Temporal and Spatiotemporal Arboviruses Forecasting by Machine Learning: A Systematic Review.

Arboviruses are a group of diseases that are transmitted by an arthropod vector. Since they are part of the Neglected Tropical Diseases that pose several public health challenges for countries around the world. The arboviruses' dynamics are governed by a combination of climatic, environmental, and human mobility factors. Arboviruses prediction models can be a support tool for decision-making by public health agents. In this study, we propose a systematic literature review to identify arboviruses prediction models, as well as models for their transmitter vector dynamics. To carry out this review, we searched reputable scientific bases such as IEE Xplore, PubMed, Science Direct, Springer Link, and Scopus. We search for studies published between the years 2015 and 2020, using a search string. A total of 429 articles were returned, however, after filtering by exclusion and inclusion criteria, 139 were included. Through this systematic review, it was possible to identify the challenges present in the construction of arboviruses prediction models, as well as the existing gap in the construction of spatiotemporal models.

Alphavirus Identification in Neotropical Bats.

Alphaviruses (Togaviridae) are arthropod-borne viruses responsible for several emerging diseases, maintained in nature through transmission between hematophagous arthropod vectors and susceptible vertebrate hosts. Although bats harbor many species of viruses, their role as reservoir hosts in emergent zoonoses has been verified only in a few cases. With bats being the second most diverse order of mammals, their implication in arbovirus infections needs to be elucidated. Reports on arbovirus infections in bats are scarce, especially in South American indigenous species. In this work, we report the genomic detection and identification of two different alphaviruses in oral swabs from bats captured in Northern Uruguay. Phylogenetic analysis identified Río Negro virus (RNV) in two different species: Tadarida brasiliensis (n = 6) and Myotis spp. (n = 1) and eastern equine encephalitis virus (EEEV) in Myotis spp. (n = 2). Previous studies of our group identified RNV and EEEV in mosquitoes and horse serology, suggesting that they may be circulating in enzootic cycles in our country. Our findings reveal that bats can be infected by these arboviruses and that chiropterans could participate in the viral natural cycle as virus amplifiers or dead-end hosts. Further studies are warranted to elucidate the role of these mammals in the biological cycle of these alphaviruses in Uruguay.

Special Issue "Mosquito-Borne Virus Ecology".

Mosquito-borne viruses (MBVs), also known as moboviruses, are associated mainly with mosquitoes and are able to infect humans and other vertebrates [...].

Glycosaminoglycan binding by arboviruses: a cautionary tale.

Arboviruses are medically important arthropod-borne viruses that cause a range of diseases in humans from febrile illness to arthritis, encephalitis and hemorrhagic fever. Given their transmission cycles, these viruses face the challenge of replicating in evolutionarily divergent organisms that can include ticks, flies, mosquitoes, birds, rodents, reptiles and primates. Furthermore, their cell attachment receptor utilization may be affected by the opposing needs for generating high and sustained serum viremia in vertebrates such that virus particles are efficiently collected during a hematophagous arthropod blood meal but they must also bind sufficiently to cellular structures on divergent organisms such that productive infection can be initiated and viremia generated. Sulfated polysaccharides of the glycosaminoglycan (GAG) groups, primarily heparan sulfate (HS), have been identified as cell attachment moieties for many arboviruses. Original identification of GAG binding as a phenotype of arboviruses appeared to involve this attribute arising solely as a consequence of adaptation of virus isolates to growth in cell culture. However, more recently, naturally circulating strains of at least one arbovirus, eastern equine encephalitis, have been shown to bind HS efficiently and the GAG binding phenotype continues to be associated with arbovirus infection in published studies. If GAGs are attachment receptors for many naturally circulating arboviruses, this could lead to development of broad-spectrum antiviral therapies through blocking of the virus-GAG interaction. This review summarizes the available data for GAG/HS binding as a phenotype of naturally circulating arbovirus strains emphasizing the importance of avoiding tissue culture amplification and artifactual phenotypes during their isolation.

Machine learning and deep learning techniques to support clinical diagnosis of arboviral diseases: A systematic review.

