Hepatitis
B
Antigen
in Infants
Born to Mothers With Chronic Antigenemia in Taiwan
Hepatitis
B
Karl E. Anderson, MD; Cladd E. Stevens, MD; Julia J. Tsuei, MD; Wy-Chan Lee, MD; Shih-Chien Sun, MD; R. Palmer Beasley, MD
Hepatitis B antigen (HB Ag) was deby complement fixation (CF) in serum samples of 7.5% of 1,106 pregnant Chinese women tested in Taipei, Taiwan. HB Ag persisted in all but one of 42 women followed for 1 to 18 months (average, nine months) after delivery, and 27 of the 43 infants (63%) born to those women became antigen-positive. Persistence of the antigen was more common than transient or intermittent antigenemia. Twelve had antigenemia when first tested, while 15 later developed antigenemia, usually during the first six months of life. Only one infant developed antibody to HB Ag (anti-HB Ag), and this occurred after tran\s=b\
tected
Received for publication Sept 23, 1974; accepted Nov 12. From the departments of clinical investigation (Drs Anderson and Lee), microbiology (Drs Stevens and Beasley), and pathology (Dr Sun), US Naval Medical Research Unit No. 2 and the Maternity and Child Center, Veterans' General Hospital, (Dr Tsuei) Taipei, Taiwan, and the Department of Epidemiology and International Health, School of Public Health and Community Medicine, University of Washington, Seattle (Drs Stevens and Beasley). Dr Anderson is now with the Rockefeller University Hospital, New York and Dr Tsuei is now with the Department of Obstetrics and Gynecology, University of Hawaii School of Medicine, Honolulu. The opinions and assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval Service at large. Reprint requests to Publications Office, NAMRU-2, Box 14, APO San Francisco, CA 96263.
sient antigenemia. The HB Ag was found in two of 32 (6%) fathers, and in 18 of 27 (67%) older siblings. The antigen was more common among siblings of antigen\x=req-\ positive than among those of antigen-negative infants. These findings demonstrate that in Taiwan, infants born to mothers who are asymptomatic carriers of HB Ag commonly become infected by hepatitis B (HB) virus. Exposure of infants near the time of birth may be important in maintaining the high, chronic HB Ag carrier rate in Taiwan. (Am J Dis Child 129:1389-1392, 1975)
Hepatitis
Australia
antigen (HB Ag) or antigen is associated
virus infection.1·2 with hepatitis Acute hepatitis, chronic forms of hep¬ atitis, cirrhosis, and malignant hepatoma may occur in some individuals infected by this virus.'4 A chronic, asymptomatic carrier state commonly associated with much less evidence of liver disease also occurs.5-7 The preva¬ lence of chronic HB antigenemia varies considerably throughout the world. Carrier rates are particularly high in some tropical and subtropical countries,1 and in Taiwan the carrier rates have been reported to be 6% to 15%.4-6·' " Such high carrier rates are unexplained, but poor sanitation, poor
nutrition, improperly sterilized nee¬ dles, arthropod vectors, and genetic
factors are possible causes.1·6·10 The HB virus is often transmitted to infants when acute hepatitis de¬ velops in the mother during preg¬ nancy, especially late pregnancy.11-13 Reports of familial clusterings of liver disease and antigenemia around antigen-positive mothers have also suggested the possibilities of maternal-fetal and maternal-in¬ fant transmission." '" However, HB Ag determinations in parents of adult HB Ag carriers in North Amer¬ ica17·18 have not provided evidence that in these locations maternal-in¬ fant transmission is very important in spreading HB virus or in producing chronic carriers. This study was de¬ signed to determine whether or not infants in Taiwan, born to Chinese women who are carriers, commonly develop HB antigenemia. METHODS
During 1972, a total of 1,106 pregnant Chinese women were tested for HB Ag at the time of their initial prenatal visit to the Obstetrics Clinic of the Veterans' Gen¬ eral Hospital, Taipei, Taiwan. Forty-two antigen-positive mothers with their 43 in¬ fants (including a set of twins) consented to be followed up. The length of follow-up
Downloaded From: http://archpedi.jamanetwork.com/ by a Monash University Library User on 06/18/2015
Results of HB
Ag Testing in 43
Cord Blood Infant
Specimens
1-30
31-60
+
61-90 91-120 HB Ag Result + +
121-150 151-180 181-270
>270
+
+
+ _7_+_+_++ + _8_+_+ _9_+_+_ JO_+_+_ + JJ_+_+ + 12_+_+ -_+_ J3_ + 14_+ _-_+ J5_-_+_ + +_+_+_ J6_+ _17_-_+_++ + J8_-_+ _+_ 19_-_+_ 20_-_+_ + _21__+ 22_-_-_+_ 23_-_+_ + +_+ _24_+ +_+ _25_+_ + -
+_+ _26_-_ +_-_ _27__-_-_ 28_-_29_-_-_-_2_ 30_-_ _3J_-_-_-_-_ 32_-_-_-_ 33_-_-_^_ 34_-_-_-_ 35 -
-
-
-
-
-
-
-
-
_-_ 38_39_-_-_ 40 41
~42 ~43
averaged nine months (range, 1 to 18 months) after delivery. Umbilical cord blood samples were available from ten of these deliveries. Other available family members were also tested for Hb Ag, in¬ cluding 32 fathers, 18 older siblings, and 11 other relatives. The HB Ag was detected by complement fixation (CF),19 radioimmunoassay (RIA), or both. Equine antiserum20 was used for CF at an optimal dilution of 1:8 or 1:16, as determined by block titration. A serum CF titer of 1:4 or greater was considered posi-
-
-
Mothers
As in previous studies of apparent¬ ly healthy adults in Taiwan,4·"·8·9 a high carrier rate of Ag was found.
