1 figure omitted
In 2002, transfusion-associated transmission (TAT) of West Nile virus
(WNV) infection acquired through blood transfusion marked the emergence of
a new threat to the U.S. blood supply.1 Although
mosquito-borne transmission remains the predominant mode of WNV transmission,2 identification of TAT underscored the need for
WNV screening of donated blood. In June 2003, blood-collection agencies (BCAs)
implemented investigational WNV nucleic acid–amplification tests (NATs)
to screen all blood donations and identify potentially infectious donations
for quarantine and retrieval. This screening was performed on approximately
6 million units during June-December 2003, resulting in the removal of at
least 818 viremic blood donations from the blood supply. This report summarizes
the results of blood-donation screening tests conducted during 2003 and describes
six cases of WNV TAT that occurred because of transfusion of components containing
low levels of virus not detected by the testing algorithm. These data indicate
that blood screening for WNV has improved blood safety. However, a small risk
of WNV transfusion-associated transmission remains. To address this risk,
changes to screening strategies are planned for 2004.
In June 2003, under the Food and Drug Administration's (FDA) investigational
new drug (IND) mechanism, BCAs began screening donations by using NATs from
two test-kit manufacturers. Initial screening protocols included NAT performed
on mini-pools (MP NAT) of samples from six or 16 donations, depending on the
test-kit manufacturer. Donation samples that were part of reactive mini-pools
were tested individually. Any reactive samples were retested by individual
donation testing (IDT NAT). In certain cases, an alternate sample from the
same donation or an alternate NAT might have been used for retesting. In addition,
selected blood banks serving areas with epidemic activity stopped using this
MP NAT screening algorithm and implemented IDT NAT screening during limited
periods of the epidemic season. Donors of IDT NAT–reactive samples identified
by either screening method were asked to participate in a BCA-directed follow-up
study to confirm WNV infection and evaluate for the persistence of WNV RNA
in blood samples collected subsequently. Both follow-up samples and the index-donation
samples were tested for WNV-specific IgM antibody. Donations that were IDT
NAT–reactive were not released for transfusion; these donors were deferred
from donating blood again until ≥28 days after the date of collection for
the last NAT-reactive sample and the documented development of WNV-specific
To determine the sensitivity of the MP NAT–screening algorithm,
certain BCAs performed retrospective testing studies in selected areas that
experienced high rates of viremic donations. In these studies, individual
components of archived MP NAT–negative donation samples were retested
by IDT NAT.
For surveillance purposes, a donation that was repeatedly reactive on
IDT NAT was considered to be from a presumptive viremic donor (PVD). Cooperating
local blood centers provided reports of PVDs (including donor age, sex, postal
code, and date of donation) to state health departments, which provided reports
to ArboNET, the national arbovirus surveillance system.
As of March 31, 2004, state and local health departments had reported
818 PVDs to ArboNET; dates of collection ranged from June 25 to December 2,
2003 (Figure). Complete information was available for 811 (99%) of these PVDs;
six (1%) had West Nile viral encephalitis or meningitis subsequent to donation
(median age: 45 years, range: 28-76 years), 137 (17%) had West Nile fever
(median age: 46 years, range: 17-76 years), and 654 (81%) remained asymptomatic.
Of the PVDs reported to ArboNET, 691 (85%) were residents of nine states (Colorado,
Kansas, Nebraska, New Mexico, North Dakota, Oklahoma, South Dakota, Texas,
and Wyoming). These states experienced WNV epidemics in 2003 and accounted
for 60% of reported cases of West Nile viral encephalitis or meningitis.
Since 2002, public health authorities have been encouraged to investigate
reports of WNV illness among patients who had received blood transfusions
<4 weeks before illness onset and to report these suspected TAT cases to
CDC. A probable TAT was defined as transfusion to a recipient who (1) had
a confirmed WNV infection3 and (2) had received
a blood product from a NAT-reactive index donation associated with a donor
with WNV-specific IgM antibody in the index donation or a follow-up collection.
A confirmed TAT case was defined as meeting the criteria for a probable case
and having any one of the following criteria: (1) unlikely mosquito exposure
during the 14 days before recipient illness onset; (2) testing of remaining
diagnostic samples from the hospitalized transfusion recipient indicating
that WNV infection occurred at the time of transfusion; or (3) transfusion
of a co-component of the infectious donation into another recipient who then
had a confirmed WNV infection. A case was classified as a noncase if WNV infection
could not be confirmed in the recipient <4 weeks after the implicated transfusions,
if WNV RNA was not identified in any implicated donation, or if all implicated
donors were seronegative for WNV. If samples were not available to satisfy
the criteria for probable, confirmed, or noncase classification, the case
was considered inconclusive.
During 2003, a total of 23 suspected cases of WNV TAT were reported
to CDC. Public health authorities reported 15 suspected cases of WNV TAT among
patients who had WNV illness after receiving transfusions. Another eight suspected
cases were in recipients of components derived from low-level viremic donations
that were identified during special retrospective studies of MP-negative blood
retested with IDT NAT by two BCAs. Follow-up of these eight cases was performed
to determine if WNV infection had resulted from the implicated transfusions.
As a result of these 23 investigations, six cases were classified as confirmed
or probable WNV TAT, 11 as noncases, and three as inconclusive. As of March
27, 2004, three cases remained under investigation.
In each of these six confirmed or probable cases, the recipient received
components from multiple donations; however, only one infectious blood component
was found in each case. All six of these infectious donations had been collected
during July 29–September 18, 2003, and were not identified in MP screening.