BACKGROUND: Neglected tropical diseases (NTDs) primarily affect the poorest populations, often living in remote, rural areas, urban slums or conflict zones. Arboviruses are a significant NTD category spread by mosquitoes. Dengue, Chikungunya, and Zika are three arboviruses that affect a large proportion of the population in Latin and South America. The clinical diagnosis of these arboviral diseases is a difficult task due to the concurrent circulation of several arboviruses which present similar symptoms, inaccurate serologic tests resulting from cross-reaction and co-infection with other arboviruses. OBJECTIVE: The goal of this paper is to present evidence on the state of the art of studies investigating the automatic classification of arboviral diseases to support clinical diagnosis based on Machine Learning (ML) and Deep Learning (DL) models. METHOD: We carried out a Systematic Literature Review (SLR) in which Google Scholar was searched to identify key papers on the topic. From an initial 963 records (956 from string-based search and seven from a single backward snowballing procedure), only 15 relevant papers were identified. RESULTS: Results show that current research is focused on the binary classification of Dengue, primarily using tree-based ML algorithms. Only one paper was identified using DL. Five papers presented solutions for multi-class problems, covering Dengue (and its variants) and Chikungunya. No papers were identified that investigated models to differentiate between Dengue, Chikungunya, and Zika. CONCLUSIONS: The use of an efficient clinical decision support system for arboviral diseases can improve the quality of the entire clinical process, thus increasing the accuracy of the diagnosis and the associated treatment. It should help physicians in their decision-making process and, consequently, improve the use of resources and the patient's quality of life.

Evidence of co-circulation of multiple arboviruses transmitted by Aedes species based on laboratory syndromic surveillance at a health unit in a slum of the Federal District, Brazil.

BACKGROUND: Vector-borne diseases, especially arboviruses transmitted by Aedes sp. mosquitos, should be a health policy priority in Brazil. Despite this urgency, there are significant limitations in the traditional surveillance system, mainly in vulnerable areas. This study aimed to investigate the circulation of dengue (DENV), Zika (ZIKV), and chikungunya viruses (CHIKV) by laboratory syndromic surveillance (LSS) in a slum area of the Federal District of Brazil, comparing the results with traditional surveillance data. METHODS: LSS for acute febrile and/or exanthematous symptoms was developed at a health unit of Cidade Estrutural, in order to identify the circulation of arboviruses transmitted by Aedes sp. mosquitos. Between June 2019 and March 2020, 131 valid participants were identified and sera tested by reverse transcription polymerase chain reaction (RT-PCR) for DENV (by serotype), ZIKV, and CHIKV acute infection and by immunoglobulin M enzyme-inked immunosorbent assay (ELISA-IgM) for DENV and CHIKV 15-21 days after symptom onset, when the participant reported no respiratory signs (cough and/or coryza). The results obtained were compared with traditional surveillance data for the study area and period. RESULTS: At least three DENV-1 (2.3%), four DENV-2 (3%), and one CHIKV (0.7%) cases were confirmed in the laboratory, showing evidence of hyperendemicity even though LSS had not reached the historic peak dengue fever months in the Federal District (April-May). When the results obtained here were compared with traditional surveillance, a significant discrepancy was observed, including underreporting of CHIKV infection. CONCLUSIONS: In addition to the risks posed to the study population, the area investigated with its respective socio-environmental profile may be a potential site for spread of the virus, given the cosmopolitan presence of Aedes sp. and human mobility in the Federal District. It is also suggested that traditional epidemiological surveillance may be reporting acute viral infections other than DENV as dengue fever, while underreporting other arboviruses transmitted by Aedes sp. mosquitos in the Federal District.

Single-cell analysis of arthritogenic alphavirus-infected human synovial fibroblasts links low abundance of viral RNA to induction of innate immunity and arthralgia-associated gene expression.

