- Email: [email protected]
The treatment of eczema in infants and children
THE
TREATMENT
OF
ECZEMA
IN
INFANTS
AND
CHILDREN
PART I V LEWIS WEBB IIILL, 3/I.D. BOSTON, ~/~ASS. "Immunology is a mixture of established fact, half knowledge, hopeful guessings and frank bewilderment. ~ --W.
W . C. T a p l e y :
immunology, particularly psychologic, may greatly aggravate it. IMMUNOLOGIC TREATMENT
A'~ O u t l i n e o f I , ~ m u n i t y ,
William "Wood & Co., 1933.
In order to make an a t t e m p t to understand the rationale of immunologic t r e a t m e n t it is first necessary to consider in some detail the immunophysiologic principles involved. The a n t i b o d y (atopie reagin) which has to do with atopic dermatitis is fixed iu the vascular loops in the papillae of the corium, and can often also be detected in the blood, contained mostly or possibly entirely in the g a m m a globulin fraction. The commonly accepted t h e o r y has been that when antigen, inhaled or ingested, reaches the sensitized skin tissue, an immunologic reaction results with the p r o d u c t i o n of an irritating end product, possibly histamine, and consequent dilatation and increased permeability of the small cutaneous vessels, with a resulting inflammatory reaction and the histologic changes of
ATOPIC DERMATITIS T O P I C d e l ~ a t i t i s is brought about b y the same abnormal constitution which underlies h a y fever and asthma, and is often the first manifestation of this constitution. I t is not u n c o m m o n for children to be afflicted with all three at the same time. A b o u t half of the infants who have atopic dermatitis later develop r e s p i r a t o r y allergy. Atopic dermatitis is a disease of the young, although it m a y last well into adult life, and is occasionally even seen in the aged. A l t h o u g h it has been called b y different names at different age periods, it is one and the same disease at all ages, and is best calked atopic dermatitis at all ages. 11 I t is as much a constitutional disease as diabetes or pernicious anemia; w h a t r e t a r d s the t r e a t m e n t more t h a n a n y t h i n g else is that it is not possible to change the constitution that is responsible for it. Like asthma, its f u n d a m e n t a l basis is abnormal immunology, and, also like asthma, other stimuli not related to
A
eczema.
J~ditor~s N o t e : Despite the notice in the August issue that reprints would not be available of Dr. Hill's series of papers on "The
Treatment of Eczema in Infants and Children," many requests are being received. As previously stated, no reprints are available as the articles will be published in book form.
:~HilI, L. W., and Sulzberger, lVI. B. : Evolution of Atopie Dermatitis, Arch. Dermat. & Syph. 3~: 451, 1935.
There are those who have said t h a t scratch or intraeutaneous tests are entirely useless in the determination of etiology, and t h a t the immediate urticarial type reaction so obtained has nothing to do with the eczema, for the eczematous reaction is a delayed t w e n t y - f o u r - h o u r type reaction, and is vesicular or p a p u l a r and never urticarial. I n order to determine etiology the test reaction should produce the
648
~IILL:
T R E A T M E N T OF E C Z E M A
lesion of the disease in the same way that eczema (the lesion of the disease) is produced b y the patch test. There is some evidence in favor of this point of view, and some against it. 1. The skin of a patient who has ragweed hay fever gives an immediate urticarial type scratch or intracutaneous test. So does the skin of a patient who has atopic dermatitis due to ragweed pollen, and only v e r y r a r e l y a positive patch test. If the urticarial type skin test is of etiological significance in atopie dermatitis due to ragweed, w h y do not all patients with ragweed hay fever who show this test have atopic dermatitis as well? 2. I f a person with h a y fever but no eczema is given too much ragweed e x t r a c t by inoculation, he is likely to develop urticaria, practically n e v e r eczema. A person with atopic dermatitis f r o m ragweed, with or without h a y fever, has exactly the same sort of skin test t h a t the person with hay fever alone has. Yet his tolerance to injected ragweed extract is v e r y low, much lower t h a n t h a t of the patient with h a y fever alone, and if he is given any but a v e r y small dose of r a g w e e d e x t r a c t his existing eczema will p r o b a b l y become worse, and he is likely to develop new eczema in places where he did not have it before. This is a delayed twenty-four-hour t y p e reaction. The amount of antigen when injected or ingested which will worsen eczema or produce new eczema in a patient who already has eczema is a great deal less t h a n that which will produce urticaria or respirat o r y symptoms in a patient who has r e s p i r a t o r y allergy alone. W h y is this ? It seems clear that there is some predisposing condition in the skin,
649
immunologic or otherwise, in persons with atopic dermatitis, which is not present in those who have h a y fever alone, although t h e y both give identical wheal t y p e scratch tests. It is likely that this condition, whatever it m a y be, in combination with the urticarial type sensitivity, is responsible for the production of dermatitis, and that atopic dermatitis is not produced without it. Let us eall this the Xfactor. 3. If I sensitize a small place on m y own skin with an egg white reagin containing serum from an eezematous baby, and then eat an egg, or indeed sometimes only an infinitesimal amount of egg white, in about t w e n t y minutes an urticarial wheal appears on the sensitized s i t e - - n e v e r eczema. If every day I eat small amounts of egg white below the amount necessary to produce urticaria, no eczema ever develops. It is either immediate urticaria or nothing: there is no cumulative reaction. I cannot produce eczema oil myself by eating a food to which my skin is sensitized, no m a t t e r in what amount I eat it. I can produce only urticaria, presumably because the X-factor is not there. 4. I t is true that m a n y times people with atopic dermatitis ean eat the foods which give positive skin tests with impunity, so t h a t these tests are often entirely without etiological significance. In Louis T u f t ' s well-known " d u s t patient, ''12 there were positive intraeutaneous tests to twenty-seven different foods, and yet his eczema was proved to be entirely due to house dust, and had nothing l~Tuft, L o u i s , T u f t , H a r o l d S., a n d t t e c k , V. Muriel: Atopie Dermatitis, an Experimental C l i n i c a l S t u d y of t h e R o l e of I n h a l a n t A l l e r gens, ft. A l l e r g y 21: 181, 1950.
650
THE
JOURNAL
whatever to do with the foods to which he gave positive tests. This is a classical paper, and everyone seriously interested in atopic dermatitis should r e a d it. I n spite of these objections which I have enumerated there can be no doubt that sometimes positive scratch or intracutaneous tests indicate etiology, and are of great value in planning treatment. I think t h a t almost all allergists would agree to this, and possibly an occasional dermatologist. Is it possible to reconcile these somewhat c o n t r a d i c t o r y observations? I think it may be. The following hypothesis, which seems to me to follow logically from the observed facts, is suggested. The wheal test reaction is of no significance in atopic dermatitis b y itself; it is significant only if it is accompanied b y another factor, the X-factor. I have no idea whatever w h a t this added factor may be.
The wheal reaction is, however, sometimes indicative of etiology because it is sometimes accompanied by the Xfactor. B y itself it is of no moment so far as eczema is concerned. It was shown a good many years ago by Oscar Schloss, 1~ who was in his day the foremost research pediatrist in America, and who has been rarely equalled and never surpassed, that a new food when introduced into the diet of a young infant is often followed by the development of a positive skin test. This is a normal phenomenon. The degree of sensitivity is never high, and the positive test lasts for only a short time. Later B r u n n e r and Walzer 1~ showed that even in l~Sebloss, O s c a r : T h e I n t e s t i n a l A b s o r p t i o n of A n t i g e n i c P r o t e i n , T h e H a r v e y L e c t u r e s , p. 156, 1924-1925. ~ B r u n n e r , M a t t h e w , a n d ~vValzer, M a t t h e w : A b s o r p t i o n of U n d i g e s t e d P r o t e i n in H u m a n B e i n g s , A r c h . I n t . Meal. 4~: 172, 1928.
