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PapersProspective investigation of transfusion transmitted infection in recipients of over 20 000 units of bloodFiona A M Regan National Blood Service, London and South East
Zone, North London Centre, London NW9 5BG
Correspondence to: P Hewitt patricia.hewitt@nbs.nhs.uk Abstract Objectives: To follow up recipients of 20 000
units of blood to identify any transmissions of infections
through blood transfusion. Introduction In recent years there has been increased public
concern about the safety of blood transfusion with respect to
transfusion transmitted infections. HIV-1, HIV-2,
hepatitis B, hepatitis C, and human T cell
leukaemia/lymphoma virus are transmissible by transfusion
and are associated with important clinical disease. Every
effort is made to minimise the risk of disease transmission, and
in the United Kingdom blood is collected from voluntary, unpaid donors
after careful questioning and selection. All donations are
screened for hepatitis B surface antigen and antibodies to HIV-1
and HIV-2, hepatitis C virus, and syphilis with assays of steadily
increasing sensitivity. A theoretical possibility of transmission
remains if the donor is in the "window period" of an
infection (that is, infectious but has not developed detectable markers
of infection) or if the donor is a "low level carrier,"
in whom the level of markers of chronic infection is below the
sensitivity of currently used assays (for example, for
hepatitis B surface antigen). In addition, rare strain
variants of a virus may not be detectable by certain
routine tests, and possibilities of technical or clerical
errors in screening or quarantining blood components
remain, although these are increasingly rare as automation and
computerised information transfer improves. Previously, estimates of the incidence of
transfusion transmitted infection have relied on reported cases of
infection, but these are often asymptomatic and even when
obvious are underreported. A study in the United Kingdom
before screening for anti-hepatitis C virus showed that
the incidence of post-transfusion non-A, non-B hepatitis
was 0.26%.1 A study in the United States
between 1985 and 1988 showed that transmission
of HIV (and human T cell leukaemia/lymphoma virus) was
possible from donations which had been screened for
anti-HIV.2 There have been no
corresponding UK data for transmission of infections,
which is needed so that informed decisions regarding
transfusion practice can be made by clinicians and
patients. This will be particularly relevant if informed
consent for transfusion is ever introduced in the United
Kingdom. This prospective study aimed to estimate directly
the incidence of transfusion transmitted infections: hepatitis B and
C and HIV, for which donated blood is tested, and also
human T cell leukaemia/lymphoma virus, for which blood is
not currently tested in the United Kingdom. At the start
of the study in 1991 we planned to study recipients
of 20 000 units of blood; this was based on estimates
of the residual risks of infections at that time. Current estimates
of risk in the United States3 and the
United Kingdom (Barbara J and Soldan K, personal
communication, 1999), based on the incidence, prevalence,
and window periods of infections in donors, indicate lower
risks of infection, so that a prospective study following
a large enough number of recipients to define precisely
the risk of infections would not be feasible. Follow up of
recipients of even 20 000 units of blood, however, would provide
direct evidence of the level of safety, within defined limits,
in the absence of screening for antibodies to hepatitis B
core antigen and anti-human T cell leukaemia/lymphoma virus.
Methods Participants and samples Initially, a team member explained the study and
the tests entailed. Participation was voluntary, and patients were
free to withdraw at any time. Written consent was
obtained, and a pretransfusion serum sample was stored
frozen at -20°C. The identity of the red cells transfused
was documented. The study assessed the infectious risk
only of red cells, though we also estimated the numbers of other
blood components (fresh frozen plasma, platelets, cryoprecipitate)
transfused, by extrapolation from known data for 100 patients
from each of four hospitals.
Nine months after transfusion each patient was
counselled, and, from those still willing to participate, we obtained
written consent for testing and a 20 ml sample of
blood. Serum was separated within 12 hours and stored
at -20°C. To complete the study on time the last 940 patients
were followed up at six rather than nine months after
transfusion as tests with enhanced sensitivity became
available.4 Microbiological testing Table 1.
Table 2. When we calculated the risk of infection
transmitted by transfusion, units received by patients with
pre-existing infections were discounted. Results We recruited 9220 patients (fig 2).
