Symposium on Diseases of the Liver
Epidemiology of Virus B Hepatitis Eugene R. Schiff, M.D. *
The discovery of the Australia antigen, presently referred to as hepatitis B surface antigen (HBsAg), and antibody to HBsAg (anti-HBs), provided the epidemiologic tags which have allowed for a more definitive characterization of virus B hepatitis. 5 Subtyping of the HBsAg determinants has further enhanced epidemiologic studies. A relationship between subtype and virulence has not been unequivocally established. However, there is an association of subtype with geographic origin of the subject and with a particular route of infectionY Krugman and co-workers' demonstration that virus B can be transmitted by the feeding of infectious serum to susceptible human subjects 22 negated the belief that type B hepatitis, formerly referred to as "serum hepatitis," is transmitted only by parenteral routes. Ultimately, human beings transmit the virus via biologic fluids and excreta. Subhuman primates may also serve as a reservoir for the virus. HBsAg and anti-HBs have been detected in the sera of chimpanzees, but only virus A disease has been associated with the transmission of hepatitis from subhuman primates to human beings. 27 The virus propagates in the livers of human beings with acute and chronic hepatitis as well as those of asymptomatic carriers. The incubation period of virus B hepatitis, which varies from 28 to 160 days, contrasts with the shorter incubation period (2 to 6 weeks) of virus A hepatitis. An incubation period between 2 and 4 months is seen in most cases. Both dose and route of infection affect the duration of the incubation period. Infection with larger doses of virus, e.g., transfusion, is associated with shorter periods. Feeding of infectious serum as compared to parenteral inoculation of smaller doses lengthens the incubation period. 3
HEPATITIS B SURFACE ANTIGEN HBsAg can be detected approximately 1 to 2 months prior to, and as long as 1 to 2 months after, the onset of the icteric phase. The HBsAg may be present only for a few days or weeks during the course of acute viral hepatitis. If HBsAg is present in the serum for longer than 13 weeks, the patient becomes a chronic carrier, usually with chronic hepa"Associate Professor of Medicine, University of Miami School of Medicine; Chief, Hepatology Section, Veterans Administration Hospital, Miami, Florida
Medical Clinics of North America- Vo!. 59, No. 4, July 1974
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titis.44 Approximately 5 per cent of patients with acute hepatitis will become chronic carriers of HBsAg. The prevalence of HBs-antigenemia in a given population is related to geographic,~ socioeconomic, immunologic, and genetic factors. Inferior socioeconomic conditions, usually associated with bad sanitation and often associated with overcrowding, may be the primary factor responsible for the high incidence of antigenemia noted in warmer and subtropical regions. Whether or not one will become a chronic carrier of HBsAg, given a high degree of exposure and subsequent infection by the virus, seems to depend on immunologic and perhaps genetic factors. Immunologic deficiency states are associated with a high incidence of chronic HBs-antigenemia. A high carrier rate is found among patients with lepromatous leprosy, lymphoma, chronic renal dialysis patients, patients with Down's syndrome who have lived in large institutions, and in patients receiving immunosuppressive therapy. Dudley et al.lO have hypothesized that the persistence of HBsAg is related to a cell-mediated immune deficiency. Whether or not genetic predisposition to tolerate persistent antigenemia exists is not clear. Studies of familial clustering of virus B hepatitis infection tend to support a genetic predispositionY In general males have a higher incidence of HBsAg-positivity than females, but there are no significant racial differences in carrier rates. Regardless of the factors involved in the development of a carrier state, there is a wide spectrum of histological patterns, mostly abnormal, in the liver biopsies of such subjects. 39
ROUTES OF INFECTION HUMAN BLOOD. Very small amounts of infected blood are necessary to transmit hepatitis by parenteral routes. Barker et al. 4 demonstrated that inoculation of a milliliter of a 10-4 dilution of a pool of HBsAg-positive plasma could cause clinical hepatitis in the recipient. This undoubtedly accounts for the wide variety of parenteral modes of transmission. Even in the absence of detectable HBsAg, one cannot exclude the presence of virus B in the blood. Hoofnagle et al. 20 detected antibody to the hepatitis B core antigen (anti-HBc) in implicated donor blood specimens negative for HBsAg and anti-HBs. SALIVA. HBsAg has been detected by radioimmunoassay in the saliva of 76 per cent of patients with acute virus B hepatitis,43 primarily during the first 2 or 3 weeks after the onset of symptoms, and disappearing while still detectable in the serum. Anti-HBs was detected in the salivary secretions of these patients following the disappearance of the antigen and before the antibody was detectable in the serum. The HBsAg was intermittently found in the saliva of 86 per cent of chronic carriers. Anti-HBs was not detected in the saliva of the carriers. The presence of antigen in the saliva of all subjects studied was not related to blood contamination. Heathcote et al. IS found HBsAg in the saliva of 24 HBsAg-positive subjects. Serum/saliva ratios ranged from 50/1 to 25,000/1. Subtyping of the antigen detected in the serum and salivary samples confirmed the validity of the results. Data from other investiga-
