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Efficacy of immune serum globulin in an outbreak of hepatitis A virus infection in adults
Journal of Infection (1988) I7, 2,65-270
EPIDEMIOLOGY Efficacy of immune serum globulin in an outbreak of hepatitis A virus infection in adults M a n f r e d S. Green and Keren D o t a n
Medical Corps, Israel Defence Force, Israel Accepted for publication 3 May 1988 Summary While immune serum globulin has been shown to be highly effective in preventing hepatitis A infection when administered before exposure to the virus, its efficacy when given after exposure is less clear. T i m i n g of administration appears critical and the question of whether it modifies the clinical manifestations of the disease with possible asymptomatic seroconversion has not been conclusively answered. These aspects were examined in a common-source outbreak of I9 cases of hepatitis A in a military unit. I m m u n e serum globulin administered between 2 and 3 weeks after suspected exposure to the virus did not modify clinical manifestations of the disease. Furthermore, in a subgroup studied serologically, there were eight clinical cases and only one case of asymptomatic seroconversion. T h u s , late administration of immune serum globulin appears to have little effect on the clinical course of hepatitis A infection and does not appear to result in any significant degree of active-passive immunity.
Introduction Passive immunisation with pooled i m m u n e serum globulin ( I S G ) before exposure to hepatitis A virus (HAV), has been shown to be highly effective in preventing the disease. 1.2 T h e extent to which it prevents infection w h e n given after exposure, however, is less clear. ~-5 T i m i n g of its administration appears to be important 6 and the question of w h e t h e r it prevents the disease completely or modifies the clinical manifestations, while permitting seroconversion, h a s not been answered conclusively. 5 Early investigators believed that seroconversion u n d e r cover of immunisation was c o m m o n 2 '7 M o r e recently, however, it has been shown that such an o u t c o m e m a y be relatively rare. 5' 8.9 In general, it is believed that I S G m u s t be administered within 2 weeks of exposure in order to be effective. 5 O n the other hand, in recent reports 1°' n it has been suggested that even where I S G given is as late as 3 weeks after exposure, n e w cases m a y be prevented. In the present study, the efficacy of I S G administered b e t w e e n 2 and 3 weeks after suspected exposure to the hepatitis A virus, was examined in a c o m m o n - s o u r c e outbreak in a unit of the Israel D e f e n c e Force ( I D F ) . T h e aim of the study was to evaluate possible modification of s y m p t o m s b y I S G and to determine the rate of asymptomatic seroconversion u n d e r cover of I S G . Address correspondence to: Dr Manfred Green, Military Post o2149, Israel Defence Force, Israel. o163-4453/88/o6o265 +06 $02.00/0
© I988 The British Society for the Study of Infection
266
M.S. GREEN
A N D K. D O T A N
Materials and m e t h o d s The outbreak
A soldier from a field unit in the I D F became ill on 30 May I987. He was admitted to hospital on I June I987. On II June 1987, a second case was reported from the same unit and on I2 June I987 each member of the unit was given 5 m l I S G intramuscularly (approximately o'6cc/kg). New cases continued to appear and by I7 July I987, I9 cases of hepatitis had been diagnosed at the base. Further cases were not reported from this unit during the subsequent month. During the epidemiological investigations, it transpired that the first case (who became ill on 3o May I987) worked in the unit's kitchen and assisted in the preparation of food during the week before his illness began. Since the second case presented I3 days after the first, it was assumed that the disease was transmitted by food contaminated by the first case. It was not possible to identify the source of the first patient's infection. S y m p t o m a t i c cases
Anyone who presented at the unit clinic with complaints compatible with the early stage of viral hepatitis was admitted to hospital. Diagnosis was confirmed by abnormal liver enzymes and an increase in serum bilirubin. Most patients were also tested for anti-HAV IgM antibodies. Data were also collected on the physical signs and symptoms of the illness as well as biochemical and haematological findings. Group for serological study
T h e base comprises several subunits. Each subunit trains separately and has its own sanitary facilities and mess tent. Food is supplied to the subunits from a central kitchen. One subunit, in which the highest rate of clinical cases was observed, was selected for more extensive serological evaluation. T h e subunit comprised 83 persons all aged between I9 and 22 years. Eight of the cases were from this unit. Blood was taken from them on I7 August I987 (about 8o days after suspected exposure). Serological tests
Blood samples were first tested for total anti-HAV antibodies by means of a non-immunoglobulin-specific radioimmunoassay (HAVAB, Abbott Laboratories, North Chicago, IL). Those samples positive for total HAV antibodies were then tested for the presence of serum immunoglobulin M (IgM) which was determined by specific radioimmunoassay (HAVAB-M, Abbott Laboratories, North Chicago, IL). T h e antibody titre of the I S G used was tested by means of radioimmunoassay and found to have a reciprocal antibody titre greater than 2ooo. Results
T h e epidemic curve for the outbreak is shown in Fig. I. T h e median incubation period was 22 days; nearly all cases appeared between 13 and 32 days after suspected exposure. T h e distribution of reported symptoms and
Hepatitis A outbreak
267
3g o ~6
Z
r
o
3
5
7
9
II
13 15 17 r9 21 23 25 2 7 2 9 31 3 3 3 5 37 39 41
43 45 47
Time after index case (days)
Fig. z. Symptomatic hepatitis A cases relative to date of onset of index case in a common source outbreak in the Israel Defence Force in I987.
