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Median quantification of renal damage in four dengue fatal cases (n = 4) compared to control cases (n = 4). (A) Vascular congestion in renal cortical regions (p = 0.0040). (B) Tubular degeneration (p ≤ 0.0001). (C) Renal cortical infiltrates (p ≤ 0.0001). (D) Vascular congestion in renal medullary regions (p = 0.1280). (E) Tubular necrosis (p = 0.0008). (F) Infiltrates in renal medullary regions (p ≤ 0.0001).
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Dengue virus (DENV) infections may result in asymptomatic cases or evolve into a severe disease, which involves multiple organ failure. Renal involvement in dengue can be potentially related to an increased mortality. Aiming to better understand the role of DENV in renal injury observed in human fatal cases, post-mortem investigations were performe...
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DISCLOSURE The author of this report has no competing interest in this subject and the preparation of this report is totally funded by the Ministry of Health, Malaysia. iii EXECUTIVE SUMMARY Background Dengue fever is an important mosquito-borne human viral disease globally caused by the infections of four dengue virus serotypes (DENV 1-4). The inc...
Dengue virus (DENV) infection requires cholesterol as a pro-viral factor although statin treatment did not show antiviral efficacy in dengue patients. Here, we show that DENV infection manipulates cholesterol metabolism in cells residing in low oxygen microenvironments (hypoxia) such as the liver, spleen and lymph nodes. DENV infection induced prop...
Dengue virus (DENV) transmission from humans to mosquitoes is a poorly documented, but critical component of DENV epidemiology. Magnitude of viremia is the primary determinant of successful human-to-mosquito DENV transmission. People with the same level of viremia, however, can vary in their infectiousness to mosquitoes as a function of other facto...
Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses of public health relevance. Both viruses circulate in the same endemic settings and acute infections generally manifest similar symptoms. This highlights the importance of accurate diagnosis for clinical management and outbreak control. One of the commonly used acute diagnostic markers for...
Citations
... 4 Furthermore, the observation of microtubule reticular structures and dilation of the endoplasmic reticulum in necrotic cells, along with dense virus-like particles in glomeruli in a transmission electron microscope (TEM), suggests viral infection. 5 Analysis of kidney samples from DENV-infected human cases revealed parenchymal and circulatory damage. 6 Tubular necrosis, evidenced by the presence of pyknotic nuclei of epithelial cells, thickening of the glomerular basement membrane, mesangial proliferation, glomerular congestion and hyalinosis, interstitial areas with focal fibrosis, diffuse mononuclear infiltrate, and hemorrhage foci in the cortical and medullary regions, and the increase in populations of CD68+ and CD4+ cells have been reported. ...
This case report highlights a rare occurrence of nephrotic syndrome in a previously healthy 20-year-old gentleman. The patient exhibited bilateral lower limb swelling, facial puffiness, and abdominal distension. Notably, he had been hospitalized two weeks prior with dengue fever, characterized by a transient reduction in platelet counts. Routine examinations revealed proteinuria, with creatinine at 0.97 and albumin at 2.2. A renal biopsy confirmed focal segmental glomerulosclerosis (FSGS)- NOS type. This case underscores the significance of considering renal complications in individuals with recent dengue fever, especially when presented with atypical symptoms. The scarcity of reported cases depicting nephrotic syndrome as a sequelae to dengue fever further emphasizes the uniqueness of this scenario.
... inflammatory cells, (24) in glomerular endothelial cells, in mesangial cells, (21,22) in hematopoietic cells (25) and in circulating macrophages and monocytes. (6) Additionally, the detection of DENV RNA through molecular technique has been reported in kidney. ...
Background:
Dengue is a disease caused by dengue virus (DENV-1 through -4). Among the four serotypes, DENV-4 remains the least studied. Acute kidney injury is a potential complication of dengue generally associated with severe dengue infection.
Objectives:
The goal of this study was to investigate the alterations caused by experimental dengue infection in the kidney of adult BALB/c mice.
Methods:
In this study, BALB/c mice were infected through the intravenous route with a DENV-4 strain, isolated from a human patient. The kidneys of the mice were procured and subject to histopathological and ultrastructural analysis.
Findings:
The presence of the viral antigen was confirmed through immunohistochemistry. Analysis of tissue sections revealed the presence of inflammatory cell infiltrate throughout the parenchyma. Glomerular enlargement was a common find. Necrosis of tubular cells and haemorrhage were also observed. Analysis of the kidney on a transmission electron microscope allowed a closer look into the necrotic tubular cells, which presented nuclei with condensed chromatin, and loss of cytoplasm.