women tested were 83 antigen-posi¬ (7.5%) by CF, tive (CF titer of 1:4 or greater). The Ag was present in all maternal serum samples tested by RIA with a CF titer of 1:4 or greater, in 13 (76%) of 17 serum samples with a CF titer of 1:2, and in 23 (8.6%) of 267 serum samples with a CF titer of less than 1:2. Of the 42 women who returned with their infants, all but one were demonstrated to have chronic anti¬ genemia during follow-up periods of 2 to 19 months. Antigen titers by CF were 1:16 or greater in 36 women, 1:8 in two, 1:4 in three, 1:2 in two, and < 1:2 (positive by RIA only) in one. All mothers with antigen titers of 1:16 or greater were also positive by rheophoresis. One mother had a his¬ tory that was consistent with acute hepatitis during a previous preg¬ nancy, but no other mothers were jaundiced or had other features of acute hepatitis during the study. Twelve of 37 mothers tested had mild SGOT elevation (44 to 156 KU).
Of the 1,106 pregnant
Cord Blood
Samples
Three of the ten cord blood
samples antigen-positive by RIA, and each of the corresponding three in¬ fants developed antigenemia. One of these infants (No. 4, Table) was posi¬ tive when first tested during the sec¬ were
-
36 37
RESULTS
Antigenemia
Age, Days ,-»-, +
1 2
Infants Whose Mothers Had HB
^~
.
tive for HB Ag. All such serum samples were also positive by RIA. When the CF ti¬ ter was sufficiently high ( > 1:16), rheophoresis21 was used to confirm the presence of HB Ag. All serum samples from the 43 infants were tested for anti-HB Ag by pas¬ sive hemagglutination and titers of 1:8 or greater were considered positive. Serum glutamic oxaloacetic transaminase (SGOT) levels were measured in 37 mothers and in six antigen-positive infants with a twochannel autoanalyzer. Values over 40 Kar¬ inen units (KU) were considered elevated.
ond month of life. The other two (No. 14 and 25) had intervening negative serum samples and developed anti¬ genemia two to six months after birth. Three of the seven infants with negative cord blood tests also became
antigen-positive.
Infants
The HB Ag was found at least once in 27 (No. 1 to 27, Table) (63%) of the 43 infants studied. Antigen titers were 1:16 or greater in 23 of these (all except No. 3, 6, 15, and 27) and the presence of HB Ag was confirmed by
rheophoresis. Antigenemia persisted in 18 of the 21 infants in whom
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one or
more
blood samples were available af¬
ter the first positive specimen (followup period was 2 to 12 months after
the first positive specimen); the other three (No. 5, 6, and 27) were tran¬
siently or intermittently HB Ag-posi-
tive. Jaundice and other signs of hep¬ atitis were not observed. Mild SGOT elevation (43 to 73 KU) appeared to be present in the six antigen-positive babies tested. However, more SGOT determinations in HB Ag-positive in¬ fants, and comparisons with HB Agnegative infants are needed. Infants No. 1 to 12 were positive for HB Ag when first tested. Half of these, however, were not bled until after 2 months of age. Fifteen in¬ fants (No. 13 to 27) initially had no detectable HB Ag (even by RIA), but
subsequently developed antigenemia. This appeared to occur most com¬ monly between 1 and 4 months of age (Table). In all but three of the 27 anti¬ gen-positive infants, HB Ag was first
detected within the first six months of life (Table). All specimens from 16 infants (No. 28 to 43) were antigen-negative. Al¬ though only half of these were bled before 2 months of age, it seems un¬ likely that early transient anti¬ genemia was missed. We seldom ob¬ served transient antigenemia in this study, and none of the babies who re¬ mained HB Ag-negative developed anti-HB Ag. Most of these 16 babies (all but four) were tested for HB Ag and were negative during the second six months of life. Combining the data from all 43 in¬ fants revealed that antigenemia oc¬ curred in one of ten (10%) infants tested at 1 to 30 days of age; eight of 29 (28%) tested at 31 to 90 days; 20 of 33 (61%) tested at 91 to 180 days; and 17 of 31 (55%) tested after 180 days. These combined data also indicate that the prevalence of HB anti¬ genemia increases during the first six months of life. Anti-HB Ag was found in only one infant (No. 6). This baby had tran¬ sient antigenemia, and anti-HB Ag (titer >1:16) developed after HG Ag was no longer detectable. Other
Serum
Family Members
samples
from 32 fathers
tested and only two (6%) con¬ tained HB Ag. In contrast, 18 of 27 (67%) older siblings of the study in¬ fants were positive. Furthermore, HB Ag-positive infants had a higher pro¬ portion (14 of 17) of positive siblings than did antigen-negative infants (three of ten). Two of 11 other rela¬ tives, a maternal aunt and a maternal grandmother, were positive for HB were
Ag.
