Abstract

Background

   Dengue fever can progress to dengue hemorrhagic fever (DHF), a more
   serious and occasionally fatal form of the disease. Indicators of
   serious disease arise about the time the fever begins to reduce
   (typically 3 to 7 days following symptom onset). There are currently no
   effective antivirals available. Drug repurposing is an emerging drug
   discovery process for rapidly developing effective DHF therapies.
   Through network pharmacology modeling, several US Food and Drug
   Administration (FDA)-approved medications have already been researched
   for various viral outbreaks.

Objective

   We aimed to identify potentially repurposable drugs for DHF among
   existing FDA-approved drugs for viral attacks, symptoms of viral
   fevers, and DHF.

Methods

   Using target identification databases (GeneCards and DrugBank), we
   identified human–DHF virus interacting genes and drug targets against
   these genes. We determined hub genes and potential drugs with a
   network-based analysis. We performed functional enrichment and network
   analyses to identify pathways, protein-protein interactions, tissues
   where the gene expression was high, and disease-gene associations.

Results

   Analyzing virus-host interactions and therapeutic targets in the human
   genome network revealed 45 repurposable medicines. Hub network analysis
   of host-virus-drug associations suggested that aspirin, captopril, and
   rilonacept might efficiently treat DHF. Gene enrichment analysis
   supported these findings. According to a Mayo Clinic report, using
   aspirin in the treatment of dengue fever may increase the risk of
   bleeding complications, but several studies from around the world
   suggest that thrombosis is associated with DHF. The human interactome
   contains the genes prostaglandin-endoperoxide synthase 2 (PTGS2),
   angiotensin converting enzyme (ACE), and coagulation factor II,
   thrombin (F2), which have been documented to have a role in the
   pathogenesis of disease progression in DHF, and our analysis of most of
   the drugs targeting these genes showed that the hub gene module
   (human-virus-drug) was highly enriched in tissues associated with the
   immune system (P=7.29 × 10^–24) and human umbilical vein endothelial
   cells (P=1.83 × 10^–20); this group of tissues acts as an anticoagulant
   barrier between the vessel walls and blood. Kegg analysis showed an
   association with genes linked to cancer (P=1.13 × 10^–14) and the
   advanced glycation end products–receptor for advanced glycation end
   products signaling pathway in diabetic complications (P=3.52 × 10^–14),
   which indicates that DHF patients with diabetes and cancer are at risk
   of higher pathogenicity. Thus, gene-targeting medications may play a
   significant part in limiting or worsening the condition of DHF
   patients.

Conclusions

   Aspirin is not usually prescribed for dengue fever because of bleeding
   complications, but it has been reported that using aspirin in lower
   doses is beneficial in the management of diseases with thrombosis. Drug
   repurposing is an emerging field in which clinical validation and
   dosage identification are required before the drug is prescribed.
   Further retrospective and collaborative international trials are
   essential for understanding the pathogenesis of this condition.

   Keywords: dengue hemorrhagic fever, drug reprofiling, network
   pharmacology, network medicine, DHF, repurposable drugs, viral fevers,
   drug repurposing

Introduction

   Dengue fever, also known as “breakbone fever,” is characterized by
   acute, severe fever in patients 3 to 14 days after they are bitten by
   an infected mosquito. Migraine, retro-orbital pain, myalgia, muscle
   ache, signs of hemolytic anemia, rash, and a low white blood cell count
   are only a few of the symptoms [[35]1]. Dengue hemorrhagic fever (DHF),
   a severe and sometimes fatal manifestation of the disease, affects
   certain patients with dengue fever. These patients may show warning
   signs of serious disease close to the period the fever begins to
   diminish (typically 3 to 7 days following symptom onset). Severe
   abdominal discomfort, continuous vomiting, a significant change in
   temperature (from fever to hypothermia), hemorrhagic manifestations, or
   a change in mental status (eg, irritability, confusion, or obtundation)
   are also warning indicators [[36]2]. Restlessness, chilly, clammy skin,
   a rapid, weak pulse, and a narrowing of pulse pressure (both systolic
   blood pressure and diastolic blood pressure) are all early indications
   of shock. Patients with dengue fever should be advised to return to the
   hospital if any of these symptoms appear.

   According to one estimate, 390 million dengue virus infections occur
   each year (95% credible interval [CI] 284 million to 528 million), with
   96 million (95% CI 67 million to 136 million) showing clinical symptoms
   of any severity [[37]3]. According to the World Health Organization
   (WHO), 3.9 billion individuals are at risk of contracting the dengue
   virus. Although there is a risk of infection in 129 nations, Asia bears
   70% of the actual burden. Over the last 2 decades, the number of dengue
   cases reported to the WHO has increased more than 8 times, from 505,430
   cases in 2000 to over 2.4 million in 2010 and 5.2 million in 2019.
   Between 2000 and 2015, the number of deaths reported grew from 960 to
   2032. This worrying rise in case numbers can be explained in part by a
   shift in national practices for recording and reporting dengue fever to
   health ministries and the WHO. However, it also symbolizes the
   government’s acknowledgment of the problem, and hence the need to