Of these, 3641 (39.4%) were withdrawn before follow up, either
because they died (657), they were untraceable (250), or
were too ill to participate (2734). We successfully
followed up 5579 (60.5%; 3000 women and 2579 men).
The mean (range) age was 67 (16-96) years, and in total
they received 21 923 units of red cells (mean (range)
3.9 (1 to 98) units per patient). This
represented about 10% of blood issued to participating hospitals
during the period. This low proportion reflects the strict
exclusion criteria for patients, particularly a life expectancy less
than nine months. The mean (range) interval between transfusion and
follow up sample was 10.7 (range 6-50) months.
We did not identify any transfusion transmitted
infections. We calculated the risk of transmission through blood as 0 in
21 043 units of red cells for hepatitis B virus (95%
confidence interval of risk 0 to 1 in 5706 recipients);
0 in 21 800 units for hepatitis C virus (0 to
1 in 5911 recipients); 0 in 21 923 units for HIV
(0 to 1 in 5944 recipients); and 0 in 21 902
units for human T cell leukaemia/lymphoma virus (0 to
1 in 5939 recipients). Although the results are
based on the number of red cells received, we estimated
that patients would also have received fresh frozen plasma
from 1630 donors, platelets from 3819 donors, and
cryoprecipitate from 279 donors. This constitutes an
additional 5728 donation exposures. An overall
donation exposure of 27 000 represents about 26 000
individual donors (Gay N, personal communication, 1998). Samples from three patients whose pretransfusion
samples had yielded negative results showed markers of hepatitis B
virus infection, indicating acquisition during or after
admission to hospital (table 3). None of
the relevant donors showed evidence of hepatitis B virus,
and we could not identify any risk factors in patients
other than their hospital treatment. Many patients had
pre-existing infections, of which they were usually unaware (fig
2).
Table 3. Table 4. No transmitted infections were found after
transfusion of 21 923 units of red cells, and inclusion of
exposures to other components resulted in an even smaller
calculated risk of infection. Before this study, UK
estimates of transfusion transmitted hepatitis B and C
virus were 1 in 20 000 and 1 in 13 000 units,5
respectively, compared with 1 in 200 000 and 1 in
3300 in the United States.6 Recent
UK estimates suggest the risk for hepatitis B virus is 1 in
50 000 to 170 000; for hepatitis C virus is <1 in 200 000;
and for HIV is <1 in 2 million units (Barbara J and
Soldan K, personal communication,1999). Current US
estimates are 1 in 63 000, 1 in 103 000,
and 1 in 493 000, respectively.3
In Canada, there was no transmission of hepatitis B virus
to 4588 patients and four to six transmissions of
hepatitis C virus per 10 000 units transfused at
introduction of "first generation" screening for
antibodies to hepatitis C virus.7 This study provides direct data on the lack of
transfusion transmission of HIV, hepatitis B and C virus, and human T
cell leukaemia/lymphoma virus in the United Kingdom.
Elsewhere, donations are tested for antibodies to
hepatitis B core antigen,8 which can
detect infectious donors undetectable by tests for hepatitis B
surface antigen.9 In the United States,
testing for antibody to hepatitis B core antigen may
prevent 33% to 50% of cases of hepatitis B potentially
transmissible from donors who test negative for hepatitis
B surface antigen.10 In the United
Kingdom, the potential benefits of routine testing for
antibodies to hepatitis B core antigen are considered not
to outweigh the disadvantages (such as uncertainties in
confirmation of infection and wastage of falsely positive
units11). The United States introduced HIV p24 antigen
testing to reduce the HIV "window period" amid concerns
that donors might seek a superior test of HIV status,
unavailable outside blood centres.12
The gain, however, is far less than projected (Holland P,
personal communication, 1997). Before anti-human T cell
leukaemia/lymphoma virus testing of donors in the United
States, risk of transmission was 1 in 4192 units
transfused.2 Donated blood in the United
Kingdom is not currently tested for human T cell
leukaemia/lymphoma virus. The prevalence of human T cell
leukaemia/lymphoma virus among donors in north London was
1 in 19 34413 but in Leeds
was <1 in 80 000.14 Our
finding of no transmissions from 21 000 units transfused
was therefore not unexpected. Three patients had markers for hepatitis B virus
at follow up but their pretransfusion samples yielded negative
results. If we can assume that the samples were correctly
identified, the patients must have acquired the virus
between transfusion and follow up as donors of all
components transfused were excluded and all three
recipients identified no other risk for hepatitis B virus.