OF
PEDIATRICS
older children and adults the passage of unsplit food pcotein t h r o u g h the gastrointestinal nlucosa and thence to the blood is a normal phenomenon. In atopic people this circulating protein sensitizes the skin more readily than it does in the normal person, and the positive skin tests which result are of much greater degree and last longer, sometimes for m a n y years (fish, nuts). The same is true of environmental allergens, which reach the blood by inhalation. Many of these positive tests, p a r t i c u l a r l y those to foods, may be looked upon as normal for the atopic person and have nothing to do with his symptoms, whether t h e y be those of eczema, h a y fever, or asthma. I think the main reasons for this are two : A. The X-factor is not present; therefore eczema is not produced. B. The degree of tissue sensitization is not high enough to react with the amount of antigen absorbed. The immunologic reaction we are diseussfftg depends upon two variables :
(1) The amount of a n t i b o d y fixed in the tissue. (2) The amount of antigen which contacts it. If there is a small amount of antib o d y it takes a large amount of antigen to produce a reaction, and vice versa. Several years ago I did some immunologic experiments on myself with the help of Miss Margaret Scully, who was in charge of the allergy laboratory of the Children's Hospital at that time. It is not necessary to go into the details of these investigations. The gist of them was that if
HILL:
TREATIVIENT OF ECZES/[A
a high degree of passive sensitization was p r o d u c e d on m y skin b y the i n t r a e u t a n e o u s injection of a serum containing food reagins f r o m an eczematous infant, the eating of the corr e s p o n d i n g food in only small a m o u n t caused a wheal to a p p e a r on the sensitized site in about twenty minutes. W e studied egg white, chicken, peanut, wheat, a n d potato. I f the degree of sensitization was only m o d e r a t e or slight, as d e t e r m i n e d b y serial titration of the sites, no reaction would t a k e place, either u r t i c a r i a l or eczema~ tous, even if the food were eaten in large amounts. This simple principle applies to a n y tissue as well as to the skin, and seems to me of f u n d a m e n t a l i m p o r t a n c e in clinical allergy. Skin Testing.--Skin testing is often a valuable p r o c e d u r e in atopie dermatitis as a help in p l a n n i n g t r e a t m e n t . I t s value has, however, been g r e a t l y e x a g g e r a t e d , too m u c h a t t e n t i o n has been p a i d to it, a n d h a r m has been done, p a r t i c u l a r l y in babies a n d in y o u n g children b y too rigorous dieting solely on the basis of skin tests. W h a t the m o t h e r has actually seen h a p p e n to the child is more i m p o r t a n t . Skin testing is a l a b o r a t o r y procedure, a n d like all other l a b o r a t o r y procedures it m u s t be e v a l u a t e d in relation to the p a t i e n t a n d not b y itself. Too m u c h a t t e n t i o n to laboratory tests and too little attention to the patient is one of the defects of modern medicine, and is often carried to an absurdity. I saw not long ago a bottle-fed eczematous b a b y 7 months old whose f a m i l y had m o v e d to Boston f r o m a large m i d w e s t e r n city. The m o t h e r b r o u g h t with her a t y p e d r e p o r t of the skin tests t h a t had been done there in a t h r i v i n g p r i v a t e clinic. E i g h t y tests h a d been done b y the
651
indirect method, forty-six of which were r e p o r t e d positive. Some of the things tested for were tobacco, camel hair, mustard, cinnamon, auspice, ginger, p a p r i k a , garlic, vanilla, strawberry, and cucumber. This is not an isolated example b y a n y means. W h e n one sees such things he begins to believe t h a t there is as m u c h foolishness in m o d e r n medicine as there was in the time of William Shakespeare, and he is not f a r f r o m right. There is no need of doing a large n u m b e r of skin tests on a b a b y with eczema. I f he is tested with most of the foods he is eating, plus egg white, and w i t h a few of the e n v i r o n m e n t a l allergens to which he is exposed, t h a t is enough. I n e v e r do an intracutaneous test until a scratch test has been done first and is negative, a n d would not do an i n t r a e u t a n e o u s test with egg white on a n y baby, no m a t t e r w h a t the scratch test showed. I t is sometimes desirable to do a few i n t r a c u t a n e o u s tests with other allergens on eczematous babies, as the skin sensitivity is often of low degree and the i n t r a e u t a n e o u s test m a y be positive when the scratch test is negative. I h a v e not used the indirect method of testing f o r over ten y e a r s except for investigative w o r k - - i t is more bother t h a n it is worth. This could be discussed at considerable l e n g t h - - I will simply say t h a t I do not t h i n k m u c h of it. As a m a t t e r of fact, it is possible to treat most babies who have atopic dermatitis v e r y well without doing a n y skin tests at all. I find m y s e l f doing f e w e r a n d fewer, and the patients seem to do a b o u t as well as when I was careful to do complete testing on e v e r y patient. Older children, whose
652
THE JOURI',TAL OF PEDIATRICS
trouble is likely to be coming from the environmental allergens, particularly pollen and dust, can be understood better and t r e a t e d b e t t e r if p r e t t y complete testing with the environmental allergens is done. In a series of 100 eczematous babies u n d e r 1 year of age, who gave positive scratch tests to something, the positive tests to foods were as follows : Egg white 1Vfilk Wheat Oat Barley Beef Potato Haddock Tomato
86 26 17 8 6 6 4 3 3
Corn Spinach Pea Carrott Orange Lamb Codfish Chicken
2 2 2 2 2 2 1 ]
t~ifty-six gave positive tests to something they were eating, thirty-nine gave positive tests to egg white alone. It must be understood that this series of 100 was not made up of consecutive c a s e s - - t h e y were all babies with atopic dermatitis who reacted to something; no babies who had negative skin tests were included. In a series of thirty-eight u n d e r 1 y e a r of age, tested b y the scratch method with fifteen environmental allergens, only f o u r children gave positive r e a c t i o n s - - t h e allergens were silk, cat hair, and: wool. However, in a series of f o r t y - f o u r which had negative scratch tests to dust and feathers, thirty-one had positive intraeutaneous tests to dust and twenty-five to feathers. At the time these tests were made the high percentage of positive reactions was surprising to me, and still is. It m a y be that some of these were irritative reactions, as fairly strong testing solutions were used, but they gave no reactions on normal babies, and in a good m a n y of these babies reagins for dust and for
feathers were present as well as positive skin tests. In older children positive scratch tests to a v a r i e t y of environmental allergens become more frequent. In a large series the ratio between positive reactions to foods and to environmental allergens was 2.5 to 1, in a series of infants u n d e r the age of ] y e a r it was as 20 to I. The Egg White Reaction.--Thc egg white reaction is so i m p o r t a n t in the atopic dermatitis of infants that it w a r r a n t s special discussion. It has been f o u n d (Moro, Woringer, Hill) that most infants who have atopic dermatitis give strongly positive skin reactions to egg white, the m a j o r i t y of which are accompanied by circulating reagins and clinical sensitivity. Many of these babies are so exquisitely sensitive to egg white t h a t the ingestion of only minute amounts is followed by stormy symptoms (urticaria, vomiting, shock). Horesh is has pointed out, and with truth, that even the smell of egg white m a y cause symptoms, and that eczematous babies who are sensitive to it should be kept out of the kitchen when eggs are being broken for use in cooking. This is entirely right. Egg sensitivity lasts a long time, sometimes well into childhood. I have no accurate figures, but I doubt that it often lasts into adult life, and even in childhood its frequency is considerably diminished from what it is in infancy. I t is a curious fact that in infants who have asthma, the egg white reaction i s uncommon, unless the asthma is accompanied by eczema. The egg white reaction a p p a r e n t l y has to do p a r t i c u l a r l y with eczema. In a series of ]00 asthmatic ~'~I:[oresh, A. J. : Allergy to Food Odors, J. Allergy 14: 335, 1943.
HILL:
TREATMENT
children, a b o u t half of w h o m had had eczema in infancy, twenty-one gave positive scratch tests to egg white, but only eleven were clinically sensit i r e to it. A positive scratch test to egg white is of some value in differential diagnosis, for the chances are t h a t if it is absent; w h a t the b a b y has is ~mt atopic dermatitis. This, however, is b y no means certain, for some babies with atopie dermatitis give negative egg tests. I t h i n k the absence of a positive reaction is p r o b a b l y also of some prognostic value, a n d t h a t one is justified in telling the mothers of such patients t h a t the child is certainly not a highly allergic child, and t h a t he has b e t t e r t h a n an even chance of escaping h a y fever and asthma. The direct influence of egg white in causing eczema in y o u n g babies is not great, for most mothers a n d doctors k n o w enough now to keep it a w a y f r o m atlergie babies. I t is in this respect s o m e w h a t more i m p o r t a n t in older children whose diet is not so well controlled, and who m a y be eating enough egg-containing food to get into trouble. While the actual eating of egg white is of little i m p o r t a n c e as a cause of eczema in most infants, I h a v e a suspicion t h a t the fact of egg sensitization m a y be of considerable importance. This is the p r i m a r y sensitization for most of these infants. I t is a sensitization of high degree, much more so than most of the others which follow it, and it has been thought, p a r t i c u l a r l y b y Moro, with whom I agree, that such sensitization, once it has taken place, makes the individual more susceptible to other sensitizations. It puts the stamp of allergy
OF
ECZEMA
653
upon h i m - - o n c e he has become egg sensitive he has been admitted to the allergic fraternity, and is likely to continue his membership for a long time. A good m a n y years ago, B r e t Ratner, 16 after some painstaking laboratory work and considerable clinical observation, came to the conclusion that sensitization to egg white as it occurs in infants, and sometimes to other potent allergens such as fish and nuts, is congenital, and due to placenta] transmission of the allergen. This is active sensitization. I have always a g r e e d with this. I do not see how it could t a k e place in any other way, as most of these babies have n e v e r even seen an egg, let alone eating it, Some very competent allergists and immnnologists have, however, disagreed, l a r g e l y because positive skin tests to egg white are r a r e l y obtained in newborn infants. O n e . s e r i o u s defect of these observations is t h a t in order to arrive at a n y worth-while conclusions these tests should be done on a large series of infants whose mothers or f a t h e r s h a v e h a y f e v e r - - t h i s has n e v e r been done. Testing the inrants of n o r m a l mothers and f a t h e r s means but little, for it is l a r g e l y the children of p a r e n t s with h a y fever w h o have eczema, and not so often those of normal parents. It is true that often a baby, when tested at the seeond or third month, will have a negative egg white test, and w h e n tested again at the sixth or seventh month it m a y be strongly positive in spite of the faet that he has not come into contact with egg' during the intervening months. It is also often true that just about the ~ R a t n e r , J~ret: ~ l~ossibte C a u s a l J~actor of Food A l l e r g y in C e r t a i n I n f a n t s , Am. J. I)is. Child. 36: 277, 1928.