Main conclusions:
Even though the kidney is probably not a primary target of dengue infection in mice, the inoculation of the virus in the blood appears to damage the renal tissue through local inflammation.
... Dengue virus (DENV) infection, like other arbovirus infections, is associated with dysfunctions in different organs [6,7]. The correlation between dengue virus infection and renal injury have been demonstrated in adults [8][9][10] and in children [11,12]. In this context, the dengue virus infection can cause glomerulonephritis (inflammation of the renal glomerulus), lead the patient to show signs of acute renal injury (ARI) and consequently triggers proteinuria (abnormal presence of proteins in the urine) and hematuria (abnormal presence of erythrocytes in the urine), which usually occur during or shortly after the acute phase of infection [13]. ...
... Different studies support the use of the evaluation of alterations in serum levels of creatinine and urea as a parameter to measure the function state of this organ [14,15]. Previous reports of our group observed morphological alterations and detected dengue virus antigens, and pro-inflammatory cytokines/chemokines, such as IFN-γ, TNF-α and RANTES, in the kidney of dengue virus-infected adult patients, as well as the subpopulation of CD4 + T, CD8 + T and CD68 + Mø cells [7,10,16]. Additionally, we also observed a fibrosis process along with the detection of other inflammatory mediators and biomarkers, such as adhesion molecules in renal tissue. These findings could also be fully or partially noted in other studies approaching dengue virus infection consequences in different organs (heart, spleen, thymus, and pancreas) in mice and humans [16][17][18][19]. ...
... These previous findings corroborate the idea of organ damage in the present study. Another parameter that was also evaluated, based on quantification, was the presence of inflammatory infiltrate, which represents a process that occurs due to the recruitment of immune cells to the site of infection, which was also observed in previous studies [10,18]. In this study, it was observed in all three cases with similar intensities. ...
Dengue virus (DENV) infection represents a worldwide public health concern and can cause damage to multiple organs, including the kidney. In this work, we investigated the histopathological changes caused by dengue virus infection along with the detection of inflammatory mediators, cytokines, and cell expression patterns in the renal tissue of three fatal cases in children. Hematoxylin and Eosin staining was performed to analyze these histopathological changes. Immunohistochemistry allowed for the detection of immunological inflammatory markers in renal tissues that were quantified and further analyzed. Vascular congestion, edema and glomerular infiltrate were observed in the three cases, in addition to the thickening of the matrix area around the glomerular capillaries and mononuclear infiltrate associated with vascular congestion in the medullary region. The renal tissues exhibited collagen deposition and high expression of CD68+ Mø, CD8+ T, CD56+ cells and MMP-9, and the cytokine profile was mainly characterized by the expression of IFN-γ and TNF-α. Additionally, the expression of RANTES, VEGFR-2 and VCAM-1 were observed. The replication of DENV was evidenced by the detection of the NS3 protein. These results contributed to clarifying the main factors that may be involved in changes in the renal tissue of fatal cases of dengue in children.
... Due to the populations' susceptibility to this newly introduced serotype, explosive epidemics occurred and in 2012, DENV-4 was prevalent and detected in 63% of the cases reported in Brazil. Despite the highest notification in 2013 (1,452,289 cases), DENV-4 circulation was associated with mild cases, but severe and fatal cases due to this serotype were also reported [43]. In Rio de Janeiro, the virus was first isolated in 2011 and resulted in the emergence of this serotype in the state in 2012, characterized by isolation of this serotype in 48.7% of confirmed cases and, in 2013, DENV-4 was responsible for the largest number of cases in the state [28]. ...
Introduction: It is a consensus that inflammatory mediators produced by immune cells contribute to changes in endothelial permeability in dengue. We propose to relate inflammatory mediators seen in dengue patients with the in vitro alteration of endothelial cells (ECs) cultured with serum from these patients. Methods: Patients with mild (DF) to moderate and severe dengue (DFWS/Sev) were selected. ELISA quantified inflammatory mediators. Expression of adhesion molecules and CD147 were evaluated in the ECs cultured with the patient's serum by flow cytometry. We assessed endothelial permeability by measuring transendothelial electrical resistance in cocultures of ECs with patient serum. Results: Dengue infection led to an increase in inflammatory mediators-the IL-10 distinguished DF from DFWS/Sev. There were no changes in CD31, CD54, and CD106 but decreased CD147 expression in ECs. DFWS/Sev sera induced a greater difference in endothelial permeability than DF sera. Correlation statistical test indicated that low IL-10 and IFN-γ and high CCL5 maintain the integrity of ECs in DF patients. In contrast, increased TNF, IFN-γ, CXCL8, and CCL2 maintain EC integrity in DFWS/Sev patients. Conclusions: Our preliminary data suggest that a subset of inflammatory mediators may be related to the maintenance or loss of endothelial integrity, reflecting the clinical prognosis.
