Dengue: a potential transfusion‐transmitted disease

Dengue is caused by four related RNA viruses of the genus Flavivirus, dengue virus (DENV)−1, −2, −3, and −4. Infection with DENV is usually asymptomatic but each DENV is capable of causing the full spectrum of clinical disease from mild, undifferentiated acute febrile illness, to classic dengue fever and more severe disease including dengue hemorrhagic fever and dengue shock syndrome. Severe disease manifestations including hypovolemic shock and clinically significant hemorrhage are more commonly observed among patients during their second or subsequent episodes of DENV infection.1 Infection with one DENV produces lifelong immunity against that DENV type and short-term (≤2 months) cross-protection against infection with the other three DENVs. Therefore, an individual has a lifetime risk of up to four DENV infections. DENVs are transmitted from person to person through the bite of an infected Aedes aegypti mosquito (less commonly Aedes albopictus or Aedes polynesiensis).2 Unlike other related flaviviruses such as West Nile virus, humans are the main amplifying host for DENV. While there is a sylvatic nonhuman primate cycle of DENV transmission, it rarely crosses to humans, and antibodies to the sylvatic virus appear to protect against human DENV. The transmission cycle begins when a mosquito ingests DENV in a blood meal from an infected person (Fig. 1). DENV replicates and disseminates within the mosquito and reaches the salivary glands after 8 to 12 days (extrinsic incubation period). Higher ambient temperatures may reduce the extrinsic incubation period and increase the chance they will infect a human before dying.3 The mosquito remains infectious for life (typically less than 1 month) and can transmit infection with 102 viral particles.4 DENV replicates in humans for an intrinsic incubation period of 3 to 14 days before symptom onset. Infected persons can transmit DENV to mosquitoes as early as 1 to 2 days before symptoms develop5 and throughout the approximately 7-day viremic period. Infected persons, even those who remain asymptomatic, have concentrations as high as 107 viral RNA copies per milliliter of blood.6,7 Dengue virus transmission cycle (source: Dengue Virus Net). During the viremic period, which occurs in symptomatic and asymptomatic infections, DENV can become a blood-borne infection.8 Cases of dengue after receipt of blood products or donor organs or tissue and after occupational exposure in a health care setting have been reported.8-10 However, the true incidence of transfusion-transmitted dengue is unknown because there is no surveillance for such events, and if a case is suspected, it is difficult to prove transfusion transmission (vs. vector-borne transmission) in recipients from endemic countries. Nevertheless, transfusion risk models and assessments of viremia prevalence among blood donations indicate the potential for transfusion transmission of DENV in endemic areas.6-8,11,12 Risk is high in endemic areas as most DENV infections are asymptomatic and the viremia is high titered, long lasting, and detectable among asymptomatic individuals. In addition, DENV can be transmitted from mother to fetus in utero or to infants at parturition (perinatal transmission).13 The determinants of perinatal transmission and the rate at which transmission occurs are unknown.14 However, some evidence from case series suggest that perinatal transmission may be more likely when women are acutely ill (and viremic) within 1 week of delivery. Dengue is a major public health problem throughout the tropics and subtropics, an estimated 50 million cases occur annually15,16 and 40% of the world's population live in areas where there is risk of DENV transmission17 (Fig. 2). In the last three decades, dengue has rapidly reemerged throughout Mexico, Central and South America, and the Caribbean.18 Four million people reside in US territories where dengue is endemic—Puerto Rico,19 US Virgin Islands, and American Samoa—and millions of Americans travel to dengue-endemic countries each year20 (Fig. 3). In a recent study of 17,353 ill travelers, dengue was the leading cause of febrile illness among travelers returning from the Caribbean, South America, South Central Asia, and Southeast Asia.21 In some case studies, dengue is the second most common cause of hospitalization (malaria is the most common) among travelers returning from the tropics.22 Worldwide areas at risk for dengue virus transmission including transfusion transmission. Areas at risk for dengue virus transmission in Mexico, Central and South America, and the Caribbean including Puerto Rico and US Virgin Islands. Dengue is not endemic in the continental US, Hawaii, or Alaska;23-25 however, several dengue outbreaks with local transmission have occurred in Texas,26 Hawaii,27 and Florida in the past decade with most recent outbreaks occurring in Florida in 2009 and 201028 and Hawaii in 2011.29 Determinants of local transmission in nonendemic areas include introduction of DENV (e.g., via returning viremic traveler), presence of A. aegypti or A. albopictus, and a susceptible population. According to the Centers for Disease Control and Prevention (CDC), 16 states have reported having A. aegypti and 35 states have A. albopictus (source: ArboNET, Division of Vector-Borne Diseases, CDC). Although all the determinants for local DENV transmission are present in many areas of the United States where dengue is not endemic, the lack of sustained local DENV transmission may be in part due to infrequent contact between people and the vector.26,30 Nevertheless, physicians need to have a high index of suspicion of dengue among returning travelers with acute febrile illness so that opportunities to reduce morbidity, prevent additional cases among household contacts, and detect outbreaks are not missed. Cases among returning US travelers are largely unrecognized