654
THE JOURNAL OF PEDIATRICS
time the egg white test becomes positive an eczema which has p r e v i o u s l y not a m o u n t e d to m u c h m a y t u r n into a v e r y severe one, even to the erythrodermic point. These are the f a c t s - - t h e explanation is obscure. I t h i n k in the last y e a r some light m a y have been shed on it. The y o u n g b a b y does not m a k e g a m m a globulin as a rule until he is about 4 to 12 weeks old2 7 W h a t he has of it before this he has obtained f r o m his mother. Until he can m a k e his own g a m m a globulin he does not begin to m a k e egg white antibodies, and until he does this he does not have a positive skin test to egg white. The w e a k point of this t h e o r y is t h a t he has h a d no contact with the antigen since he was in utero. I t is not k n o w n how long egg antigen m a y persist in the body, but it is well k n o w n t h a t other protein antigens m a y persist for several months. Sensitivity to egg white is such a common a n d such a striking phenomenon in infants w i t h eczema, it is so m u c h g r e a t e r in degree t h a n the other sensitizations which exist, and I h a v e seen so m a n y babies with a high degree of egg white sensitivity in w h o m no other sensitivity could be d e m o n s t r a t e d t h a t I h a v e always h a d a suspicion t h a t it m a y have something to do with the eczema even if there is no contact with the antigen (egg white). This is, of course, immunologic heresy, and I h a v e no idea w h a t e v e r how it m i g h t work. REGULATION OF THE DIET
M a n y positive skin tests to foods are of no etiological significance. This is not so likely to be true for ~TDr. David Gitlin, Immunology Laboratory, Children's lViedical Center, Boston. Personal communication.
babies as for older children. I t is p r o b a b ] y best in dealing with babies to omit those foods which have given w e l l - m a r k e d positive scratch tests, p r o v i d e d there are not too m a n y of them, a n d see w h a t happens. W i t h moderation, a n d the a d m i x t u r e of a good measure of eommonsense, the same is t r u e for older children. I will s a y a g a i n t h a t no i n f a n t or child should be placed u p o n a p o o r l y ba]anced or insufficient diet, no m a t t e r w h a t the skin tests show. I f there is going to be i m p r o v e m e n t f r o m the rem o r a l of a food, this will not t a k e place at once, because the skin has been damaged, and it will not r e t u r n to n o r m a l in a h u r r y , no m a t t e r w h a t is done. I f there is not decided irap r o v e m e n t at the end of two weeks, it is f a i r to conclude t h a t the food in question has n o t h i n g to do w i t h the eczema. I f there is considerable imp r o v e m e n t , a n d several foods have been removed, so t h a t there is doubt as to which are the i m p o r t a n t ones, one food at a time over three-day periods is added, and results noted. A n almost routine basic diet which I use in dealing w i t h atopic dermatitis is as follows: l~ice Lamb Milk (or sometimes s o y b e a n food) Carrots S t r i n g bea~s Squash P o t a t o (for older children)
Bananas Applesauce Apricots Pears Peaches Jell-o V i - P e n t a drops
This is a well-balanced diet, and a b a b y can s t a y on it for a long time. Most babies will eat the same thing d a y a f t e r day. T h e y do not need a large v a r i e t y of foods, 11o m a t t e r w h a t the m o t h e r thinks a b o u t it, and the present f a d of feeding fifty-seven different varieties of foods to v e r y
HILL:
TREATMENT
young" babies, to my mind has no sense to it, although I am sorry that I cannot say t r u t h f u l l y that I have seen it do much harm, except to some allergic babies. All allergic babies with symptoms of any sort referable to allergy should be on a simple diet containing relatively few foods. SPECIAL FOODS
A few foods are important enough to deserve special discussion. Mi~k.~Milk contains four proteins: lactalbumin, casein, lactoglobulin, and opalisin. Opalisin exists only in traces, lactoglobulin in v e r y small amounts; it is probable that they are of little or no importance in allergy. Lactalbumin and casein are the important ones, and of these lactalbumin is by far the more important. Sensitivity to casein exists, but it not so common as sensitivity to ]actalbumin, as casein is coagulated in the stomach and is not readily absorbed before digestion, while laetalbumin is a soluble protein, and is therefore more easily absorbed in antigenic form. In 153 eczematous infants under 1 year of age, from m y old records, there were seventeen positive scratch tests to either taeta]bumin or casein or to both. Most were to both proteins, but as it is impossible to obtain a casein preparation which is entirely free of laetalbumin, the authenticity of some of the casein reactions is open to doubt. In a series of sixty-three infants who had negative scratch tests to ]aetalbumin, about 50 per cent gave positive intracutaneous tests. It has seemed to me that positive scratch tests to milk are almost always of etiological importance in infantile eczema --positive intracutaneous tests sometimes are. In eczema the sensitivity
OF
ECZEMA
655
to milk is not of high degree; if it were it would not be possible for the infant to take a n y milk without violent symptoms, and still he drinks a quart a day with no adverse symptoms except perhaps a bit of colic, and thrives except for his eczema. I think that at the present time altogether too concentrated milk mixtures are being fed to too y o u n g babies, and that this is p a r t l y responsible for the increase in eczema and other allergic symptoms.
I see not a few babies who
are taking' as much as 3 ounces of whole milk per pound of weight per day. This represents an enormous intake of protein for such a small creature. It is not a bad idea, although it m a y be difficult with some h u n g r y babies, to stick to the old rule of 11/~ to 2 ounces of whole milk or its equivalent per pound per day. I f the skin test to milk is positive it is best to remove milk from the diet and to substitute one of the milk-free foods. Sobee, Mull-Soy, Soyolac, and N u t r a m i g e n are at present the most popular. The first three are made from soybean flour with the addition of various fats, carbohydrates, salts, and vitamins.