... Nonetheless, DENV has been detected in different tissues [7,62,63], and neurological, renal, muscular, cardiac and pulmonary manifestations and disorders during severe dengue cases have been reported [8,9,23]. Unusual manifestations may be underreported and, since the majority of studies concern autopsy samples, data on different tissues involvement during non-severe cases of dengue are scarce [6,[64][65][66]. Therefore, here, we aimed to evaluate alterations induced by the infection of two DENV-2 lineages in lung, heart and skeletal muscle using the immunocompetent BALB/c as an experimental model. ...
Dengue virus (DENV) infection by one of the four serotypes (DENV-1 to 4) may result in a wide spectrum of clinical manifestations, with unpredictable evolution and organ involvement. Due to its association with severe epidemics and clinical manifestations, DENV-2 has been substantially investigated. In fact, the first emergence of a new lineage of the DENV-2 Asian/American genotype in Brazil (Lineage II) in 2008 was associated with severe cases and increased mortality related to organ involvement. A major challenge for dengue pathogenesis studies has been a suitable animal model, but the use of immune-competent mice, although sometimes controversial, has proven to be useful, as histological observations in infected animals reveal tissue alterations consistent to those observed in dengue human cases. Here, we aimed to investigate the outcomes caused by two distinct lineages of the DENV-2 Asian/American genotype in the lung, heart and skeletal muscle tissues of infected BALB/c mice. Tissues were submitted to histopathology, immunohistochemistry, histomorphometry and transmission electron microscopy (TEM) analysis. The viral genome was detected in heart and skeletal muscle samples. The viral antigen was detected in cardiomyocytes and endothelial cells of heart tissue. Heart and lung tissue samples presented morphological alterations comparable to those seen in dengue human cases. Creatine kinase serum levels were higher in mice infected with both lineages of DENV-2. Additionally, statistically significant differences, concerning alveolar septa thickening and heart weight, were observed between BALB/c mice infected with both DENV-2 lineages, which was demonstrated to be an appropriate experimental model for dengue pathogenesis studies on lung, heart and skeletal muscle tissues.
... The increase in the cellularity resulted in congested capillaries and edema. Nunes [27] and Pagliari [43] also observed congestion in capillaries in glomeruli; however, no mesangial proliferation was reported. ...
... This hypothesis is supported by authors who believe that altered vascular permeability in dengue is caused by immunological host response, rather than by infection of endothelial cells or cell death [84][85][86]. Moreover, our histopathological findings showed hemorrhage foci and small mononuclear cells infiltrates in the cortical area of kidney of the DENV-2 infected mice and corroborates studies carried out with human cases of DENV-3 and -4 infection, and BALB/c mice infected with DENV-3 [17,27,74,75,87]. ...
... Studies on human autopsy tissues have described tubular necrosis on dengue cases [17,27,43]. Mohsin [76] reported a case of ARF with tubular necrosis in a dengue patient who did not present signs of hemorrhagic fever, only classic dengue symptoms. ...
Dengue virus type 2 (DENV-2) is, traditionally, the most studied serotype due to its association with explosive outbreaks and severe cases. In Brazil, almost 20 years after the first introduction in the 1990s, a new lineage (Lineage II) of the DENV-2 Asian/American genotype emerged and caused an epidemic with severe cases and hospitalizations. Severe dengue includes multiple organ failure, and renal involvement can be potentially related to increased mortality. In order to better understand the role of DENV infection in renal injury, here we aimed to investigate the outcomes of infection with two distinct lineages of DENV-2 Asian/American genotype in the kidney of a murine model. BALB/c mice were infected with Lineages I and II and tissues were submitted to histopathology, immunohistochemistry, histomorphometry and ultrastructural analysis. Blood urea nitrogen (BUN) was detected in blood sample accessed by cardiac puncture. A tendency in kidney weight increase was observed in mice infected with both lineages, but urea levels, on average, were increased only in mice infected with Lineage II. The DENV antigen was detected in the tissue of mice infected with Lineage II and morphological changes were similar to those observed in human dengue cases. Furthermore, the parameters such as organ weight, urea levels and morphometric analysis, showed significant differences between the two lineages in the infected BALB/c, which was demonstrated to be a suitable experimental model for dengue pathophysiology studies in kidneys.