Infection by (re-)emerging RNA arboviruses including Chikungunya virus (CHIKV) and Mayaro virus primarily cause acute febrile disease and transient polyarthralgia. However, in a significant subset of infected individuals, debilitating arthralgia persists for weeks over months up to years. The underlying immunopathogenesis of chronification of arthralgia upon primary RNA-viral infection remains unclear. Here, we analysed cell-intrinsic responses to ex vivo arthritogenic alphaviral infection of primary human synovial fibroblasts isolated from knee joints, one the most affected joint types during acute and chronic CHIKV disease. Synovial fibroblasts were susceptible and permissive to alphaviral infection. Base-line and exogenously added type I interferon (IFN) partially and potently restricted infection, respectively. RNA-seq revealed a CHIKV infection-induced transcriptional profile that comprised upregulation of expression of several hundred IFN-stimulated and arthralgia-mediating genes. Single-cell virus-inclusive RNA-seq uncovered a fine-tuned switch from induction to repression of cell-intrinsic immune responses depending on the abundance of viral RNA in an individual cell. Specifically, responses were most pronounced in cells displaying low-to-intermediate amounts of viral RNA and absence of virus-encoded, fluorescent reporter protein expression, arguing for efficient counteraction of innate immunity in cells expressing viral antagonists at sufficient quantities. In summary, cell-intrinsic sensing of viral RNA that potentially persists or replicates at low levels in synovial fibroblasts and other target cell types in vivo may contribute to the chronic arthralgia induced by alphaviral infections. Our findings might advance our understanding of the immunopathophysiology of long-term pathogenesis of RNA-viral infections.

Simbu Viruses' Infection of Livestock in Israel-A Transient Climatic Land.

Important lessons have been learned by the Israeli veterinary community regarding Simbu serogroup viruses infections. This serogroup of viruses might cause the births of neonatal malformation in susceptible ruminant's populations. Until 2012, only Akabane virus was connected with the births of malformed ruminants in Israel. However, serological and genomic detection tests, coupled with viral isolations, revealed that more than a single Simbu serogroup serotype could be present concurrently in the same farm or even in the same animal. From 2012 to date, Aino, Shuni, Shamunda, Satuperi, Peaton, Schmallenberg, and Sango viruses have been found in Israel either by serological or genomic investigation. Israel is located in the Eastern Mediterranean Basin, a terrestrial and climatic bridge between the three old continents. The Eastern Mediterranean shores benefit from both the tropical/subtropical and the continental climatic conditions. Therefore, the Eastern Mediterranean basin might serve as an optimal investigatory compound for several arboviral diseases, acting as a sentinel. This review summarizes updated information related to the presence of Simbu serogroup viruses in Israel.

Mosquito-borne arboviruses in Uganda: history, transmission and burden.

Mosquito-transmitted arboviruses constitute a large proportion of emerging infectious diseases that are both a public health problem and a threat to animal populations. Many such viruses were identified in East Africa, a region where they remain important and from where new arboviruses may emerge. We set out to describe and review the relevant mosquito-borne viruses that have been identified specifically in Uganda. We focused on the discovery, burden, mode of transmission, animal hosts and clinical manifestation of those previously involved in disease outbreaks. A search for mosquito-borne arboviruses detected in Uganda was conducted using search terms 'Arboviruses in Uganda' and 'Mosquitoes and Viruses in Uganda' in PubMed and Google Scholar in 2020. Twenty-four mosquito-borne viruses from different animal hosts, humans and mosquitoes were documented. The majority of these were from family Peribunyaviridae, followed by Flaviviridae, Togaviridae, Phenuiviridae and only one each from family Rhabdoviridae and Reoviridae. Sixteen (66.7%) of the viruses were associated with febrile illnesses. Ten (41.7%) of them were first described locally in Uganda. Six of these are a public threat as they have been previously associated with disease outbreaks either within or outside Uganda. Historically, there is a high burden and endemicity of arboviruses in Uganda. Given the many diverse mosquito species known in the country, there is also a likelihood of many undescribed mosquito-borne viruses. Next generation diagnostic platforms have great potential to identify new viruses. Indeed, four novel viruses, two of which were from humans (Ntwetwe and Nyangole viruses) and two from mosquitoes (Kibale and Mburo viruses) were identified in the last decade using next generation sequencing. Given the unbiased approach of detection of viruses by this technology, its use will undoubtedly be critically important in the characterization of mosquito viromes which in turn will inform other diagnostic efforts.

Thrombotic microangiopathy associated with arboviral infection: Report of 3 cases.

