<div>Introduction</div><div>The incidence of hepatitis B virus (HBV) infection is expected to reduce
in the future with the implementation of HBV mother-to-child infection
prevention projects and universal HBV vaccination. In addition, the
development of antiviral drugs for HBV has contributed to the reduction
of the infection rate. However, to date, no countermeasures have been
established against horizontal infection such as paternal infection of
HBV in non-vaccinated children. Here, we report a case of paternal HBV
infection that resulted in different clinical courses of HBV infection
between siblings.</div><div>Case History</div><div>Case 1</div><div>The first patient was a 1-year-4-month-old girl. Her birth and medical
history were unremarkable. She presented with vomiting 3 days and
diarrhea 2 days before being admitted to our hospital with a diagnosis
of acute rotavirus gastroenteritis. Her laboratory findings on admission
showed severe liver dysfunction, with an alanine aminotransferase (ALT)
level of 583 U/L and aspartate aminotransferase (AST) level of 406 U/L.
Simultaneously, the tests for hepatitis B surface antigen (HBsAg) and
immunoglobulin M antibody to hepatitis B core antigen were positive.
Therefore, she was diagnosed with acute hepatitis B. She had not been
vaccinated against HBV. With conservative treatment such as rest and
hydration, her symptoms improved without a fulminant course. She was
discharged on the 10th hospital day. Three months after the onset, her
tests revealed seroconversion. Eventually, at 8 years of age, she was
declared HBsAg negative, and virological remission was achieved (Table
1).</div><div>Case 2</div><div>The second patient was a 2-year-7-month-old girl and was an older
sibling of the first patient. She was born with a low birth weight of
2,272 g. She had neither medical history nor vaccination against HBV.
Although she had no symptoms when the first patient was diagnosed with
acute hepatitis B, her laboratory findings revealed mild liver
dysfunction, with an ALT level of 87 U/L and an AST level of 79 U/L. She
was HBsAg positive, hepatitis B envelope antigen (HBeAg) positive, and
hepatitis B envelope antibody negative. Her HBV DNA (PCR) was high
(&gt;8.2 log IU/L), and the HBV genotype was type B.
Simultaneously, she was diagnosed as an HBV carrier. Since then, she had
been followed up for inactive chronic hepatitis, and seroconversion was
detected at the age of 3 years and 8 months (Table 2). To date, she is
being followed up in an outpatient clinic as an inactive carrier of HBV.
When the first patient developed acute hepatitis, her father was HBeAg
positive, whereas her mother was HBsAg negative and anti-hepatitis B
surface antibody positive. Therefore, HBV infection of these siblings
was considered to be transmitted from their father. Their father was an
asymptomatic HBV carrier; however, the source of infection was unknown.</div><div>Discussion</div><div>In this report, we observed different clinical courses of horizontal HBV
infection in siblings, transmitted from their father. HBV is detected
not only in blood but also in urine, saliva, nasopharynx, and tears,
which may be sources of infection.<sup>1</sup> Therefore, the
risk of HBV horizontal infection in daily life exists. In the
literature, the prevalence of HBsAg carriage among children of 1 year or
older has been reported to be higher than that among those aged under 1
year.<sup>2</sup> This pattern of age distribution suggests that
horizontal infection is an important route of HBV infection during early
childhood.<sup>2</sup> Vaccine failure of mother-to-child
infection is the major cause of chronic HBV infection in Japanese
children, with paternal infection being the second most common mode of
transmission.<sup>3</sup> Although the incidence of paternal
infection has been reported to be lower than that of mother-to-child
infection, 19.2% of HBeAg-positive fathers have been reported to
transmit HBV infection to their children.<sup>4</sup> In our
report, the HBV genotype of the sibling’s father was not examined, but
we diagnosed that the route of HBV transmission of the siblings was
paternal, as no other HBV-infected person, except their father, was
detected as a possible contact. Infants are susceptible to chronic
persistent HBV infection owing to poor cytotoxic T-cell (CTL)
