ANTISTREPTOLYSIN CONTENT OF THE SERA OF NORMAL INFANTS AND CHILDREN J. E.
GORDO!N',M.D., A~D JOH~ H. JANI~EY, M.D. N E W YORK, N . Y .
examination of the blood for content of antistreptolysin has in T HE recent years received increasing clinical and epidemiologie application in diseases of man caused by beta hemolytic streptococci. Although the test is most commonly used as a diagnostic aid, some clinics have found it of help in prognosis, through ability to determine the probable presence of septicemia in severely ill persons several days in advance of isolation of streptococci from the blood. A low antistreptolysin titer in the presence of a severe streptococcus infection, or a pronounced decline after a previously observed high value, often coincides with blood stream invasion. In epidemiologic surveys the reaction offers the possibility of distinguishing between carriers of hemolytic streptococci and persons having actual infection in atypical, subclinical, or latent form. The practical application of the test rests on the fact that hemolytic streptococci produce a soluble hemolysin, which is antigenic, giving rise in experimental animals to an antistreptolysin.1 Antistreptolysin can be demonstrated in the blood of human beings after spontaneous infection, by a simple technical procedure involving neutralization of the antistreptolysin by measured quantities of standardized streptolysin. The reaction is specific, in that diseases caused by other infectious agents are not followed by an appreciable increase in ant~strepto]ysin.~ The formation of antistreptolysin is a characteristic of infection by all members of a given group of streptococci, for instance, Group A in diseases of man. The test does not differentiate infections with various serologic types within the group. Antistreptolysin seemingly has no important part in resistance to hemolytic streptococcus disease, although it serves as a useful index of infection. Streptococcus antitoxin and antistreptolysin are independent antibodies and do not necessarily parallel each other in their development during the course of acute streptococcus infection.3 Adequate knowledge of the usual level of antistreptolysin in sera of normal persons is essential to interpretation of clinical and epidemiologic results. Todd ~ considers the normal value to range between 20 and 100 units per cubic centimeter. Coburn and PaulP have reported a median value of 83.3 units for normal persons; they state that 75 per cent of the people have titers of less than 100 units, 20 per cent show values from 100 to 200 units, and about 5 per cent are in excess of 200 units. Longcope6 reports 50 units as being the usual level for adults resident in a southern city. The s t u d i e s on w h i c h t h i s r e p o r t is b a s e d w e r e m a d e u n d e r t h e a u s p i c e s of t h e Int e r n a t i o n a l H e a l t h Division of t h e R o c k e f e l l e r F ounda t i on, in c oope ra t i on w i t h t he I n s t i t u t e of H y g i e n e , Iasi, ~ u m a n i a . 587
588
THE JOURNAL OF PEDIATRICS
Practically all reports on the mean antistreptolysin titer of normal persons have dealt with adults, and singularly little information is available in respect to normal children, despite the fact that in this age group streptococcus infections are especially important and common. The best observations are those of Lippard and Johnson, 7 who report for infants aged less than 17 months, an average titer of 24 units, and for those older than 17 months, a titer of 66 units. These values were derived from the first examination of blood from siek ehildren suffering from various streptoeoeeal illnesses. They cannot, therefore, be considered as representing observations on strictly normal children, although it is well known that in streptococcus disease the antistreptolysin titer ordinarily does not increase until the second or third week of disease. Wilson, Wheeler, and Leask 8 have reported a correlation between antistreptolysin titer and age. This does not seem to hold for newborn infants; Coburn and Pauli 9 reported that 80 per cent of thirty-seven bloods from the umbilical cord contained more antistreptolysin than the corresponding maternal bloods. A comprehensive