The
base of Nutrami-
g'en consists of amino acids which have been derived from the b r e a k i n g down of casein. Fat, carbohydrate, salts, and vitamins have been added. All are excellent preparations, and will nourish a baby as well as milk, even over long periods o~ time. The trouble is t h a t the soybean preparations are altogether too likely to cause diarrhea and sore buttocks; the y o u n g e r the baby the more often this happens. It is said t h a t the new liquid Sobee is less likely to do this than the others. I cannot vouch for this f r o m personal e x p e r i e n c e - - I have used too little of
656
THE
JOURNAL
it. I t h i n k N u t r a m i g e n is the best to use for babies u n d e r 3 months. The stools with N u t r a m i g e n are of thin consistency, as it has little residue, but there is r a r e l y actual diarrhea. The trouble with N u t r a m i g e n is t h a t it has a v e r y strong taste, s o m e w h a t resembling beef tea, and babies tire of it more easily t h a n t h e y do of the soybean foods. I have seen one child, however, who was fed on it for over two years. I said t w e n t y y e a r s ago t h a t I t h o u g h t sensitivity to milk was probably the most common single cause of atopic dermatitis in infants. H o w ever, most of the eczematous babies t h a t are now b r o u g h t to me h a v e been on some milk-free f o o d for a considerable period with no benefit w h a t ever. I see, f o r the most part, only those for w h o m a milk-free diet does no good, and for a while I h a d the t h o u g h t t h a t p e r h a p s m y original ideas a b o u t milk sensitivity in eczema were wrong'. M y p e d i a t r i c friends assure me, h o w e v e r , t h a t this is not so, and that, due to extensive advertising, most pediatricians now use these foods so m u c h t h a t I see, as a eonsuItant, oMy those in w h o m t h e y do not work. This m a y be so. W h e t h e r it is so or not, I am entirely sure t h a t the milk-free :foods are being used a l t o g e t h e r too much, and, for the most part, without a g r e a t deal of intelligence, a n d t h a t the frequency of tailk sensitivity of e v e r y sort (gastrointestinal, respiratory, etc.) is being e x a g g e r a t e d ; like e v e r y good thing it is being w o r k e d to death. The t e n d e n c y is now, on account of s u p e r a d v e r t i s i n g of the soybean foods, for pediatricians to p u t e v e r y b a b y t h e y see with a n y sort of skin rash, f r o m a m m o n i a derma-
OF
PEDIATRICS
titis to flea bites, scabies, and often w h a t is obviously contact dermatitis, oi1 a milk-free diet at once. This is not only stupid, but m a y do h a r m if the b a b y develops a severe diarrhea. The milk-free foods are of g r e a t value w h e n used properly, and t h e y h a v e been a boon to m a n y babies, b u t when H a r o l d S t u a r t a n d 1is i n t r o d u c e d Sobee in 1929, we s t a r t e d something t h a t has gone too far. G o a t ' s milk t a n sometimes be used to great advantage in some forms of milk sensitivity, particularly for patients with gastrointestinal allergy and for almost all of those babies who are so violently sensitive that they go into shock from the ingestion of only a few drops of cow's milk. 19 A l t h o u g h an occasional i n f a n t with eczema due to c o w ' s milk is relieved or even cured b y the use of g o a t ' s milk, this does not h a p p e n often because the caseins of g o a t ' s a n d c o w ' s m i l k are identical immunologically and chemically, a n d while the two l a c t a l b u m i n s are s o m e w h a t different immunologically, t h e y are b y no means entirely species specific; there are m a n y Grossed reactions. Some y e a r s ago I tested f o r t y - f o u r eczematous infants who h a d given positive i n t r a e u t a n e o u s tests to cow laetalburain, w i t h a specially purified p r e p a r a tion of goat lacta]bumin. There were twenty-five positive reactions. Why it is that goat's milk is so often tolerated by infants who have severe shocklike symptoms from cow's milk, and is only occasionally of u s e in 1SHill, L e w i s , W., a n d S t u a r t , H a r o l d C. : A Soybean Food Preparation for Feeding I n f a n t s W i t h Milk I d i o s y n c r a s y , J. A. IV[. A. 93: 985, 1929. :'I-till, L e w i s W . : I m m u n o l o g i c l s ship B e t w e e n C o w ' s Milk a n d G o a t ' s l~[ilk, J. PJr 15: 157, 1939.
HILL:
TREATMENT
eczema due to c o w ' s milk, I do not know. I suspect t h a t the antibodies in the two conditions m a y be different, and t h a t the a n t i b o d y in the patients with eczema is less specific t h a n the a n t i b o d y in those w i t h shocklike symptoms. Foods E a t e n by the Cow as a Cause of E c z e m a . - - I t has been said t h a t eczema m a y be due to sensitivity to foods eaten b y the c o w - - p a r t i c u l a r l y
OF ECZEMA
tests to corn, and one to a.lfalfa--l/O positive tests to any of the others. E g g W h i t e . - - E g g white should be k e p t out of the diet of all these babies, unless there is a definitely negative scratch test to it, and it is best to do this two or three times before giving the b a b y egg. Hardboiled egg y o l k is usually t o l e r a t e d ; soft-boiled egg yolk should not be given, as it is not possible to separate
F i g . 2 3 . - - T h i s p a p u l a r e r u p t i o n ~vas e n t i r e l y d u e t o t h e i n g e s t i o n o f w h e a t . There was eczema on any other part of the body. It can be compared to a fixed drug eruption.
linseed or cottonseed. I see no reason w h y this should not be so. However, I have n e v e r seen a p a t i e n t in w h o m I t h o u g h t it was so, and once I tested a series of f o r t y - t h r e e eczematous babies u n d e r 1 y e a r of age with cottonseed, linseed, soybean, corn and alfalfa, alI foods which are used in the s t a n d a r d diet of m a n y dairies. There were three slightly positive
657
no
it entirely f r o m the white. F u r t h e r more, the b a b y should be k e p t out of the kitchen when the m o t h e r is breaking or cooking eggs (except boiled eggs). I t is almost incredible w h a t a minute a m o u n t of egg white can cause a reaction. I once h a d my a r m sensitized with a strong egg serum, and ate a piece of b r e a d t h a t h a d a little shiny glaze of egg white on the
~58
THE JOURNAL OF PEDIATRICS
crust: in t w e n t y minutes a wheal developed on the sensitized site. Wheat.--Wheat sensitivity is imp o r t a n t in m a n y eezematous babies, a~d in not a few older children. A positive scratch test is usually significant. W h e a t is not easy to deal with, for the year-old child is a great cracker eater, and the older child depends so much on all sorts of wheatcontaining foods. I t is important to explain to the mother exactly what wheat flour is, and w h a t articles of diet contain it. 9This statement may sound superfluous, but it is b y no means so. Some women do not even know t h a t b r e a d is made o~ wheat, others think t h a t the only wheat-containing b r e a d is whole wheat bread, m a n y women do not know that graham crackers are made f r o m wheat, and so on ad nauseam. F o r babies the " H a p p y T a p p y " * crackers are excellent. T h e y contain tapioea flour, apple juice, and dried milk. The trouble with them is that they are no good for babies who are sensitive to milk as well as to wheat. "l~y-I(risp"~ wafers serve the same purpose. They are swallowed better if they are spread with butter and apple jelly. Practically all rye breads contain wheat. F o r the older child, the mother can learn to make corn cake, biscuits from rice flour, or sweetened cookies from either of these or from soybean flour. I have been t r y i n g for years to induce one of the largest manufacturers of infant loods to supply sweetened crackers made from rice, oat, barley, and corn flour, with no luck at all. There is need for such crackers. Tomato Juice. Tomato should never be given to any child with atopie *Nialtex Co., ]~urlington, Vt. ~Ralston P u r i n a CO., St. Louis, Mo.
dermatitis, Skin tests to tomato are uncommon, but for some u n k u o w n reason it produces skin rashes with great frequency, possibly due to the pigment it contains, possibly due to w h a t e v e r it is t h a t gives it its characteristic taste. Orange Juiee.--It is common for the mother to notice that the baby "breaks out" 'if orange juice is given. I t is probably best to remove it from the diet of all infants who have atopie dermatitis, for orange juice is of little or no value to a baby except as an antiscorbutie, and if he is taking any "multivitamin" drops he is getting an adequate amount of vitamin C. I f he is not, it is a simple matter to give him some aseorbie acid. Positive scratch tests to orange are uncommon: in 300 cases there were only four. In a series of twenty-three tested by the intraeutaneous method, however, there were eight slightly positive tests. Sensitivity to orange is almost always of low d e g r e e - - I have" seen one 4-year-old child, however, who was exquisitely sensitive to it, and who had an enormous positive scratch test. There are in orange juice three substances which may produce allergic symptoms : 1. The protein of the juice 2. The protein of t h e seed 3. The peel oil
The relative importance of these is not entirely clear. In most commereiMly prepared orange juice there is plenty of chance for peel oil and seed protein to be present. Bib e canned orange juice contains no seed protein and no peel oil, and in five infants who had allergic symptoms from ordinary orange juice, R a t h e r and his CO*Bib
Corporation, Lakeland,-Fla.
HILL:
T R E A T M E N T OF E C Z E M A
workers 2~ found that the Bib juice was tolerated. They do not say what sort of allergic symptoms were present. I have had no personal experience with it. I n orange juice, as it is prepared at home, it is not likely that any seed protein is present, and the amount of peel oil must be very small, although possibly enough to produce symptoms. The oil of orange peel in addition to being a sensitizer (its active principle is dextrolimonene, which is closely allied to turpentine) is a p r i m a r y irritant, and dermatitis of the fingers from it has been known for a long time and is common in adults whose work in2~l~atner, B r e t , U n t r a e h t , S a m u e l , M a l o n e H. John, a n d Retsina, M a r y : A l l e r g e n i e i t y of O r a n g e S t u d i e d in M a n , J. PEDIAT. 43: 421, 1953.
659
volves the cutting up of oranges. It seems likely that if sensitivity to orange peel oil existed in infants it would be epidermal r a t h e r than dermal, and would therefore not be demonstrated by scratch or intracntaneous tests. Sensitivity to the juice protein or to the seed protein is shown b y urticarial type scratch or intraeutaneous tests. R a t n e r and his co-workers 2~ in a painstaking s t u d y showed clearly that the protein of orange juice is not readily absorbed from the digestive tract in an unsplit antigenic condition, and said, "What we call allergy to citrus fruit may in truth not be allergy in all instances, but irritation from the peel." This seems likely. (To be concl~tded.)
