Dengue\'s lack of specific treatments beyond supportive care prompts a focus on uncovering additional pathophysiological factors. Dengue-associated hemophagocytic lymphohistiocytosis (HLH), characterized by dysregulated macrophage activation and cytokine storm, remains underexplored despite its potential to worsen disease severity and mortality. While rare, dengue-associated HLH disproportionately affects severe cases, significantly impacting mortality rates. To mitigate high mortality, early identification and familiarity with dengue-associated HLH are imperative for prompt treatment by clinicians. This narrative review therefore aims to examine the current clinical and therapeutic knowledge on dengue-associated HLH, and act as a resource for clinicians to improve their management of HLH associated with severe dengue. Dengue-associated HLH should be considered for all cases of severe dengue and may be suspected based on the presence of prolonged or recurrent fever for >7 days, or anemia without intravascular hemolysis or massive bleeding. Diagnosis relies on fulfilling at least five of the eight HLH-2004 criteria. Treatment predominantly involves short courses (3-4 days) of high-dose steroids (e.g., dexamethasone 10 mg/m2), with additional therapies considered in more severe presentations. Notably, outcomes can be favorable with steroid therapy alone.

Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.

The flavivirus West Nile virus (WNV) naturally circulates between mosquitoes and birds, potentially affecting humans and horses. Different species of mosquitoes play a role as vectors of WNV, with those of the Culex pipiens complex being particularly crucial for its circulation. Different biotic and abiotic factors determine the capacity of mosquitoes for pathogen transmission, with the mosquito gut microbiota being recognized as an important one. Here, we review the published studies on the interactions between the microbiota of the Culex pipiens complex and WNV infections in mosquitoes. Most articles published so far studied the interactions between bacteria of the genus Wolbachia and WNV infections, obtaining variable results regarding the directionality of this relationship. In contrast, only a few studies investigate the role of the whole microbiome or other bacterial taxa in WNV infections. These studies suggest that bacteria of the genera Serratia and Enterobacter may enhance WNV development. Thus, due to the relevance of WNV in human and animal health and the important role of mosquitoes of the Cx. pipiens complex in its transmission, more research is needed to unravel the role of mosquito microbiota and those factors affecting this microbiota on pathogen epidemiology. In this respect, we finally propose future lines of research lines on this topic.

Flaviviruses infect arthropods and mammals and their pathologies are a considerable global health problem, affecting about 400 million people per year. The symptoms of these flaviviruses range from mild manifestations such as nausea, vomiting, and headache to more serious cases such as hemorrhage, meningitis, microcephaly, kidney, and liver failure. This review aims to compile the morphological changes that occur due to infections caused by dengue, yellow fever, and Zika viruses, as well as to describe possible mechanisms of action of such flaviviruses in the liver. PRISMA guidelines were used to search for studies associating flavivirus with liver disorders. Two independent reviewers selected the studies on PubMed/Medline, Web of Science, and Scopus search platforms. The SYRCLE software was used for the evaluation of the study\'s quality. Eighteen experimental articles were included. The experimental animals often used in experiments were monkeys (5 %), hamsters (10 %), chicken embryos (10 %), and mice (75 %). It is evident that there is a strong hepatic interaction with flaviviruses, and the main hepatic alterations found were steatosis, apoptosis, necrosis, hemorrhage, elevation of ALT and AST levels, and total bilirubin. Flavivirus infection, in general, trigger an upregulation of pro-inflammatory cytokines, leading to structural changes in mitochondria that activate cascades of cellular death and promote insulin resistance. The majority of the studies primarily focus on dengue and yellow fever viruses, while the findings related to Zika virus exposure are still relatively limited and require further investigation.

The Flaviviridae family comprises positive-sense single-strand RNA viruses mainly transmitted by arthropods. Many of these pathogens are especially deleterious to the nervous system, and a myriad of neurological symptoms have been associated with infections by Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) in humans. Studies suggest that viral replication in neural cells and the massive release of pro-inflammatory mediators lead to morphological alterations of synaptic spine structure and changes in the balance of excitatory/inhibitory neurotransmitters and receptors. Glutamate is the predominant excitatory neurotransmitter in the brain, and studies propose that either enhanced release or impaired uptake of this amino acid contributes to brain damage in several conditions. Here, we review existing evidence suggesting that glutamatergic dysfunction-induced by flaviviruses is a central mechanism for neurological damage and clinical outcomes of infection. We also discuss current data suggesting that pharmacological approaches that counteract glutamatergic dysfunction show benefits in animal models of such viral diseases.

UNASSIGNED: Since 1952 when Zika Virus (ZIKV): a Flavivirus, was first discovered in humans, it has not received enough scientific research compared to some of the other members of the family Flaviviridae; like Dengue Virus (DENV). However, this has not stopped the virus from infecting the human population globally. In particular, the global spread of ZIKV has led to a surge in observational studies.
UNASSIGNED: Regarding recently published ZIKV-related literature, we are not aware of any reviews strictly focusing on ZIKV from the perspective of observational studies. Therefore, we reviewed recently published observational studies exploring the global spread of ZIKV and its association with Congenital ZIKV Infection (CZI) and clinical manifestations in adults. Online databases including google scholar, PubMed and Elsevier were used for retrieving relevant studies.
UNASSIGNED: ZIKV cases have been reported in different parts of the world, with certain regions reporting more cases than the rest, like Brazil. ZIKV causes a wide spectrum of diseases and disorders including microcephaly, developmental disorders, and Guillain-Barre syndrome to name a few. Furthermore, CZI in neonates mainly manifests into neurological disorders and diseases, whereas ZIKV in adults\' targets various organs.
UNASSIGNED: ZIKV poses a serious threat to human population and observational studies provide a different perspective on the damaging capabilities of ZIKV in real-life settings. Moreover, there are gaps in the literature regarding ZIKV-related-complications that future experimental studies need to address. These complications include in-utero transmission, Guillain-Barre syndrome, cross-reactivity, sexual transmission, along with its persistence in the male reproductive tract.