EPIDEMIOLOGY OF VIRUS
B
HEPATITIS
837
tors have shown a lower incidence of HBsAg in saliva or negative results.46 The finding of HBsAg in saliva raises the possibility that saliva is a major vehicle of nonparenteral modes of transmission. However, the degree of infectivity of HBsAg-positive saliva and the potentially protective role of anti-HBs-positive saliva remains to be established. Virus B hepatitis may subsequently be shown to be transmitted by oral contact, as in kissing, if the infectivity of HBsAg-positive saliva is proven. Villarejos et: al.43 suggests that salivary transmission of hepatitis may occur among young children who share small toys and candies which they have chewed on. NASOPHARYNGEAL SECRETIONS. HBsAg has been detected by radioimmunoassay in 43 per cent of 40 sneeze specimens taken from HBsAg-positive subjects. 43 This finding raises the possibility that airborne transmission of HBsAg-positive droplets from carriers with upper respiratory infections may be a possible mechanism for spread of virus B hepatitis in closely confined quarters. SEMEN. Ten of 19 samples of semen from men with antigenemia were found to be HBsAg positive. '8 The serum/semen ratio varied between 1,250/1 and 250,000/1. All 10 men with positive semen also had positive saliva samples. Serum and semen subtypes were identical. URINE. HBsAg has been detected in urine. When concentrated specimens were tested with a radioimmunoassay technique, only a small percentage of patients with HBsAg-positive blood had detectable antigen in the urine. 43 Infectious urine, particularly in patients with urinary incontinence, could represent a potential mode of transmission. FECES. The presence of HBsAg in feces has not been unequivocally established. Villarejos et al.43 consistently failed to detect the hepatitis B antigen in any of 120 fecal extracts from positive carriers. The feeding of feces from patients with virus B hepatitis in an experimental setting has failed to produce hepatitis among the recipients. 25 Data regarding the presence of HB sAg in bile and in feces are contradictory.2, 15, 16,38 The observation that homogenates of human feces or intestinal mucosa when incubated with HBsAg-positive sera inhibit subsequent detection of antigen suggests that fecal transmission of virus B hepatitis seldom occurs,z°
MODES OF TRANSMISSION It is apparent that type B hepatitis can be transmitted both orally and parenterally. However, the fecal-oral route does not seem to represent a significant pathway in the transmission of virus B disease, and large epidemics of long-incubation hepatitis traced to a common source of contaminated food or water have not been observed. In view of the findings of Mahoney et al. 26 that HB sAg can be detected in clams harvested from waters contaminated by untreated sewage from a coastal hospital, the possibility of a shellfish-associated epidemic of long-incubation hepatitis exists but has not been established. In general, nonparenteral forms of virus B disease occur sporadically among adults. Recent trends in the epidemiology of viral hepatitis in the United
838
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States have been reported by the Center For Disease Control. 6 A shift of virus B hepatitis has resulted in more cases among teenagers and young adults than among older adults since 1966. A growing number of cases of virus B hepatitis have been associated with parenteral drug abuse. In 1966,55 per cent of hepatitis B cases were associated with transfusion. In 1972 this percentage fell to 14 per cent, although over 60 per cent of the adults age 30 or older with virus B hepatitis had transfusion-associated disease. In 1966,34 per cent of the hepatitis B cases were associated with parenteral drug abuse, and in 1972 this percentage rose to 70 per cent. The largest increase in drug-associated hepatitis B disease was in the 15 to 29 year age group, which rose from 67% in 1966, peaked at 88% in 1968, and diminished slightly to 79 per cent in 1972. Paralleling these changes has been a decrease in the case-fatality ratio from 8.7 per cent in 1966 to 2 per cent in 1972. The case-fatality ratio remained greater than 5 per cent, however, among individuals age 30 or older whose hepatitis was primarily transfusion associatf'd. Another trend has been an increase in the percentage of virus B hepatitis cases with a history of nonparenteral personal contact. Undoubtedly, many of the cases reported as hepatitis A or unspecified hepatitis represent hepatitis B disease. Personal Contact In an epidemiologic survey designed to determine the source of infection in patients with virus B hepatitis, Heathcote and Sherlock 17 found nonparenteral spread more common than parenteral spread. Sexual or domestic contact was the definite or likely source of infection in 40 per cent of the 67 patients studied. Several investigations have revealed an association of an increased prevalence of HBsAg and antiHBs in sexually promiscuous and homosexual subjects. Fulford et al,12 noted that 13 per cent of patients in a venereal disease clinic who had negative serologic studies for virus B disease were either