TREATMENT
OF
ECZEMA
IN
INFANTS
AND
CHILDREN
PART I V LEWIS WEBB IIILL, 3/I.D. BOSTON, ~/~ASS. "Immunology is a mixture of established fact, half knowledge, hopeful guessings and frank bewilderment. ~ --W.
W . C. T a p l e y :
immunology, particularly psychologic, may greatly aggravate it. IMMUNOLOGIC TREATMENT
A'~ O u t l i n e o f I , ~ m u n i t y ,
William "Wood & Co., 1933.
In order to make an a t t e m p t to understand the rationale of immunologic t r e a t m e n t it is first necessary to consider in some detail the immunophysiologic principles involved. The a n t i b o d y (atopie reagin) which has to do with atopic dermatitis is fixed iu the vascular loops in the papillae of the corium, and can often also be detected in the blood, contained mostly or possibly entirely in the g a m m a globulin fraction. The commonly accepted t h e o r y has been that when antigen, inhaled or ingested, reaches the sensitized skin tissue, an immunologic reaction results with the p r o d u c t i o n of an irritating end product, possibly histamine, and consequent dilatation and increased permeability of the small cutaneous vessels, with a resulting inflammatory reaction and the histologic changes of
ATOPIC DERMATITIS T O P I C d e l ~ a t i t i s is brought about b y the same abnormal constitution which underlies h a y fever and asthma, and is often the first manifestation of this constitution. I t is not u n c o m m o n for children to be afflicted with all three at the same time. A b o u t half of the infants who have atopic dermatitis later develop r e s p i r a t o r y allergy. Atopic dermatitis is a disease of the young, although it m a y last well into adult life, and is occasionally even seen in the aged. A l t h o u g h it has been called b y different names at different age periods, it is one and the same disease at all ages, and is best calked atopic dermatitis at all ages. 11 I t is as much a constitutional disease as diabetes or pernicious anemia; w h a t r e t a r d s the t r e a t m e n t more t h a n a n y t h i n g else is that it is not possible to change the constitution that is responsible for it. Like asthma, its f u n d a m e n t a l basis is abnormal immunology, and, also like asthma, other stimuli not related to
A
eczema.
J~ditor~s N o t e : Despite the notice in the August issue that reprints would not be available of Dr. Hill's series of papers on "The
Treatment of Eczema in Infants and Children," many requests are being received. As previously stated, no reprints are available as the articles will be published in book form.
:~HilI, L. W., and Sulzberger, lVI. B. : Evolution of Atopie Dermatitis, Arch. Dermat. & Syph. 3~: 451, 1935.
There are those who have said t h a t scratch or intraeutaneous tests are entirely useless in the determination of etiology, and t h a t the immediate urticarial type reaction so obtained has nothing to do with the eczema, for the eczematous reaction is a delayed t w e n t y - f o u r - h o u r type reaction, and is vesicular or p a p u l a r and never urticarial. I n order to determine etiology the test reaction should produce the
648
~IILL:
T R E A T M E N T OF E C Z E M A
lesion of the disease in the same way that eczema (the lesion of the disease) is produced b y the patch test. There is some evidence in favor of this point of view, and some against it. 1. The skin of a patient who has ragweed hay fever gives an immediate urticarial type scratch or intracutaneous test. So does the skin of a patient who has atopic dermatitis due to ragweed pollen, and only v e r y r a r e l y a positive patch test. If the urticarial type skin test is of etiological significance in atopie dermatitis due to ragweed, w h y do not all patients with ragweed hay fever who show this test have atopic dermatitis as well? 2. I f a person with h a y fever but no eczema is given too much ragweed e x t r a c t by inoculation, he is likely to develop urticaria, practically n e v e r eczema. A person with atopic dermatitis f r o m ragweed, with or without h a y fever, has exactly the same sort of skin test t h a t the person with hay fever alone has. Yet his tolerance to injected ragweed extract is v e r y low, much lower t h a n t h a t of the patient with h a y fever alone, and if he is given any but a v e r y small dose of r a g w e e d e x t r a c t his existing eczema will p r o b a b l y become worse, and he is likely to develop new eczema in places where he did not have it before. This is a delayed twenty-four-hour t y p e reaction. The amount of antigen when injected or ingested which will worsen eczema or produce new eczema in a patient who already has eczema is a great deal less t h a n that which will produce urticaria or respirat o r y symptoms in a patient who has r e s p i r a t o r y allergy alone. W h y is this ? It seems clear that there is some predisposing condition in the skin,
649
immunologic or otherwise, in persons with atopic dermatitis, which is not present in those who have h a y fever alone, although t h e y both give identical wheal t y p e scratch tests. It is likely that this condition, whatever it m a y be, in combination with the urticarial type sensitivity, is responsible for the production of dermatitis, and that atopic dermatitis is not produced without it. Let us eall this the Xfactor. 3. If I sensitize a small place on m y own skin with an egg white reagin containing serum from an eezematous baby, and then eat an egg, or indeed sometimes only an infinitesimal amount of egg white, in about t w e n t y minutes an urticarial wheal appears on the sensitized s i t e - - n e v e r eczema. If every day I eat small amounts of egg white below the amount necessary to produce urticaria, no eczema ever develops. It is either immediate urticaria or nothing: there is no cumulative reaction. I cannot produce eczema oil myself by eating a food to which my skin is sensitized, no m a t t e r in what amount I eat it. I can produce only urticaria, presumably because the X-factor is not there. 4. I t is true that m a n y times people with atopic dermatitis ean eat the foods which give positive skin tests with impunity, so t h a t these tests are often entirely without etiological significance. In Louis T u f t ' s well-known " d u s t patient, ''12 there were positive intraeutaneous tests to twenty-seven different foods, and yet his eczema was proved to be entirely due to house dust, and had nothing l~Tuft, L o u i s , T u f t , H a r o l d S., a n d t t e c k , V. Muriel: Atopie Dermatitis, an Experimental C l i n i c a l S t u d y of t h e R o l e of I n h a l a n t A l l e r gens, ft. A l l e r g y 21: 181, 1950.
650
THE
JOURNAL
whatever to do with the foods to which he gave positive tests. This is a classical paper, and everyone seriously interested in atopic dermatitis should r e a d it. I n spite of these objections which I have enumerated there can be no doubt that sometimes positive scratch or intracutaneous tests indicate etiology, and are of great value in planning treatment. I think t h a t almost all allergists would agree to this, and possibly an occasional dermatologist. Is it possible to reconcile these somewhat c o n t r a d i c t o r y observations? I think it may be. The following hypothesis, which seems to me to follow logically from the observed facts, is suggested. The wheal test reaction is of no significance in atopic dermatitis b y itself; it is significant only if it is accompanied b y another factor, the X-factor. I have no idea whatever w h a t this added factor may be.
The wheal reaction is, however, sometimes indicative of etiology because it is sometimes accompanied by the Xfactor. B y itself it is of no moment so far as eczema is concerned. It was shown a good many years ago by Oscar Schloss, 1~ who was in his day the foremost research pediatrist in America, and who has been rarely equalled and never surpassed, that a new food when introduced into the diet of a young infant is often followed by the development of a positive skin test. This is a normal phenomenon. The degree of sensitivity is never high, and the positive test lasts for only a short time. Later B r u n n e r and Walzer 1~ showed that even in l~Sebloss, O s c a r : T h e I n t e s t i n a l A b s o r p t i o n of A n t i g e n i c P r o t e i n , T h e H a r v e y L e c t u r e s , p. 156, 1924-1925. ~ B r u n n e r , M a t t h e w , a n d ~vValzer, M a t t h e w : A b s o r p t i o n of U n d i g e s t e d P r o t e i n in H u m a n B e i n g s , A r c h . I n t . Meal. 4~: 172, 1928.
