From: Subject: Dengue and Blood Safety | CDC EID Date: Sun, 28 Dec 2008 12:03:54 -0800 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C968E4.5B2C6C80" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C968E4.5B2C6C80 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.cdc.gov/eid/content/15/1/8.htm Dengue and = Blood Safety | CDC EID
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EID Journal=20 Home > Volume = 15,=20 Number 1=96January 2009

Volume 1, Number 1=96January 2009

Perspective

Threat of Dengue to Blood Safety in Dengue-Endemic Countries

Annelies Wilder-Smith, 3D"Comments Lin H. Chen, Eduardo Massad, and Mary E.=20 Wilson
Author affiliations: National University Singapore, = Singapore=20 (A. Wilder-Smith); Harvard Medical School, Boston, Massachusetts, USA = (L.H.=20 Chen, M.E. Wilson); Harvard School of Public Health, Boston (M.E. = Wilson); Mount=20 Auburn Hospital, Cambridge, Massachusetts, USA (L.H. Chen, M.E. Wilson); = and=20 University of S=E3o Paulo, S=E3o Paulo, Brazil (E. Massad)

Suggested = citation=20 for this article

Abstract
Dengue, the most common arbovirus = infection=20 globally, is transmitted by mosquito vectors. Healthcare-related = transmission,=20 including transmission by blood products, has been documented, although = the=20 frequency of these occurrences is unknown. Dengue is endemic to = Singapore, a=20 city-state in Asia. Using mathematical modeling, we estimated the risk = for=20 dengue-infected blood transfusions in Singapore in 2005 to be = 1.625=966/10,000=20 blood transfusions, assuming a ratio of asymptomatic to symptomatic = infections=20 of 2:1 to 10:1. However, the level of viremia required to cause clinical = dengue=20 cases is person-dependent and unknown. Further studies are needed to = establish=20 the magnitude of the threat that dengue poses to blood safety in = countries where=20 it is endemic. It will then be possible after this information is = obtained to=20 assess whether screening is feasible and to identify approaches that are = most=20 cost-effective on the basis of characteristics of local populations and=20 seasonality of dengue.

Emerging infectious diseases pose threats to the general human = population,=20 including recipients of blood transfusions. Dengue is an expanding = problem in=20 tropical and subtropical regions and is now the most frequent arboviral = disease=20 in the world, with an estimated annual 100 million cases of dengue = fever,=20 250,000 cases of dengue hemorrhagic fever, and 25,000 deaths per year = (1). Dengue = virus=20 infections have been reported in >100 countries; 2.5 billion people = live in=20 areas where dengue is endemic (1). It is = also=20 increasingly reported to occur in international travelers (2). Dengue = is of=20 major international public health concern because of the expanding = geographic=20 distribution of the virus amd competent mosquito vectors, increased = frequency of=20 epidemics, cocirculation of multiple virus serotypes, and emergence of = dengue=20 hemorrhagic fever in new areas.

Dengue virus belongs to the family Flaviviridae and is = transmitted=20 by mosquitoes of the genus Aedes (1). = Flaviviruses are=20 small, lipid-enveloped, positive-stranded RNA viruses (1). Dengue = infection=20 has a viremic phase that lasts 4=968 days (3), and = most=20 infections remain subclinical (4). = Viremia can=20 precede the onset of symptoms in persons with clinical disease. Plasma = viral RNA=20 levels range from 105.5 to 109.3 copies/mL, and = blood=20 collected during this phase may be infective when transfused into = susceptible=20 hosts (5).

A literature search conducted in March 2008 on blood transfusion and = dengue=20 did not identify any published reports of blood transfusion=96associated = dengue in=20 dengue-endemic countries. Healthcare-associated transmission is = difficult to=20 ascertain in dengue-endemic countries, although there is 1 report of = possible=20 transmission of dengue in a healthcare setting in Hong Kong, Special=20 Administrative Region, People's Republic of China, attributed to a = viremic=20 resident of Hong Kong (6). In = contrast,=20 healthcare-acquired dengue infections in countries in which dengue is = not=20 endemic can be determined. Several reports have described travelers who = returned=20 from dengue-endemic countries to those not endemic for dengue and = transmitted=20 dengue infection to healthcare workers by needlestick injury or = mucocutaneous=20 exposure to blood (7,8).

Healthcare-associated transmission of viruses among humans has been = recently=20 reviewed for dengue and other flaviviruses such as West Nile virus (WNV) = and=20 yellow fever virus (9). Routes = of=20 transmission include percutaneous, mucous membrane, bone marrow = transplant,=20 organ transplant, hemodialysis, and transfusion of blood products = (6=968,10=9625) (Table) However, despite good evidence for its = transmission in healthcare settings, dengue is currently not considered = a risk=20 to blood safety.