The median age of the six recipients was 63 years (range: 13-82 years); four
had WNV encephalitis, one had West Nile fever, and one critically ill patient
did not have discernible WNV-compatible illness despite confirmed WNV infection.
A sufficient index-donation sample was available to estimate the titer of
the implicated donor's viremia in four of six cases: the median estimated
viremia was 0.11 plaque-forming units per milliliter (pfu/mL) (range: 0.06-0.5
pfu/mL). Two of these six cases were reported previously4;
a description of a third case follows.
On August 31, 2003, a male aged 13 years was admitted to a hospital
with multiple injuries. On September 1, he received three units of packed
red blood cells. On September 9, after hospital discharge, he had a maculopapular
rash. On September 12, he was readmitted to the hospital with fever, headache,
vomiting, and diarrhea, consistent with West Nile fever; blood drawn on that
day was positive for WNV-specific IgM antibody.
The three transfused blood units had been collected during the second
week of August 2003. No donors of this blood reported symptoms of WNV illness
before or after donation. Samples from these donations were nonreactive for
WNV RNA by MP NAT performed on six-specimen mini-pools. All other components
derived from these three donations were quarantined immediately; there were
no co-component recipients. Recalled plasma samples from the three index donations
were WNV IgM negative. One donor seroconverted evidenced by development of
WNV-specific IgM antibody in serum collected 50 days after donation. Recalled
plasma from this donor was reactive when tested by IDT NAT. CDC confirmed
results by using polymerase chain reaction; the estimated viral load was 0.09
pfu/mL. The recipient recovered without sequelae.
S Kleinman, MD, American Assoc of Blood Banks, Victoria, British Columbia,
Canada. M Busch, MD, Blood Systems Research Institute, San Francisco, California.
S Caglioti, Blood Systems Laboratories, Tempe, Arizona. SL Stramer, PhD, R
Dodd, PhD, American Red Cross, Gaithersburg, Maryland. DM Strong, PhD, Puget
Sound Blood Center, Seattle, Washington. W Dickey, MD, Belle Bonfils Memorial
Blood Center, Denver, Colorado. B Salvidar, MS, M Gilchrist, PhD, Univ of
Iowa Hygienic Laboratory, Iowa City; S Brend, MPH, Iowa Dept of Public Health.
H Nakhasi, PhD, J Epstein, MD, J Goodman, MD, Center for Biologics Evaluation
and Research, Food and Drug Administration. M Chamberland, MD, M Kuehnert,
MD, Div of Viral and Rickettsial Diseases. L Petersen, MD, N Crall, A Marfin,
MD, Div of Vector-Borne Infectious Diseases, National Center for Infectious
Diseases; T Boo, MD, S Montgomery, DVM, EIS officers, CDC.
Previous studies have documented that an estimated 80% of WNV-infected
persons remain asymptomatic but are believed to have viremia lasting a median
of 6.5 days.5,6 Asymptomatic
WNV-infected persons with viremia likely represent the largest risk group
of blood donors. Because symptom screening at the time of blood donation will
not identify most viremic donors, screening by NAT was implemented rapidly
to identify potentially infectious blood donations by detecting WNV RNA.
Use of blood-donor screening for WNV by NAT under the IND mechanism
has enhanced the safety of the blood supply. Despite this enhanced safety,
documentation of the six WNV TAT cases in 2003 indicates that blood components
containing low levels of virus might escape detection and that at least some
of these might be infectious. Virus loads in infectious donations were considerably
lower in 2003 than in 2002.1 In 2002, the
estimated viremia levels in implicated donations were 0.8-75 pfu/mL, compared
with 0.06-0.5 pfu/mL for TAT cases during 2003. The reasons for this lower
range are unclear, and the lower limit of donor viremia that can lead to transfusion-associated
infection is unknown.
Data collected during 2003 will be considered by the blood supply community
in collaboration with public health authorities when developing screening
strategies for 2004, when widespread seasonal transmission of WNV is expected
to continue. MP screening will continue to identify most persons who donate
during the short viremic period, but prospective IDT might be implemented
in regions with high WNV-infection rates (i.e., high MP-screening–test
yields). However, the capacity of laboratory equipment and personnel for performing
IDT and the availability of reagents are limited, and the higher false-positive
rate of IDT (compared with MP screening) could have a negative short-term
impact on the availability of blood in these regions.
Approximately 4.5 million persons receive blood or blood products annually.
Although persons needing blood transfusions should be aware of the limited
risk for WNV infection, the benefits of receiving needed transfusions outweigh
the potential risk for WNV infection. In addition, blood donation poses no
risk to the donor for acquiring WNV, and the U.S. Public Health Service encourages
blood donation. FDA, CDC, and the blood-collection community will continue
to evaluate WNV-screening strategies to ensure blood safety.
This report is based in part on contributions by L Pietrelli, Roche
Molecular Systems, Alameda, California. T Gahan, L DesJardin PhD, Univ of
Iowa Hygienic Laboratory, Iowa City, Iowa. RS Lanciotti, PhD, A Lambert, A
Noga, R Hochbein, Div of Vector-Borne Infectious Diseases, CDC.
Update: West Nile Virus Screening of Blood Donations and Transfusion-Associated Transmission—United States, 2003. JAMA. 2004;291(18):2184-2188. doi:10.1001/jama.291.18.2184