These patients probably acquired the virus during their stay
in hospital but not through transfusion of the units recorded in
the hospital records. Giving the wrong blood to patients is a
known hazard of transfusion15; this
cannot be excluded, although it is unlikely. Transmission
of hepatitis B virus 16 17
and hepatitis C virus18 to
patients from healthcare workers and other patients19
has been reported; transmission through contaminated equipment
could also occur. The patients underwent surgery in different
hospitals and no sources of infection were identified. Two
patients underwent gastrointestinal surgery and the third had
coronary artery bypass graft surgery. In conclusion, patients and clinicians can now
make decisions about transfusions on the basis of the study finding
that directly assessed current risks of known transfusion
transmitted infections in the United Kingdom are very
small, though the possibility of new or unrecognised
agents always remains. Hospital acquired infections are
more likely to arise from sources other than transfusion as transmission
by this route has become so rare. Clinicians must remain
alert for infections after transfusion but should also consider
routes of such infections other than transfusion.
What is already
known on this topic
Every effort is made to minimise the risk
of transfusion transmitted infection, but a theoretical
possibility of transmission remains Previously, estimates of the frequency of
transfusion transmitted infection have relied on reported
cases of infection, but these are often underreported What this paper
adds
This prospective study directly estimated
the incidence of transfusion transmitted infections -
hepatitis B and C and HIV - for which donated blood is
tested, and also human T cell leukaemia/lymphoma virus, for
which blood is not currently tested in the United Kingdom Direct data are provided on the safety of
the blood supply with regard to these infections and indicate
the minimum level of safety of transfusion in the United
Kingdom Hospital acquired infections are more
likely to arise from sources other than transfusion, as
transmission by this route has become so rare
The TTI Study Group comprises Mhairi Bailey, Dr David Howell, Julia McCartney, Anna Nolan, Annette Rochford, Beverley Vincent, Fiona Regan, Patricia Hewitt, John Barbara, and Marcela Contreras. Susan Kilbane, Kellie Lawlor, Amanda Robotham were the administrative assistants for the study team; Dr Mary Brennan, Dr Therese Callaghan, Dr Gillian Century, Dr Joan Heyse-Moore, Dr Edith LeCoeur, Dr Diana Simons, Cindy Mooring, and Eleanor Dukes are previous members of the clinical team. We are grateful to the following participating hospitals and NHS Trusts, particularly staff of transfusion departments and ward nursing staff for their cooperation in recruiting patients into the study: Ashford (Middlesex), Barnet General, Royal Brompton, Central Middlesex, Charing Cross, Chelsea and Westminster, Ealing, Edgware, Hemel Hempstead and St Albans, Hertford County (East Herts), Hillingdon, Lister (North Herts), Mount Vernon and Watford, Northwick Park and St Marks, Q E II (East Herts), Royal National Orthopaedic (Stanmore), St Mary's, St Vincent's, West Middlesex University, and Whittington. We thank Professor Richard Tedder, professor of medical virology, department of virology, Royal Free and University College Medical School, and Kate Soldan, NBA/CDSC Surveillance Officer, Central Public Health Laboratory, Colindale, for their expert advice. We are also indebted to all the general practitioners who assisted with the follow up of patients who lived outside the area. Contributors: FAMR was responsible for execution
of the study, accrual and analysis of data, regular review, and
analysis of the paper. PH was responsible for overall design and
execution of the study, regular review, and analysis and corrections
in the paper. JAJB was responsible for overall study design, expert
microbiological advice, test results, regular review of execution of
the study, and analysis of the paper. MC was responsible for overall
study design, obtaining funding, regular review of execution of the
study, and analysis of the paper. MC is the guarantor. Footnotes Funding: North West Thames Regional Health Authority. Competing interests: None declared.
(Accepted 29 November 1999)
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