OF
PEDIATRICS
older children and adults the passage of unsplit food pcotein t h r o u g h the gastrointestinal nlucosa and thence to the blood is a normal phenomenon. In atopic people this circulating protein sensitizes the skin more readily than it does in the normal person, and the positive skin tests which result are of much greater degree and last longer, sometimes for m a n y years (fish, nuts). The same is true of environmental allergens, which reach the blood by inhalation. Many of these positive tests, p a r t i c u l a r l y those to foods, may be looked upon as normal for the atopic person and have nothing to do with his symptoms, whether t h e y be those of eczema, h a y fever, or asthma. I think the main reasons for this are two : A. The X-factor is not present; therefore eczema is not produced. B. The degree of tissue sensitization is not high enough to react with the amount of antigen absorbed. The immunologic reaction we are diseussfftg depends upon two variables :
(1) The amount of a n t i b o d y fixed in the tissue. (2) The amount of antigen which contacts it. If there is a small amount of antib o d y it takes a large amount of antigen to produce a reaction, and vice versa. Several years ago I did some immunologic experiments on myself with the help of Miss Margaret Scully, who was in charge of the allergy laboratory of the Children's Hospital at that time. It is not necessary to go into the details of these investigations. The gist of them was that if
HILL:
TREATIVIENT OF ECZES/[A
a high degree of passive sensitization was p r o d u c e d on m y skin b y the i n t r a e u t a n e o u s injection of a serum containing food reagins f r o m an eczematous infant, the eating of the corr e s p o n d i n g food in only small a m o u n t caused a wheal to a p p e a r on the sensitized site in about twenty minutes. W e studied egg white, chicken, peanut, wheat, a n d potato. I f the degree of sensitization was only m o d e r a t e or slight, as d e t e r m i n e d b y serial titration of the sites, no reaction would t a k e place, either u r t i c a r i a l or eczema~ tous, even if the food were eaten in large amounts. This simple principle applies to a n y tissue as well as to the skin, and seems to me of f u n d a m e n t a l i m p o r t a n c e in clinical allergy. Skin Testing.--Skin testing is often a valuable p r o c e d u r e in atopie dermatitis as a help in p l a n n i n g t r e a t m e n t . I t s value has, however, been g r e a t l y e x a g g e r a t e d , too m u c h a t t e n t i o n has been p a i d to it, a n d h a r m has been done, p a r t i c u l a r l y in babies a n d in y o u n g children b y too rigorous dieting solely on the basis of skin tests. W h a t the m o t h e r has actually seen h a p p e n to the child is more i m p o r t a n t . Skin testing is a l a b o r a t o r y procedure, a n d like all other l a b o r a t o r y procedures it m u s t be e v a l u a t e d in relation to the p a t i e n t a n d not b y itself. Too m u c h a t t e n t i o n to laboratory tests and too little attention to the patient is one of the defects of modern medicine, and is often carried to an absurdity. I saw not long ago a bottle-fed eczematous b a b y 7 months old whose f a m i l y had m o v e d to Boston f r o m a large m i d w e s t e r n city. The m o t h e r b r o u g h t with her a t y p e d r e p o r t of the skin tests t h a t had been done there in a t h r i v i n g p r i v a t e clinic. E i g h t y tests h a d been done b y the
651
indirect method, forty-six of which were r e p o r t e d positive. Some of the things tested for were tobacco, camel hair, mustard, cinnamon, auspice, ginger, p a p r i k a , garlic, vanilla, strawberry, and cucumber. This is not an isolated example b y a n y means. W h e n one sees such things he begins to believe t h a t there is as m u c h foolishness in m o d e r n medicine as there was in the time of William Shakespeare, and he is not f a r f r o m right. There is no need of doing a large n u m b e r of skin tests on a b a b y with eczema. I f he is tested with most of the foods he is eating, plus egg white, and w i t h a few of the e n v i r o n m e n t a l allergens to which he is exposed, t h a t is enough. I n e v e r do an intracutaneous test until a scratch test has been done first and is negative, a n d would not do an i n t r a e u t a n e o u s test with egg white on a n y baby, no m a t t e r w h a t the scratch test showed. I t is sometimes desirable to do a few i n t r a c u t a n e o u s tests with other allergens on eczematous babies, as the skin sensitivity is often of low degree and the i n t r a e u t a n e o u s test m a y be positive when the scratch test is negative. I h a v e not used the indirect method of testing f o r over ten y e a r s except for investigative w o r k - - i t is more bother t h a n it is worth. This could be discussed at considerable l e n g t h - - I will simply say t h a t I do not t h i n k m u c h of it. As a m a t t e r of fact, it is possible to treat most babies who have atopic dermatitis v e r y well without doing a n y skin tests at all. I find m y s e l f doing f e w e r a n d fewer, and the patients seem to do a b o u t as well as when I was careful to do complete testing on e v e r y patient. Older children, whose
652
THE JOURI',TAL OF PEDIATRICS
trouble is likely to be coming from the environmental allergens, particularly pollen and dust, can be understood better and t r e a t e d b e t t e r if p r e t t y complete testing with the environmental allergens is done. In a series of 100 eczematous babies u n d e r 1 year of age, who gave positive scratch tests to something, the positive tests to foods were as follows : Egg white 1Vfilk Wheat Oat Barley Beef Potato Haddock Tomato
86 26 17 8 6 6 4 3 3
Corn Spinach Pea Carrott Orange Lamb Codfish Chicken
2 2 2 2 2 2 1 ]
t~ifty-six gave positive tests to something they were eating, thirty-nine gave positive tests to egg white alone. It must be understood that this series of 100 was not made up of consecutive c a s e s - - t h e y were all babies with atopic dermatitis who reacted to something; no babies who had negative skin tests were included. In a series of thirty-eight u n d e r 1 y e a r of age, tested b y the scratch method with fifteen environmental allergens, only f o u r children gave positive r e a c t i o n s - - t h e allergens were silk, cat hair, and: wool. However, in a series of f o r t y - f o u r which had negative scratch tests to dust and feathers, thirty-one had positive intraeutaneous tests to dust and twenty-five to feathers. At the time these tests were made the high percentage of positive reactions was surprising to me, and still is. It m a y be that some of these were irritative reactions, as fairly strong testing solutions were used, but they gave no reactions on normal babies, and in a good m a n y of these babies reagins for dust and for
feathers were present as well as positive skin tests. In older children positive scratch tests to a v a r i e t y of environmental allergens become more frequent. In a large series the ratio between positive reactions to foods and to environmental allergens was 2.5 to 1, in a series of infants u n d e r the age of ] y e a r it was as 20 to I. The Egg White Reaction.--Thc egg white reaction is so i m p o r t a n t in the atopic dermatitis of infants that it w a r r a n t s special discussion. It has been f o u n d (Moro, Woringer, Hill) that most infants who have atopic dermatitis give strongly positive skin reactions to egg white, the m a j o r i t y of which are accompanied by circulating reagins and clinical sensitivity. Many of these babies are so exquisitely sensitive to egg white t h a t the ingestion of only minute amounts is followed by stormy symptoms (urticaria, vomiting, shock). Horesh is has pointed out, and with truth, that even the smell of egg white m a y cause symptoms, and that eczematous babies who are sensitive to it should be kept out of the kitchen when eggs are being broken for use in cooking. This is entirely right. Egg sensitivity lasts a long time, sometimes well into childhood. I have no accurate figures, but I doubt that it often lasts into adult life, and even in childhood its frequency is considerably diminished from what it is in infancy. I t is a curious fact that in infants who have asthma, the egg white reaction i s uncommon, unless the asthma is accompanied by eczema. The egg white reaction a p p a r e n t l y has to do p a r t i c u l a r l y with eczema. In a series of ]00 asthmatic ~'~I:[oresh, A. J. : Allergy to Food Odors, J. Allergy 14: 335, 1943.
HILL:
TREATMENT
children, a b o u t half of w h o m had had eczema in infancy, twenty-one gave positive scratch tests to egg white, but only eleven were clinically sensit i r e to it. A positive scratch test to egg white is of some value in differential diagnosis, for the chances are t h a t if it is absent; w h a t the b a b y has is ~mt atopic dermatitis. This, however, is b y no means certain, for some babies with atopie dermatitis give negative egg tests. I t h i n k the absence of a positive reaction is p r o b a b l y also of some prognostic value, a n d t h a t one is justified in telling the mothers of such patients t h a t the child is certainly not a highly allergic child, and t h a t he has b e t t e r t h a n an even chance of escaping h a y fever and asthma. The direct influence of egg white in causing eczema in y o u n g babies is not great, for most mothers a n d doctors k n o w enough now to keep it a w a y f r o m atlergie babies. I t is in this respect s o m e w h a t more i m p o r t a n t in older children whose diet is not so well controlled, and who m a y be eating enough egg-containing food to get into trouble. While the actual eating of egg white is of little i m p o r t a n c e as a cause of eczema in most infants, I h a v e a suspicion t h a t the fact of egg sensitization m a y be of considerable importance. This is the p r i m a r y sensitization for most of these infants. I t is a sensitization of high degree, much more so than most of the others which follow it, and it has been thought, p a r t i c u l a r l y b y Moro, with whom I agree, that such sensitization, once it has taken place, makes the individual more susceptible to other sensitizations. It puts the stamp of allergy
OF
ECZEMA
653
upon h i m - - o n c e he has become egg sensitive he has been admitted to the allergic fraternity, and is likely to continue his membership for a long time. A good m a n y years ago, B r e t Ratner, 16 after some painstaking laboratory work and considerable clinical observation, came to the conclusion that sensitization to egg white as it occurs in infants, and sometimes to other potent allergens such as fish and nuts, is congenital, and due to placenta] transmission of the allergen. This is active sensitization. I have always a g r e e d with this. I do not see how it could t a k e place in any other way, as most of these babies have n e v e r even seen an egg, let alone eating it, Some very competent allergists and immnnologists have, however, disagreed, l a r g e l y because positive skin tests to egg white are r a r e l y obtained in newborn infants. O n e . s e r i o u s defect of these observations is t h a t in order to arrive at a n y worth-while conclusions these tests should be done on a large series of infants whose mothers or f a t h e r s h a v e h a y f e v e r - - t h i s has n e v e r been done. Testing the inrants of n o r m a l mothers and f a t h e r s means but little, for it is l a r g e l y the children of p a r e n t s with h a y fever w h o have eczema, and not so often those of normal parents. It is true that often a baby, when tested at the seeond or third month, will have a negative egg white test, and w h e n tested again at the sixth or seventh month it m a y be strongly positive in spite of the faet that he has not come into contact with egg' during the intervening months. It is also often true that just about the ~ R a t n e r , J~ret: ~ l~ossibte C a u s a l J~actor of Food A l l e r g y in C e r t a i n I n f a n t s , Am. J. I)is. Child. 36: 277, 1928.