homosexual or bisexual. In contrast, 24 per cent of the HBsAg-positive group and 53 per cent of the anti-HBs-positive group were homosexual or bisexual. Thirty-eight per cent of the anti-HBs-positive group had sexual contact with 3 to 7 partners in the 6 months preceding the testing, in contrast to only 15 per cent of the group serologically negative for virus B disease. Papaevangelou et al,29 noted a prevalence of anti-HBs in prostitutes greater than twice that in the control group of pregnant women of similar age and socioeconomic levels. The prevalence of anti-HBs increased with increasing number of years in prostitution. Jeffries et al. 21 found higher rates of HBs-antigenemia among homosexual patients as compared to heterosexual control groups. The presence of HBsAg in saliva, semen, and serum suggests that the ingestion of any of these biologic fluids during close personal contact could result in the transmission of hepatitis, but this remains to be proven. A case of virus B hepatitis transmitted by a human bite has been reported and underscores the probable infectivity of saliva. Medical Environments The frequency of anti-HBs among health care personnel studied by Lewis et al. 23 was found to be twice that of matched controls with no ex-
EPIDEMIOLOGY OF VIRUS
B
HEPATITIS
839
po sure to patients or blood products. A history of hepatitis was also more common. Medical and para-medical personnel who have frequent contact with blood and blood products seem to be particularly at risk. The severity of this problem was brought to light by Rosenberg et al. 35 who epidemiologically linked four surgeons with HBsAg-positive hepatitis to a surgical patient requiring multiple transfusions in whom HBsAg-positive hepatitis subsequently developed. All the surgeons had admitted to finding holes in their gloves and cuts on their hands following major surgical procedures, especially when wire sutures were used, which was the case with their patient. Personnel handling the blood specimens of patients with hepatitis may inadvertently ingest serum while pipetting, spill blood on their hands that have sustained minor cuts and abrasions, or accidently stick themselves with contaminated needles at the time of a venosection or giving parenteral medications. Two high-risk areas in the hospital setting are the dialysis and oncology units. A survey of dialysis facilities in the United States by the Center for Disease Control revealed that over 80 per cent of the centers reported cases of viral hepatitis. l3 Similar experiences have been noted in European countries. In a recent survey of 15 dialysis centers, 50 per cent of the patients and 34 per cent of the staff had serologic evidence, either HBsAg or anti-HBs, of virus B exposure. 40 HBsAg was detected in approximately 16 per cent of the patients, a prevalence rate approximately 7-fold greater than that of the staff. This reservoir of antigen undoubtedly accounts for the frequently reported outbreaks of hepatitis among personnel in dialysis units. In general, hepatitis tends to run a milder, often inapparent clinical course in patients, as compared to the more overt and clinically severe course seen in staff members. The milder clinical course and the predisposition to develop chronic antigenemia in the dialysis patients, as contrasted with the staff patients, may be explained on the basis of immunologic differences in host responsiveness. The mode of transmission of hepatitis, usually from patient to staff, has not been clearly defined. Undoubtedly, direct contact with blood from the dialysis patients resulting in infection through skin breaks, puncture wounds of the skin, or accidental ingestion accounts for many cases. Hemodialysis technicians who work primarily with blood and blood-contaminated equipment, but who have less contact with the patients than nurses or physicians, are a group particularly at risk. 47 Although previous transfusions are thought to be the most likely explanation for the higher incidence of hepatitis among dialysis patients, patient to patient contact may be playing an important role in transmission. Air-borne transmission via droplets of blood or nasopharyngeal secretions has been suggested but certainly not documented. 3 , 43 Other consequences of the hepatitis reservoir in the dialysis unit include an increased incidence of hepatitis among renal transplant patients, an increased incidence in the hospital's local laboratories, and an increased risk for the development of hepatitis among family and close contacts at homeY A similar hospital-based focus of hepatitis is the oncology unit, where patients are more likely to develop virus B hepatitis because of their need for multiple transfusions of blood and blood products. These
