Download Journal of Clinical Virology The importance of being earnest

Journal of Clinical Virology 49 (2010) 79–81
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Journal of Clinical Virology
journal homepage: www.elsevier.com/locate/jcv
Virology Question and Answer Scheme (VIROQAS)
The importance of being earnest: Following up a low level hepatitis B
surface antigen (HBsAg) result
Cillian F. De Gascun ∗ , Marianne Fraher, Margaret Crean, Jeff Connell, William W. Hall
National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e
i n f o
Article history:
Received 16 October 2009
Received in revised form 6 May 2010
Accepted 8 May 2010
Case description
A 24 yr old Lithuanian woman (LA) resident in Ireland presented
to the antenatal service of her local (regional) hospital for the first
time at 36 weeks gestation in July 2008. Blood was drawn (sample
date 08/07) and sent to the National Virus Reference Laboratory
(NVRL) for antenatal screening for evidence of infection with
human immunodeficiency virus (HIV), hepatitis B virus (HBV),
and hepatitis C virus (HCV). The sample was weakly positive in
the HBsAg Abbott Architect (reading/cut-off: 0.29/0.05) and was
confirmed by neutralization in the Abbott Murex HBsAg assay. No
∗ Corresponding author. Tel.: +353 1 716 1349.
E-mail address: [email protected] (C.F. De Gascun).
1386-6532/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jcv.2010.05.001
other marker of HBV infection (including HBV e antigen (HBeAg),
e antibody (anti-HBe), HBcIgM, and anti-HBc) was detected. HIV
and HCV serological results were negative.
What is your interpretation of these results?
What further investigations are indicated?
How would you treat this lady’s newborn baby?
See evidence-based opinion overleaf
80
C.F. De Gascun et al. / Journal of Clinical Virology 49 (2010) 79–81
Virology Question and Answer Scheme (VIROQAS)
Evidence-based opinion
What is your interpretation of these results?
The serological profile would be consistent with three possible scenarios: (i) early HBV infection1 ; (ii) cross-reactivity as
the result of recent vaccination with recombinant HBsAg2 ; or
(iii) non-specific cross-reactivity within the assay, perhaps due
to the physiological state of pregnancy, as has been reported
with enzyme-linked immunosorbent assays (ELISA) for other viral
infections.3 Reactivity in the HBsAg assay was neutralized with specific anti-sera and this would suggest the presence of HBsAg, due
either to early infection or recent vaccination.
What further investigations are indicated?
Health-care providers should test all pregnant women for HBsAg
during an early prenatal visit (e.g., first trimester) in each pregnancy, even if they have been previously vaccinated or tested.4–6
In addition, those women who engage in behaviours that put them
at high risk for infection (e.g., injection-drug use, multiple sexual
partners in previous 6 months, evaluation or treatment for a sexually transmitted infection [STI]), and those with clinical hepatitis
should be re-tested at the time of admission to the hospital for
delivery. At present, there are no recommendations for the use
of hepatitis B DNA testing in pregnancy. However, maternal HBV
viraemia has been implicated as the most important factor associated with failure of neonatal vaccination to prevent transmission
of infection.7,8
In the case presented here, no further investigations were performed on the initial sample. However, the low level HBsAg result
was phoned to the referring hospital and a follow-up sample –
intended primarily to exclude early HBV infection – requested. A
small gradual increase in reactivity in the Abbott Architect HBsAg
assay was observed in three follow-up samples received on 14/07
(sample 2), 22/07 (sample 3), and 10/08 (sample 4), with OD/CO
ratios of 0.40/0.05, 0.65/0.05, and 2.16/0.05, respectively (Table 1).
However, all other markers of HBV infection remained undetected.
LA presented to her primary care physician for the infant’s 6week check-up on 01/10/08 (sample 5). As requested in the hospital
discharge letter, blood was drawn for HBV serology. HBsAg was not
detected. In addition HBeAg was not detected; however HBcIgM
(>200 mIU/ml), anti-HBc, anti-HBe, and anti-HBs were detected.
Based on these results, HBV DNA investigations using the Roche
COBAS Amplicor HBV Monitor were performed retrospectively on
previous samples received in which sufficient volume remained.
HBV DNA was detected in the first (July 8) and second (July 14) samples with viral loads of 1530 IU/ml and 2200 IU/ml, respectively.
There was insufficient sample volume remaining to test samples 3
and 4; HBV DNA was not detected in sample 5. Furthermore, a final
sample collected 14/10 (sample 6), confirmed a serological profile
consistent with recent but resolving HBV infection: again, HBV DNA
was not detected.
How would you treat this lady’s newborn baby?
Perinatally acquired HBV results in chronic infection in more
than 90% of infected infants, up to 25% of whom will eventually develop HBV related hepatocellular carcinoma or cirrhosis.