T a b l e I Reported characteristics of the illness among I 9 " cases of hepatitis A infection in an outbreak in the Israel Defence Force in I 9 8 7 Symptoms Mean temperature Malaise Abdominal pain Nausea/vomiting Diarrhoea Headache Arthralgia Myalgia Signs Yellow eyes Dark urine Enlarged liver Enlarged spleen Course of illness Mean number of days in hospital Mean number of days off duty
37"8 °C (range 36"5-39"7 °C) 84"o % 79'o % 73'7 % 31.6 %
2I'1% 5"o % o-o % 89"5 % 84'2 % 47"4 % Io'5 % I I-2 23'6
(range 6-23) (range I4-32 )
* Data were missing for two persons for some values. signs a n d c o u r s e o f t h e illness a m o n g t h e 19 cases o f h e p a t i t i s is g i v e n in T a b l e I. T h e b i o c h e m i c a l a n d h a e m a t o l o g i c a l f i n d i n g s are g i v e n in T a b l e I I . R e s u l t s o f s e r o l o g i c a l t e s t s o n 83 p e r s o n s in t h e s u b u n i t e x a m i n e d are s h o w n in T a b l e I I I . A t t h e t i m e o f t h e b l o o d test, 5o w e r e s e r o p o s i t i v e f o r total a n t i H A V a n t i b o d i e s . O f t h e s e , n i n e w e r e p o s i t i v e for a n t i - H A V I g M a n d e i g h t o f
268
M . S . G R E E N A N D K. D O T A N
T a b l e I I Biochemical and haematological findings among x9* cases of hepatitis A infection in an outbreak in the Israel Defence Force in I987 (ranges given
in parentheses) Variable
Laboratory normal values
Mean maximum total bilirubin Mean maximum SGOT Mean maximum SGPT Mean leucocyte count Percentage lymphocyte count Percentage with atypical lymphocytes Mean haemoglobin concentration
I i6"28 mmol/1
(Range) (32'49-I71"oo retool/l)
<8"55mmol/1
r613 IU 2328 IU 6.435 x io9/1 37"9 %
(300-3500 IU) (535-4974 IU) (3'7-I3'8 x IO9/1) (I 8--50%)
3-30 IU 3-27 IU 4"8-io-2 x Ioa/l 20--40 % 0%
47"4% i4.i g/dl
I4"O-I8-O g/dl
(I2"5-I5'9 g/dl)
* Data were missing for two persons for some values. T a b l e I I I Serological findings in 83 persons associated with an outbreak of hepatitis A infection in the Israel Defence Force and bled 80 days after
suspected exposure Presence of anti-HAV antibodies
Symptoms
No. of persons bled
Total
IgM
Absent Present Total
75 8 83
42 8 50
I 8 9
t h e m had h ad clinically recognisable disease. T h u s 4 2 o f the 83 (50"6 %) in this u n it were susceptible to hepatitis at the begi nni ng o f the outbreak. O f these, eight h ad clinical illness and one s e r o c o n v e r t e d w i t h o u t clinically a p p a r e n t disease. T h i s yielded an attack rate a m o n g the susceptibles o f 2 I ' 4 % and a s y m p t o m a t i c to a s y m p t o m a t i c ratio o f 8 : I. Discussion
I n the p r e s e n t study, I S G was given b e t w e e n 2 and 3 weeks after p r o b a b l e e x p o s u r e to hepatitis A virus. M o s t s y m p t o m a t i c cases c o n t i n u e d to appear for nearly 3 weeks after the I S G had be e n a d m i n i s t e r e d ; one case a p p e a r e d nearly 5 weeks later. T h i s s uppor t s the c o n t e n t i o n that I S G m u s t be given within 2 weeks o f ex p o s u r e in o r d e r to be effective. 4' ~ It does not s u p p o r t the view o f L e d n a r et al. a° that clinical disease will n o t appear m o r e t h a n a b o u t 8 days after
Hepatitis A outbreak
269