study of antistreptolysin in the bloods of normal people has had as its end an effort to determine the usefulness of antistreptolysin determinations in the study of epidemics of streptococcus infection. For clinical application to the individual patient, an upward movement of the curve is of itself significant It has developed, however, that well-defined differences exist between the mean antistreptolysin titer for children as compared with that for adults, a correlation which enters into clinical interpretation. The pertinent features of a study of normal children of ages ranging from birth to 14 years are reported. IVIETHODS
All persons included in the study were in good health at the time sera were obtained. These studies were made in Rumania, and sera were obtained by personal visits to the homes of the people. Conditions are rarely so favorable for obtaining samples of blood from average healthy children, especially those in the younger age groups. All were living in a normal everyday environment. None were attending outpatient departments or well-baby clinics, or were resident in institutions. Most of the sera for deteITnination of antistreptolysin were obtained from blood drawn by venepuncture. Samples from the newborn infants represent blood taken from the umbilical cord at the .time of birth. With very young infants it was sometimes neeessary to take blood from the longitudinal sinus. The examinations were usually made within the subsequent two or three days, the sera being stored in the icebox without preservative, in tubes stoppered with paraffined corks. The technique of the antistreptolysin reaction employed in these studies has been previously described2 ~
GORDON AND J A N N E Y :
ANTISTREPTOLu
CONTENT OF SERA
589
RESULTS
The normal median level of antistreptolysin for women of childbearing age, that is, 15 to 49 years, was determined to be 62.5 units. Sera from twenty-nine mothers and their newborn infants were then examined, all samples of blood having been taken at the time of parturition. We wished to determine whether there was a regular relationship between the antistreptolysin titer of the infant and that of the mother. The actual value might conceivably be close to that of the adult, through passively transferred immunity, or it might be lowered or even absent. Unexpectedly, the antistreptolysin content of the blood of newborn infants was consistently higher than that of their mothers. The results are presented in Table I. TABLE ANTISTI~EPTOLu
TITEI~S OF
TWENTY-~INE
MOTHERS
AND
THEIR
I~ESPECTIVE
NEWBORN INFANTS
(units per cubiv centimeter) IV[OTHERS 10 31.7 31.7 50 50 50 50 50 62.5 62.5 62.5 62,.5 62.5 62.5 62.5 62..5 62..5 62,.5 62,.5 62,.5 62~.5 83.3 83.3 IO0 100 125 159 200 250 Median = 62.5
NEWBORN
INFANTS
3:1.7 31.7 62.5 4 50 62.5 83.3 83.3 50 62.5 62.5 62.5 83.3 83.3 83.3 100 100 125 125 125 159 100 159 125 159 100 2OO 2OO 312 Median = 83.3
In Mmost all instances the infant's antistreptolysin titer paralleled that of the mother. With few exceptions, if the mother had a low titer, the value for the infant was also relatively low. No instance was found in which the mother had a relatively high titer and the infant a normal or low value. The median antistreptolysin titer for mothers in this series was 62.5 units, and for infants, 83.3 units. The antistreptolysin titer of newborn infants approximated the highest value found for any subsequent age group, that of persons aged 15
590
THE JOURNAL OF PEDIATRICS
to 19 years. There was a r a p i d and progressive decline in titer following birth, so that the mean for infants in the first three months of life was about 20 units. The low point for all age groups was reached at age 3 to 5 months when the mean titer corresponded to 10 units per cubic centimeter. Thereafter, a progressive rise was noted, reaching a m a x i m u m in adolescence. D u r i n g the second six months of life, the low value of the second trimester practically doubled, to give an average value of 20 units b y the time the infants had attained one year of age. TABLE 1]: ANTISTREFTOLu
IN ~ERA OF HEALTI-IY CHILDEEN~ BY AGE
NO. OF CASES
AGE
Newborn 1 day- 2 too. 3- 5 t o o . 6-11 mo. 1 yr. 2 yr. 3 yr. 4 yr. 5- 9 yr. 10-14 yr. 15-19 yr.
