What are Emerging therapy for Dengue? know the best treatment for Dengue Virus

Introduction:

The most common and significant arboviral infection in the world is dengue fever (DF), which is brought on by the dengue virus (DENV). Roughly 390 million infections are thought to happen yearly, of which 96 million show clinical symptoms. DENV is a member of the Flavivirus genus, which is also home to a number of other clinically significant human infections, including the viruses that cause Zika, Japanese encephalitis, West Nile, and Yellow Fever. Three structural proteins (capsid, prM/M, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 which are translated during the viral replication cycle) are encoded by the single-stranded positive-sense RNA that makes up the DENV genome. The virus is present in both sylvatic and urban environments and is transmitted by an infected mosquito bite during a blood meal. The virus is spread by mosquitoes that are common in forests to non-human primates (NHPs) in the sylvatic cycle of DENV transmission.

In contrast, the virus is maintained in the human population through urban mosquitoes like Aedes aegypti in the urban cycle of transmission. DENV is expected to spread farther since these vectors geographic ranges are getting wider. Additional means of transmission encompass organ transplantation, vertical transfer, and blood products. Dendritic cells are believed to be the initial cellular target of dengue in humans, after which it spreads lymphatically and eventually reaches macrophages and monocytes. Investigations are ongoing, but it’s possible that the entire host of infected in vivo cells includes myocytes, hepatocytes, and other cell types. Given that DENV comes in four serotypes (DENV1-4), it’s probable that a person will come into contact with the virus more than once in their lifetime. According to the most recent estimates of dengue transmission, 4 million cases are expected to require hospitalization annually.

Dengue clinical course:

Common flu-like symptoms, such as fever, nausea, myalgia, and headache, are the first signs of dengue fever (DF). DF is a minor condition that resolves on its own, but some patients may progress to the severe variant, which is marked by shock, bleeding, and plasma leakage. Dengue disease is classified as DF, DF with warning signs, and severe dengue. Hepatomegaly, abdominal pain, mucosal bleeding, and increasing haematocrit concurrent with rapidly declining platelets are signs of dengue.

The three stages of dengue are as follows:

Febrile Stage: This is the stage of dengue fever when the patient has a high fever due to viremia, or an abundance of virus in the blood. They may experience severe nausea throughout this period.
Critical Stage: The person reaches the crucial period after the fever begins to subside. Their body may begin to leak fluid during this period, even though their temperature is starting to go down and they may have low platelet counts (thrombocytopenia). Swelling and hemoconcentration a condition where the blood thickens as a result of fluid loss into tissues can result from this. Severe instances of this leakage may result in hazardous side effects.
Recovery Stage: The individual moves into the recovery phase when the critical sage ends. They are now starting to recover as their body begins to reabsorb the excess fluid. Even though they may still feel weak, they are improving.

If bleeding and vascular problems arise during the critical period, the illness may sometimes be referred to as dengue hemorrhagic fever (DHF). Patients with DHF may experience multiorgan failure and shock, often known as dengue shock syndrome (DSS), if treatment is not received.

General Features of Dengue virus:

Virology
Family- Flaviviridae
Diameter- 50 nm
Genetic Material- ss RNA
Presentation
Incubation- 3–10 days
Fever- Saddleback fever (with 2 peaks)
Headache- 45–95%
Myalgia- 12%
Cough- 21.5%
Dyspnoea- 9.5–95.2%
Diarrhoea -6%
Abdominal pain- 17–25%
Vomiting- 30–58%
Cutaneous manifestation: Skin flushing that blanch on pressure, petechiae, and convalescent rash.
Warning signs: Persistent vomiting, mucosal bleeding, difficulty in breathing, lethargy/restlessness, postural hypotension, liver enlargement and progressive increases in hematocrit.

Laboratory Findings :

Thrombocytopenia- 69.51–100%
Leukopenia- 20–82.2%
Lymphopenia- 63%
Raised AST- 63–97%
Raised ALT- 45–97%
Raised D-dimer- 13–87%

Risk factors for dengue:

Viral characteristics: Viral titer correlates with disease severity. There may be strain and serotype differences in pathogenicity.

Host factors: Age (infant), Women, especially pregnant women. Patients with chronic medical conditions, including diabetes, asthma, obesity and heart disease. Patients with secondary DENV infection.

Diagnostic tests for dengue:

Virus isolation
Nucleic acid detection
RT-PCR
Real-time RT-PCR

iii. Isothermal amplification methods

Detection of antigens
Serological tests
MAC-ELISA
IgG ELISA

iii. IgM/IgG ratio

IgA
Hemagglutination-inhibition test (RBC test)
Hematological tests

Rationale for treating dengue:

Dengue is currently mostly treated with supportive care and mild to moderate infections are treated with paracetamol for fever. No approved therapeutic medication exists. Numerous clinical trials have been carried out and several more are ongoing to investigate treatment strategies for acute dengue. These treatments focus on the virus, the host’s immune system, or host components that DENV needs to finish its replication cycle.

Treatment for dengue: supportive care during the initial infection.

Currently, the cornerstone of treating acute dengue fever is prudent medication in order to avoid complications like shock, hemorrhage, organ failure, and plasma leakage. But too much fluid can lead to fluid overload.

In terms of results, there isn’t a certain benefit to using colloids instead of crystalloids. To rapidly improve hemodynamic status in severe (pulse pressure ≤10 mmHg) or refractory shock, colloids may be chosen.