Dengue fever and chikungunya are viral diseases that have spread rapidly throughout the world in recent decades. The occurrence of complications is well known, including prerenal acute kidney injury (AKI), which is usually thought to be caused by dehydration and fluid loss. Thrombotic microangiopathy (TMA) is an uncommon aggravation of dengue fever and chikungunya, with only a few cases described in the medical literature. The aim of this study is to present 3 cases of TMA associated with arboviral infection. Three patients with clinical history, laboratory test, and kidney biopsy results compatible with TMA were selected for the study, 2 of whom had a serological diagnosis of dengue fever and 1 of chikungunya. The 3 patients were followed up at the Federal University of Maranhão Hospital's Nephrology Service in 2018. A targeted gene panel sequencing (TGPS) plus multiple to atypical hemolytic uremic syndrome (aHUS) multiplex ligation-dependent probe amplification (MLPA) was performed in 2 of the patients and revealed in the patient 1 a heterozygous pathogenic variant in the gene THBD, as well as heterozygous deletions in CFH, CFHR1, and CFHR3. In the patient 2, there were heterozygous pathogenic variant in the genes CFI and CFB, in addition to heterozygous deletions in the genes CFHR1 and CFHR3. Both received treatment with eculizumab and undergone recovery of renal function. The third patient had TMA not classified as either aHUS or thrombotic thrombocytopenic purpura (TTP); he abandoned the treatment and returned to the service after 2 years for a dialysis emergency. Patients with arboviral infectious disease and changes that suggest TMA should have appropriate support to establish early diagnosis and useful treatment.

Minireview: Epidemiological impact of arboviral diseases in Latin American countries, arbovirus-vector interactions and control strategies.

Mosquitoes are the most crucial insects in public health due to their vector capacity and competence to transmit pathogens, including arboviruses, bacterias and parasites. Re-emerging and emerging arboviral diseases, such as yellow fever virus (YFV), dengue virus (DENV), zika virus (ZIKV), and chikungunya virus (CHIKV), constitute one of the most critical health public concerns in Latin America. These diseases present a significant incidence within the human settlements increasing morbidity and mortality events. Likewise, among the different genus of mosquito vectors of arboviruses, those of the most significant medical importance corresponds to Aedes and Culex. In Latin America, the mosquito vector species of YFV, DENV, ZIKV, and CHIKV are mainly Aedes aegypti and Ae. Albopictus. Ae. aegypti is recognized as the primary vector in urban environments, whereas Ae. albopictus, recently introduced in the Americas, is more prone to rural settings. This minireview focuses on what is known about the epidemiological impact of mosquito-borne diseases in Latin American countries, with particular emphasis on YFV, DENV, ZIKV and CHIKV, vector mosquitoes, geographic distribution, and vector-arbovirus interactions. Besides, it was analyzed how climate change and social factors have influenced the spread of arboviruses and the control strategies developed against mosquitoes in this continent.

An Aedes aegypti-Derived Ago2 Knockout Cell Line to Investigate Arbovirus Infections.

Mosquitoes are known as important vectors of many arthropod-borne (arbo)viruses causing disease in humans. These include dengue (DENV) and Zika (ZIKV) viruses. The exogenous small interfering (si)RNA (exo-siRNA) pathway is believed to be the main antiviral defense in arthropods, including mosquitoes. During infection, double-stranded RNAs that form during viral replication and infection are cleaved by the enzyme Dicer 2 (Dcr2) into virus-specific 21 nt vsiRNAs, which are subsequently loaded into Argonaute 2 (Ago2). Ago2 then targets and subsequently cleaves complementary RNA sequences, resulting in degradation of the target viral RNA. Although various studies using silencing approaches have supported the antiviral activity of the exo-siRNA pathway in mosquitoes, and despite strong similarities between the siRNA pathway in the Drosophila melanogaster model and mosquitoes, important questions remain unanswered. The antiviral activity of Ago2 against different arboviruses has been previously demonstrated. However, silencing of Ago2 had no effect on ZIKV replication, whereas Dcr2 knockout enhanced its replication. These findings raise the question as to the role of Ago2 and Dcr2 in the control of arboviruses from different viral families in mosquitoes. Using a newly established Ago2 knockout cell line, alongside the previously reported Dcr2 knockout cell line, we investigated the impact these proteins have on the modulation of different arboviral infections. Infection of Ago2 knockout cell line with alpha- and bunyaviruses resulted in an increase of viral replication, but not in the case of ZIKV. Analysis of small RNA sequencing data in the Ago2 knockout cells revealed a lack of methylated siRNAs from different sources, such as acute and persistently infecting viruses-, TE- and transcriptome-derived RNAs. The results confirmed the importance of the exo-siRNA pathway in the defense against arboviruses, but highlights variability in its response to different viruses and the impact the siRNA pathway proteins have in controlling viral replication. Moreover, this established Ago2 knockout cell line can be used for functional Ago2 studies, as well as research on the interplay between the RNAi pathways.

