Research Article: Lower Low-Density Lipoprotein Cholesterol Levels Are Associated with Severe Dengue Outcome

Date Published: September 3, 2015

Publisher: Public Library of Science

Author(s): Hope H. Biswas, Aubree Gordon, Andrea Nuñez, Maria Angeles Perez, Angel Balmaseda, Eva Harris, Scott B Halstead. http://doi.org/10.1371/journal.pntd.0003904

Abstract: Dengue virus (DENV) is a flavivirus of worldwide importance, with approximately 4 billion people across 128 countries at risk of infection, and up to 390 million infections and 96 million clinically apparent cases estimated annually. Previous in vitro studies have shown that lipids and lipoproteins play a role in modifying virus infectivity. However, the relationship between development of severe dengue and total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, is unclear. We analyzed data from 789 laboratory-confirmed dengue cases and 447 other febrile illnesses (OFI) in a prospective pediatric hospital-based study in Managua, Nicaragua between August 2005 and January 2013, using three different classifications of dengue severity: World Health Organization (WHO) 1997, WHO 2009, and standardized intervention categories. Total serum cholesterol and LDL-C levels decreased over the course of illness and were generally lower with increasing dengue severity, regardless of classification scheme. Greater decreases in LDL-C than HDL-C were observed among dengue-positive patients compared to patients with OFI and among severe dengue compared to mild dengue cases. Furthermore, daily cholesterol levels declined with daily albumin blood levels. To examine the effect of cholesterol at presentation on subsequent risk of development of severe dengue, relative risks and 95% confidence intervals were calculated using multivariable modified Poisson models. We found that lower total serum cholesterol and LDL-C levels at presentation were associated with subsequent risk of developing dengue hemorrhagic fever/dengue shock syndrome using the WHO 1997 dengue severity classification, and thus that the reduction in LDL-C is likely driving the decreases observed in total serum cholesterol levels among dengue-positive patients. Our results suggest that cholesterol blood levels are important correlates of dengue pathophysiology and should be explored as part of a prognostic biomarker panel for severe dengue.

Partial Text: Dengue virus (DENV) is a flavivirus of worldwide importance, with approximately 4 billion people across 128 countries at risk of DENV infection [1]. Of the estimated 390 million annual DENV infections, 96 million are symptomatic, and a subset of individuals develop severe forms of the disease, which consist of hemorrhagic manifestations and vascular leakage, leading to hypovolemic shock [2,3]. In vitro studies of the pathophysiology of DENV and other flavivirus (e.g., Japanese encephalitis virus, West Nile virus) infections suggest that lipids and lipoproteins may play a role in modifying virus infectivity of target cells. Cholesterol-rich lipid rafts have been shown to be required for flavivirus entry [4–6], and the related hepatitis C virus enters host cells via low-density lipoprotein (LDL) receptors [7]. The addition of cholesterol during viral adsorption blocks Japanese encephalitis virus and DENV infectivity [4]. Further, lovastatin, an inhibitor of cholesterol synthesis, also inhibits DENV replication [8,9] and is currently in clinical trials as a potential dengue therapeutic [10]. After infection, DENV, West Nile virus and Japanese encephalitis virus mimic or hijack lipid metabolic pathways [9,11–15] by increasing lipid raft formation, intracellular levels of total cholesterol, and LDL receptors on the surface of infected cells [15]. Together, these studies suggest that cholesterol is beneficial for DENV replication and that DENV infection modulates cholesterol metabolism.

Of the 1,440 patients in the dengue hospital study, 69 patients <1 year of age, 11 patients with nephrotic syndrome, and 9 patients with obesity (BMI ≥32) were excluded from the analysis (see Fig 1). An additional 69 patients missing all cholesterol measurements, 2 patients with inadequate samples for laboratory testing, and 44 patients with an indeterminate result of dengue testing were excluded, leaving 1,236 patients available for analysis. Of the 1,236 patients, 789 (64%) were laboratory-confirmed as DENV-positive. Among the dengue cases, 149 were classified as DHF and 48 as DSS using the 1997 WHO classification, and 66 were classified as Dengue without Warning Signs, 466 as Dengue with Warning Signs, and 257 as Severe Dengue using the 2009 WHO classification. Of the 257 with Severe Dengue, 94 had hypotensive shock, 180 had compensated shock, 74 had fluid accumulation with respiratory difficulty, 2 had alteration in AST or ALT, 9 had change in CNS, and 52 had suspected myocardiopathy. The remaining 447 patients (36%) tested negative for DENV and were classified as OFI. While other studies have examined cholesterol levels during a particular phase of dengue illness (acute, critical or convalescent) [19,20] or on day of admission to the hospital [17,18], ours is the first study of which we are aware to analyze changes in cholesterol levels by day of illness in dengue patients, and to use time-ordered analysis that enables prediction of disease severity level based on cholesterol levels at presentation. We found that total serum cholesterol, LDL-C, and HDL-C levels were significantly lower in dengue-positive patients compared to dengue-negative patients, and that LDL-C levels showed greater decreases and thus appeared to drive the reduction in total cholesterol. Total, LDL-C, and HDL-C levels were lower in severe compared to mild dengue during the course of illness regardless of severity classification scheme. Finally, we found that lower total serum cholesterol and LDL-C levels at presentation were associated with subsequent development of DHF/DSS. Source: http://doi.org/10.1371/journal.pntd.0003904

 

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