the administration of I S G even w h e n it is administered late in the incubation period. T h e possibility that I S G modifies the course or severity of infection even w h e n given late in the incubation period is not s u p p o r t e d by the results of our study. T h e clinical signs and s y m p t o m s and the clinical course of those involved in the outbreak were similar to those f o u n d in other patients with H A V infection w h o had not received I S G . 12' 13 Even so, the possibility that the I S G p r e v e n t e d some cases completely cannot be excluded. T h e question of passive-active i m m u n i t y is not completely resolved. In early studies, induction of passive-active i m m u n i t y was reported. 3'7 It has been suggested that the degree of passive-active i m m u n i t y may d e p e n d on the dose of I S G g i v e n ) L o w doses w o u l d permit passive-active i m m u n i t y whereas higher doses w o u l d tend to prevent the disease completely. O n the other hand, Rackela et al. 14 reported a relatively low percentage of apparent passive-active i m m u n i t y despite intense exposure to the virus. F u r t h e r m o r e , in a study among Swedish soldiers in Sinai, 9 the use of I S G offered almost complete passive protection without evidence of active-passive immunisation. In the present study, only one case o f a s y m p t o m a t i c seroconversion occurred in the subunit where there were eight clinical cases. T h e r e was therefore little evidence of passive-active immunity. This m a y have been due to the fact that I S G was given more than 2 weeks after exposure. H o w e v e r , recently, L e d n a r et al. 1° as well as T a s s o p o u l o s e t a l . ~1 claimed to have observed significant passive-active i m m u n i t y w h e n I S G was given as late as 3 weeks after exposure. O n e difficulty in evaluating results of such studies is that inapparent illness m a y arise regardless of w h e t h e r I S G is used. T h e role of I S G in so-called passive-active i m m u n i t y m a y therefore be difficult to distinguish. T h e high ratio of s y m p t o m a t i c to asymptomatic cases ( 8 : I ) observed in the present study is compatible with the view that most adults infected develop symptoms. 1°'~2'~3 Studies of the ratio of symptomatic to asymptomatic cases have p r o d u c e d varying results. Some have indicated that the ratio m a y be as low as I : I2 in children 3 to more than 3 : I ratio in adults, al It is possible that the very high s y m p t o m a t i c to asymptomatic ratio in the present study may have been partly due to the administration of a high dose of I S G , which did not prevent disease in persons late in their incubation period, yet completely prevented the disease in those in an earlier stage of incubation. Conclusions
Several conclusions m a y be drawn from this study. First, I S G administered more than 2 weeks after exposure to the virus is largely ineffective in modifying the course of the disease. Second, at least when I S G is administered late in the incubation period, there is little if any evidence of active-passive immunisation. Finally, H A V infection in late adolescence and the early 2os appears to be largely s y m p t o m a t i c with icterus almost always being present.
