
Figure 1 shows the incidence of clinical milk sensitivity and positive tests to milk at various ages. A total of 37 infants had posi-tive scratch tests to milk although only 33 were sensitive to milk clinically. Table V shows the individual combinations of skin reactions and clinical sensitivity, in which we find a decline in the number of children with a positive test to milk or clinical reac-tions to milk with increasing age.
Although our primary interest was in sen-sitivity to milk, we present in Figure 2 the incidence of positive scratch tests to aller-gens other than milk in these same children at different ages. Approximately one half (48 of 109) had a positive test to egg, most of these occurred in the children over 1 year of age. Other foods reacted in 75 babies (69%), inhalants in 77 (71%), and pollen in
25%. These percentages are in general agree-ment with data recently published by Rat-ner
et
al.2 on 27 allergic infants under 2 years of age whom he tested intradermally.Stool Eosinophilia
We did not find stool eosinophilia in a single instance in smears made from chil-dren with gastrointestinal symptoms in this
0-,0
100-80
60
40
20
PER CENT OF POSITIVE SCRATCH TESTS AND CLINICAL MILK ALLERGY IN 109 ALLERGIC INFANTS OF VARYING AGES
#{149}‘CLINICAL MILK O.SCRATCH TEST MILK
FIG. 1. Percentages of patients with clinical milk allergy at various ages are
5
I
9
13
‘Total patients 5
11
8 9 33 54 109
Number
Tested 8 9 33
54-A
/\
/ \
--__.a
/
---.
.---.‘-A--/ p
/ / //
I,,.’
0.... POLLEN #{149}#{149}#{149}‘O
FIG. 2. Percentage
#{149}EGG I INHALANTS A #{149}OTHER FOODS
TABLE V
CORRELATION OF POSITIVE SKIN ‘FESTS TO MILK WITH CLINICAL EVIDENCE OF SENSITIVITY
Reaction to 5111k Age 0-3 ma Age 3-6 ma Age 6-9 ma Age 9-12 ma Age J_3 yr Total Patients
Clinical eVi(leflce + 2 5 5 4 8 24
Skin test +
Clinical eVi(Ience +
Skin test
-Clinical evidence
-Skin test +
Clinical evidence
-Skuni test
-1
1 3 23 35 63
series. In view of this and our experience with negative smears in most of the well babies we were studying at the same time,1 we did not do this as a routine test in these allergic infants. In sporadic allergic patients in the past we have obtained smears at proc-toscopy from mucus in which eosinophils were easily demonstrated. We agree with Nance3 that their presence is suggestive of allergy-but we feel that the test is too fre-quently negative to be worthwhile as a routine procedure.
DISCUSSION
The purpose of this report has been to
study allergy to cow’s milk in allergic
in-fants, and to contrast this with a similar
study in well babies. It is not an attempt to
discuss allergy in infancy in all its
ramifica-tions. We have sacrificed equality in
num-ber and similarity of age distribution in
the two groups, in order to confine our
ob-servations to the patients seen concurrently in 2 consecutive years. This decision was made in an attempt to minimize the
van-100
80
0j
l0
40
20
PER CENT OF POSITIVE SCRATCH TESTS IN 109 ALLERGIC INFANTS OF VARYING AGES
MONTHS 3 6
1 “ I
9 2 24
of allergic infants showing scratch tests positive to vat ions
agnose it correctly when it exists. ables of changing fashions (in feeding
pro-grams, antibiotics, antihistaminics, steroid
therapy) which have greatly changed the
management and many features of allergy in recent years. Selecting this arbitrary time
period has meant that there are fewer young
infants in the allergic group than in the well
baby group. The same degree of detail for
the genesis and decline of early symptoms
could not be elicited from the histories of
the allergic infants for the period before
they were referred to us that was
main-tamed after they entered the study. We
were unable to use the historical infonma-tion from the allergic infants’ first few months for direct comparison with the same peniO(l for the well babies because of the notorious variations in reliability of in-formation from parents. For example, since most of the allergic infants were more than 6 months old before referral, the data on colic in the two groups cannot be compared, and is not included in the tabulation of
symptoms, except as observed by ourselves.
A history of colic was obtained in one-half
of all the allergic infants seen, hut in the light of our experience with those well babies we followed regularly, we felt that the symptoms which are called colic by different mothers are too variable to be
ac-cepte(l at face value in a study such as this,
or to be related to milk allergy.
Comparison of our findings with other re-ports such as Clein’s on allergy to cow’s milk is difficult since he does not state from
what total number of allergic infants or
well infants his 206 infants allergic to cow’s milk were gathered, nor over what period of time his observations extended. His definition of allergy to milk encompasses so many more symptoms that it cannot be di-rectlv compared to ours.