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patients are predisposed to developing chronic antigenemia, probably because of their immunosuppressed state, in part a result of chemotherapy. Wands et al.4 5 reported a 19.5 per cent frequency of HBsAg-positive blood among 87 patients with tumor in an oncology unit. Rising titers of HBsAg were noted with the institution of high dose chemotherapy. Approximately 10 per cent of the personnel working in this unit developed clinically severe virus B hepatitis. Dental Environment Feldman and Schiff reported a significantly higher incidence of hepatitis among dentists than a control group of lawyers. 34 The highest rate was found among oral surgeons, who had an attack rate of 21 per cent as compared with a 5 per cent attack rate in general dentists. There have been two recent reports of virus B hepatitis transmission by dentists to their patients. Levin et a}.24 reported the development of virus B hepatitis in 12 patients treated by a HBsAg-positive dentist over a 4 month interval. Rimland and Parkin collected 53 clinical cases of virus B hepatitis over a 4 year period which they traced to a single oral surgeon. 33 An investigation revealed the implicated dentist to be an asymptomatic carrier of HBsAg of the same subtype as 6 of the 7 cases tested. A blood-oral mode of transmission was hypothesized on the basis of a history of frequent cuts on his fingers. The increased risk of hepatitis among dentists may be related to the failure to employ adequate prophylactic measures, particularly the wearing of gloves during procedures when treating high-risk patients such as drug abusers. Gloves would also prevent transmission of virus from cuts on the hand of a HBsAg carrier to a susceptible patient. Post-Transfusion Hepatitis Reports on the percentage of cases of post-transfusion hepatitis that can be attributed to virus B have varied from 25 to 80 per cent. 37 ,38 Whether or not the recipient of blood transfusions will develop hepatitis is dependent primarily on the source of the donor blood, the number of transfusions given, and the immune status of the recipient in reference to prior exposure to the hepatitis viruses. Commercial donor blood is associated with a 6-fold greater risk for the development of hepatitis among recipients. 37 A greater percentage of HBsAg-positive units is also found among commercial as compared to volunteer sources. Screening of donor blood for HBsAg had led to a decrease in the incidence of HBsAgpositive hepatitis; however, the overall decrease was below expectations, and it has recently become apparent that another virus or viruses may be responsible for HBsAg-negative long-incubation hepatitis. 32 The absence of HBsAg in donor blood, as determined by sensitive methodology such as radioimmunoassay, does not eliminate the possibility that the hepatitis B virus is present. Assays for HBcAg have demonstrated this and may ultimately become the best screening parameters for the presence of virus B.20 A progressive but nonlinear increase in the risk of developing hepatitis roughly parallels an increase in the number of units transfused. 38 Recipients who had prior exposure to virus B may be carriers of HBsAg or, more likely, may have developed anti-HBs, both of which would
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preclude the development of acute virus B hepatitis following transfusion with blood harboring the virus. Cherubin7 has demonstrated that the risk of developing post-transfusion hepatitis in recipients of HBsAgpositive blood is lower in a lower socioeconomic area, particularly where drug addiction was common, because of the high incidence of prior exposure to the hepatitis B virus. Transfusion of blood containing anti-HBs appears to carry no added risk. Aach et aLl showed that there was no significant difference in biochemical or overt virus B hepatitis or in serologic response to the hepatitis B virus among susceptible patients who received at least 1 unit of HBsAg-negative blood containing antiHBs. Concentrates of coagulation factors prepared from pooled plasma are notably fraught with a high risk to the recipient for the development of hepatitis. 2B Workers processing these concentrates from plasma in one facility w'ere found by Taylor et al. 42 to have a prevalence of 1.92 per cent HBs-antigenemia and a mean from 55 to 92 per cent of anti-HBs, depending on the degree of exposure to plasma. 42
OTHER PARENTERAL MODES The most common parenteral mode of transmission of virus B in recent years has been drug abuse (see the following article by Seeff). Any mechanism that involves the transfer of blood harboring virus B to a susceptible recipient is likely to lead to transmission of virus B hepatitis. Ear piercing, tatooing, injections with contaminated syringes and needles, and the sharing of razors have all been implicated. Blood-sucking insects, particularly mosquitos, harbor HBsAg but probably do not replicate the virus. 9 Mechanical transmission of the virus via mosquitoes may be responsible for otherwise unexplained virus B disease in tropical areas as well as some high density, lower socioeconomic urban areas in the United States. An unusual mode of transmission occurs among trackfinders in Scandinavia who frequently sustain cuts and scratches on their bodies and develop virus B hepatitis after bathing in contaminated waters. 34
Neonatal Hepatitis Schweitzer et aP6 have observed that virus B hepatitis in pregnancy results in a high frequency of chronic HBsAg-positive hepatitis in the infants, if the mother develops the illness in the third trimester or the immediate postpartum period. The mother who is a chronic carrier or contracts acute virus B hepatitis early in pregnancy is much less likely to transmit the disease to her infant. Transplacental transfer of virus B is apparently not the mode of transmission, and transmission probably occurs as a result of exposure at the time of delivery. The neonate subsequently develops HBsAg-positive antigenemia within 5 to 12 weeks.