Arboviral diseases and poverty in Alabama, 2007-2017.

Mosquito-borne viruses cause diseases of great public health concern. Arboviral disease case distributions have complex relationships with socioeconomic and environmental factors. We combined information about socio-economic (population, and poverty rate) and environmental (precipitation, and land use) characteristics with reported human cases of arboviral disease in the counties of Alabama, USA, from 2007-2017. We used county level data on West Nile virus (WNV), dengue virus (DENV), chikungunya virus (CHIKV), Zika virus (ZIKV), California serogroup virus, Eastern equine encephalitis virus, and Saint Louis encephalitis virus to provide a detailed description of their spatio-temporal pattern. We found a significant spatial convergence between incidence of WNV and poverty rate clustered in the southern part of Alabama. DENV, CHIKV and ZIKV cases showed a different spatial pattern, being mostly located in the northern part, in areas of high socioeconomic status. The results of our study establish that poverty-driven inequities in arboviral risk exist in the southern USA, and should be taken into account when planning prevention and intervention strategies.

At the tip of an iceberg: citizen science and active surveillance collaborating to broaden the known distribution of Aedes japonicus in Spain.

BACKGROUND: Active surveillance aimed at the early detection of invasive mosquito species is usually focused on seaports and airports as points of entry, and along road networks as dispersion paths. In a number of cases, however, the first detections of colonizing populations are made by citizens, either because the species has already moved beyond the implemented active surveillance sites or because there is no surveillance in place. This was the case of the first detection in 2018 of the Asian bush mosquito, Aedes japonicus, in Asturias (northern Spain) by the citizen science platform Mosquito Alert. METHODS: The collaboration between Mosquito Alert, the Ministry of Health, local authorities and academic researchers resulted in a multi-source surveillance combining active field sampling with broader temporal and spatial citizen-sourced data, resulting in a more flexible and efficient surveillance strategy. RESULTS: Between 2018 and 2020, the joint efforts of administrative bodies, academic teams and citizen-sourced data led to the discovery of this species in northern regions of Spain such as Cantabria and the Basque Country. This raised the estimated area of occurrence of Ae. japonicus from < 900 km2 in 2018 to > 7000 km2 in 2020. CONCLUSIONS: This population cluster is geographically isolated from any other population in Europe, which raises questions about its origin, path of introduction and dispersal means, while also highlighting the need to enhance surveillance systems by closely combining crowd-sourced surveillance with public health and mosquito control agencies' efforts, from local to continental scales. This multi-actor approach for surveillance (either passive and active) shows high potential efficiency in the surveillance of other invasive mosquito species, and specifically the major vector Aedes aegypti which is already present in some parts of Europe.

Mosquito-borne arboviruses in Uganda: history, transmission and burden.

Mosquito-transmitted arboviruses constitute a large proportion of emerging infectious diseases that are both a public health problem and a threat to animal populations. Many such viruses were identified in East Africa, a region where they remain important and from where new arboviruses may emerge. We set out to describe and review the relevant mosquito-borne viruses that have been identified specifically in Uganda. We focused on the discovery, burden, mode of transmission, animal hosts and clinical manifestation of those previously involved in disease outbreaks. A search for mosquito-borne arboviruses detected in Uganda was conducted using search terms 'Arboviruses in Uganda' and 'Mosquitoes and Viruses in Uganda' in PubMed and Google Scholar in 2020. Twenty-four mosquito-borne viruses from different animal hosts, humans and mosquitoes were documented. The majority of these were from family Peribunyaviridae, followed by Flaviviridae, Togaviridae, Phenuiviridae and only one each from family Rhabdoviridae and Reoviridae. Sixteen (66.7 %) of the viruses were associated with febrile illnesses. Ten (41.7 %) of them were first described locally in Uganda. Six of these are a public threat as they have been previously associated with disease outbreaks either within or outside Uganda. Historically, there is a high burden and endemicity of arboviruses in Uganda. Given the many diverse mosquito species known in the country, there is also a likelihood of many undescribed mosquito-borne viruses. New generation diagnostic platforms have great potential to identify new viruses. Indeed, four novel viruses, two of which were from humans (Ntwetwe and Nyangole viruses) and two from mosquitoes (Kibale and Mburo viruses) including the 2010 yellow fever virus (YFV) outbreak were identified in the last decade using next generation sequencing. Given the unbiased approach of detection of viruses by this technology, its use will undoubtedly be critically important in the characterization of mosquito viromes which in turn will inform other diagnostic efforts.

