Search Results (40)

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may be triggered by infections such as dengue virus. Due to overlapping features with severe dengue and sepsis, diagnosis of HLH in dengue-infected patients remains challenging. Methods: We conducted a narrative review and individual patient data meta-analysis of published cases of dengue-associated HLH. Eligible studies were identified through a search of PubMed and Scopus databases up to 5 March 2025. Clinical, laboratory, microbiological, treatment, and outcome data were extracted and analyzed. Results: A total of 133 patients from 71 studies were included. The median patient age was 18 years, and 56.8% were male. Common clinical features included fever (96.9%), cytopenias, organomegaly, and liver dysfunction. ALT elevation, jaundice, and hypofibrinogenemia were associated with mortality. DENV-1 was the most common serotype (57.4%) and was negatively associated with death. Overall, 19.3% of patients died. Multivariate analysis did not identify independent mortality predictors. Conclusions: Dengue-associated HLH predominantly affects young individuals and carries significant mortality. Key indicators of poor prognosis include hepatic dysfunction and the presence of shock or organ failure. Early recognition and prompt immunomodulatory treatment, particularly corticosteroids, may improve outcomes. Full article

(1) Background: Murine typhus, caused by Rickettsia typhi, is a neglected rickettsial disease and an underdiagnosed cause of acute febrile illness (AFI), particularly in endemic regions such as Indonesia. (2) Case description: We report a case series of four patients presenting with AFI of less than seven days in duration. Three patients were admitted with moderate disease, while one presented with septic shock with the macrophage activation-like syndrome (MALS) phenotype. Common clinical features included myalgia and headache; additional symptoms included cough, sore throat, and abdominal pain. Laboratory findings revealed bicytopenia, elevated transaminases, and raised inflammatory and bacterial infection markers. Common tropical infections—dengue, typhoid fever, and leptospirosis—and other potential sources of infection were excluded early during hospitalization. Diagnosis was confirmed by nucleic acid amplification testing (NAAT), which detected R. typhi in all patients. Doxycycline was initiated following confirmation, leading to defervescence within 36–48 h. (3) Conclusions: Murine typhus remains an underrecognized cause of febrile illness in Indonesia. In the near future, the inclusion of rickettsial testing in the diagnostic protocol of AFI will be crucial, as it enables timely administration of effective, low-cost treatment. Full article

Dengue virus (DENV) infection is strongly associated with dengue hemorrhagic fever and dengue shock syndrome, both of which carry mortality risks. Addressing the urgent need for effective dengue therapeutics, we identified sofalcone, a gastroprotective agent with antioxidant and anti-inflammatory properties, as a potential inhibitor of DENV replication. Sofalcone demonstrated efficacy against all four DENV serotypes, with the dose inhibiting 50% (IC50) value of 28.1 ± 0.42 μM against viral replication of DENV serotype 2, without significant cytotoxicity. Additionally, sofalcone significantly improved survival rates and reduced viral titers in DENV-infected ICR-suckling mice. Mechanistically, sofalcone induced heme oxygenase-1 (HO-1) expression via the nuclear factor-erythroid 2-reated factor 2 (Nrf2) pathway, which in turn suppressed viral protease activity and restored antiviral interferon (IFN) responses. This included dose-dependent stimulation of IFN downstream antiviral genes such as 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Given its established clinical use as an anti-gastric ulcer drug, sofalcone offers promising potential for rapid application in treating DENV infection. Full article