COMMENT
This study demonstrates that, in Taiwan, infants born to mothers who are chronic HB Ag carriers fre¬ quently become antigen-positive dur¬ ing the first six months of life. Of 43 infants followed up, 63% were posi¬
tive at least once, and most had per¬ sistent antigenemia. In view of the known incubation period of HB virus2 and the fact that many of these infants were initially antigen-nega¬ tive only to become positive several months after birth, the perinatal pe¬ riod seems a likely time for infection to have occurred. Contact with mater¬ nal blood is especially great during la¬ bor and delivery, and infection could be acquired at that time through small skin abrasions, swallowed blood, or inapparent leakage of ma¬ ternal blood across the placenta. Such leakage during labor and delivery could explain our observation that two infants (No. 14 and 25) had posi¬ tive cord blood samples followed by negative peripheral blood specimens, and then later developed anti¬
genemia. Although transmission of HB virus
from carrier mothers to their infants seems a very likely explanation for our findings, in a highly endemic area it is difficult to exclude other sources of infection. Injections are frequently given for minor illnesses in Taiwan, at times with improperly sterilized needles. Because these babies were born and followed up at a hospital where disposable or properly ster¬ ilized needles are used, injections are an unlikely source in this study. Fa¬ thers were usually antigen-negative and so are also unlikely to be impor¬ tant sources. Antigen-positive sib¬ lings were more commonly found in families of infants who developed
HB antigenemia, and some may have transmitted the virus to the infants. But it is also possible that many of these antigen-positive siblings have been carriers since early infancy. Further family studies are needed in Taiwan to see if HB virus commonly spreads among siblings and to deter¬ mine if some carrier mothers more consistently transmit the virus to their infants. Schweitzer et al11"" have demon¬ strated in a less endemic area that ac¬ quisition of the HB Ag carrier state is common in infants born to women who have acute type hepatitis, es¬ pecially if it occurs in the third tri¬ mester of pregnancy or soon after de¬ livery. But in studies other than ours, infants born to asymptomatic carrier mothers have seldom been shown to develop antigenemia. Skinhoj et al22 in Denmark followed up 36 babies for four to five months, retested 16 of these by immunodiffusion at 10 to 12 months of age, and none became anti¬ gen-positive. In Greece,23 transient antigenemia was found in only 2 of 11 infants. In Pakistan,24 1 of 18 infants tested by immunodiffusion or counterelectrophoresis became antigenpositive. Schweitzer et al" in Los An¬ geles reported that only 1 of 21 infants (followed up for three months) whose mothers were chronic carriers developed antigenemia as measured by RIA. A report from Thailand,23 which like Taiwan has a high carrier rate, includes 14 women who had antigenemia (probably
pregnancy; during the first six months of life, none of their infants' serum samples was an¬ tigen-positive by immunodiffusion. Length and frequency of infant follow-up and the sensitivity of meth¬ ods used to detect HB Ag may be im¬ portant in comparing studies of in¬ fants born to chronic carrier mothers. But there may be true geographic dif¬ ferences in the mechanisms and fre¬ quencies of HB virus transmission to infants, and in their response to in¬ fection. Our findings in Taiwan, and those of others elsewhere, concerning infants whose mothers are chronic carriers need to be confirmed, and then extended with regard to factors in infancy that might influence HB
chronic) during
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virus transmission and development of the chronic carrier state.
This investigation was supported in part by the Bureau of Medicine and Surgery, Navy Department, for Work Unit MR041.09.010114A3GX. V.J. Cabasso, Cutter Laboratories, provided equine antiserum to HBAg. The physicians and nurses of the Maternity and Child Center of Veterans' General Hospital, the public health nurses of NAMRU-2, George S. Irving, Howard S. Berg, MD, Raymond H. Watten, MD, and the Data Processing Department, US Naval Research Unit No. 2 provided assist¬ ance.
T.T. Chiù and others
provided technical assist¬
ance.