We draw parallels from recent experiences with West Nile fever and=20 encephalitis in the United States. WNV first appeared in the United = States in=20 1999 and has since spread throughout the country, resulting in thousands = of=20 cases of disease (26). = Approximately=20 80% of WNV infections are asymptomatic (27). By = 2002, 23=20 patients in the United States were confirmed to have acquired WNV = through=20 transfused blood and blood products (erythrocytes, platelets, and = fresh-frozen=20 plasma) (23). The = estimated=20 risk for virus transmission through transfusion during the 1999 WNV = epidemic in=20 New York was 1.8/10,000=962.7/10,000 donations, and ≈2.0 viremic = donations/10,000=20 donors in the borough of Queens (28). Of = the 2.5=20 million blood donations screened for WNV from June through December = 2003, 0.05%=20 were positive at the first screening and 0.02% were confirmed (29). In = response to=20 these findings, by 2003, essentially all blood donations in the United = States=20 were being tested for WNV. In contrast, no screening of blood products = is=20 conducted for dengue, although dengue virus is estimated to affect = >100=20 million persons annually in tropical and subtropical regions. A recent = study in=20 Puerto Rico reported nucleic acid testing for dengue virus in the blood = supply=20 and found the viral RNA prevalence to be 7.3/10,000 U of blood = donations, which=20 approximates the prevalence of WNV in the United States during the = transmission=20 season (30).=20 In addition, screening of donors in Honduras and Brazil has identified = dengue=20 virus RNA (0.37% and 0.06% of blood donations or 37/10,000 and 6/10,000 = blood=20 donations, respectively) by using a transcription-mediated amplification = assay=20 (31).

We postulate that dengue virus poses a greater threat worldwide to = blood=20 safety than WNV but that this hypothesis has been neglected because = dengue=20 occurs predominantly in developing countries. We used mathematical = modeling to=20 estimate the risk for dengue in Singapore. Singapore is an = industrialized Asian=20 city-state in which dengue is endemic. This city-state has the capacity = to=20 implement blood screening for dengue. The dengue seroprevalence rate in = the=20 adult population in Singapore, which has a population of ≈4 = million persons, is=20 45% (32). In=20 2005, 14,209 cases of symptomatic dengue infections were reported in = Singapore,=20 a large proportion (≈80%) of which were in adolescents or adults = (33). We = calculated=20 the force of infection in this population. The force of infection is = defined as=20 follows: per capita new cases in a finite period =3D rate of contacts by = potentially infective persons =D7 (no. viremic persons in a population = in a finite=20 period/total population in a finite period).

If one assumes that there were 11,367 reported adult cases in = Singapore in=20 2005 (80% of 14,209) and a ratio of asymptomatic to symptomatic cases of = 2:1, a=20 total of 34,101 viremic adults in 2005 would have viremia that lasts=20 <1 week. This finding indicates there would be 656 infective = persons=20 per week, which translates to 0.00016 viremic persons in a finite period = per=20 total population in a finite period. If one considers that there are = ≈80,000=20 blood transfusions in Singapore per year, there would be 1,538 = transfusions per=20 week. Therefore, the force of infection for 2005 in Singapore was = ≈13 infective=20 blood donations.

However, if we assume a ratio of asymptomatic to symptomatic cases of = 10:1,=20 we then have 125,037 viremic persons, or ≈2,405 infective persons = per week. This=20 finding indicates that the number of viremic persons in the population = in a=20 finite period/total population in a finite period is 0.00060115. We = would then=20 end up with a force of infection for 2005 of 48 infective donations. = Depending=20 on the ratio of asymptomatic to symptomatic infections, there were = ≈13=9648 dengue=20 infected blood donations in Singapore in 2005. With ≈80,000 blood = transfusions=20 annually in Singapore, the proportion of infected blood transfusions = would be=20 ≈1.625=966/10,000 transfusions, which is consistent with reported = dengue RNA=20 prevalence in blood donations in Puerto Rico, Brazil, and Honduras = (30,31). This = proportion is similar or even higher than the estimated risk for WNV=20 transmission by transfusion during the 1999 epidemic in New York, which = was=20 reported to be 1.8/10,000=962.7/10,000 donations (28). A = total of=20 1.625=966/10,000 blood transfusions would translate to 3.25=9612 = potentially=20 infective blood transfusions/1 million persons in Singapore, if one = assumes a=20 ratio of asymptomatic to symptomatic case between 2:1 and 10:1. Further, = a=20 recent report provides well-documented evidence of a cluster of blood=20 transfusion=96associated dengue infections in Singapore (34).