... A very early study, in 1973, of 24 children presented with abnormal urinalysis in DVI. Proteinuria, glycosuria, ketonuria, occult blood, microscopic hematuria, and an abnormally high number of tubular cells were found in 71, 19,38,38,80, and 90% of the cases, respectively. 5 ...
Dengue fever is considered the most prolific vector-borne disease in the world, with its transmission rate increasing more than eight times in the last two decades. While most cases present mild to moderate symptoms, 5% of patients can develop severe disease. Although the mechanisms are yet not fully comprehended, immune-mediated activation leading to excessive cytokine expression is suggested as a cause of the two main findings in critical patients: increased vascular permeability that may shock and thrombocytopenia, and coagulopathy that can induce hemorrhage. The risk factors of severe disease include previous infection by a different serotype, specific genotypes associated with more efficient replication, certain genetic polymorphisms, and comorbidities such as diabetes, obesity, and cardiovascular disease. The World Health Organization recommends careful monitoring and prompt hospitalization of patients with warning signs or propensity for severe disease to reduce mortality. This review aims to update the diagnosis and management of patients with severe dengue in the intensive care unit.
Acute kidney injury (AKI) can occur in adult patients with severe dengue (SD) and have serious clinical outcomes. This study aimed to determine the prevalence, characteristics, risk factors, and clinical outcomes of AKI in adult patients with SD; the correlation of dengue virus (DENV) serological and virological profiles with AKI; and the clinical features of patients with severe AKI who received renal replacement treatment (RRT). This multicenter study was conducted in Guangdong Province, China, between January 2013 and November 2019. A total of 242 patients were evaluated, of which 85 (35.1%) developed AKI and 32 (13.2%) developed severe AKI (stage 3). Patients with AKI had a higher fatality rate (22.4% versus 5.7%; P < 0.001) and longer length of hospital stay (median: 13 versus 9 days; P < 0.001). Independent risk factors for AKI were hypertension (odds ratio [OR]: 2.03; 95% CI: 1.10–3.76), use of nephrotoxic drugs (OR: 1.90; 95% CI: 1.00–3.60), respiratory distress (OR: 4.15; 95% CI: 1.787–9.632), high international normalized ratio (INR) levels (OR: 6.44; 95% CI: 1.89–21.95), and hematuria (OR: 2.12; 95% CI: 1.14–3.95). There was no significant association between DENV serological and virological profiles and the presence or absence of AKI. Among patients with severe AKI, those who received RRT had a longer length of hospital stay and similar fatality rate. Hence, adult patients with SD should be closely monitored for the development of AKI to enable timely and appropriate therapy.
The incidence of dengue in Latin America has increased dramatically during the last decade. Understanding the pathogenic mechanisms in dengue is crucial for the identification of biomarkers for the triage of patients. We aimed to characterize the profile of cytokines (IFN-γ, TNF-α, IL-1β, IL-6, IL-18 and IL-10), chemokines (CXCL8/IL-8, CCL2/MCP-1 and CXCL10/IP-10) and coagulation mediators (Fibrinogen, D-dimer, Tissue factor-TF, Tissue factor pathway inhibitor-TFPI and Thrombomodulin) during the dengue-4 epidemic in Brazil. Laboratory-confirmed dengue cases had higher levels of TNF-α (p < 0.001), IL-6 (p = 0.005), IL-10 (p < 0.001), IL-18 (p = 0.001), CXCL8/IL-8 (p < 0.001), CCL2/MCP-1 (p < 0.001), CXCL10/IP-10 (p = 0.001), fibrinogen (p = 0.037), D-dimer (p = 0.01) and TFPI (p = 0.042) and lower levels of TF (p = 0.042) compared to healthy controls. A principal component analysis (PCA) distinguished between two profiles of mediators of inflammation and coagulation: protective (TNF-α, IL-1β and CXCL8/IL-8) and pathological (IL-6, TF and TFPI). Lastly, multivariate logistic regression analysis identified high aspartate aminotransferase-to-platelet ratio index (APRI) as independent risk factors associated with severity (adjusted OR: 1.33; 95% CI 1.03–1.71; p = 0.027), the area under the receiver operating characteristics curve (AUC) was 0.775 (95% CI 0.681–0.869) and an optimal cutoff value was 1.4 (sensitivity: 76%; specificity: 79%), so it could be a useful marker for the triage of patients attending primary care centers.
