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Persistence of hepatitis B surface antigen in blood in a chronic haemodialysis patient following vaccination booster

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Abstract

Patients receiving haemodialysis are at an increased risk of hepatitis B infection; regular screening for incident infection and vaccination of susceptible individuals is recommended. Haemodialysis patients often require repeated high-dose hepatitis B vaccination boosters because of impaired response. Since the hepatitis B surface antigen is used as an immunogenic agent for vaccination and as a marker of hepatitis B infection, it has occasionally been detected in the blood shortly after vaccine administration and can be mistaken for a new infection. These transient results, however, are unlikely to persist for longer than 14 days after vaccination. We report the case of a haemodialysis patient who tested weakly positive for hepatitis B surface antigen 52 days after a vaccine booster. This is the longest vaccine-induced antigenaemia described in the literature and indicates that vaccination can cause weakly positive hepatitis B surface antigen results for longer than previously reported.
CASE REPORT
Persistence of hepatitis B surface antigen
in blood in a chronic haemodialysis patient
following vaccination booster
Giorgio Calisti,
1
Omar Herman,
1
Michelle Powley,
2
Tanzina Haque
1
1
Department of Virology, Royal
Free London NHS Foundation
Trust, London, UK
2
Department of Renal
Medicine, Royal Free London
NHS Foundation Trust, London,
UK
Correspondence to
Dr Giorgio Calisti,
giorgiocalisti@gmail.com
Accepted 25 May 2014
To cite: Calisti G,
Herman O, Powley M, et al.
BMJ Case Rep Published
online: [please include Day
Month Year] doi:10.1136/
bcr-2013-202191
SUMMARY
Patients receiving haemodialysis are at an increased risk
of hepatitis B infection; regular screening for incident
infection and vaccination of susceptible individuals is
recommended. Haemodialysis patients often require
repeated high-dose hepatitis B vaccination boosters
because of impaired response. Since the hepatitis
B surface antigen is used as an immunogenic agent for
vaccination and as a marker of hepatitis B infection, it
has occasionally been detected in the blood shortly after
vaccine administration and can be mistaken for a new
infection. These transient results, however, are unlikely
to persist for longer than 14 days after vaccination. We
report the case of a haemodialysis patient who tested
weakly positive for hepatitis B surface antigen 52 days
after a vaccine booster. This is the longest vaccine-
induced antigenaemia described in the literature and
indicates that vaccination can cause weakly positive
hepatitis B surface antigen results for longer than
previously reported.
BACKGROUND
Hepatitis B virus (HBV) is a highly infectious virus
that can be transmitted through exposure to blood
and other bodily uids. HBV can survive for long
periods on environmental surfaces and contact with
small amount of infected blood can transmit the
infection. Owing to the repeated exposure to bodily
uids during dialysis procedures, the increased likeli-
hood to be hospitalised to undergo interventional
procedures and to require blood product transfu-
sions, patients receiving chronic haemodialysis (HD)
are at an increased risk of HBV infection.
1
Furthermore, due to the uraemia-associated immune
dysfunction, HD patients are also more likely to
become chronic carriers once infected.
2
The key
principles of HBV infection control in dialysis units
include screening of all HD patients, segregation of
those who are infectious and vaccination of suscep-
tible individuals.
3
The widespread implementation of
these measures has led to a dramatic decline in the
incidence of HBV infection in dialysis patients over
the past decades; however, sporadic outbreaks con-
tinue to occur even in developed countries, due to
breaches in infection control procedures and subopti-
mal immunisation of susceptible individuals.
4
Hepatitis B surface antigen (HBsAg), a protein
component of the viral envelope, is the serological
hallmark of a current HBV infection and is the most
commonly used marker to screen for the presence
of HBV in the blood. All hepatitis B vaccines
currently available contain puried HBsAg. In
responders, they induce production of antibodies
(hepatitis B surface antibody, HbsAb) against the
HBsAg that confer protection against acute HBV
infection. A three-dose course of hepatitis B vaccine
induces a response dened as a titre of HBsAb
>10 IU/L in >90% of healthy individuals.
5
Unfortunately, responsiveness rates are reduced in
end-stage renal failure and HD patients, and even in
responders HBsAb titres tend to decline more
rapidly.
6
For this reason, regular screening for hepa-
titis B serological markers for all patients and yearly
double-dose vaccination boosters when HBsAb
titres decline are often required.
3
Since HBsAg is used as an immunogenic agent
for vaccination and as a marker of HBV infection,
recent vaccination may result in transiently detect-
able levels of HBsAg in blood. These false-positive
results, however, usually do not persist beyond
14 days postvaccination, although few cases of
more prolonged antigenaemia have been reported,
the longest being 28 days in a HD patient.
7
We report the case of a patient who tested
weakly positive for HBsAg 52 days after administra-
tion of a double-dose vaccination booster for
declining HBsAb titres. Owing to the long-time
interval, the link between the vaccination booster
and the HBsAg detection was not initially recog-
nised and this led to the patient being dialysed in
segregation until the results of the conrmatory
investigations became available and the causative
link with the booster was nally elucidated.