11
J I N 17
2,70
M. S. GREEN AND K. DOTAN
References
I. A cooperative Study. Prophylactic gamma globulin for prevention of endemic hepatitis. Effects of US gamma globulin upon the incidence of viral hepatitis and other infectious diseases in US soldiers abroad. Arch Intern Med I97I ; 128: 723-738. 2. Kark JD. Pre-exposure prophylaxis with immune serum globulin for prevention of viral hepatitis in army recruits, ff Epidemiol Community Health 1982; 36: 176-182. 3. Krugman S, Ward R, Giles JP, Jacobs A. Studies on the effect of gamma globulin on the incidence of inapparent infection. J A M A 196o; 174: 823-830. 4. Mosley JW, Reiser DM, Brachott D, Roth D, Weiser J. Comparison of two lots of immune serum globulin for prophylaxis of infectious hepatitis. Am J Epidemiol 1968; 87: 539-550. 5- Robinson WS. Hepatitis A virus. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases. New York: John Wiley, I985: 829-84o. 6. Carl M, Francis DP, Maynard JE. Food-borne hepatitis A: recommendations for control. J Infect Dis I983; 148: II33-II35. 7. Stokes J, Farquar JA, Drake ME et al. Infectious hepatitis. Length of protection by immune serum globulin (gamma globulin) during epidemics. J A M A 1951 ; I47: 714-719. 8. Krugman SJ. Effect of human immune serum globulin on infectivity of hepatitis A virus. J Infect Dis 1976; I34:70-74 • 9. Weiland O, Niklasson B, Berg R, Lundbergh P, Tidestrom L. Clinical and subclinical hepatitis A occurring after immunoglobulin prophylaxis among Swedish UN soldiers in Sinai. Scand J Gastroenterol 1981; 16: 967-982. lO. Lednar WM, Lemson SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol 1985; 122: 226-233. I I. Tassopoulos NC, Roumeliotou-Karayannis A, Sakka M e t al. An epidemic of hepatitis A in an institution for young children. Am J Epidemiol 1987; 125: 302-307. 12. Routenberg JA, Dienstag JL, Harrison WO. A food-borne outbreak of hepatitis A. Am J Med Sci 1979; 278: 123-137. 13. Wacker WEC, Riodan JF, Snodgrass PJ et al. The Holy Cross hepatitis outbreak: Clinical and chemical abnormalities. Arch Intern Med 1972; 13o: 357-360. 14. Rakela J, Nugent E, Mosley JW. Viral assays and serological procedures in the study of an epidemic. Am J Epidemiol 1977; lO6: 493-5Ol.
EPIDEMIOLOGY Efficacy of immune serum globulin in an outbreak of hepatitis A virus infection in adults M a n f r e d S. Green and Keren D o t a n
Medical Corps, Israel Defence Force, Israel Accepted for publication 3 May 1988 Summary While immune serum globulin has been shown to be highly effective in preventing hepatitis A infection when administered before exposure to the virus, its efficacy when given after exposure is less clear. T i m i n g of administration appears critical and the question of whether it modifies the clinical manifestations of the disease with possible asymptomatic seroconversion has not been conclusively answered. These aspects were examined in a common-source outbreak of I9 cases of hepatitis A in a military unit. I m m u n e serum globulin administered between 2 and 3 weeks after suspected exposure to the virus did not modify clinical manifestations of the disease. Furthermore, in a subgroup studied serologically, there were eight clinical cases and only one case of asymptomatic seroconversion. T h u s , late administration of immune serum globulin appears to have little effect on the clinical course of hepatitis A infection and does not appear to result in any significant degree of active-passive immunity.
Introduction Passive immunisation with pooled i m m u n e serum globulin ( I S G ) before exposure to hepatitis A virus (HAV), has been shown to be highly effective in preventing the disease. 1.2 T h e extent to which it prevents infection w h e n given after exposure, however, is less clear. ~-5 T i m i n g of its administration appears to be important 6 and the question of w h e t h e r it prevents the disease completely or modifies the clinical manifestations, while permitting seroconversion, h a s not been answered conclusively. 5 Early investigators believed that seroconversion u n d e r cover of immunisation was c o m m o n 2 '7 M o r e recently, however, it has been shown that such an o u t c o m e m a y be relatively rare. 5' 8.9 In general, it is believed that I S G m u s t be administered within 2 weeks of exposure in order to be effective. 5 O n the other hand, in recent reports 1°' n it has been suggested that even where I S G given is as late as 3 weeks after exposure, n e w cases m a y be prevented. In the present study, the efficacy of I S G administered b e t w e e n 2 and 3 weeks after suspected exposure to the hepatitis A virus, was examined in a c o m m o n - s o u r c e outbreak in a unit of the Israel D e f e n c e Force ( I D F ) . T h e aim of the study was to evaluate possible modification of s y m p t o m s b y I S G and to determine the rate of asymptomatic seroconversion u n d e r cover of I S G . Address correspondence to: Dr Manfred Green, Military Post o2149, Israel Defence Force, Israel. o163-4453/88/o6o265 +06 $02.00/0