Transmission of perinatal infection can be prevented in ∼95% of
infants born to HBsAg-positive mothers by early active and passive
immunoprophylaxis of the infant.4
The American Academy of Pediatrics (Red Book) recommends
that infants born to HBsAg-positive mothers receive the initial
dose of hepatitis B vaccine within 12 h of birth, and that hepatitis B immunoglobulin (HBIG) is given concurrently, but at a
different anatomic site.4 In contrast, the UK Department of Health
(Green Book) recommends HBV vaccination for all infants born to
HBsAg-positive mothers, whereas HBIG is only recommended if the
mother’s anti-HBe status is negative or unknown, or if the mother
had acute HBV infection during pregnancy.5 Irish (Blue Book) recommendations concur with those of the AAP.6
The infant in this case received HBV vaccine at birth (and will
complete the course at 2 months, 4 months, and 6 months of age
as part of the national universal childhood immunization [6 in 1]
schedule); hepatitis B immunoglobulin was not administered, as
it was believed – wrongly, it transpires – the HBsAg result was
unlikely to be significant.
Discussion
This case highlights the importance of follow-up testing when a
weak positive HBsAg result is generated: of particular importance is
the requirement to perform anti-HBc investigation even if HBsAg is
not detected on follow-up. If the first and final samples in this case
were tested for HBsAg only, it is probable the patient would not
have been identified as HBV infected. Whilst it is unusual HBeAg
was not detected in this case, this may have been detectable for a
short time between samples 4 and 5 (10/8 and 1/10). Of note, the
patient was infected with wild type virus as anti-HBe was detected
and also the probable source of infection – subsequently identified as the patient’s partner who was diagnosed with chronic HBV
infection on a sample dated 01/10/08 – tested HBeAg positive.
The patient described was asymptomatic through the course of
the acute HBV infection. Although anicteric infection in itself is not
that unusual,10 this case does highlight the importance of antenatal screening programmes as a means of identifying individuals
unknowingly infected with a vertically (and horizontally) transmissible infectious disease. That being said, it is also possible that the
non-specific HBV-associated symptoms were in this case attributed
by the patient to pregnancy.
With the benefit of hindsight, the diagnosis of HBV infection
could have been confirmed earlier with DNA testing. However,
it has been our policy not to utilise molecular assays for screening/diagnostic (as against confirmatory/monitoring) purposes, as
low level DNA results may be generated that are the result of nonspecificity within the assay rather than true infection.11
Table 1
Hepatitis B serological progression from July to October 2008.
Sample date
HBsAg (reading/cut-off)
Anti-HBs (mIU/ml)
HBeAg
Anti-HBe
Anti-HBc
HBcIgM
HBV DNA (IU/ml)
July 8
July 14
July 22
August 10
October 1
October 14
0.29/0.05
0.40/0.05
0.65/0.05
2.16/0.05
Negative
Negative
Negative
Negative
ins
ins
128
228
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
ins
Negative
Positive
Positive
Negative
Negative
ins
Negative
Positive
Positive
Negative
Negative
Negative
Negative
Positive
Positive
1530
2200
ins
ins
nd
nd
nd, not detected; ins, insufficient sample volume for test.
C.F. De Gascun et al. / Journal of Clinical Virology 49 (2010) 79–81
The HBV status of the infant in this case was assessed at 8 months
of age, following completion of the course of vaccination against
HBV. At that time, the infant tested negative for HBsAg, HBeAg, antiHBe, anti-HBc, and HBV DNA: anti-HBs was detected at a level of
134 mIU/ml, indicating the child had not become infected with HBV
(despite not having received HBIg at birth). While maternal acute
hepatitis B infection does not necessarily pose a significant risk to
the neonate if the mother has had time to clear her hepatitis before
delivery, the fact that acute HBV in the third trimester of pregnancy
– as reported here – did not result in neonatal infection is unusual.7
However, it may be explained in this case by the low level HBV
viraemia observed in the mother, as transmission is more likely
to occur when the mother’s viral load is high.8,9 Nevertheless, in
keeping with the Green Book Recommendations, HBIg (in addition
to HBV vaccination) should have been administered to the neonate
at birth to reduce the risk of neonatal infection.5
Conclusion
This case illustrates the importance of not dismissing weakly
positive HBsAg results, and raises the issue of whether HBV DNA
testing should be routinely performed in this patient cohort with
limited serological evidence of HBV infection. The use of serological assays – even those that are highly sensitive and specific –
is compromised by the generation of false-positive results especially when testing low-risk populations, e.g., in national screening
programmes.12 In the case presented here, the potential outcome
was highly significant.
Competing interest
None declared.
81
Ethical approval
Not required.
Funding
None.
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