CASE PRESENTATION
As part of a routine three monthly screening for
blood born viruses, a patient on regular HD tested
weakly positive for HBsAg by chemiluminescent
microparticle immunoassay. The HBsAg neutralisa-
tion assay was positive, ruling out a non-specic
reactivity in the HBsAg screening assay. While
awaiting the results of further investigations, the
patient needed to receive dialysis in isolation as
recommended for a patient with suspected hepatitis
B infection. Other than the HD, no risk factors for
hepatitis B acquisition were identied and no
known breaches in the HD procedures had
occurred in the preceding months. The patient did
not present symptoms suggestive of an acute viral
hepatitis, and alanine aminotransferase value was
within the normal range. Looking back at previous
serology results, 12 weeks prior to the positive
HBsAg result the patient was HBsAg negative,
Calisti G, et al.BMJ Case Rep 2014. doi:10.1136/bcr-2013-202191 1
Reminder of important clinical lesson
hepatitis B core total antibody negative and had an HBsAb titre
of 39 IU/L.
INVESTIGATIONS
On the following day the results of the conrmatory investiga-
tions on the same serum sample that tested weakly positive
for HBsAg became available. No HBV DNA was detected
(<10 IU/L), hepatitis B core IgM and total antibodies tested
negative and HBsAb were detected at a titre of 303 IU/L.
OUTCOME AND FOLLOW-UP
Enquiring further about the vaccination history, it became clear
that the patient received a double-dose (40 μg) booster of hepa-
titis B vaccine (HBVaxPro) 52 days prior to the weak HBsAg
positivity. Retested after 4 days, at 56 days from booster admin-
istration, the HBsAg was negative. Three months later the
patient died of an unrelated cause.
DISCUSSION
The presence of HBsAg in blood indicates current HBV infec-
tion and patients tested HBsAg positive are regarded as infec-
tious. HBsAg is the earliest serological marker of an acute HBV
infection and its persistence for longer than 6 months indicates
a chronic HBV infection. HBsAg is usually detected by immu-
noassays that use HBsAb to capture antigen in the sample. As
with all immunoassays, non-specic binding can produce false-
positive results. Usually, a non-specic binding induces a weakly
positive result but exceptions are not uncommon. The more
specic neutralisation tests are commonly used to conrm
HbsAg-positive results. In neutralisation tests, a reactive sample
is incubated with reagent HBsAb and then run in parallel with
an aliquot of sample that has not been treated with the reagent
antibody. If truly present in the sample, HBsAg is neutralised by
the antibody and a reduction of signal is seen when compared
with the untreated aliquot of sample (positive neutralisation
test). A positive neutralisation test result virtually rules out a
non-specic HBsAg reactivity and is considered the denitive
test result for HBsAg. Our patients weak positivity in the
HBsAg screening assay was conrmed by a positive neutralisa-
tion test, indicating the actual presence of HBsAg in the serum.
This narrowed the spectrum of possibilities to endogenous pro-
duction of HBsAg, as a result of a current hepatitis B infection,
or exogenous inoculation of HBsAg, as a result of hepatitis
B vaccination. The possibility of an acute hepatitis B seemed
very unlikely because no breaches in the HD infection control
procedures had occurred in the preceding months, nor other
risk factors for hepatitis B infection could be identied, and
because the patient did not present any clinical or biochemical
sign of an acute viral hepatitis. Furthermore, the patient had
been fully immunised for hepatitis B prior to starting HD and
had responded to the vaccination course demonstrating an
HBsAb titre >100 IU/L at the end of it, although the HBsAb
titre had declined to 39 IU/L in the most recent sample.
Nonetheless, cases of breakthrough hepatitis B infection in pre-
viously immunised patients have been reported, caused by HBV
genotypes E and F towards which current vaccines do not
confer full protection.
89
The most likely explanation for the
weakly positive HBsAg result in our patient seemed a recent
vaccination; however, given the long interval between the
vaccine booster administration and the HBsAg positivity the
causative link was not initially recognised and the patient was
dialysed in isolation for one session.
In the rst years following the introduction of hepatitis B vac-
cination, it was thought that hepatitis B antigenaemia as a result
of immunisation did not occur; this assumption was based on
Katkovs study that reported no positive HBsAg result 1 and
24 h after administration of the plasma-derived hepatitis
B vaccine Heptavax-B.
10
However, subsequent studies using the
yeast-derived recombinant vaccine Engerix-B showed relatively
high rates of HBsAg detection in the rst few days following
vaccination in infants as well as in adults.
11 12
In adults, most of
the cases are seen in HD patients; in a recent retrospective ana-
lysis of the vaccine-induced HBsAg weakly reactive tests
observed in a tertiary care medical centre in a 17-month period,
10 of 11 cases occurred in HD patients.