OBSERVED ANTISTREPTOLYSIN VALUES, U N I T S PER C.C. MINIMU:~r
4 4 2 2 4 8 12.5 8 12.5 16.0 40.0
29 16 17 32 41 38 ]8 20 165 174 39
]YfAXIMUM
g E D I A N TITER
MEAN TITER
312 50 159 250 250
83.3 25.0 10.0 20,0 40.0
82.65 + 1.10 19.11_+1.13 10.28 _+1.2,4 20.39 + 1.13 34.21 • 1.12 57.27 • 1.09 62.30 • 1.11 71.62 • 1.10 75.65 • 1.03 79.86 • 1.03 86.37 • 1.08
260
62.5
200 200 312 833 312
62.5 83.3 83.3 83.3 83.3
LOG.OF
TITE~5
1.90
--
1.80
--
1.70 --
1.6O
--
1.50 --
I 40
1.30
--
-
-
1.20 --
I, i o - -
I.O0
--
AC~
I
i
0
I
I 2
1 3
I 4
i
~
5
6
r 7
I
8
9
r
t
t
I
I
~0
~2
13
14
15
IN YEA~S
Fig. 1.--Antistreptolysin
content
of sera
of healthy
children.
Mean
titers by age from
newborn to 14 years.
D u r i n g the second year of life the antistreptolysin content again increased markedly, so that the mean value was now 34 units, and thus
GORD0~ AI~D JANI~TEu
ANTISTREPTOLYSIN CONTENT OF SERA
591
continued during the third year. By the end of the fourth year, the mean titer was found to be in approximate agreement with the mean for all ages. Titers for the age group from 5 to 9 years old showed some increase over those characteristic for children aged 4 years. Maximum values were attained during ages 10 to i9 years, when the antistreptolysin titer approximated that at birth. The progressive changes described are illustrated in Fig. 1. s u ~ A ~ z AND CO-'~CLUSm~S The mean antistreptolysin titer of sera from newborn infants is higher than at any other time in life. It is greater than the average titer of the mothers of the infants. For individual infants, the value is related to that of the mother, being regularly high for infants with mothers of high titer and low when the mother's titer is low. The high titer of the newborn infant, presumably passively acquired, declines sharply to reach a low point at ages from 3 to 6 months. Thereafter a progressive increase occurs, so that by the age of 15 years, the titer again approximates that at birth. Presumably this is due to actively acquired immunity, the result of intereurrent hemolytic streptococcus infection. These measurements of the antistrepto]ysin titer of 550 healthy inrants and children in Rumania give additional evidence of the time elements in infection and in natural immunity response of the human being to experience with a common type of infectious agent, beta hemolyric streptococci. It would be expected that the results would be essentially the same in the northern United States. In southern states the shape of the curve should be the same, but the values in time and degree might well be different. The mean normal antistreptolysin content of the blood of young children differs significantly from that of adults. Correction for this differenee is necessary in the interpretation of clinical and epidemiologic data. It remains to be determined if young children with low normal antistreptolysin titers react to known infection in the same manner, in respect to degree and rapidity of antistreptolysin response, as do older children, adolescents, and adults. REFERENCES ]. 2. 3. 4. 5. 6. 7. 8.
Todd, E. W.: J. Exper. Med. 55: 267, 1932. Todd, E. W.: J. Fath. & Baet. 39: 299, 1934. Todd, E. W., Lauren]t, L. J. M., and iqill, i~. ~. : J. Path. & Bact. 36: 201, ]933. Todd, E. W.: J. Exper. Path. 13: 248, 1932. Coburn, A. ~., and Pauli, 1~. H.: J. Exper. 1V[ed. 56: 651, ]932. Longcope, W. T.: J. Clin. Investigation 15: 269, 1936. Lippard, V. W., and Johnson, P.: Am. J. Dis. Child. 49: 1411, 1935. Wilson, M. G., Wheeler, G. W.~ and Leask, M. M. : Proc. Soc. Exper. Biol. & Meal. 31: 1001, 1934. 9. Coburn, A. F., and Pauli, R. ]~.: J. Clin. Investigation 14: 769, 1935. 10. Gordon, J. E., and Balteanu, E. ~ . : La r~action de l'antistreptolysine, Arch. roumaines de path. expdr, et de microbioL 10: 24, 1937.