Why has transfusion-associated dengue not yet been widely recognized = as a=20 problem in dengue-endemic countries? Lack of recognition is likely due = to lack=20 of awareness that dengue is transmitted not only by vectors but also by = blood=20 products. Because of the effects of infection and recurring epidemics in = dengue-endemic countries, isolated cases of healthcare-acquired = infections will=20 go unnoticed. In many healthcare facilities, patients are not protected = from=20 mosquitoes, and it is therefore difficult to ascertain whether = infections were=20 related to blood transfusions or exposure to vectors. Further, risk for=20 transmission by transfusion may depend on the level of viremia, which = has been=20 shown to correlate with severity of disease (35). It = is likely,=20 although not proven, that viremia is lower and shorter in duration in=20 asymptomatic persons than in symptomatic persons. The risk for=20 transfusion-associated dengue will vary greatly from 1 country to = another,=20 depending on the epidemiologic pattern of dengue and the immunity level = in the=20 population. In countries where dengue is mainly a childhood disease, = risk for=20 blood transfusion=96transmitted dengue will be lower because of lack of = overlap of=20 infected and blood-donating populations. However, risk for nosocomial=20 transmission from needlesticks and other blood exposures would exist in = all=20 areas with dengue.

Blood transfusion=96related dengue will likely represent only a small = proportion of all dengue cases in dengue-endemic countries. Screening = blood for=20 dengue antigens in dengue-endemic countries would be costly and should = therefore=20 be recommended only after careful assessment of risk for infection and = cost per=20 blood product=96associated dengue infection averted. Therefore, the = first step is=20 to quantify this risk in a systematic study. Risk will vary by = geographic region=20 and season and may change over time. We suggest targeted nucleic acid=20 amplification testing of individual donations in high-prevalence = regions, a=20 strategy that was implemented successfully for screening of WNV in the = United=20 States in 2004 (36); = nucleic acid=20 amplification tests of minipools of several samples of donated blood = have also=20 been proposed (36). A = prototype=20 nucleic acid test, which is suitable for high-throughput screening, has = been=20 developed for detection of dengue virus RNA in blood donations (31). The = initial=20 study should be conducted during the dengue transmission season to = identify=20 maximum incidence of viremic donations. This testing would provide a = baseline=20 estimate of risk for transmission of infective blood. If the risk is = found to be=20 substantial, healthcare providers would need to decide at what threshold = screening should be instituted. Policies will also be influenced by = economic=20 resources available and healthcare priorities of a country or = region.

Dr Wilder-Smith is director of the Travellers' Screening and = Vaccination=20 Clinic at the National University Hospital of Singapore and associate=20 professor at the National University of Singapore. Her research = interests are=20 dengue, meningococcal disease, and travel health.

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Table

Table. Reported = healthcare-associated=20 transmission of flaviviruses

Suggested Citation for this Article

Wilder-Smith A, Chen LH, Massad E, Wilson ME. Threat of dengue to = blood=20 safety in dengue-Endemic countries. Emerg Infect Dis [serial on the = Internet].=20 2009 Jan [date cited]. Available from=20 http://www.cdc.gov/EID/content/15/1/8.htm

DOI: 10.3201/eid1501.071097

Comments to the Authors

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Annelies Wilder-Smith, Department of Medicine, National University = Singapore,=20 119407 Singapore; email: epvws@pacific.net.sg

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BACKGROUND-IMAGE: = url(http://www.cdc.gov/ts/images/cdc/div_hrz_blackdot.gif); MARGIN: 5px = 0px; WIDTH: 310px; BACKGROUND-REPEAT: repeat-x; HEIGHT: 1px } #upchrblackdot { CLEAR: both; FONT-SIZE: 1px; BACKGROUND-IMAGE: = url(http://www.cdc.gov/ts/images/cdc/div_hrz_blackdot.gif); MARGIN: 5px = 0px; WIDTH: 420px; BACKGROUND-REPEAT: repeat-x; HEIGHT: 1px } #tocnav { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px; LIST-STYLE-TYPE: none } #tocnav LI { BACKGROUND-POSITION: 5px 7px; PADDING-LEFT: 13px; FONT-SIZE: 0.9em; = BACKGROUND-IMAGE: = url(http://www.cdc.gov/ts/images/cdc/icon_red_arrow.gif); = PADDING-BOTTOM: 2px; MARGIN: 0px; COLOR: #666666; PADDING-TOP: 1px; = BACKGROUND-REPEAT: no-repeat; LIST-STYLE-TYPE: none } #tocnav LI A { FONT-WEIGHT: bold; FONT-SIZE: 1.1em } #abstract { BORDER-RIGHT: #ccccb7 1px solid; PADDING-RIGHT: 10px; BORDER-TOP: = #ccccb7 1px solid; PADDING-LEFT: 10px; PADDING-BOTTOM: 0px; MARGIN: 0px = 0px 10px; 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