654
THE JOURNAL OF PEDIATRICS
time the egg white test becomes positive an eczema which has p r e v i o u s l y not a m o u n t e d to m u c h m a y t u r n into a v e r y severe one, even to the erythrodermic point. These are the f a c t s - - t h e explanation is obscure. I t h i n k in the last y e a r some light m a y have been shed on it. The y o u n g b a b y does not m a k e g a m m a globulin as a rule until he is about 4 to 12 weeks old2 7 W h a t he has of it before this he has obtained f r o m his mother. Until he can m a k e his own g a m m a globulin he does not begin to m a k e egg white antibodies, and until he does this he does not have a positive skin test to egg white. The w e a k point of this t h e o r y is t h a t he has h a d no contact with the antigen since he was in utero. I t is not k n o w n how long egg antigen m a y persist in the body, but it is well k n o w n t h a t other protein antigens m a y persist for several months. Sensitivity to egg white is such a common a n d such a striking phenomenon in infants w i t h eczema, it is so m u c h g r e a t e r in degree t h a n the other sensitizations which exist, and I h a v e seen so m a n y babies with a high degree of egg white sensitivity in w h o m no other sensitivity could be d e m o n s t r a t e d t h a t I h a v e always h a d a suspicion t h a t it m a y have something to do with the eczema even if there is no contact with the antigen (egg white). This is, of course, immunologic heresy, and I h a v e no idea w h a t e v e r how it m i g h t work. REGULATION OF THE DIET
M a n y positive skin tests to foods are of no etiological significance. This is not so likely to be true for ~TDr. David Gitlin, Immunology Laboratory, Children's lViedical Center, Boston. Personal communication.
babies as for older children. I t is p r o b a b ] y best in dealing with babies to omit those foods which have given w e l l - m a r k e d positive scratch tests, p r o v i d e d there are not too m a n y of them, a n d see w h a t happens. W i t h moderation, a n d the a d m i x t u r e of a good measure of eommonsense, the same is t r u e for older children. I will s a y a g a i n t h a t no i n f a n t or child should be placed u p o n a p o o r l y ba]anced or insufficient diet, no m a t t e r w h a t the skin tests show. I f there is going to be i m p r o v e m e n t f r o m the rem o r a l of a food, this will not t a k e place at once, because the skin has been damaged, and it will not r e t u r n to n o r m a l in a h u r r y , no m a t t e r w h a t is done. I f there is not decided irap r o v e m e n t at the end of two weeks, it is f a i r to conclude t h a t the food in question has n o t h i n g to do w i t h the eczema. I f there is considerable imp r o v e m e n t , a n d several foods have been removed, so t h a t there is doubt as to which are the i m p o r t a n t ones, one food at a time over three-day periods is added, and results noted. A n almost routine basic diet which I use in dealing w i t h atopic dermatitis is as follows: l~ice Lamb Milk (or sometimes s o y b e a n food) Carrots S t r i n g bea~s Squash P o t a t o (for older children)
Bananas Applesauce Apricots Pears Peaches Jell-o V i - P e n t a drops
This is a well-balanced diet, and a b a b y can s t a y on it for a long time. Most babies will eat the same thing d a y a f t e r day. T h e y do not need a large v a r i e t y of foods, 11o m a t t e r w h a t the m o t h e r thinks a b o u t it, and the present f a d of feeding fifty-seven different varieties of foods to v e r y
HILL:
TREATMENT
young" babies, to my mind has no sense to it, although I am sorry that I cannot say t r u t h f u l l y that I have seen it do much harm, except to some allergic babies. All allergic babies with symptoms of any sort referable to allergy should be on a simple diet containing relatively few foods. SPECIAL FOODS
A few foods are important enough to deserve special discussion. Mi~k.~Milk contains four proteins: lactalbumin, casein, lactoglobulin, and opalisin. Opalisin exists only in traces, lactoglobulin in v e r y small amounts; it is probable that they are of little or no importance in allergy. Lactalbumin and casein are the important ones, and of these lactalbumin is by far the more important. Sensitivity to casein exists, but it not so common as sensitivity to ]actalbumin, as casein is coagulated in the stomach and is not readily absorbed before digestion, while laetalbumin is a soluble protein, and is therefore more easily absorbed in antigenic form. In 153 eczematous infants under 1 year of age, from m y old records, there were seventeen positive scratch tests to either taeta]bumin or casein or to both. Most were to both proteins, but as it is impossible to obtain a casein preparation which is entirely free of laetalbumin, the authenticity of some of the casein reactions is open to doubt. In a series of sixty-three infants who had negative scratch tests to ]aetalbumin, about 50 per cent gave positive intracutaneous tests. It has seemed to me that positive scratch tests to milk are almost always of etiological importance in infantile eczema --positive intracutaneous tests sometimes are. In eczema the sensitivity
OF
ECZEMA
655
to milk is not of high degree; if it were it would not be possible for the infant to take a n y milk without violent symptoms, and still he drinks a quart a day with no adverse symptoms except perhaps a bit of colic, and thrives except for his eczema. I think that at the present time altogether too concentrated milk mixtures are being fed to too y o u n g babies, and that this is p a r t l y responsible for the increase in eczema and other allergic symptoms.
I see not a few babies who
are taking' as much as 3 ounces of whole milk per pound of weight per day. This represents an enormous intake of protein for such a small creature. It is not a bad idea, although it m a y be difficult with some h u n g r y babies, to stick to the old rule of 11/~ to 2 ounces of whole milk or its equivalent per pound per day. I f the skin test to milk is positive it is best to remove milk from the diet and to substitute one of the milk-free foods. Sobee, Mull-Soy, Soyolac, and N u t r a m i g e n are at present the most popular. The first three are made from soybean flour with the addition of various fats, carbohydrates, salts, and vitamins.
