Dengue Virus and Blood Transfusion.

In this issue of The Journal of Infectious Diseases, Sabino et al [1] present the results of the largest study to date on transfusion-transmitted (TT) dengue. Until now, TT dengue has been rarely reported, with 5 convincingly documented clusters [2–6]. This well-conducted investigation, performed during an outbreak of dengue virus 4 (DENV-4) infection in 2 large Brazilian cities, Recife and Rio de Janeiro, compiled compelling laboratorial and chronological evidence of another 6 TT cases judiciously sorted from 42 DENV RNA–positive units that were transfused to 35 recipients. These 6 cases, analyzed in the context of another 10 susceptible recipients exposed to viremic blood, which remained negative for virus RNA and immunoglobulin M (IgM) in the follow-up period, allowed the authors to estimate a transmissibility rate of 37.5%. Transmission was independent of the viral load, and, interestingly, all 3 components usually obtained from blood donations (plasma, red blood cells, and platelets) were able to transmit DENV-4. This has also been previously observed in one of the clusters from Singapore [2], where 3 recipients were infected by DENV-2 from the same viremic donation, with one developing symptoms that would be today be classified as dengue with warning signs. Performing such a TT study in a setting of high dengue endemicity provided an ideal situation to detect episodes of transmission, but it also demanded a thoughtful evaluation of the different patterns of reactivity demonstrated among donor/recipient pairs. This is illustrated by the classification of 5 viremic recipients as nonsusceptible to TT dengue, since they presented with either viral RNA or IgM antibody before undergoing transfusion, despite the fact that administered units harbored DENV RNA. Another 2 recipients were found to be viremic but underwent transfusion with viral RNA negative–units and were considered as vectorial cases. Moreover, several clinical manifestations associated with dengue are common among blood recipients, including fever, headache, and thrombocytopenia, which may hamper the establishment of a cause-effect relationship. Nevertheless, an increase in mortality up to 30 days after transfusion of viremic blood was demonstrated, although this increase was marginally statistically significant. The single DENV type detected in this epidemic was DENV-4, and the study by Sabino et al was performed during the initial introduction of this serotype in Recife and Rio de Janeiro. Considering that almost 90% of the population in these cities is currently seropositive for DENVspecific IgG, we can suppose that many recipients were exposed to heterotypic DENV RNA in transfusion components from asymptomatic donors, as the % of viremic donors peaked at 1%–2% in both cities. The absence of acute and moresevere symptomatic dengue cases among these recipients is an argument against the validity of the antibody-dependent enhancement (ADE) theory [7] when the infectious source is a blood component, since proponents of the ADE theory suggest that preexisting heterotypic antibodies are responsible for the exacerbation of the clinical picture. Furthermore, it is common to transfuse dengue patients when their platelet levels are low [8]—one of the hallmarks of the disease—suggesting that the reverse situation is also not uncommon (ie, that viremic recipients are exposed to donor antibodies present in plasma). It is intriguing to contemplate that a tiny volume of virus inmosquito saliva injected in the skin can bemuchmore harmful than 200–300 mL of virus in a blood bag from a viremic donor. This suggests that the amount of virus is less important than the form in which it is presented to the immune system. It has been shown that the structure of the viral particle changes according to body temperature [9], which differs between mosquitoes and humans. In addition, mosquito saliva, the vehicle for the viral particles injected in the skin, has important immunomodulatory and antigenic properties [10, 11], which are absent from the TT model. Moreover, the initial replication in keratinocytes and Langerhans cells may provide access to the lymphoid tissue and bone marrow, sites where intense viral replication takes place. A humanized animal model of dengue successfully demonstrated higher levels of and more-sustained viremia, larger erythema indices, and lower platelets count nadirs when the virus was delivered to mice by a mosquito bite, rather than when they were inoculated by intradermal injection, again reinforcing the key role played by the extrinsic replication phase in influencing the clinical course in humans [11]. Reasonably, Received and accepted 2 June 2015. Correspondence: J. E. Levi, Fundação Pró-Sangue, Departamento de Biologia Molecular, Rua Dr Enéas de Carvalho Aguiar 155, 1° andar, CEP 05403-000, São Paulo–SP, Brazil (dudilevi@usp.br). The Journal of Infectious Diseases 2016;213:689–90 © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com. DOI: 10.1093/infdis/jiv322