CONCLUSION It has been established that virus B hepatitis can be transmitted by nonparenteral anu parenteral means. Recent evidence suggests that the
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fecal-oral route is not a significant mode of transmission. To further elucidate the epidemiology of this disease, it is incumbent upon every physician caring for a patient with hepatitis to attempt to determine the source and mode of transmission of the virus. All cases should be reported to the local Health Department, which has the facilities to further investigate the problem. Hepatology Section Veterans Administration Hospital 1201 N. W. 16th Street Miami, Florida 33125
Epidemiology of Virus B Hepatitis Eugene R. Schiff, M.D. *
The discovery of the Australia antigen, presently referred to as hepatitis B surface antigen (HBsAg), and antibody to HBsAg (anti-HBs), provided the epidemiologic tags which have allowed for a more definitive characterization of virus B hepatitis. 5 Subtyping of the HBsAg determinants has further enhanced epidemiologic studies. A relationship between subtype and virulence has not been unequivocally established. However, there is an association of subtype with geographic origin of the subject and with a particular route of infectionY Krugman and co-workers' demonstration that virus B can be transmitted by the feeding of infectious serum to susceptible human subjects 22 negated the belief that type B hepatitis, formerly referred to as "serum hepatitis," is transmitted only by parenteral routes. Ultimately, human beings transmit the virus via biologic fluids and excreta. Subhuman primates may also serve as a reservoir for the virus. HBsAg and anti-HBs have been detected in the sera of chimpanzees, but only virus A disease has been associated with the transmission of hepatitis from subhuman primates to human beings. 27 The virus propagates in the livers of human beings with acute and chronic hepatitis as well as those of asymptomatic carriers. The incubation period of virus B hepatitis, which varies from 28 to 160 days, contrasts with the shorter incubation period (2 to 6 weeks) of virus A hepatitis. An incubation period between 2 and 4 months is seen in most cases. Both dose and route of infection affect the duration of the incubation period. Infection with larger doses of virus, e.g., transfusion, is associated with shorter periods. Feeding of infectious serum as compared to parenteral inoculation of smaller doses lengthens the incubation period. 3
HEPATITIS B SURFACE ANTIGEN HBsAg can be detected approximately 1 to 2 months prior to, and as long as 1 to 2 months after, the onset of the icteric phase. The HBsAg may be present only for a few days or weeks during the course of acute viral hepatitis. If HBsAg is present in the serum for longer than 13 weeks, the patient becomes a chronic carrier, usually with chronic hepa"Associate Professor of Medicine, University of Miami School of Medicine; Chief, Hepatology Section, Veterans Administration Hospital, Miami, Florida
Medical Clinics of North America- Vo!. 59, No. 4, July 1974
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titis.44 Approximately 5 per cent of patients with acute hepatitis will become chronic carriers of HBsAg. The prevalence of HBs-antigenemia in a given population is related to geographic,~ socioeconomic, immunologic, and genetic factors. Inferior socioeconomic conditions, usually associated with bad sanitation and often associated with overcrowding, may be the primary factor responsible for the high incidence of antigenemia noted in warmer and subtropical regions. Whether or not one will become a chronic carrier of HBsAg, given a high degree of exposure and subsequent infection by the virus, seems to depend on immunologic and perhaps genetic factors. Immunologic deficiency states are associated with a high incidence of chronic HBs-antigenemia. A high carrier rate is found among patients with lepromatous leprosy, lymphoma, chronic renal dialysis patients, patients with Down's syndrome who have lived in large institutions, and in patients receiving immunosuppressive therapy. Dudley et al.lO have hypothesized that the persistence of HBsAg is related to a cell-mediated immune deficiency. Whether or not genetic predisposition to tolerate persistent antigenemia exists is not clear. Studies of familial clustering of virus B hepatitis infection tend to support a genetic predispositionY In general males have a higher incidence of HBsAg-positivity than females, but there are no significant racial differences in carrier rates. Regardless of the factors involved in the development of a carrier state, there is a wide spectrum of histological patterns, mostly abnormal, in the liver biopsies of such subjects. 39
ROUTES OF INFECTION HUMAN BLOOD. Very small amounts of infected blood are necessary to transmit hepatitis by parenteral routes. Barker et al. 4 demonstrated that inoculation of a milliliter of a 10-4 dilution of a pool of HBsAg-positive plasma could cause clinical hepatitis in the recipient. This undoubtedly accounts for the wide variety of parenteral modes of transmission. Even in the absence of detectable HBsAg, one cannot exclude the presence of virus B in the blood. Hoofnagle et al. 20 detected antibody to the hepatitis B core antigen (anti-HBc) in implicated donor blood specimens negative for HBsAg and anti-HBs. SALIVA. HBsAg has been detected by radioimmunoassay in the saliva of 76 per cent of patients with acute virus B hepatitis,43 primarily during the first 2 or 3 weeks after the onset of symptoms, and disappearing while still detectable in the serum. Anti-HBs was detected in the salivary secretions of these patients following the disappearance of the antigen and before the antibody was detectable in the serum. The HBsAg was intermittently found in the saliva of 86 per cent of chronic carriers. Anti-HBs was not detected in the saliva of the carriers. The presence of antigen in the saliva of all subjects studied was not related to blood contamination. Heathcote et al. IS found HBsAg in the saliva of 24 HBsAg-positive subjects. Serum/saliva ratios ranged from 50/1 to 25,000/1. Subtyping of the antigen detected in the serum and salivary samples confirmed the validity of the results. Data from other investiga-