The
base of Nutrami-
g'en consists of amino acids which have been derived from the b r e a k i n g down of casein. Fat, carbohydrate, salts, and vitamins have been added. All are excellent preparations, and will nourish a baby as well as milk, even over long periods o~ time. The trouble is t h a t the soybean preparations are altogether too likely to cause diarrhea and sore buttocks; the y o u n g e r the baby the more often this happens. It is said t h a t the new liquid Sobee is less likely to do this than the others. I cannot vouch for this f r o m personal e x p e r i e n c e - - I have used too little of
656
THE
JOURNAL
it. I t h i n k N u t r a m i g e n is the best to use for babies u n d e r 3 months. The stools with N u t r a m i g e n are of thin consistency, as it has little residue, but there is r a r e l y actual diarrhea. The trouble with N u t r a m i g e n is t h a t it has a v e r y strong taste, s o m e w h a t resembling beef tea, and babies tire of it more easily t h a n t h e y do of the soybean foods. I have seen one child, however, who was fed on it for over two years. I said t w e n t y y e a r s ago t h a t I t h o u g h t sensitivity to milk was probably the most common single cause of atopic dermatitis in infants. H o w ever, most of the eczematous babies t h a t are now b r o u g h t to me h a v e been on some milk-free f o o d for a considerable period with no benefit w h a t ever. I see, f o r the most part, only those for w h o m a milk-free diet does no good, and for a while I h a d the t h o u g h t t h a t p e r h a p s m y original ideas a b o u t milk sensitivity in eczema were wrong'. M y p e d i a t r i c friends assure me, h o w e v e r , t h a t this is not so, and that, due to extensive advertising, most pediatricians now use these foods so m u c h t h a t I see, as a eonsuItant, oMy those in w h o m t h e y do not work. This m a y be so. W h e t h e r it is so or not, I am entirely sure t h a t the milk-free :foods are being used a l t o g e t h e r too much, and, for the most part, without a g r e a t deal of intelligence, a n d t h a t the frequency of tailk sensitivity of e v e r y sort (gastrointestinal, respiratory, etc.) is being e x a g g e r a t e d ; like e v e r y good thing it is being w o r k e d to death. The t e n d e n c y is now, on account of s u p e r a d v e r t i s i n g of the soybean foods, for pediatricians to p u t e v e r y b a b y t h e y see with a n y sort of skin rash, f r o m a m m o n i a derma-
OF
PEDIATRICS
titis to flea bites, scabies, and often w h a t is obviously contact dermatitis, oi1 a milk-free diet at once. This is not only stupid, but m a y do h a r m if the b a b y develops a severe diarrhea. The milk-free foods are of g r e a t value w h e n used properly, and t h e y h a v e been a boon to m a n y babies, b u t when H a r o l d S t u a r t a n d 1is i n t r o d u c e d Sobee in 1929, we s t a r t e d something t h a t has gone too far. G o a t ' s milk t a n sometimes be used to great advantage in some forms of milk sensitivity, particularly for patients with gastrointestinal allergy and for almost all of those babies who are so violently sensitive that they go into shock from the ingestion of only a few drops of cow's milk. 19 A l t h o u g h an occasional i n f a n t with eczema due to c o w ' s milk is relieved or even cured b y the use of g o a t ' s milk, this does not h a p p e n often because the caseins of g o a t ' s a n d c o w ' s m i l k are identical immunologically and chemically, a n d while the two l a c t a l b u m i n s are s o m e w h a t different immunologically, t h e y are b y no means entirely species specific; there are m a n y Grossed reactions. Some y e a r s ago I tested f o r t y - f o u r eczematous infants who h a d given positive i n t r a e u t a n e o u s tests to cow laetalburain, w i t h a specially purified p r e p a r a tion of goat lacta]bumin. There were twenty-five positive reactions. Why it is that goat's milk is so often tolerated by infants who have severe shocklike symptoms from cow's milk, and is only occasionally of u s e in 1SHill, L e w i s , W., a n d S t u a r t , H a r o l d C. : A Soybean Food Preparation for Feeding I n f a n t s W i t h Milk I d i o s y n c r a s y , J. A. IV[. A. 93: 985, 1929. :'I-till, L e w i s W . : I m m u n o l o g i c l s ship B e t w e e n C o w ' s Milk a n d G o a t ' s l~[ilk, J. PJr 15: 157, 1939.
HILL:
TREATMENT
eczema due to c o w ' s milk, I do not know. I suspect t h a t the antibodies in the two conditions m a y be different, and t h a t the a n t i b o d y in the patients with eczema is less specific t h a n the a n t i b o d y in those w i t h shocklike symptoms. Foods E a t e n by the Cow as a Cause of E c z e m a . - - I t has been said t h a t eczema m a y be due to sensitivity to foods eaten b y the c o w - - p a r t i c u l a r l y
OF ECZEMA
tests to corn, and one to a.lfalfa--l/O positive tests to any of the others. E g g W h i t e . - - E g g white should be k e p t out of the diet of all these babies, unless there is a definitely negative scratch test to it, and it is best to do this two or three times before giving the b a b y egg. Hardboiled egg y o l k is usually t o l e r a t e d ; soft-boiled egg yolk should not be given, as it is not possible to separate
F i g . 2 3 . - - T h i s p a p u l a r e r u p t i o n ~vas e n t i r e l y d u e t o t h e i n g e s t i o n o f w h e a t . There was eczema on any other part of the body. It can be compared to a fixed drug eruption.
linseed or cottonseed. I see no reason w h y this should not be so. However, I have n e v e r seen a p a t i e n t in w h o m I t h o u g h t it was so, and once I tested a series of f o r t y - t h r e e eczematous babies u n d e r 1 y e a r of age with cottonseed, linseed, soybean, corn and alfalfa, alI foods which are used in the s t a n d a r d diet of m a n y dairies. There were three slightly positive
657
no
it entirely f r o m the white. F u r t h e r more, the b a b y should be k e p t out of the kitchen when the m o t h e r is breaking or cooking eggs (except boiled eggs). I t is almost incredible w h a t a minute a m o u n t of egg white can cause a reaction. I once h a d my a r m sensitized with a strong egg serum, and ate a piece of b r e a d t h a t h a d a little shiny glaze of egg white on the
~58
THE JOURNAL OF PEDIATRICS
crust: in t w e n t y minutes a wheal developed on the sensitized site. Wheat.--Wheat sensitivity is imp o r t a n t in m a n y eezematous babies, a~d in not a few older children. A positive scratch test is usually significant. W h e a t is not easy to deal with, for the year-old child is a great cracker eater, and the older child depends so much on all sorts of wheatcontaining foods. I t is important to explain to the mother exactly what wheat flour is, and w h a t articles of diet contain it. 9This statement may sound superfluous, but it is b y no means so. Some women do not even know t h a t b r e a d is made o~ wheat, others think t h a t the only wheat-containing b r e a d is whole wheat bread, m a n y women do not know that graham crackers are made f r o m wheat, and so on ad nauseam. F o r babies the " H a p p y T a p p y " * crackers are excellent. T h e y contain tapioea flour, apple juice, and dried milk. The trouble with them is that they are no good for babies who are sensitive to milk as well as to wheat. "l~y-I(risp"~ wafers serve the same purpose. They are swallowed better if they are spread with butter and apple jelly. Practically all rye breads contain wheat. F o r the older child, the mother can learn to make corn cake, biscuits from rice flour, or sweetened cookies from either of these or from soybean flour. I have been t r y i n g for years to induce one of the largest manufacturers of infant loods to supply sweetened crackers made from rice, oat, barley, and corn flour, with no luck at all. There is need for such crackers. Tomato Juice. Tomato should never be given to any child with atopie *Nialtex Co., ]~urlington, Vt. ~Ralston P u r i n a CO., St. Louis, Mo.
dermatitis, Skin tests to tomato are uncommon, but for some u n k u o w n reason it produces skin rashes with great frequency, possibly due to the pigment it contains, possibly due to w h a t e v e r it is t h a t gives it its characteristic taste. Orange Juiee.--It is common for the mother to notice that the baby "breaks out" 'if orange juice is given. I t is probably best to remove it from the diet of all infants who have atopie dermatitis, for orange juice is of little or no value to a baby except as an antiscorbutie, and if he is taking any "multivitamin" drops he is getting an adequate amount of vitamin C. I f he is not, it is a simple matter to give him some aseorbie acid. Positive scratch tests to orange are uncommon: in 300 cases there were only four. In a series of twenty-three tested by the intraeutaneous method, however, there were eight slightly positive tests. Sensitivity to orange is almost always of low d e g r e e - - I have" seen one 4-year-old child, however, who was exquisitely sensitive to it, and who had an enormous positive scratch test. There are in orange juice three substances which may produce allergic symptoms : 1. The protein of the juice 2. The protein of t h e seed 3. The peel oil
The relative importance of these is not entirely clear. In most commereiMly prepared orange juice there is plenty of chance for peel oil and seed protein to be present. Bib e canned orange juice contains no seed protein and no peel oil, and in five infants who had allergic symptoms from ordinary orange juice, R a t h e r and his CO*Bib
Corporation, Lakeland,-Fla.
HILL:
T R E A T M E N T OF E C Z E M A
workers 2~ found that the Bib juice was tolerated. They do not say what sort of allergic symptoms were present. I have had no personal experience with it. I n orange juice, as it is prepared at home, it is not likely that any seed protein is present, and the amount of peel oil must be very small, although possibly enough to produce symptoms. The oil of orange peel in addition to being a sensitizer (its active principle is dextrolimonene, which is closely allied to turpentine) is a p r i m a r y irritant, and dermatitis of the fingers from it has been known for a long time and is common in adults whose work in2~l~atner, B r e t , U n t r a e h t , S a m u e l , M a l o n e H. John, a n d Retsina, M a r y : A l l e r g e n i e i t y of O r a n g e S t u d i e d in M a n , J. PEDIAT. 43: 421, 1953.
659
volves the cutting up of oranges. It seems likely that if sensitivity to orange peel oil existed in infants it would be epidermal r a t h e r than dermal, and would therefore not be demonstrated by scratch or intracntaneous tests. Sensitivity to the juice protein or to the seed protein is shown b y urticarial type scratch or intraeutaneous tests. R a t n e r and his co-workers 2~ in a painstaking s t u d y showed clearly that the protein of orange juice is not readily absorbed from the digestive tract in an unsplit antigenic condition, and said, "What we call allergy to citrus fruit may in truth not be allergy in all instances, but irritation from the peel." This seems likely. (To be concl~tded.)