© I988 The British Society for the Study of Infection
266
M.S. GREEN
A N D K. D O T A N
Materials and m e t h o d s The outbreak
A soldier from a field unit in the I D F became ill on 30 May I987. He was admitted to hospital on I June I987. On II June 1987, a second case was reported from the same unit and on I2 June I987 each member of the unit was given 5 m l I S G intramuscularly (approximately o'6cc/kg). New cases continued to appear and by I7 July I987, I9 cases of hepatitis had been diagnosed at the base. Further cases were not reported from this unit during the subsequent month. During the epidemiological investigations, it transpired that the first case (who became ill on 3o May I987) worked in the unit's kitchen and assisted in the preparation of food during the week before his illness began. Since the second case presented I3 days after the first, it was assumed that the disease was transmitted by food contaminated by the first case. It was not possible to identify the source of the first patient's infection. S y m p t o m a t i c cases
Anyone who presented at the unit clinic with complaints compatible with the early stage of viral hepatitis was admitted to hospital. Diagnosis was confirmed by abnormal liver enzymes and an increase in serum bilirubin. Most patients were also tested for anti-HAV IgM antibodies. Data were also collected on the physical signs and symptoms of the illness as well as biochemical and haematological findings. Group for serological study
T h e base comprises several subunits. Each subunit trains separately and has its own sanitary facilities and mess tent. Food is supplied to the subunits from a central kitchen. One subunit, in which the highest rate of clinical cases was observed, was selected for more extensive serological evaluation. T h e subunit comprised 83 persons all aged between I9 and 22 years. Eight of the cases were from this unit. Blood was taken from them on I7 August I987 (about 8o days after suspected exposure). Serological tests
Blood samples were first tested for total anti-HAV antibodies by means of a non-immunoglobulin-specific radioimmunoassay (HAVAB, Abbott Laboratories, North Chicago, IL). Those samples positive for total HAV antibodies were then tested for the presence of serum immunoglobulin M (IgM) which was determined by specific radioimmunoassay (HAVAB-M, Abbott Laboratories, North Chicago, IL). T h e antibody titre of the I S G used was tested by means of radioimmunoassay and found to have a reciprocal antibody titre greater than 2ooo. Results
T h e epidemic curve for the outbreak is shown in Fig. I. T h e median incubation period was 22 days; nearly all cases appeared between 13 and 32 days after suspected exposure. T h e distribution of reported symptoms and
Hepatitis A outbreak
267
3g o ~6
Z
r
o
3
5
7
9
II
13 15 17 r9 21 23 25 2 7 2 9 31 3 3 3 5 37 39 41
43 45 47
Time after index case (days)
Fig. z. Symptomatic hepatitis A cases relative to date of onset of index case in a common source outbreak in the Israel Defence Force in I987.
T a b l e I Reported characteristics of the illness among I 9 " cases of hepatitis A infection in an outbreak in the Israel Defence Force in I 9 8 7 Symptoms Mean temperature Malaise Abdominal pain Nausea/vomiting Diarrhoea Headache Arthralgia Myalgia Signs Yellow eyes Dark urine Enlarged liver Enlarged spleen Course of illness Mean number of days in hospital Mean number of days off duty
37"8 °C (range 36"5-39"7 °C) 84"o % 79'o % 73'7 % 31.6 %
2I'1% 5"o % o-o % 89"5 % 84'2 % 47"4 % Io'5 % I I-2 23'6
(range 6-23) (range I4-32 )
* Data were missing for two persons for some values. signs a n d c o u r s e o f t h e illness a m o n g t h e 19 cases o f h e p a t i t i s is g i v e n in T a b l e I. T h e b i o c h e m i c a l a n d h a e m a t o l o g i c a l f i n d i n g s are g i v e n in T a b l e I I . R e s u l t s o f s e r o l o g i c a l t e s t s o n 83 p e r s o n s in t h e s u b u n i t e x a m i n e d are s h o w n in T a b l e I I I . A t t h e t i m e o f t h e b l o o d test, 5o w e r e s e r o p o s i t i v e f o r total a n t i H A V a n t i b o d i e s . O f t h e s e , n i n e w e r e p o s i t i v e for a n t i - H A V I g M a n d e i g h t o f
268
M . S . G R E E N A N D K. D O T A N
T a b l e I I Biochemical and haematological findings among x9* cases of hepatitis A infection in an outbreak in the Israel Defence Force in I987 (ranges given
in parentheses) Variable
Laboratory normal values
Mean maximum total bilirubin Mean maximum SGOT Mean maximum SGPT Mean leucocyte count Percentage lymphocyte count Percentage with atypical lymphocytes Mean haemoglobin concentration
I i6"28 mmol/1
(Range) (32'49-I71"oo retool/l)
<8"55mmol/1
r613 IU 2328 IU 6.435 x io9/1 37"9 %
(300-3500 IU) (535-4974 IU) (3'7-I3'8 x IO9/1) (I 8--50%)