EPIDEMIOLOGY OF VIRUS
B
HEPATITIS
837
tors have shown a lower incidence of HBsAg in saliva or negative results.46 The finding of HBsAg in saliva raises the possibility that saliva is a major vehicle of nonparenteral modes of transmission. However, the degree of infectivity of HBsAg-positive saliva and the potentially protective role of anti-HBs-positive saliva remains to be established. Virus B hepatitis may subsequently be shown to be transmitted by oral contact, as in kissing, if the infectivity of HBsAg-positive saliva is proven. Villarejos et: al.43 suggests that salivary transmission of hepatitis may occur among young children who share small toys and candies which they have chewed on. NASOPHARYNGEAL SECRETIONS. HBsAg has been detected by radioimmunoassay in 43 per cent of 40 sneeze specimens taken from HBsAg-positive subjects. 43 This finding raises the possibility that airborne transmission of HBsAg-positive droplets from carriers with upper respiratory infections may be a possible mechanism for spread of virus B hepatitis in closely confined quarters. SEMEN. Ten of 19 samples of semen from men with antigenemia were found to be HBsAg positive. '8 The serum/semen ratio varied between 1,250/1 and 250,000/1. All 10 men with positive semen also had positive saliva samples. Serum and semen subtypes were identical. URINE. HBsAg has been detected in urine. When concentrated specimens were tested with a radioimmunoassay technique, only a small percentage of patients with HBsAg-positive blood had detectable antigen in the urine. 43 Infectious urine, particularly in patients with urinary incontinence, could represent a potential mode of transmission. FECES. The presence of HBsAg in feces has not been unequivocally established. Villarejos et al.43 consistently failed to detect the hepatitis B antigen in any of 120 fecal extracts from positive carriers. The feeding of feces from patients with virus B hepatitis in an experimental setting has failed to produce hepatitis among the recipients. 25 Data regarding the presence of HB sAg in bile and in feces are contradictory.2, 15, 16,38 The observation that homogenates of human feces or intestinal mucosa when incubated with HBsAg-positive sera inhibit subsequent detection of antigen suggests that fecal transmission of virus B hepatitis seldom occurs,z°
MODES OF TRANSMISSION It is apparent that type B hepatitis can be transmitted both orally and parenterally. However, the fecal-oral route does not seem to represent a significant pathway in the transmission of virus B disease, and large epidemics of long-incubation hepatitis traced to a common source of contaminated food or water have not been observed. In view of the findings of Mahoney et al. 26 that HB sAg can be detected in clams harvested from waters contaminated by untreated sewage from a coastal hospital, the possibility of a shellfish-associated epidemic of long-incubation hepatitis exists but has not been established. In general, nonparenteral forms of virus B disease occur sporadically among adults. Recent trends in the epidemiology of viral hepatitis in the United
838
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SCHIFF
States have been reported by the Center For Disease Control. 6 A shift of virus B hepatitis has resulted in more cases among teenagers and young adults than among older adults since 1966. A growing number of cases of virus B hepatitis have been associated with parenteral drug abuse. In 1966,55 per cent of hepatitis B cases were associated with transfusion. In 1972 this percentage fell to 14 per cent, although over 60 per cent of the adults age 30 or older with virus B hepatitis had transfusion-associated disease. In 1966,34 per cent of the hepatitis B cases were associated with parenteral drug abuse, and in 1972 this percentage rose to 70 per cent. The largest increase in drug-associated hepatitis B disease was in the 15 to 29 year age group, which rose from 67% in 1966, peaked at 88% in 1968, and diminished slightly to 79 per cent in 1972. Paralleling these changes has been a decrease in the case-fatality ratio from 8.7 per cent in 1966 to 2 per cent in 1972. The case-fatality ratio remained greater than 5 per cent, however, among individuals age 30 or older whose hepatitis was primarily transfusion associatf'd. Another trend has been an increase in the percentage of virus B hepatitis cases with a history of nonparenteral personal contact. Undoubtedly, many of the cases reported as hepatitis A or unspecified hepatitis represent hepatitis B disease. Personal Contact In an epidemiologic survey designed to determine the source of infection in patients with virus B hepatitis, Heathcote and Sherlock 17 found nonparenteral spread more common than parenteral spread. Sexual or domestic contact was the definite or likely source of infection in 40 per cent of the 67 patients studied. Several investigations have revealed an association of an increased prevalence of HBsAg and antiHBs in sexually promiscuous and homosexual subjects. Fulford et al,12 noted that 13 per cent of patients in a venereal disease clinic who had negative serologic studies for virus B disease were either homosexual or