Dengue virus is the most prevalent arthropod-borne viral disease in humans. Severe dengue, defined by hemorrhagic fever and dengue shock syndrome, can develop quickly in people who have warning indications such as abdominal pain, mucosal bleeding, and a significant decrease in platelet count. Laboratory markers such as hematocrit, platelet count, liver enzymes, and coagulation tests are critical for early diagnosis and prognosis. This retrospective study was carried out from January 2023 to December 2024 at a super-specialty tertiary care hospital. There were 283 adult patients with dengue with warning signs, who were categorized into 102 with platelet transfusion and 181 with no platelet transfusion. Data on patient demographics, clinical history, laboratory values, and radiological findings were systematically obtained from hospital records at the time of admission. Laboratory parameters such as white blood cell (OR = 2.137), hemoglobin (OR = 2.15), aPTT (OR = 5.815), AST²/ALT (OR = 2.431), platelet count (OR = 26.261) and NS1 (OR = 4.279) were found to be significantly associated (p < 0.01) with platelet transfusion. Similarly, an increased prothrombin time (OR = 2.432) contributed to prolonged hospital stays and the presence of ascites (OR = 5.059), gallbladder wall thickening (OR = 4.212), and pleural effusion (OR = 2.917), contributing to the severity of the dengue infection. These significant laboratory markers help with identifying patients with dengue who may develop severe dengue, requiring platelet transfusion, thereby prioritizing patient care and enabling the implementation of targeted interventions. Full article

Dengue fever, caused by the dengue virus (DENV), poses a significant global health challenge, particularly in tropical and subtropical regions. Recent increases in indigenous DENV cases in Europe are concerning, reflecting rising incidence linked to climate change and the spread of Aedes albopictus mosquitoes. These vectors thrive under environmental conditions like temperature and humidity, which are increasingly influenced by climate change. Additionally, global travel accelerates the cross-border spread of mosquito-borne diseases. DENV manifests clinically in a spectrum from asymptomatic cases to severe conditions like dengue hemorrhagic fever and dengue shock syndrome, influenced by viral serotype and host factors. In 2024, Brazil experienced a fourfold increase in dengue cases compared to 2023, accompanied by higher mortality. Conventional control measures, such as vector control, community engagement, and vaccination, proved insufficient as climate change exacerbated mosquito proliferation, challenging containment efforts. In this regard, our review analyzes prevention measures and therapeutic protocols during the outbreak while addressing DENV transmission dynamics, clinical presentations, and epidemiological shifts. It also evaluates diagnostic strategies combining clinical assessment with serological and molecular testing, providing information to improve diagnostic and preventive measures. The global expansion of dengue-endemic regions, including outbreaks in Europe, highlights the urgent need for enhanced surveillance, proactive interventions, and international collaboration to mitigate the growing threat of Dengue and other arboviruses like West Nile, Zika, Chikungunya, Oropouche, and Yellow Fever viruses. Full article

Background: Dengue virus (DENV) is the most widespread mosquito-borne virus, which can cause dengue fever with mild symptoms, or progress to fatal dengue hemorrhagic fever and dengue shock syndrome. As the main target cells of DENV, macrophages are responsible for the innate immune response against the virus. Methods: In this study, we investigated the role of pyroptosis in the pathogenic mechanism of dengue fever by examining the level of pyroptosis in DENV-1-infected macrophages and further screened differentially expressed microRNAs by high-throughput sequencing to predict microRNAs that could affect the pyroptosis of the macrophage. Results: Macrophages infected with DENV-1 were induced with decreased cell viability, decreased release of lactate dehydrogenase and IL-1β, activation of NLRP3 inflammasome and caspase-1, cleavage of GSDMD to produce an N-terminal fragment bound to cell membrane, and finally induced macrophage pyroptosis. MicroRNA expression profiles were obtained by sequencing macrophages from all periods of DENV-1 infection and comparing with the negative control. Sixty-three microRNAs differentially expressed in both the early and later stages of infection were also identified. In particular, miR-223-3p, miR-148a-3p, miR-125a-5p, miR-146a-5p and miR-34a-5p were recognized as small molecules that may be involved in the regulation of inflammation. Conclusions: In summary, this study aimed to understand the pathogenic mechanism of DENV through relevant molecular mechanisms and provide new targets for dengue-specific therapy. Full article