The virome of vector mosquitoes.

Mosquitoes are the major vectors for arthropod-borne viruses (arboviruses) of medical importance. Aedes aegypti and A. albopictus are the most prolific and widespread mosquito vectors being responsible for global transmission of dengue, Zika and Chikungunya viruses. Characterizing the collection of viruses circulating in mosquitoes, the virome, has long been of special interest. In addition to arboviruses, mosquitoes carry insect-specific viruses (ISVs) that do not directly infect vertebrates. Mounting evidence indicates that ISVs interact with arboviruses and may affect mosquito vector competence. Here, we review our current knowledge about the virome of vector mosquitoes and discuss the challenges for the field that may lead to novel strategies to prevent outbreaks of arboviruses.

Arboviral central nervous system infections.

PURPOSE OF REVIEW: This review provides an overview of arthropod-borne virus (arbovirus) infections that are important causes of human neurological infections world-wide. As many of the individual viruses in a specific genus or family cause overlapping clinical syndromes, this review discusses important viruses in groups to highlight some of the similarities and differences in groups of neuroinvasive arbovirus infections. RECENT FINDINGS: Arboviruses that cause neurological infections in humans continue to emerge and distribute to new regions. The geographic range of the vectors, the hosts and subsequent arbovirus infections in humans continues to expand and evolve. As emerging arboviruses move into new geographic regions, it is important to examine the associated epidemiological and clinical impacts of these infections as they enter new populations. SUMMARY: Arboviruses from the Flaviviridae, Togaviridae and Bunyaviridae families continue to emerge and spread into new regions. The arboviruses within these virus families cause characteristic neuroinvasive diseases in human populations. A complete understanding of the epidemiological and clinical features of the neuroinvasive arboviruses is important such that these pathogens can be recognized and diagnosed in humans as they emerge. Ongoing research to develop rapid, accurate diagnostics, therapeutic options and vaccines for these pathogens is needed to address future outbreaks of disease in human populations.

Host Factors That Control Mosquito-Borne Viral Infections in Humans and Their Vector.

Mosquito-borne viral infections are responsible for a significant degree of morbidity and mortality across the globe due to the severe diseases these infections cause, and they continue to increase each year. These viruses are dependent on the mosquito vector as the primary means of transmission to new vertebrate hosts including avian, livestock, and human populations. Due to the dynamic host environments that mosquito-borne viruses pass through as they are transmitted between vector and vertebrate hosts, there are various host factors that control the response to infection over the course of the pathogen's life cycle. In this review, we discuss these host factors that are present in either vector or vertebrate models during infection, how they vary or are conserved between hosts, and their implications in future research pertaining to disease prevention and treatment.

Peripheral spectrum neurological disorder after arbovirus infection is associated with HLA-F variants among Northeastern Brazilians.

INTRODUCTION: Non-classical class I human leukocyte antigens (HLA) molecules are known to modulate the function of cytotoxic cells (NK and T CD8+) during viral infection by interacting with inhibitory/activating receptors. However, little is known about the HLA-E/-F genetic variability on arbovirus infections. METHODS: We evaluated by massive parallel sequencing the full HLA-E/-F genetic diversity among patients infected during the arbovirus (ZIKV, DENV, and CHIKV) outbreak leading to a broad range of neurological complications in the Brazilian State of Pernambuco. In parallel, healthy blood donors from the same area were also studied. Plink and R software were used for genetic association study. To limit the false-positive results and enhance the reliability of the results, we adopted P-values <0.01 as significant levels. RESULTS: Compared to controls, the HLA-F alleles: -1610 C (rs17875375), +1383 G (rs17178385), and +3537 A (rs17875384), all in complete linkage disequilibrium with each other (r2 = 1), were overrepresented in patients presenting peripheral spectrum disorders (PSD). The HLA-F*Distal-D haplotype that harbored the -1610 C allele exhibited a trend increase in PSD group. No associations were found for HLA-E. CONCLUSIONS: Our findings showed that the HLA-F genetic background seems to be more important than HLA-E on the susceptibility to PSD complications.