bisexual. In contrast, 24 per cent of the HBsAg-positive group and 53 per cent of the anti-HBs-positive group were homosexual or bisexual. Thirty-eight per cent of the anti-HBs-positive group had sexual contact with 3 to 7 partners in the 6 months preceding the testing, in contrast to only 15 per cent of the group serologically negative for virus B disease. Papaevangelou et al,29 noted a prevalence of anti-HBs in prostitutes greater than twice that in the control group of pregnant women of similar age and socioeconomic levels. The prevalence of anti-HBs increased with increasing number of years in prostitution. Jeffries et al. 21 found higher rates of HBs-antigenemia among homosexual patients as compared to heterosexual control groups. The presence of HBsAg in saliva, semen, and serum suggests that the ingestion of any of these biologic fluids during close personal contact could result in the transmission of hepatitis, but this remains to be proven. A case of virus B hepatitis transmitted by a human bite has been reported and underscores the probable infectivity of saliva. Medical Environments The frequency of anti-HBs among health care personnel studied by Lewis et al. 23 was found to be twice that of matched controls with no ex-
EPIDEMIOLOGY OF VIRUS
B
HEPATITIS
839
po sure to patients or blood products. A history of hepatitis was also more common. Medical and para-medical personnel who have frequent contact with blood and blood products seem to be particularly at risk. The severity of this problem was brought to light by Rosenberg et al. 35 who epidemiologically linked four surgeons with HBsAg-positive hepatitis to a surgical patient requiring multiple transfusions in whom HBsAg-positive hepatitis subsequently developed. All the surgeons had admitted to finding holes in their gloves and cuts on their hands following major surgical procedures, especially when wire sutures were used, which was the case with their patient. Personnel handling the blood specimens of patients with hepatitis may inadvertently ingest serum while pipetting, spill blood on their hands that have sustained minor cuts and abrasions, or accidently stick themselves with contaminated needles at the time of a venosection or giving parenteral medications. Two high-risk areas in the hospital setting are the dialysis and oncology units. A survey of dialysis facilities in the United States by the Center for Disease Control revealed that over 80 per cent of the centers reported cases of viral hepatitis. l3 Similar experiences have been noted in European countries. In a recent survey of 15 dialysis centers, 50 per cent of the patients and 34 per cent of the staff had serologic evidence, either HBsAg or anti-HBs, of virus B exposure. 40 HBsAg was detected in approximately 16 per cent of the patients, a prevalence rate approximately 7-fold greater than that of the staff. This reservoir of antigen undoubtedly accounts for the frequently reported outbreaks of hepatitis among personnel in dialysis units. In general, hepatitis tends to run a milder, often inapparent clinical course in patients, as compared to the more overt and clinically severe course seen in staff members. The milder clinical course and the predisposition to develop chronic antigenemia in the dialysis patients, as contrasted with the staff patients, may be explained on the basis of immunologic differences in host responsiveness. The mode of transmission of hepatitis, usually from patient to staff, has not been clearly defined. Undoubtedly, direct contact with blood from the dialysis patients resulting in infection through skin breaks, puncture wounds of the skin, or accidental ingestion accounts for many cases. Hemodialysis technicians who work primarily with blood and blood-contaminated equipment, but who have less contact with the patients than nurses or physicians, are a group particularly at risk. 47 Although previous transfusions are thought to be the most likely explanation for the higher incidence of hepatitis among dialysis patients, patient to patient contact may be playing an important role in transmission. Air-borne transmission via droplets of blood or nasopharyngeal secretions has been suggested but certainly not documented. 3 , 43 Other consequences of the hepatitis reservoir in the dialysis unit include an increased incidence of hepatitis among renal transplant patients, an increased incidence in the hospital's local laboratories, and an increased risk for the development of hepatitis among family and close contacts at homeY A similar hospital-based focus of hepatitis is the oncology unit, where patients are more likely to develop virus B hepatitis because of their need for multiple transfusions of blood and blood products. These
840
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patients are predisposed to developing chronic antigenemia, probably because of their immunosuppressed state, in part a result of chemotherapy. Wands et al.4 5 reported a 19.5 per cent frequency of HBsAg-positive blood among 87 patients with tumor in an oncology unit. Rising titers of HBsAg were noted with the institution of high dose chemotherapy. Approximately 10 per cent of the personnel working in this unit developed clinically severe virus B hepatitis. Dental Environment Feldman and Schiff reported a significantly higher incidence of hepatitis among dentists than a control group of lawyers. 34 The highest rate was found among oral surgeons, who had an attack rate of 21 per cent as compared with a 5 per cent attack rate in general dentists. There have been two recent reports of virus B hepatitis transmission by dentists to their patients. Levin et a}.24 reported the development of virus B hepatitis in 12 patients treated by a HBsAg-positive dentist over a 4 month interval. Rimland and Parkin collected 53 clinical cases of virus B hepatitis over a 4 year period which they traced to a single oral surgeon. 