References 1. Blumberg BS, Sutnick AI, London WT: Australia antigen as a hepatitis virus: Variation in host response. Am J Med 48:1-8, 1970. 2. Krugman S, Giles JP: Viral hepatitis: New light on an old disease. JAMA 212:1019-1029, 1970. 3. Prince AM: Role of serum hepatitis virus in chronic liver disease. Gastroenterology 60:913\x=req-\ 921, 1971. 4. Tong MJ, Sun SC, Schaeffer BT, et al: Hepatitis-associated antigen and hepatocellular carcinoma in Taiwan. Ann Intern Med 75:687-691,
60 Years
1971. 5. Reinicke V, Dybkjaer E, Poulsen H, et al: A study of Australia-antigen-positive blood donors and their recipients with special reference to hepatic histology. N Engl J Med 286:867-870,1972. 6. Anderson KE, Sun SC, Berg HS, et al: Liver function and histology in asymptomatic Chinese military personnel with hepatitis B antigenemia. Am J Dig Dis 19:693-703, 1974. 7. Sun SC, Anderson KE, Hsu CP, et al: Hepatocellular ultrastructure in asymptomatic hepatitis B antigenemia. Arch Pathol 97:373-379, 1974. 8. Shih PL, Chang CK, Sung JL: Hepatitis-associated antigen and antibody in Taiwan. J Formosan Med Assoc 70:697-706, 1971. 9. Hsia S, Chen SC, Shen FC, et al: Australia antigen and antibody in blood donors and patients with blood disorders. Transfusion 13:89\x=req-\ 93, 1973. 10. Brotman B, Prince AM, Godfrey HR: Role of arthropods in transmission of hepatitis-B virus in the tropics. Lancet 1:1305-1308, 1973. 11. Schweitzer IL, Wing A, McPeak C, et al: Hepatitis and hepatitis-associated antigen in 56 mother-infant pairs. JAMA 220:1092-1095,1972. 12. Schweitzer IL, Dunn AEG, Peters RL, et al: Viral hepatitis B in neonates and infants. Am J Med 55:762-771, 1973. 13. Schweitzer IL, Mosley JW, Ashcavai M, et al: Factors influencing neonatal infection by hepatitis B virus. Gastroenterology 65:277-283,1973. 14. Ohbayashi A, Okochi K, Mayumi M: Familial clustering of asymptomatic carriers of Australia antigen and patients with chronic liver disease or primary liver cancer. Gastroenterology 62:618-625, 1972. 15. Wright R, Perkins JR, Bower RD, et al:
Ago in AJDC Duodenal Ulcer in
Since 1909, numerous reports have appeared which have substantiated the frequent occurrence of duodenal ulcers in infancy. The etiology of gastric and duodenal ulcer is still a much debated question. In ten out of fourteen ulcers from two series diplococci were found in the ulcer base, and in all eight ulcers of our present series diplococci were found in the ulcer in such numbers and in such a position that they presumably are of etiologic . In one of the cases a significance. Streptococcus viridans was isolated from the duodenal ulcer, which on injection into rabbits and dogs localized in the pyloric end of the stomach and duodenum and there produced hemorrhages and ulcerations. Rosenow4 has recently shown that from .
.
.
.
.
.
.
.
.
.
.
.
.
Cirrhosis associated with Australia antigen in an infant who acquired hepatitis from her mother. Br Med J 4:719-721, 1970. 16. Bancroft WH, Warkel RL, Talbert AA, et al: Family with hepatitis associated antigen: Spectrum of liver pathology. JAMA 217:1817\x=req-\ 1820, 1971. 17. Szmuness W, Prince AM, Hirsch RL, et al: Familial clustering of hepatitis B antigen. N Engl J Med 289:1162-1166, 1973. 18. Berris B, Wrobel DM, Sinclair JC, et al: Hepatitis B antigen in families of blood donors. Ann Intern Med 79:690-693, 1973. 19. Purcell RH, Holland PV, Walsh JH, et al: A complement-fixation test for measuring Australia antigen and antibody. J Infect Dis 120:383\x=req-\ 386, 1969. 20. Cabasso VJ, Nieman R, Schroeder DD, et al: Preparation and standardization of an Australia antigen antibody of equine origin. Appl Microbiol 21:1017-1023, 1971. 21. Jambazian A, Holper JC: Rheophoresis: A sensitive immunodiffusion method for detection of hepatitis associated antigen. Proc Soc Exp Biol Med 140:560-564, 1972. 22. Skinhoj P, Oleson H, Cohn J, et al: Hepatitis-associated antigen in pregnant women. Acta Pathol Microbiol Scand 80:362-366, 1972. 23. Papaevangelou GJ: Hepatitis B in infants. N Engl J Med 288:972, 1973. 24. Aziz MA, Khan G, Khanum T, et al: Transplacental and postnatal transmission of the hepatitis-associated antigen. J Infect Dis 127:110\x=req-\ 112, 1973. 25. Punyagupta S, Olson LC, Harinasuta U, et al: The epidemiology of hepatitis B antigen in a high prevalence area. Am J Epidemiol 97:349\x=req-\ 354, 1973.
.
.
.
.
.
.
.
duodenal and
eration,
a
Infancy:
An Infectious Disease
gastric ulcers removed at op-
streptococcus viridans
can
be
constantly isolated, which when injected intravenously into dogs and rabbits will tend to localize in the stomach and duode¬ num and there produce first hemorrhage and later ulcers. In explanation of this phenomenon he assumes that the strepto¬ coccus producing duodenal ulcer finds in the duodenum conditions peculiarly favor¬ able for its development, and therefore tends to localize there. We can assume that at times the streptococcus takes on characteristics which make it tend to local¬ ize in the duodenum when infecting an in¬ fant. We have thus a working hypothesis which explains very readily the epidemic appearance of duodenal ulcers; namely, that we have an infection with a very defi¬ nite organism, which, carried to the infant .
.
.
...
through the digestive
tract or the air passages, tends to localize in the duodenum. This same tendency has been shown by Rosenow to be true of the streptococcus isolated from cases of rheumatic fever, endocarditis, appendicitis and herpes zoster, when injected into ani¬ mals. Not only is the organism specific when isolated from the characteristic le¬ sion, but usually when isolated from the portal of entry, such as the tonsils, an al¬ veolar abscess, etc. Rosenow has quite con¬ clusively established the fact that gastric and duodenal ulcer of the adult are the re¬ sult of an infection with a streptococcus of particular virulence. That this holds good for duodenal ulcers of the infant also is .—"Duodenal Ul¬ very definitely shown. cer in Infancy: An Infections Disease," L. Gerdine, MD, H. F. Helmholz, MD, Chicago
either
through
Downloaded From: http://archpedi.jamanetwork.com/ by a Monash University Library User on 06/18/2015
.