DENV belongs to the Flaviviridae family and possesses a single-stranded RNA genome of positive polarity. DENV infection manifests in mild subclinical forms or severe forms that may be dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Despite a lot of effort worldwide, the exact mechanism underlying the pathogenesis of severe DENV infection remains elusive. It is believed that both host and viral factors contribute to the outcome of dengue disease. The host factors are age at the time of infection, sex, nutrition, and immune status, including the presence of pre-existing antibodies or reactive T cells. Viral factors include the serotype, genotype, and mutation(s) due to error-prone RNA-dependent polymerase leading to the development of quasispecies. Accumulating bodies of literature have depicted that DENV has many ways to invade and escape the immune system of the host. These invading strategies are directed to overcome innate and adaptive immune responses. Like other viruses, once the infection is established, the host also mounts a series of antiviral responses to combat and eliminate the virus replication. Nevertheless, DENV has evolved a variety of mechanisms to evade the immune system. In this review, we have emphasized the strategies that DENV employs to hijack the host innate (interferon, IFN; toll-like receptors, TLR; major histocompatibility complex, MHC; autophagy; complement; apoptosis; RNAi) and adaptive (antibody-dependent enhancement, ADE; T cell immunity) immune responses, which contribute to the severity of DENV disease. Full article

Few studies have investigated whether SARS-CoV-2 infections increase the incidence of dengue haemorrhagic fever/shock syndrome (DHF/DSS) and/or severe dengue (SD) in dengue virus (DENV)-infected patients. This study was performed on a site with high incidences of classical dengue, but relatively few DHF/DSS or SD cases as defined by the WHO 1997 or 2009 criteria, respectively. Clinical, haematological/biochemical, and viral diagnostic data were collected from febrile patients before, during, and after the COVID-19 epidemic to assess whether (a) DENV-infected patients with prior SARS-CoV-2 infections or (b) DENV-SARS-CoV-2-co-infected patients had increased incidences of SD/DHF/DSS using logistic regression and machine learning models. Higher numbers of DHF/DSS/SD occurred during the COVID-19 epidemic, particularly in males and 18–40-year-olds. Significantly increased symptoms in the DENV-SARS-CoV-2-co-infected cases were (a) haemoconcentration (p < 0.0009) and hypotension (p < 0.0005) (DHF/DSS and SD criteria), (b) thrombocytopenia and mucosal bleeding (DHF/DSS-criteria), (c) abdominal pain, persistent vomiting, mucosal bleeding, and thrombocytopenia (SD warning signs) and (d) dyspnoea, but without fluid accumulation. DENV-infected patients with prior SARS-CoV-2 infections had significantly increased incidences of thrombocytopenia (DHF/DSS-criteria) and/or abdominal pain and persistent vomiting and also thrombocytopenia (SD warning signs), but without significant haemoconcentration or hypotension. DENV-SARS-CoV-2 co-infections significantly increased the incidence of DHF/DSS/SD, while DENV-infected patients with prior SARS-CoV-2 infections displayed significantly increased incidences of thrombocytopenia (DHF/DSS-criteria) and three important SD warning signs, which are therefore very important for health workers/clinicians in assessing patients’ DHF/DSS/SD risk factors and planning their optimal therapies. Full article

The dengue virus, the primary cause of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome, is the most widespread mosquito-borne virus worldwide. In recent decades, the prevalence of dengue fever has increased markedly, presenting substantial public health challenges. Consequently, the development of an efficacious vaccine against dengue remains a critical goal for mitigating its spread. Our research utilized Celcradle™, an innovative tidal bioreactor optimized for high-density cell cultures, to grow Vero cells for dengue virus production. By maintaining optimal pH levels (7.0 to 7.4) and glucose concentrations (1.5 g/L to 3.5 g/L) during the proliferation of cells and viruses, we achieved a peak Vero cell count of approximately 2.46 × 10⁹, nearly ten times the initial count. The use of Celcradle™ substantially decreased the time required for cell yield and virus production compared to conventional Petri dish methods. Moreover, our evaluation of the immunogenicity of the Celcradle™-produced inactivated DENV4 through immunization of mice revealed that sera from these mice demonstrated cross-reactivity with DENV4 cultured in Petri dishes and showed elevated antibody titers compared to those from mice immunized with virus from Petri dishes. These results indicate that the dengue virus cultivated using the Celcradle™ system exhibited enhanced immunogenicity relative to that produced in traditional methods. In conclusion, our study highlights the potential of the Celcradle™ bioreactor for large-scale production of inactivated dengue virus vaccines, offering significant promise for reducing the global impact of dengue virus infections and accelerating the development of effective vaccination strategies. Full article