13
This could be due to
the fact that HD patients are screened on a regular basis, are
more likely to receive vaccine booster and are usually immu-
nised with double dose (40 μg) of vaccine. It has also been
hypothesised that the decreased ability to produce neutralising
HBsAb following vaccination may result in a less-effective clear-
ance of the inoculated HBsAg. Indeed, Santana Rodriguez et al
reported a signicant association between the presence of transi-
ent antigenaemia and the non-responder status in a group of
HD patients. In their study, they also reported a rate of HBsAg
positivity following vaccination of 31.5%, with no cases of anti-
genaemia persisting for longer than 11 days.
14
As far as the duration of the antigenaemia is concerned, previ-
ous studies suggest that it is unlikely to persist for longer than
14 days.
13
Nonetheless, a case of antigenaemia persisting for up
to 28 days has been reported in a HD patient.
7
The 52-day dur-
ation that we report is the longest that has been described so
far. Notably, our patient was a vaccine responder and mounted
a good response also to the last booster, as demonstrated by the
increase in the HBsAb titre from 39 to 303 IU/L. Indeed, our
patient had no dened immunodeciency and the total lympho-
cyte count was within the normal range. Other factors, such as
differences in body composition, tissue absorption, blood ow
and density of antigen-presenting cells in the muscle, might
have all contributed to the long antigenaemia described.
In conclusion, the case we report suggests that recent adminis-
tration of hepatitis B vaccine, especially when given at a double
dose, should be considered among the possible explanations for
a newly detectable HBsAg for longer than previously thought.
Learning points
Haemodialysis patients are at increased risk of hepatitis
B infection and susceptible individuals should be regularly
screened and vaccinated.
Vaccination response is impaired in haemodialysis patients,
and even responders require repeated boosters of high-dose
vaccine due to rapid decline of hepatitis B surface antibody
titres.
Owing to hepatitis B surface antigen (HBsAg) being used as
a marker of current hepatitis B virus infection and as the
immunogenic agent in the vaccine, transiently detectable
levels of HBsAg can occur following vaccination and can be
mistaken for a new infection.
Although vaccine-induced hepatitis B surface antigenaemia
usually resolves within 2 weeks of vaccination, rarely it can
persist for up to 78 weeks.
Contributors All authors were involved in the patient care and contributed to the
preparation of the manuscript.
2 Calisti G, et al.BMJ Case Rep 2014. doi:10.1136/bcr-2013-202191
Reminder of important clinical lesson
Competing interests None.
Patient consent None.
Provenance and peer review Not commissioned; externally peer reviewed.
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Calisti G, et al.BMJ Case Rep 2014. doi:10.1136/bcr-2013-202191 3
Reminder of important clinical lesson
... 6,14,22 Los pacientes con IRC en diálisis crónica poseen características inmunológicas que facilitan la infección por virus de hepatitis B y su transmisión nosocomial. 1,8,9,23 en las últimas décadas la incidencia y prevalencia de hepatitis B en estos pacientes ha disminuido, 11,24 los resultados de esta investigación coinciden con los hallazgos reportados en estudios realizados en provincias del Occidente y Oriente de Cuba. 5,6,17 Países con baja endemicidad que mantienen la pesquisa rutinaria de donantes y hemoderivados y un programa de vacunación contra la hepatitis B muestran resultados similares. ...
... 2,12,19,25 Es conocido que la respuesta entre los hemodializados crónicos es inferior que en la población general, reportes internacionales estiman que menos de 60% de los pacientes hemodializados están protegidos. 8,11,23,[25][26][27][28] Un estudio longitudinal de 8 años realizado en Brasil estableció que el grado de protección se incrementaba tras la seroconversión alcanzada en pacientes hemodializados inicialmente no respondientes, que recibían dosis de refuerzo con la vacuna contra la hepatitis B. 25 Los resultados registrados en la presente investigación son alentadores con más de 70 % de pacientes protegidos contra la hepatitis B pero la ausencia de información epidemiológica acerca de los aspectos relacionados con la vacunación limita el alcance de los resultados en cuanto a durabilidad y magnitud de la respuesta, vinculo con el tiempo de diálisis y grado de insuficiencia renal, aspectos que pudieran constituir puntos de comparación con otros estudios. 25,29,30 Los pacientes no protegidos constituyen un grupo vulnerable de infección por HBV esta es la base de investigaciones que evalúan la eficacia de la vacunación en la seroconversión de los no respondedores. ...
... In two studies on neonates 17-55% were positive at day 1-3, and all negative at two weeks following HBV vaccination [1,2]. Later, similar data were reported for a low number of adult blood donors, with 47% positive [3]; however, there are reports on hemodialysis patients with a HBsAg finding up to 52 days post-vaccination [4][5][6][7]. Because a vaccine-related HBsAg finding can have important consequences, by wrongly guiding clinical diagnostic work and by causing permanent disqualification of a healthy blood donor, we set out to determine the frequency and duration of blood HBsAg positivity in a larger series of vaccinated subjects. ...
... Occult infection occurs when HBsAg is undetectable despite the presence of HBV DNA (66)(67)(68). Transient HBsAg positivity can occur up to 18 days following vaccination (up to 52 days among hemodialysis patients) and is clinically insignificant (69). ...
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