response.<sup>5</sup> Therefore, the CTL response of the second
patient might have been weaker than that of her sibling. In addition,
genetic variants in the HLA-DP locus, including HLA-DPA1 and HLA-DPB1,
are associated with the chronicity of hepatitis B in
literature.<sup>6</sup> Therefore, the second patient may have
genetic variants in the HLA-DP gene.</div><div>To prevent mother-to-child HBV infection, HBV screening and preventive
measures for pregnant women have been created. In contrast, HBV
screening of fathers and other family members is necessary to prevent
horizontal infection.<sup>7</sup> The World Health Organization
recommends universal vaccination to eradicate HBV.<sup>8</sup>Despite routine immunization of infants with HBV vaccine being initiated
in 2016 in Japan, many children are unvaccinated. Therefore, we must
remember that some children do not benefit from the HBV vaccine,
especially those who are out of their routine vaccination age.</div><div>In conclusion, we reported a case of paternal HBV infection that
resulted in varying clinical presentations of HBV infection in the
offspring. Our findings suggest that we should encourage the
administration of HBV vaccination for all children and screening of HBV
infection to all family members, including fathers. These measures are
expected to minimize horizontal infection of HBV.</div><div>Conflicts of interest</div><div>None declared</div><div>Acknowledgement</div><div>No relevant acknowledgments.</div><div>Author Contributions:</div><div>YS wrote the manuscript. HK critically reviewed the manuscript. All
authors read and approved the final manuscript.</div><div>References</div><div>1. Kidd-Ljunggren K, Holmberg A, Bläckberg J, et al. High levels of
hepatitis B virus DNA in body fluids from chronic carriers. <i>J Hosp
Infect</i> 2006;64:352-357.</div><div>2. Yao GB. Importance of perinatal versus horizontal transmission of
hepatitis B virus infection in China. <i>Gut</i> 1996;38:S39-42.</div><div>3. Komatsu H, Inui A, Sogo T, et al. Source of transmission in children
with chronic hepatitis B infection after the implementation of a
strategy for prevention in those at high risk. <i>Hepatol Res</i>2009;39:569-576.</div><div>4. Hann HWL, Hann RS, Maddrey WC. Hepatitis B virus infection in 6,130
unvaccinated Korean-Americans surveyed between 1988 and 1990. <i>Am J
Gastroenterol</i> 2007;102:767-772.</div><div>5. Rehermann B, Chang KM, McHutchinson J, et al. Differential cytotoxic
T-lymphocyte responsiveness to the hepatitis B and C viruses in
chronically infected patients. <i>J Virol</i> 1996;70:7092-7102.</div><div>6. Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide
association study identifies variants in the HLA-DP locus associated
with chronic hepatitis B in Asians. <i>Nat Genet</i> 2009;41:591-595.</div><div>7. Bhat M, Ghali P, Deschenes M, et al. Prevention and management of
chronic hepatitis B. <i>Int J Prev Med</i> 2014;5:S200-207.</div><div>8. World Health Organization. Guidelines for the prevention, care and
treatment of persons with chronic hepatitis B infection. <i>WHO Web
site.</i>https://www.who.int/hepatitis/publications/hepatitis-b-guidelines/en/.
Published March 2015. Accessed August 26, 2020.</div><div>Table legends</div><div>Table 1. Laboratory results of the first patient</div><div><i>HBsAg:</i> Hepatitis B surface antigen, <i>Anti-HBs:</i>Anti-hepatitis B surface antibody, <i>IgM anti-HBc:</i> Immunoglobulin M
antibody to hepatitis B core antigen, <i>HBeAg:</i> Hepatitis B envelope
antigen, <i>Anti-HBe:</i> Anti-hepatitis B envelope antibody, <i>HBV
DNA:</i> Hepatitis B virus-deoxyribonucleic acid, <i>ALT:</i> alanine
aminotransferase, <i>AST:</i> aspartate aminotransferase, blank: no
result available, neg: negative, pos: positive, N.D: not detected</div><div>Table 2. Laboratory results of the second patient</div><div><i>HBsAg:</i> Hepatitis B surface antigen, <i>Anti-HBs:</i>Anti-hepatitis B surface antibody, <i>IgM anti-HBc:</i> Immunoglobulin M
antibody to hepatitis B core antigen, <i>HBeAg:</i> Hepatitis B envelope
antigen, <i>Anti-HBe:</i> Anti-hepatitis B envelope antibody, <i>HBV
DNA:</i> Hepatitis B virus-deoxyribonucleic acid, <i>ALT:</i> alanine
aminotransferase, <i>AST:</i> aspartate aminotransferase, blank: no
result available, neg: negative, pos: positive, N.D: not detected</div>