3-30 IU 3-27 IU 4"8-io-2 x Ioa/l 20--40 % 0%
47"4% i4.i g/dl
I4"O-I8-O g/dl
(I2"5-I5'9 g/dl)
* Data were missing for two persons for some values. T a b l e I I I Serological findings in 83 persons associated with an outbreak of hepatitis A infection in the Israel Defence Force and bled 80 days after
suspected exposure Presence of anti-HAV antibodies
Symptoms
No. of persons bled
Total
IgM
Absent Present Total
75 8 83
42 8 50
I 8 9
t h e m had h ad clinically recognisable disease. T h u s 4 2 o f the 83 (50"6 %) in this u n it were susceptible to hepatitis at the begi nni ng o f the outbreak. O f these, eight h ad clinical illness and one s e r o c o n v e r t e d w i t h o u t clinically a p p a r e n t disease. T h i s yielded an attack rate a m o n g the susceptibles o f 2 I ' 4 % and a s y m p t o m a t i c to a s y m p t o m a t i c ratio o f 8 : I. Discussion
I n the p r e s e n t study, I S G was given b e t w e e n 2 and 3 weeks after p r o b a b l e e x p o s u r e to hepatitis A virus. M o s t s y m p t o m a t i c cases c o n t i n u e d to appear for nearly 3 weeks after the I S G had be e n a d m i n i s t e r e d ; one case a p p e a r e d nearly 5 weeks later. T h i s s uppor t s the c o n t e n t i o n that I S G m u s t be given within 2 weeks o f ex p o s u r e in o r d e r to be effective. 4' ~ It does not s u p p o r t the view o f L e d n a r et al. a° that clinical disease will n o t appear m o r e t h a n a b o u t 8 days after
Hepatitis A outbreak
269
the administration of I S G even w h e n it is administered late in the incubation period. T h e possibility that I S G modifies the course or severity of infection even w h e n given late in the incubation period is not s u p p o r t e d by the results of our study. T h e clinical signs and s y m p t o m s and the clinical course of those involved in the outbreak were similar to those f o u n d in other patients with H A V infection w h o had not received I S G . 12' 13 Even so, the possibility that the I S G p r e v e n t e d some cases completely cannot be excluded. T h e question of passive-active i m m u n i t y is not completely resolved. In early studies, induction of passive-active i m m u n i t y was reported. 3'7 It has been suggested that the degree of passive-active i m m u n i t y may d e p e n d on the dose of I S G g i v e n ) L o w doses w o u l d permit passive-active i m m u n i t y whereas higher doses w o u l d tend to prevent the disease completely. O n the other hand, Rackela et al. 14 reported a relatively low percentage of apparent passive-active i m m u n i t y despite intense exposure to the virus. F u r t h e r m o r e , in a study among Swedish soldiers in Sinai, 9 the use of I S G offered almost complete passive protection without evidence of active-passive immunisation. In the present study, only one case o f a s y m p t o m a t i c seroconversion occurred in the subunit where there were eight clinical cases. T h e r e was therefore little evidence of passive-active immunity. This m a y have been due to the fact that I S G was given more than 2 weeks after exposure. H o w e v e r , recently, L e d n a r et al. 1° as well as T a s s o p o u l o s e t a l . ~1 claimed to have observed significant passive-active i m m u n i t y w h e n I S G was given as late as 3 weeks after exposure. O n e difficulty in evaluating results of such studies is that inapparent illness m a y arise regardless of w h e t h e r I S G is used. T h e role of I S G in so-called passive-active i m m u n i t y m a y therefore be difficult to distinguish. T h e high ratio of s y m p t o m a t i c to asymptomatic cases ( 8 : I ) observed in the present study is compatible with the view that most adults infected develop symptoms. 1°'~2'~3 Studies of the ratio of symptomatic to asymptomatic cases have p r o d u c e d varying results. Some have indicated that the ratio m a y be as low as I : I2 in children 3 to more than 3 : I ratio in adults, al It is possible that the very high s y m p t o m a t i c to asymptomatic ratio in the present study may have been partly due to the administration of a high dose of I S G , which did not prevent disease in persons late in their incubation period, yet completely prevented the disease in those in an earlier stage of incubation. Conclusions
Several conclusions m a y be drawn from this study. First, I S G administered more than 2 weeks after exposure to the virus is largely ineffective in modifying the course of the disease. Second, at least when I S G is administered late in the incubation period, there is little if any evidence of active-passive immunisation. Finally, H A V infection in late adolescence and the early 2os appears to be largely s y m p t o m a t i c with icterus almost always being present.
11
J I N 17
2,70
M. S. GREEN AND K. DOTAN
References
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