and underreported, although case detection is expected to increase since dengue became a nationally notifiable disease in 2010.31 Although dengue has historically been thought of as a childhood disease, some dengue-endemic countries have observed a gradual shift in peak attack rates toward older age groups.32-34 In Puerto Rico, 50% of all laboratory-positive cases are among adults 20 years of age or older and rates of laboratory-positive dengue have been highest among 10- to 19-year-olds for more than three decades.19 Dengue affects both sexes with no apparent differences in infection rates or disease severity.19 Some have hypothesized based on epidemiologic studies that race, specifically African ancestry, may be a protective factor against development of severe disease.35 However, studies to examine whether there is an association between genetic markers and disease severity have produced conflicting results.36,37 Most US dengue cases occur in Puerto Rico, the US Virgin Islands, and American Samoa. In Puerto Rico, dengue was first recognized in 1915, and since the late 1960s annual seasonal increases in disease incidence and periodic, island-wide outbreaks have been documented. The most recent island-wide outbreak occurred in 2010, when about 24,000 cases were reported (CDC, unpublished data). In Puerto Rico, and most of the Caribbean Basin, the principal dengue vector A. aegypti is abundant year-round. Dengue in Puerto Rico follows a seasonal pattern with low DENV transmission in the dry season (February-May) and high transmission during the rainy season (June-November). Dengue is a major cause of acute febrile illness in dengue-endemic countries with incidence rates of approximately 5%.38 No vaccine is available to prevent dengue although several are now in clinical trials, and no antiviral treatments are available. Approximately 75% of all DENV infections are asymptomatic39-43 and may vary by infecting DENV type.42-44 Importantly, infections can be asymptomatic in adults. A prospective cohort study involving 2536 adults, 18 to 66 years old, found that 76% of infections were asymptomatic,39 and a cross-sectional cohort study of pregnant women 24 to 36 years old at the time of delivery found 89% of recent infections were asymptomatic.41 Symptomatic infections most commonly result in mild to moderate disease that is frequently self-limiting although the pain can be incapacitating and hospitalization may be required for dehydration due to hyperpyrexia and anorexia. As many as 5% of all cases develop severe, life-threatening disease. Early recognition of shock and intensive supportive therapy can reduce risk of death among those with severe dengue from 10% to less than 1%.45 Other, less common clinical syndromes include myocarditis, pancreatitis, hepatitis, or neuroinvasive disease.46 Dengue is a systemic and dynamic disease. That is, a patient may appear to have mild disease for the first few days after symptom onset and then develop severe disease manifestations at the time of defervescence due to an increase in vascular permeability.47 After the incubation period, the illness typically begins abruptly and the course follows three phases: febrile, critical, and recovery or convalescent. The febrile phase typically lasts for 2 to 7 days. Fever may be biphasic and is accompanied by nonspecific signs and symptoms including muscle, joint, and/or bone pain; headache; retroorbital pain; leukopenia; mild hemorrhagic manifestations (e.g., epistaxis, petechiae); and a macular or maculopapular rash. Patients may also have chills, injected oropharynx, and facial erythema in first 24 to 48 hours after onset and an altered sense of taste, nausea, and anorexia. Patients should be advised to stay well hydrated, avoid the use of aspirin (acetylsalicylic acid), aspirin-containing drugs, and other nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) and control high temperatures. They should be told to seek medical attention immediately if they become dehydrated or develop warning signs for severe disease at the time of defervescence. Warning signs include persistent vomiting, abdominal pain, difficulty breathing, hemoconcentration, and early signs of shock and develop as a result of plasma leakage due to an increase in vascular permeability.47 The critical phase begins at the time of defervescence and typically lasts 24 to 48 hours.47 Patients with nonsevere disease begin to improve during this phase while those with clinically significant plasma leakage develop severe disease with pleural effusions and/or ascites, hypovolemic shock, thrombocytopenia, and hemorrhage. Maintenance of fluid volume and hemodynamic status is central to the management of severe cases. Patients with refractory shock may require intravenous (IV) colloids and/or blood products after an initial trial of IV crystalloids. They should be monitored for early signs of shock, overt and occult bleeding, and resolution of plasma leak to avoid medical complications including prolonged shock, end organ damage, and fluid overload. During the convalescent phase, there is a gradual reabsorption of extravasated IV fluids and pleural and abdominal effusions. As a patient's general well-being improves, hemodynamic status stabilizes (although they may be bradycardic) and diuresis ensues. During this phase, it is important to watch for signs of fluid overload and treat accordingly. The patient's hematocrit stabilizes or may fall due to dilutional effect of the reabsorbed fluid, and their white blood cell count usually starts to increase, followed by a slow recovery of platelet count. Some patients develop an erythematous rash with small circular islands of normal, unaffected skin. The convalescent rash may desquamate and be pruritic. Until recently, laboratory testing to confirm the clinical diagnosis of dengue had been difficult and not clinically useful because the most commonly available