33 An investigation revealed the implicated dentist to be an asymptomatic carrier of HBsAg of the same subtype as 6 of the 7 cases tested. A blood-oral mode of transmission was hypothesized on the basis of a history of frequent cuts on his fingers. The increased risk of hepatitis among dentists may be related to the failure to employ adequate prophylactic measures, particularly the wearing of gloves during procedures when treating high-risk patients such as drug abusers. Gloves would also prevent transmission of virus from cuts on the hand of a HBsAg carrier to a susceptible patient. Post-Transfusion Hepatitis Reports on the percentage of cases of post-transfusion hepatitis that can be attributed to virus B have varied from 25 to 80 per cent. 37 ,38 Whether or not the recipient of blood transfusions will develop hepatitis is dependent primarily on the source of the donor blood, the number of transfusions given, and the immune status of the recipient in reference to prior exposure to the hepatitis viruses. Commercial donor blood is associated with a 6-fold greater risk for the development of hepatitis among recipients. 37 A greater percentage of HBsAg-positive units is also found among commercial as compared to volunteer sources. Screening of donor blood for HBsAg had led to a decrease in the incidence of HBsAgpositive hepatitis; however, the overall decrease was below expectations, and it has recently become apparent that another virus or viruses may be responsible for HBsAg-negative long-incubation hepatitis. 32 The absence of HBsAg in donor blood, as determined by sensitive methodology such as radioimmunoassay, does not eliminate the possibility that the hepatitis B virus is present. Assays for HBcAg have demonstrated this and may ultimately become the best screening parameters for the presence of virus B.20 A progressive but nonlinear increase in the risk of developing hepatitis roughly parallels an increase in the number of units transfused. 38 Recipients who had prior exposure to virus B may be carriers of HBsAg or, more likely, may have developed anti-HBs, both of which would
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preclude the development of acute virus B hepatitis following transfusion with blood harboring the virus. Cherubin7 has demonstrated that the risk of developing post-transfusion hepatitis in recipients of HBsAgpositive blood is lower in a lower socioeconomic area, particularly where drug addiction was common, because of the high incidence of prior exposure to the hepatitis B virus. Transfusion of blood containing anti-HBs appears to carry no added risk. Aach et aLl showed that there was no significant difference in biochemical or overt virus B hepatitis or in serologic response to the hepatitis B virus among susceptible patients who received at least 1 unit of HBsAg-negative blood containing antiHBs. Concentrates of coagulation factors prepared from pooled plasma are notably fraught with a high risk to the recipient for the development of hepatitis. 2B Workers processing these concentrates from plasma in one facility w'ere found by Taylor et al. 42 to have a prevalence of 1.92 per cent HBs-antigenemia and a mean from 55 to 92 per cent of anti-HBs, depending on the degree of exposure to plasma. 42
OTHER PARENTERAL MODES The most common parenteral mode of transmission of virus B in recent years has been drug abuse (see the following article by Seeff). Any mechanism that involves the transfer of blood harboring virus B to a susceptible recipient is likely to lead to transmission of virus B hepatitis. Ear piercing, tatooing, injections with contaminated syringes and needles, and the sharing of razors have all been implicated. Blood-sucking insects, particularly mosquitos, harbor HBsAg but probably do not replicate the virus. 9 Mechanical transmission of the virus via mosquitoes may be responsible for otherwise unexplained virus B disease in tropical areas as well as some high density, lower socioeconomic urban areas in the United States. An unusual mode of transmission occurs among trackfinders in Scandinavia who frequently sustain cuts and scratches on their bodies and develop virus B hepatitis after bathing in contaminated waters. 34
Neonatal Hepatitis Schweitzer et aP6 have observed that virus B hepatitis in pregnancy results in a high frequency of chronic HBsAg-positive hepatitis in the infants, if the mother develops the illness in the third trimester or the immediate postpartum period. The mother who is a chronic carrier or contracts acute virus B hepatitis early in pregnancy is much less likely to transmit the disease to her infant. Transplacental transfer of virus B is apparently not the mode of transmission, and transmission probably occurs as a result of exposure at the time of delivery. The neonate subsequently develops HBsAg-positive antigenemia within 5 to 12 weeks.
CONCLUSION It has been established that virus B hepatitis can be transmitted by nonparenteral anu parenteral means. Recent evidence suggests that the
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fecal-oral route is not a significant mode of transmission. To further elucidate the epidemiology of this disease, it is incumbent upon every physician caring for a patient with hepatitis to attempt to determine the source and mode of transmission of the virus. All cases should be reported to the local Health Department, which has the facilities to further investigate the problem. Hepatology Section Veterans Administration Hospital 1201 N. W. 16th Street Miami, Florida 33125