.
.
.
.
B
Antigen
in Infants
Born to Mothers With Chronic Antigenemia in Taiwan
Hepatitis
B
Karl E. Anderson, MD; Cladd E. Stevens, MD; Julia J. Tsuei, MD; Wy-Chan Lee, MD; Shih-Chien Sun, MD; R. Palmer Beasley, MD
Hepatitis B antigen (HB Ag) was deby complement fixation (CF) in serum samples of 7.5% of 1,106 pregnant Chinese women tested in Taipei, Taiwan. HB Ag persisted in all but one of 42 women followed for 1 to 18 months (average, nine months) after delivery, and 27 of the 43 infants (63%) born to those women became antigen-positive. Persistence of the antigen was more common than transient or intermittent antigenemia. Twelve had antigenemia when first tested, while 15 later developed antigenemia, usually during the first six months of life. Only one infant developed antibody to HB Ag (anti-HB Ag), and this occurred after tran\s=b\
tected
Received for publication Sept 23, 1974; accepted Nov 12. From the departments of clinical investigation (Drs Anderson and Lee), microbiology (Drs Stevens and Beasley), and pathology (Dr Sun), US Naval Medical Research Unit No. 2 and the Maternity and Child Center, Veterans' General Hospital, (Dr Tsuei) Taipei, Taiwan, and the Department of Epidemiology and International Health, School of Public Health and Community Medicine, University of Washington, Seattle (Drs Stevens and Beasley). Dr Anderson is now with the Rockefeller University Hospital, New York and Dr Tsuei is now with the Department of Obstetrics and Gynecology, University of Hawaii School of Medicine, Honolulu. The opinions and assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval Service at large. Reprint requests to Publications Office, NAMRU-2, Box 14, APO San Francisco, CA 96263.
sient antigenemia. The HB Ag was found in two of 32 (6%) fathers, and in 18 of 27 (67%) older siblings. The antigen was more common among siblings of antigen\x=req-\ positive than among those of antigen-negative infants. These findings demonstrate that in Taiwan, infants born to mothers who are asymptomatic carriers of HB Ag commonly become infected by hepatitis B (HB) virus. Exposure of infants near the time of birth may be important in maintaining the high, chronic HB Ag carrier rate in Taiwan. (Am J Dis Child 129:1389-1392, 1975)
Hepatitis
Australia
antigen (HB Ag) or antigen is associated
virus infection.1·2 with hepatitis Acute hepatitis, chronic forms of hep¬ atitis, cirrhosis, and malignant hepatoma may occur in some individuals infected by this virus.'4 A chronic, asymptomatic carrier state commonly associated with much less evidence of liver disease also occurs.5-7 The preva¬ lence of chronic HB antigenemia varies considerably throughout the world. Carrier rates are particularly high in some tropical and subtropical countries,1 and in Taiwan the carrier rates have been reported to be 6% to 15%.4-6·' " Such high carrier rates are unexplained, but poor sanitation, poor
nutrition, improperly sterilized nee¬ dles, arthropod vectors, and genetic
factors are possible causes.1·6·10 The HB virus is often transmitted to infants when acute hepatitis de¬ velops in the mother during preg¬ nancy, especially late pregnancy.11-13 Reports of familial clusterings of liver disease and antigenemia around antigen-positive mothers have also suggested the possibilities of maternal-fetal and maternal-in¬ fant transmission." '" However, HB Ag determinations in parents of adult HB Ag carriers in North Amer¬ ica17·18 have not provided evidence that in these locations maternal-in¬ fant transmission is very important in spreading HB virus or in producing chronic carriers. This study was de¬ signed to determine whether or not infants in Taiwan, born to Chinese women who are carriers, commonly develop HB antigenemia. METHODS
During 1972, a total of 1,106 pregnant Chinese women were tested for HB Ag at the time of their initial prenatal visit to the Obstetrics Clinic of the Veterans' Gen¬ eral Hospital, Taipei, Taiwan. Forty-two antigen-positive mothers with their 43 in¬ fants (including a set of twins) consented to be followed up. The length of follow-up
Downloaded From: http://archpedi.jamanetwork.com/ by a Monash University Library User on 06/18/2015
Results of HB
Ag Testing in 43
Cord Blood Infant
Specimens
1-30
31-60
+
61-90 91-120 HB Ag Result + +
121-150 151-180 181-270
>270
+
+
+ _7_+_+_++ + _8_+_+ _9_+_+_ JO_+_+_ + JJ_+_+ + 12_+_+ -_+_ J3_ + 14_+ _-_+ J5_-_+_ + +_+_+_ J6_+ _17_-_+_++ + J8_-_+ _+_ 19_-_+_ 20_-_+_ + _21__+ 22_-_-_+_ 23_-_+_ + +_+ _24_+ +_+ _25_+_ + -
+_+ _26_-_ +_-_ _27__-_-_ 28_-_29_-_-_-_2_ 30_-_ _3J_-_-_-_-_ 32_-_-_-_ 33_-_-_^_ 34_-_-_-_ 35 -
-
-
-
-
-
-
-
-
_-_ 38_39_-_-_ 40 41
~42 ~43
averaged nine months (range, 1 to 18 months) after delivery. Umbilical cord blood samples were available from ten of these deliveries. Other available family members were also tested for Hb Ag, in¬ cluding 32 fathers, 18 older siblings, and 11 other relatives. The HB Ag was detected by complement fixation (CF),19 radioimmunoassay (RIA), or both. Equine antiserum20 was used for CF at an optimal dilution of 1:8 or 1:16, as determined by block titration. A serum CF titer of 1:4 or greater was considered posi-
-
-
Mothers
As in previous studies of apparent¬ ly healthy adults in Taiwan,4·"·8·9 a high carrier rate of Ag was found.