The family Flaviviridae is comprised of a diverse group of arthropod-borne viruses that are the etiological agents of globally relevant diseases in humans. Among these, infection with several of these flaviviruses-including West Nile virus (WNV), Zika virus (ZIKV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and Powassan virus (POWV)-can result in neuroinvasive disease presenting as meningitis or encephalitis. Factors contributing to the development and resolution of tick-borne flavivirus (TBEV, POWV) infection and neuropathology remain unclear, though many recently undertaken studies have described the virus-host interactions underlying encephalitic disease. With access to neural tissues despite the selectively permeable blood-brain barrier, T cells have emerged as one notable contributor to neuroinflammation. The goal of this review is to summarize the recent advances in tick-borne flavivirus immunology-particularly with respect to T cells-as it pertains to the development of encephalitis. We found that although T cell responses are rarely evaluated in a clinical setting, they are integral in conjunction with antibody responses to restricting the entry of TBFV into the CNS. The extent and means by which they can drive immune pathology, however, merits further study. Understanding the role of the T cell compartment in tick-borne flavivirus encephalitis is instrumental for improving vaccine safety and efficacy, and has implications for treatments and interventions for human disease.

The flavivirus genus contains several clinically important pathogens that account for tremendous global suffering. Primarily transmitted by mosquitos or ticks, these viruses can cause severe and potentially fatal diseases ranging from hemorrhagic fevers to encephalitis. The extensive global burden is predominantly caused by six flaviviruses: dengue, Zika, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitis. Several vaccines have been developed, and many more are currently being tested in clinical trials. However, flavivirus vaccine development is still confronted with many shortcomings and challenges. With the use of the existing literature, we have studied these hurdles as well as the signs of progress made in flavivirus vaccinology in the context of future development strategies. Moreover, all current licensed and phase-trial flavivirus vaccines have been gathered and discussed based on their vaccine type. Furthermore, potentially relevant vaccine types without any candidates in clinical testing are explored in this review as well. Over the past decades, several modern vaccine types have expanded the field of vaccinology, potentially providing alternative solutions for flavivirus vaccines. These vaccine types offer different development strategies as opposed to traditional vaccines. The included vaccine types were live-attenuated, inactivated, subunit, VLPs, viral vector-based, epitope-based, DNA and mRNA vaccines. Each vaccine type offers different advantages, some more suitable for flaviviruses than others. Additional studies are needed to overcome the barriers currently faced by flavivirus vaccine development, but many potential solutions are currently being explored.

Flaviviruses include virus species that are major public health threats worldwide. To determine the immunity landscape of these viruses, seroprevalence studies are often performed using IgG ELISA, which is a simple and rapid alternative to the virus neutralization test. In this review, we aim to describe the trends in flavivirus IgG ELISA-based serosurveys. A systematic literature review using six databases was performed to collate cohort and cross-sectional studies performed on the general population. A total of 204 studies were included in this review. The results show that most studies were performed on dengue virus (DENV), whereas Japanese Encephalitis Virus (JEV) was the least studied. For geographic distribution, serosurveys followed known disease prevalence. Temporally, the number of serosurveys increased after outbreaks and epidemics except for JEV, for which studies were performed to demonstrate the effectiveness of vaccination campaigns. Commercial kits were more commonly used than in-house assays for DENV, West Nile Virus (WNV), and Zika virus (ZIKV). Overall, most studies employed an indirect ELISA format, and the choice of antigens varied per virus. This review shows that flavivirus epidemiology is related to the regional and temporal distribution of serosurveys. It also highlights that endemicity, cross-reactivities, and kit availabilities affect assay choice in serosurveys.

Flaviviruses are a genus of single-stranded RNA viruses that impose an important and growing burden to human health. There are over 3 billion individuals living in areas where flaviviruses are endemic. Flaviviruses and their arthropod vectors (which include mosquitoes and ticks) take advantage of global travel to expand their distribution and cause severe disease in humans, and they can be grouped according to their vector and pathogenicity. The mosquito-borne flaviviruses cause a spectrum of diseases from encephalitis to hepatitis and vascular shock syndrome, congenital abnormalities, and fetal death. Neurotropic infections such as Zika virus and West Nile virus cross the blood-brain barrier and infect neurons and other cells, leading to meningoencephalitis. In the hemorrhagic fever clade, there are yellow fever virus, the prototypical hemorrhagic fever virus that infects hepatocytes, and dengue virus, which infects cells of the reticuloendothelial system and can lead to a dramatic plasma cell leakage and shock syndrome. Zika virus also causes congenital infections and fetal death and is the first and only example of a teratogenic arbovirus in humans. Diagnostic testing for flaviviruses broadly includes the detection of viral RNA in serum (particularly within the first 10 days of symptoms), viral isolation by cell culture (rarely performed due to complexity and biosafety concerns), and histopathologic evaluation with immunohistochemistry and molecular testing on formalin-fixed paraffin-embedded tissue blocks. This review focuses on 4 mosquito-borne flaviviruses-West Nile, yellow fever, dengue, and Zika virus-and discusses the mechanisms of transmission, the role of travel in geographic distribution and epidemic emergence, and the clinical and histopathologic features of each. Finally, prevention strategies such as vector control and vaccination are discussed.