The scope of our study is not broad enough to include the prophylaxis of allergy
by measures designed to minimize exposure
to cow’s milk in its relatively natural state. These have been advocated by Ratner5 in heat-denaturation of milk, and by Glaser and Johnstoneui by using soy bean milk as a substitute for cow’s milk in the initial
feeding of potentially allergic babies. The pioneers of pediatrics and allergy, Schloss Ct a!. ‘ and many other workers,
among whom are Wells and Osborne,9 Lewis and Hayden,1#{176} Ratner and Gruehl,h1 Lippard
et
al.,12 Gyorgyet
al.,1t have studiedthe immunologic reaction of young infants in respect to milk and other food allergy. Little new information on these processes has been added until recently, when Ber-ger14 reported finding complement-fixing antibodies to milk in 20 of 84 children, 7 of whom were allergic. An interesting quan-titative determination of the blood levels of egg albumin was described by Gruskay and Cooke,’5 in which they find a significantly higher absorption of egg protein in infants with diarrhea, than in normal infants, al-though all had measurable levels after a challenge feeding. It would be highly de-sirable to utilize the new immunologic tech-niques, including tagged proteins, gelatin diffusion, and electrophoresis to re-examine this problem of absorption of milk proteins. The technical difficulty of carrying out, on
young infants, procedures which are simple
in older individuals is undoubtedly the chief factor which keeps us lumbering along
purely clinical paths in this subject.
In this series of infants we found no in-stance of a severe anaphylactic reaction to milk, nor of the less common reactions such as shock, convulsions, or angio-edema, al-though we have encountered a few of the latter cases during the course of years. The literature on allergy to cow’s milk from the
early part of the Twentieth Century
con-cerns itself chiefly with this type of
reac-tion.17-2’ The reports are too numerous to detail here, hut undoubtedly most pedi-atnicians have seen a rare infant of this type. There is no question about the diagnosis nor the management of the child severely sensitive to milk. Our main concern today is rather the recognition of the infant with
less violent symptoms in whom the problem
di-SUMMARY
In a series of 172 infants under 2 years of age who were referred for allergy studies during 1954-1956, 109 were found to be
al-lergic.
Thirty-three of the one hundred nine al-lergic infants were sensitive to cow’s milk, with an incidence of 30%.
The diagnosis of cow’s milk allergy was based upon the same criteria applied to a series of well baubies. Namely, repeated
pro-duction of one or more allergic symptoms
on exposure to cow’s milk, improvement on withdrawal, and with no other apparent cause for improvement, confirmed by posi-tive skin test, and without other cause for symptoms.
The allergic symptoms due to milk were
eczema, gastrointestinal abnormalities and
less frequently asthma or rhinitis.
Scratch tests were frequently positive to
foods. Thirty-seven infants reacted with
positive skin tests to milk, of whom 33 had clinical allergy to milk. Infants from 9 to 12 months of age had the highest number of nonspecific skin reactions.
CONCLUSIONS
In allergic infants under 2 years of age
the incidence of allergy to cow’s milk is
high,
being present in one in three infants in this series, and therefore milk sensitivity is an important problem with them.This allergy most frequently involves the gastrointestinal tract and the skin.
REFERENCES
1. Bachman, Kay D., and Dees, S. C.: Milk allergy. I. Observations on incidence and symptoms in well babies. PEDIATRICS,
20:393, 1957.
2. Ratner, B., Crawford, L. V., and Flynn,
J.
C.: Allergy in the infant and pre-school child. Am.J.
Dis. Child., 91:593, 1956.3. Nance, F. D.: Stool eosinophilia in gastro-intestinal allergy of infancy.
J.
Pediat., 33:313, 1948.4. Clein, N. W.: Cow’s milk allergy in in-fants. Ped. Clin. North America, 1:949, 1954.
5. Rather, B.: The treatment of milk allergy
and its basic principles. J.A.M.A., 105: 934, 1935.
6. Glaser,
J.,
and Johnstone, D. E. : Soybean milk as a substitute for mam-malian milk in early infancy, with spe-cial reference to prevention of allergy to cow’s milk. Ann. Allergy, 10:433, 1952.
7. Schloss, 0. M., and Worthen, T. W. : The
permeability of the gastro-enteric tract of infants to undigested protein. Am.
J.
Dis. Child., 11:342, 1916.
8. Schloss, 0. M. : Allergy in infants and
children. Am.
J.
Dis. Child., 19:433,1920.
9. Wells, H. C., and Osborne, T. B: Ana-phylaxis reactions with purified proteins from milk.
J.
Infect. Dis., 29:200, 1921. 10. Lewis,J.
H., and Hayden, H. C. : Effectof heat on the antigenic properties of
milk. Am.
J.