women tested were 83 antigen-posi¬ (7.5%) by CF, tive (CF titer of 1:4 or greater). The Ag was present in all maternal serum samples tested by RIA with a CF titer of 1:4 or greater, in 13 (76%) of 17 serum samples with a CF titer of 1:2, and in 23 (8.6%) of 267 serum samples with a CF titer of less than 1:2. Of the 42 women who returned with their infants, all but one were demonstrated to have chronic anti¬ genemia during follow-up periods of 2 to 19 months. Antigen titers by CF were 1:16 or greater in 36 women, 1:8 in two, 1:4 in three, 1:2 in two, and < 1:2 (positive by RIA only) in one. All mothers with antigen titers of 1:16 or greater were also positive by rheophoresis. One mother had a his¬ tory that was consistent with acute hepatitis during a previous preg¬ nancy, but no other mothers were jaundiced or had other features of acute hepatitis during the study. Twelve of 37 mothers tested had mild SGOT elevation (44 to 156 KU).
Of the 1,106 pregnant
Cord Blood
Samples
Three of the ten cord blood
samples antigen-positive by RIA, and each of the corresponding three in¬ fants developed antigenemia. One of these infants (No. 4, Table) was posi¬ tive when first tested during the sec¬ were
-
36 37
RESULTS
Antigenemia
Age, Days ,-»-, +
1 2
Infants Whose Mothers Had HB
^~
.
tive for HB Ag. All such serum samples were also positive by RIA. When the CF ti¬ ter was sufficiently high ( > 1:16), rheophoresis21 was used to confirm the presence of HB Ag. All serum samples from the 43 infants were tested for anti-HB Ag by pas¬ sive hemagglutination and titers of 1:8 or greater were considered positive. Serum glutamic oxaloacetic transaminase (SGOT) levels were measured in 37 mothers and in six antigen-positive infants with a twochannel autoanalyzer. Values over 40 Kar¬ inen units (KU) were considered elevated.
ond month of life. The other two (No. 14 and 25) had intervening negative serum samples and developed anti¬ genemia two to six months after birth. Three of the seven infants with negative cord blood tests also became
antigen-positive.
Infants
The HB Ag was found at least once in 27 (No. 1 to 27, Table) (63%) of the 43 infants studied. Antigen titers were 1:16 or greater in 23 of these (all except No. 3, 6, 15, and 27) and the presence of HB Ag was confirmed by
rheophoresis. Antigenemia persisted in 18 of the 21 infants in whom
Downloaded From: http://archpedi.jamanetwork.com/ by a Monash University Library User on 06/18/2015
one or
more
blood samples were available af¬
ter the first positive specimen (followup period was 2 to 12 months after
the first positive specimen); the other three (No. 5, 6, and 27) were tran¬
siently or intermittently HB Ag-posi-
tive. Jaundice and other signs of hep¬ atitis were not observed. Mild SGOT elevation (43 to 73 KU) appeared to be present in the six antigen-positive babies tested. However, more SGOT determinations in HB Ag-positive in¬ fants, and comparisons with HB Agnegative infants are needed. Infants No. 1 to 12 were positive for HB Ag when first tested. Half of these, however, were not bled until after 2 months of age. Fifteen in¬ fants (No. 13 to 27) initially had no detectable HB Ag (even by RIA), but
subsequently developed antigenemia. This appeared to occur most com¬ monly between 1 and 4 months of age (Table). In all but three of the 27 anti¬ gen-positive infants, HB Ag was first
detected within the first six months of life (Table). All specimens from 16 infants (No. 28 to 43) were antigen-negative. Al¬ though only half of these were bled before 2 months of age, it seems un¬ likely that early transient anti¬ genemia was missed. We seldom ob¬ served transient antigenemia in this study, and none of the babies who re¬ mained HB Ag-negative developed anti-HB Ag. Most of these 16 babies (all but four) were tested for HB Ag and were negative during the second six months of life. Combining the data from all 43 in¬ fants revealed that antigenemia oc¬ curred in one of ten (10%) infants tested at 1 to 30 days of age; eight of 29 (28%) tested at 31 to 90 days; 20 of 33 (61%) tested at 91 to 180 days; and 17 of 31 (55%) tested after 180 days. These combined data also indicate that the prevalence of HB anti¬ genemia increases during the first six months of life. Anti-HB Ag was found in only one infant (No. 6). This baby had tran¬ sient antigenemia, and anti-HB Ag (titer >1:16) developed after HG Ag was no longer detectable. Other
Serum
Family Members
samples
from 32 fathers
tested and only two (6%) con¬ tained HB Ag. In contrast, 18 of 27 (67%) older siblings of the study in¬ fants were positive. Furthermore, HB Ag-positive infants had a higher pro¬ portion (14 of 17) of positive siblings than did antigen-negative infants (three of ten). Two of 11 other rela¬ tives, a maternal aunt and a maternal grandmother, were positive for HB were
Ag.