test, an immunoglobulin (Ig)M antibody-capture enzyme-linked immunosorbent assay,48 was usually negative in the first 4 days of the illness. If the specimen collected during the early phase of the illness was negative, a second or convalescent specimen was required for a confirmatory laboratory diagnosis. Detection of DENV during the febrile phase of the illness required cell culture for virus isolation, a process that took up to 2 weeks. Development and utilization of nucleic amplification tests, including conventional and real-time, reverse transcription–polymerase chain reaction (RT-PCR)49,50 to detect DENV early in the illness has significantly changed dengue diagnostic testing, especially when combined with testing for IgM anti-DENV. In addition, detection of DENV is now possible using immunoassays that detect soluble DENV nonstructural protein 1 (NS1) antigen, which circulates during the course of the viremic phase of the illness. A major limitation to routine use of dengue diagnostic testing has been lack of commercially produced test kits shown to have high performance levels in well designed evaluation studies. A recent multicenter study to evaluate commercially available IgM anti-DENV diagnostic tests found that of five microplate immunoassays, only three performed to acceptable levels, and that none of the available rapid diagnostic tests had acceptable levels of performance.51 Recently, an IgM anti-DENV immunoassay was approved for dengue diagnostics by the FDA.52 A multicenter evaluation of NS1 antigen detection kits is being completed and a similar evaluation of nucleic amplification tests is presently being conducted by the CDC Dengue Branch. DENV RNA can be detected in serum by a number of nucleic acid amplification methods, including RT-PCR, transcription-mediated amplification (TMA), reverse transcriptase loop-mediated isothermal amplification, and nucleic acid sequence–based amplification. The TMA, loop-mediated isothermal amplification, and nucleic acid sequence–based amplification RNA amplification methods are based on an isothermal reaction in a closed-tube format, which both circumvents the need for a thermocycler and reduces the risk of contamination. Although molecular DENV detection methods have been used in a number of research settings, they have not been incorporated into routine dengue diagnostics, they are not commercially available, and they have not been evaluated to determine their limits of detection relative to each other. DENV was identified as one of three high-priority infectious agents with actual or potential risk of transfusion transmission in the United States or Canada by AABB's Transfusion Transmitted Diseases Committee.53 The rate of asymptomatic DENV infection in blood donors has been determined retrospectively in Puerto Rico and several other countries where dengue is endemic using molecular diagnostics (e.g., TMA).6,7 Infection rates have been shown to vary with disease incidence in the community, including the seasonal variation of dengue. In Puerto Rico, nearly 1 in 1000 blood donations were positive for DENV nucleic acid by TMA during the 2005 dengue season6 versus 1 in 600 positive during the 2007 outbreak (CDC and American Red Cross, unpublished data). The prevalence of DENV nucleic acid in blood donations in Puerto Rico in 2005 was similar to that estimated for WNV in areas experiencing outbreaks in the United States in 2002 before universal screening was implemented in 2003.54 What is presently not known are rates of DENV transmission from positive donors, since a high rate of existing DENV immunity would be expected among transfusion recipients in dengue-endemic areas, and a substantial proportion could be expected to have homotypic immunity to the transfused DENV. Furthermore, the actual risk of dengue (disease) after transfusion is not known. At present, the only approach to prevent transfusion of DENV-positive blood would be screening with sensitive nucleic acid amplification tests (e.g., TMA) to detect asymptomatic DENV infections in otherwise healthy donors and asymptomatic viremia in the 24 to 48 hours before donors becoming ill with dengue. Exclusion of donors in endemic areas during the high-incidence dengue season or during an outbreak is not feasible since the entire population is at risk of DENV infection, the need for blood components is typically high during outbreaks, and outbreaks can be long lasting. Future studies are needed to establish rates of transfusion-transmitted DENV by viremic donations and their clinical consequences in recipients. These evaluations should determine the most cost and prevention-effective approaches to prevent transfusion-transmitted dengue. In non–dengue-endemic areas of the United States, asymptomatic infection is primarily associated with travelers returning from dengue-endemic areas. Importation risk is likely to increase with emergence of dengue globally and ever-increasing international travel, including among long-term visitors and new immigrants from endemic countries. Whether this donor population poses a risk for DENV transmission is not known. Mathematical models can be used to determine transfusion transmission risk levels among returning travelers and during dengue outbreaks due to local transmission and can be used to inform the development of interventions to minimize risk. Although present donor deferral policies for travelers returning from malaria-endemic countries may somewhat reduce the risk for transfusion-transmitted dengue, many of the dengue-endemic areas frequented by tourists in Central and South America, the Caribbean, and parts of Asia are largely malaria free. Future studies are needed to establish rates of dengue among returning US travelers and to determine the effect of a 1-month deferral period for travelers returning from dengue-endemic countries. None.

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