Dis. Child., 44:1211, 1932. 11. Ratner, B., and Cruehl, H. L. : Passage cfnative proteins through the normal
gastro-intestinal wall.
J.
Clin. Invest., 13:517, 1934.12. Lippard, V. W., Schloss, 0. M., and
John-son, P. A. : Immune reactions induced
in infants by intestinal absorption of
in-completely digested cow’s milk protein.
Am.
J.
Dis. Child., 51:562, 1936.13. Gyorgy, P., Moro, E., and Witebsky, E.:
Weitere Erfahrungen #{252}berTrophallergie beim Eczema infantum. Kiln. Wchnschr., 11:1172, 1932.
14. Berger, E.: Komplementbindende
Anti-korper gegen Nahrungsmittel bei
Kin-dern. Ann. paediat., 181:295, 1953.
15. Gruskay, F. L., and Cooke, R. E.: The gastrointestinal absorption of unaltered protein in normal infants and in infants recovering from diarrhea. PEDIATRICS,
16:763, 1955.
16. Baylin, C.
J.,
Sanders, A. P., Isley,J.
K.,Shingleton, W. W., Hymans,
J.
C.. Johnston, D. H., and Ruffin,J.
M.: J131 blood levels correlated with gastric emptying determined radiographically. I. Protein test meal. Proc. Soc. Exper. Biol. & Med., 89:51, 1955.17. Talbot, F. B.: Idiosyncrasy to cow’s milk;
its relation to anaphylaxis. Boston M. &
S.
J.,
175:409, 1916.18. Hill, L. W.: Immunologic relationships be-tween cow’s milk and goat’s milk.
J.
Pediat., 15:157, 1939.19. Park, E. A.: A case of hypersensitiveness to cow’s milk. Am.
J.
Dis. Child., 19:46, 1920.
D. M. K., and Irwin,
J.
W.: Allergy ininfancy and childhood. M. Clin. North
America, 38:1255, 1954.
21. Collins-Williams, C.: Acute allergic
re-actions to cow’s milk. Ann. Allergy,
13:415, 1955.
SUMMARIO IN INTERLINGUA
Allergia a Lacte. II. Observationes in Re Incidentia e Symptomas in
Infantes Allergic
Observationes in re le incidentia e le
smp-tomas de allergia a lacte de vacca esseva
execu-tate in un serie de infantes allergic de etates de
minus que 2 annos, vidite durante le mesme
periodo de duo annos (ab 1954 a 1956) in
que un serie de 403 babys in “bon” stato de
sanitate esseva studiate pro allergia a lacte. Le
diagnose de allergia a lacte de vacca esseva
basate super le mesme criterios in ambe
grup-p05. Durante le periodo mentionate, 172
in-fantes de minus que 2 annos de etate esseva presentate pro studios de allergia. Esseva con-statate que 109 de illes esseva allergic.
Trenta-tres del 109 allergicos esseva sensibile a lacte
de vacca. Isto es un incidentia de 30 pro cento.
Le symptomas allergic causate per lacte
eczema in 21 infantes, disordines
gastrointesti-nal in 10, e asthma o rhinitis in minus numerose
casos. Dece-tres del infantes sensibile a lacte
habeva le un o le altere o ambe le mentionate symptomas respiratori, sed lacte non esseva le
sol allergeno in le patientes con allergia
respi-ratori qui habeva plus que un anno de etate. Trenta-septe infantes habeva positive reactiones in tests cutanee con lacte. Trenta-tres de istes habeva allergia a lacte. Un cutireaction posi-tive a ovo esseva trovate in 48 ex 109 infantes, predominantemente de etates de plus que un anno. Infantes de etates de inter 9 e 12 menses
habeva le plus alte numero de non-specific reactiones cutanee. Nulle eosinophilos esseva trovate in iste serie in le frottis fecal ab in-fantes con symptomas gastrointestinal.
Un historia de colica esseva obtenite in un medietate del infantes in iste serie, sed proque isto habeva occurrite ante que le majoritate del infantes esseva presentate a nos, nos non
considera le correspondente datos como suffi-cientemente documentate pro comparar los con
observationes in le serie de babys in “bon”
stato de sanitate. Nulle anaphylaxis o sever
reactiones a lacte de vacca esseva constatate in iste infantes.
Es presentate un breve revista de altere
reportos de series de infantes con allergia a
lacte de vacca e del existente studios
immuno-logic in re sensibilitate a lacte.
Le sequente conclusiones esseva derivate ab
iste studio: In nostre serie de 109 infantes
al-lergic de etates de infra 2 annos nos trovava un incidentia de 30 pro cento de allergia a lacte de vacca. Nos onina que allergia a lacte
de vacca es un problema importante in iste
casos. Le allergia interessava le plus