COMMENT
This study demonstrates that, in Taiwan, infants born to mothers who are chronic HB Ag carriers fre¬ quently become antigen-positive dur¬ ing the first six months of life. Of 43 infants followed up, 63% were posi¬
tive at least once, and most had per¬ sistent antigenemia. In view of the known incubation period of HB virus2 and the fact that many of these infants were initially antigen-nega¬ tive only to become positive several months after birth, the perinatal pe¬ riod seems a likely time for infection to have occurred. Contact with mater¬ nal blood is especially great during la¬ bor and delivery, and infection could be acquired at that time through small skin abrasions, swallowed blood, or inapparent leakage of ma¬ ternal blood across the placenta. Such leakage during labor and delivery could explain our observation that two infants (No. 14 and 25) had posi¬ tive cord blood samples followed by negative peripheral blood specimens, and then later developed anti¬
genemia. Although transmission of HB virus
from carrier mothers to their infants seems a very likely explanation for our findings, in a highly endemic area it is difficult to exclude other sources of infection. Injections are frequently given for minor illnesses in Taiwan, at times with improperly sterilized needles. Because these babies were born and followed up at a hospital where disposable or properly ster¬ ilized needles are used, injections are an unlikely source in this study. Fa¬ thers were usually antigen-negative and so are also unlikely to be impor¬ tant sources. Antigen-positive sib¬ lings were more commonly found in families of infants who developed
HB antigenemia, and some may have transmitted the virus to the infants. But it is also possible that many of these antigen-positive siblings have been carriers since early infancy. Further family studies are needed in Taiwan to see if HB virus commonly spreads among siblings and to deter¬ mine if some carrier mothers more consistently transmit the virus to their infants. Schweitzer et al11"" have demon¬ strated in a less endemic area that ac¬ quisition of the HB Ag carrier state is common in infants born to women who have acute type hepatitis, es¬ pecially if it occurs in the third tri¬ mester of pregnancy or soon after de¬ livery. But in studies other than ours, infants born to asymptomatic carrier mothers have seldom been shown to develop antigenemia. Skinhoj et al22 in Denmark followed up 36 babies for four to five months, retested 16 of these by immunodiffusion at 10 to 12 months of age, and none became anti¬ gen-positive. In Greece,23 transient antigenemia was found in only 2 of 11 infants. In Pakistan,24 1 of 18 infants tested by immunodiffusion or counterelectrophoresis became antigenpositive. Schweitzer et al" in Los An¬ geles reported that only 1 of 21 infants (followed up for three months) whose mothers were chronic carriers developed antigenemia as measured by RIA. A report from Thailand,23 which like Taiwan has a high carrier rate, includes 14 women who had antigenemia (probably
pregnancy; during the first six months of life, none of their infants' serum samples was an¬ tigen-positive by immunodiffusion. Length and frequency of infant follow-up and the sensitivity of meth¬ ods used to detect HB Ag may be im¬ portant in comparing studies of in¬ fants born to chronic carrier mothers. But there may be true geographic dif¬ ferences in the mechanisms and fre¬ quencies of HB virus transmission to infants, and in their response to in¬ fection. Our findings in Taiwan, and those of others elsewhere, concerning infants whose mothers are chronic carriers need to be confirmed, and then extended with regard to factors in infancy that might influence HB
chronic) during
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virus transmission and development of the chronic carrier state.
This investigation was supported in part by the Bureau of Medicine and Surgery, Navy Department, for Work Unit MR041.09.010114A3GX. V.J. Cabasso, Cutter Laboratories, provided equine antiserum to HBAg. The physicians and nurses of the Maternity and Child Center of Veterans' General Hospital, the public health nurses of NAMRU-2, George S. Irving, Howard S. Berg, MD, Raymond H. Watten, MD, and the Data Processing Department, US Naval Research Unit No. 2 provided assist¬ ance.
T.T. Chiù and others
provided technical assist¬
ance.