Dengue is an arboviral disease that has spread globally and become a major public health concern. A small proportion of patients may progress from symptomatic dengue fever (DF) to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Findings from a previous genome-wide association study (GWAS) demonstrated that variations in the major histocompatibility complex (MHC) class I chain-related B (MICB) and the phospholipase C epsilon 1 (PLCE1) genes were related to DSS in a Vietnamese population. This study investigated associations of variations in MICB (rs3132468) and PLCE1 (rs3740360, rs3765524) with dengue severity and thrombocytopenia in both the Indonesian and Taiwanese populations. We sampled 160 patients from the Indonesian population and 273 patients from the Taiwanese population. None of the patients had DSS in the Taiwanese population. Based on age demographics, we found that dengue is more prevalent among younger individuals in the Indonesian population, whereas it has a greater impact on adults in the Taiwanese population. Our results showed the association between MICB rs3132468 and DSS. In addition, an association was identified between PLCE1 rs3740360 and DHF in secondary dengue in Indonesian patients. However, there is no association of MICB or PLCE1 variants with thrombocytopenia. This study highlights the value of genetic testing, which might be included in the clinical pathway for specific patients who can be protected from severe dengue. Full article

Dengue virus (DENV) infection is a serious global health issue as it causes severe dengue hemorrhagic fever and dengue shock syndrome. Since no approved therapies are available to treat DENV infection, it is necessary to develop new agents or supplements that can do this. In this study, grape seed proanthocyanidins extract (GSPE), which is widely consumed as a dietary supplement, dose-dependently suppressed the replication of four DENV serotypes. The inhibitory mechanism demonstrated that GSPE downregulated DENV-induced aberrant cyclooxygenase-2 (COX-2) expression, revealing that the inhibitory effect of the GSPE on DENV replication involved targeting DENV-induced COX-2 expression. Mechanistic studies on signaling regulation have demonstrated that GSPE significantly reduced COX-2 expression by inactivating NF-κB and ERK/P38 MAPK signaling activities. Administrating GSPE to DENV-infected suckling mice reduced virus replication, mortality, and monocyte infiltration of the brain. In addition, GSPE substantially reduced the expression of DENV-induced inflammatory cytokines associated with severe dengue disease, including tumor necrosis factor-α, nitric oxide synthase, interleukin (IL)-1, IL-6, and IL-8, suggesting that GSPE has potential as a dietary supplement to attenuate DENV infection and severe dengue. Full article

The aedes mosquito-borne dengue viruses cause dengue fever, an arboviral disease (DENVs). In 2019, the World Health Organization forecasts a yearly occurrence of infections from 100 million to 400 million, the maximum number of dengue cases ever testified worldwide, prompting WHO to label the virus one of the world’s top ten public health risks. Dengue hemorrhagic fever can progress into dengue shock syndrome, which can be fatal. Dengue hemorrhagic fever can also advance into dengue shock syndrome. To provide accessible and timely supportive care and therapy, it is necessary to have indispensable practical instruments that accurately differentiate Dengue and its subcategories in the early stages of illness development. Dengue fever can be predicted in advance, saving one’s life by warning them to seek proper diagnosis and treatment. Predicting infectious diseases such as dengue is difficult, and most forecast systems are still in their primary stages. In developing dengue predictive models, data from microarrays and RNA-Seq have been used significantly. Bayesian inferences and support vector machine algorithms are two examples of statistical methods that can mine opinions and analyze sentiment from text. In general, these methods are not very strong semantically, and they only work effectively when the text passage inputs are at the level of the page or the paragraph; they are poor miners of sentiment at the level of the sentence or the phrase. In this research, we propose to construct a machine learning method to forecast dengue fever. Full article