References 1. Blumberg BS, Sutnick AI, London WT: Australia antigen as a hepatitis virus: Variation in host response. Am J Med 48:1-8, 1970. 2. Krugman S, Giles JP: Viral hepatitis: New light on an old disease. JAMA 212:1019-1029, 1970. 3. Prince AM: Role of serum hepatitis virus in chronic liver disease. Gastroenterology 60:913\x=req-\ 921, 1971. 4. Tong MJ, Sun SC, Schaeffer BT, et al: Hepatitis-associated antigen and hepatocellular carcinoma in Taiwan. Ann Intern Med 75:687-691,
60 Years
1971. 5. Reinicke V, Dybkjaer E, Poulsen H, et al: A study of Australia-antigen-positive blood donors and their recipients with special reference to hepatic histology. N Engl J Med 286:867-870,1972. 6. Anderson KE, Sun SC, Berg HS, et al: Liver function and histology in asymptomatic Chinese military personnel with hepatitis B antigenemia. Am J Dig Dis 19:693-703, 1974. 7. Sun SC, Anderson KE, Hsu CP, et al: Hepatocellular ultrastructure in asymptomatic hepatitis B antigenemia. Arch Pathol 97:373-379, 1974. 8. Shih PL, Chang CK, Sung JL: Hepatitis-associated antigen and antibody in Taiwan. J Formosan Med Assoc 70:697-706, 1971. 9. Hsia S, Chen SC, Shen FC, et al: Australia antigen and antibody in blood donors and patients with blood disorders. Transfusion 13:89\x=req-\ 93, 1973. 10. Brotman B, Prince AM, Godfrey HR: Role of arthropods in transmission of hepatitis-B virus in the tropics. Lancet 1:1305-1308, 1973. 11. Schweitzer IL, Wing A, McPeak C, et al: Hepatitis and hepatitis-associated antigen in 56 mother-infant pairs. JAMA 220:1092-1095,1972. 12. Schweitzer IL, Dunn AEG, Peters RL, et al: Viral hepatitis B in neonates and infants. Am J Med 55:762-771, 1973. 13. Schweitzer IL, Mosley JW, Ashcavai M, et al: Factors influencing neonatal infection by hepatitis B virus. Gastroenterology 65:277-283,1973. 14. Ohbayashi A, Okochi K, Mayumi M: Familial clustering of asymptomatic carriers of Australia antigen and patients with chronic liver disease or primary liver cancer. Gastroenterology 62:618-625, 1972. 15. Wright R, Perkins JR, Bower RD, et al:
Ago in AJDC Duodenal Ulcer in
Since 1909, numerous reports have appeared which have substantiated the frequent occurrence of duodenal ulcers in infancy. The etiology of gastric and duodenal ulcer is still a much debated question. In ten out of fourteen ulcers from two series diplococci were found in the ulcer base, and in all eight ulcers of our present series diplococci were found in the ulcer in such numbers and in such a position that they presumably are of etiologic . In one of the cases a significance. Streptococcus viridans was isolated from the duodenal ulcer, which on injection into rabbits and dogs localized in the pyloric end of the stomach and duodenum and there produced hemorrhages and ulcerations. Rosenow4 has recently shown that from .
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Cirrhosis associated with Australia antigen in an infant who acquired hepatitis from her mother. Br Med J 4:719-721, 1970. 16. Bancroft WH, Warkel RL, Talbert AA, et al: Family with hepatitis associated antigen: Spectrum of liver pathology. JAMA 217:1817\x=req-\ 1820, 1971. 17. Szmuness W, Prince AM, Hirsch RL, et al: Familial clustering of hepatitis B antigen. N Engl J Med 289:1162-1166, 1973. 18. Berris B, Wrobel DM, Sinclair JC, et al: Hepatitis B antigen in families of blood donors. Ann Intern Med 79:690-693, 1973. 19. Purcell RH, Holland PV, Walsh JH, et al: A complement-fixation test for measuring Australia antigen and antibody. J Infect Dis 120:383\x=req-\ 386, 1969. 20. Cabasso VJ, Nieman R, Schroeder DD, et al: Preparation and standardization of an Australia antigen antibody of equine origin. Appl Microbiol 21:1017-1023, 1971. 21. Jambazian A, Holper JC: Rheophoresis: A sensitive immunodiffusion method for detection of hepatitis associated antigen. Proc Soc Exp Biol Med 140:560-564, 1972. 22. Skinhoj P, Oleson H, Cohn J, et al: Hepatitis-associated antigen in pregnant women. Acta Pathol Microbiol Scand 80:362-366, 1972. 23. Papaevangelou GJ: Hepatitis B in infants. N Engl J Med 288:972, 1973. 24. Aziz MA, Khan G, Khanum T, et al: Transplacental and postnatal transmission of the hepatitis-associated antigen. J Infect Dis 127:110\x=req-\ 112, 1973. 25. Punyagupta S, Olson LC, Harinasuta U, et al: The epidemiology of hepatitis B antigen in a high prevalence area. Am J Epidemiol 97:349\x=req-\ 354, 1973.
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duodenal and
eration,
a
Infancy:
An Infectious Disease
gastric ulcers removed at op-
streptococcus viridans
can
be
constantly isolated, which when injected intravenously into dogs and rabbits will tend to localize in the stomach and duode¬ num and there produce first hemorrhage and later ulcers. In explanation of this phenomenon he assumes that the strepto¬ coccus producing duodenal ulcer finds in the duodenum conditions peculiarly favor¬ able for its development, and therefore tends to localize there. We can assume that at times the streptococcus takes on characteristics which make it tend to local¬ ize in the duodenum when infecting an in¬ fant. We have thus a working hypothesis which explains very readily the epidemic appearance of duodenal ulcers; namely, that we have an infection with a very defi¬ nite organism, which, carried to the infant .
.
.
...
through the digestive
tract or the air passages, tends to localize in the duodenum. This same tendency has been shown by Rosenow to be true of the streptococcus isolated from cases of rheumatic fever, endocarditis, appendicitis and herpes zoster, when injected into ani¬ mals. Not only is the organism specific when isolated from the characteristic le¬ sion, but usually when isolated from the portal of entry, such as the tonsils, an al¬ veolar abscess, etc. Rosenow has quite con¬ clusively established the fact that gastric and duodenal ulcer of the adult are the re¬ sult of an infection with a streptococcus of particular virulence. That this holds good for duodenal ulcers of the infant also is .—"Duodenal Ul¬ very definitely shown. cer in Infancy: An Infections Disease," L. Gerdine, MD, H. F. Helmholz, MD, Chicago
either
through
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