The development of a dengue (DENV) vaccine remains challenging due to the heteroserotypic infection, which can result in a potentially deadly hemorrhagic fever or dengue shock syndrome, and only a tetravalent vaccine can overcome this issue. Here, we report the immunogenicity of DENV envelope protein domain 3 (ED3) from all four DENV serotypes (DENV1–4) in Swiss albino and BALB/c mice models. Firstly, we observed that despite having very similar sequences and structures, both the humoral and cellular immunogenicity of ED3s varied significantly, with strength ranging from DENV2 ED3 (2ED3)~3ED3 > 1ED3 > 4ED3, which was assessed through anti-ED3 IgG titers, and DENV1 ED3 (1ED3) > 2ED3~3ED3 > 4ED3 as determined by monitoring T-cell memory (CD44+CD62L+ T cells with IL-4 and IFN-γ expression). Secondly, anti-1ED3 sera cross-reacted with 2ED3 and 3ED3; anti-2ED3 and anti-3ED3 sera cross-reacted with each other, but anti-4ED3 was completely serotype-specific. The lack of reciprocity of anti-1ED3’s cross-reaction was unanticipated. Such disparity in the ED3 responses and cross-reaction might underlie the appearance of hemorrhagic fever and dengue shock syndrome. Hence, the development of an ED3-based tetravalent subunit vaccine would require understanding the aforementioned disparities. Full article

Dengue is a mosquito-borne flaviviral serious febrile illness, most common in the tropical and subtropical regions including Pakistan. Vitamin D is a strong immunomodulator affecting both the innate and adaptive immune responses and plays a pivotal role in pathogen-defense mechanisms. There has been considerable interest in the possible role of vitamin D in dengue viral (DENV) infection. In the present prospective cross-sectional study, we assessed a possible association between serum vitamin D deficiency (VDD) and susceptibility towards severe dengue fever (DF) illness. Serum vitamin D levels were measured at the time of hospitalization in 97 patients diagnosed with dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) at Mayo Hospital, King Edward Medical University, Lahore, PK, from 16 November 2021 to 15 January 2022. In terms of disease severity, 37 (38.1%) patients were DF, 52 (53.6%) were DHF grade 1 and 2, and 8 (8.2%) were DSS. The results revealed that most patients (75 (77.3%)) were vitamin-D-deficient (i.e., serum level < 20 ng/mL), including 27 (73.0%) in DF, 41 (78.8%) in DHF grade 1 and 2, and 7 (87.5%) in DSS. The degree of VDD was somewhat higher in DSS patients as compared to DF and DHF grade 1 and 2 patients. Overall, serum vitamin D levels ranged from 4.2 to 109.7 ng/mL, and the median (IQR) was in the VDD range, i.e., 12.2 (9.1, 17.8) ng/mL. Our results suggest that there may be a possible association between VDD and susceptibility towards severe dengue illness. Hence, maintaining sufficient vitamin D levels in the body either through diet or supplementation may help provide adequate immune protection against severe dengue fever illness. Further research is warranted. Full article

Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. While the majority of DENV infections are mild or asymptomatic, approximately 5% of the cases develop a severe form of the disease that is mainly attributed to sequential infection with different DENV serotypes. The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. Moreover, the ability of DENV to infect a wide variety of immune cells, including monocytes, macrophages, dendritic cells, mast cells, and T and B cells, further dysregulates the antiviral functions of these cells, resulting in viral dissemination. Although several risk factors associated with disease progression have been proposed, gaps persist in the understanding of the disease pathogenesis and further investigations are warranted. In this review, we discuss known mechanisms of DENV-mediated immunopathogenesis and its association with disease progression and severity. Full article