A blood product transfusion is recommended for those experiencing significant bleeding.

During the feverish stage of dengue, thrombocytopenia is frequently observed, but overt bleeding is rare. In patients who are hemodynamically stable, prophylactic platelet or fresh frozen plasma transfusion is not advised and is not useful for severe thrombocytopenia.

Medication for dengue: Focusing on the host immune system.

Corticosteroids and intravenous immunoglobulins are not advised for dengue because there is no evidence to support their use.

Mast cells may be linked to severe dengue by releasing tryptase and chymase into the bloodstream, which results in vascular leakage. Thus far, medications that stabilize macrophages have had encouraging effects in enhancing mouse model outcomes. Clinical trials are needed before using it therapeutically on humans.

Medications that target host components needed for the dengue virus to finish its life cycle.

In vitro, dengue virus (DENV) 1-4 is effectively inhibited by celgosivir, an alpha-glucosidase inhibitor. It was unable to show a reduction in viral load and a therapeutic benefit in the Phase Ib clinical study.

Chloroquine is a derivative of lysosomotriphic 4-aminoquinoline that suppresses cytokine-mediated inflammatory responses and inhibits dengue through pH-dependent phases of the viral replication cycle. Based on two randomized, double-blind investigations involving dengue patients, no therapeutic effect was noted.

Statins, which reduce cholesterol, may have anti-inflammatory and endothelial-stabilizing properties in addition to potentially having antiviral properties that target DENV assembly. Lovastatin showed advantages for survival in a DENV-infected mice model. Clinical trials are required before using it on humans.

Direct-acting antiviral medicines or medications that target dengue proteins:

Many studies have been conducted on drugs that target the entry, fusion, translation, genome replication, protein synthesis, and egress phases of the dengue replication cycle. The majority of these medications have not been researched in people or animal models.

Balapiravir works by preventing RNA synthesis that is dependent on NS5 and RdRP. It is the sole DAA (direct-acting antiviral) that has been put through a clinical trial. Balapiravir therapy, however, was unable to lower dengue patients’ virus loads, fever clearance times, or NS1 antigenemia. Viral downregulation of the interferon response is prevented by NS4B inhibitors, which function by inhibiting viral replication. It may be possible to employ therapeutic mAbs against homologous serotypes that bind to the quaternary structures of envelope proteins and potently neutralize DENV without the need for antibody-dependent enhancement. Thus far, no licensed DAA are currently available.

Things to eat for fast recovery from dengue fever:

Broccoli is a great source of vitamin K and aids in blood platelet regeneration, thus it’s imperative that a dengue sufferer include it in their diet. In addition, this wonder vegetable is a rich source of antioxidants and other sorts of minerals. Rich in iron and omega-3 fatty acids, spinach helps raise platelet counts and strengthens the body’s immune system. Since dengue dehydrates people severely, adding coconut water to your daily diet can help prevent further issues and difficulties during the illness. It also aids in the removal of toxins from the body and prolongs a feeling of health and hydration. Kiwi is one of the foods that is most frequently advised during dengue, as it has good levels of vitamins E and A along with potassium. Kiwi also balances the body’s electrolyte levels and reduces hypertension and high blood pressure.

Plant based bioactive compounds for treating dengue:

Numerous bioactive chemicals derived from plants have been identified as possessing anti-dengue properties both in vitro and in vivo. These have been compiled in a recent study. Among these, Carica papaya leaf extract (CPLE) has been shown to have an influence on platelets in dengue patients, both young and old. The administration of CPLE three times a day improved the pace of platelet recovery, according to the results of these randomized, placebo-controlled clinical trials. The intervention group’s platelet counts increased statistically significantly starting on day three of treatment. A recent study suggests that CPLE increases the expression of the myeloproliferative leukemia protein (cMpl), also known as the thrombopoietin receptor (CD110), on platelets and megakaryocytes, which is crucial for megakaryocyte proliferation and platelet formation, even though the exact mechanism of action is still unknown. Due to their strong immunomodulatory properties, micronutrient supplements are frequently recommended for dengue patients in addition to their regular supportive treatment. as vitamin E supplementation was added to supportive therapy for dengue patients, clinical trials demonstrated a decrease in liver derangements and an increase in platelet recovery as compared to the control group. Other, smaller RCTs with zinc supplementation and vitamin D demonstrated a lower relative risk of DHF and a shorter length of hospital stay, respectively. Patients who received vitamin C supplementation had shorter hospital stays and improved platelet recovery, according to a retrospective observational study examining the impact of the vitamin on dengue illness. Two phase-II clinical trials are now filed to investigate the effectiveness of vitamin C (SLCTR/2017/028, Sri Lanka) and the vitamin C and B1 combination (CTRI/2019/09/021244, India) in lowering dengue patients’ morbidity.

Dengue vaccination:

Dengvaxia (CYD-TDV): This is a vaccine made by Sanofi Pasteur to protect against dengue fever. It was approved in 2015 and is used in about 20 countries.
Serostatus Test: A study done in 2017 looked at people who got the vaccine. It found that those who hadn’t been exposed to dengue before were more likely to get severe dengue and need hospital care after getting the vaccine.
Dengue Vaccination Candidates: Other vaccines for dengue fever are also being tested.
Protection from Dengue Infection: Getting dengue naturally can give long-lasting protection against the specific type of dengue virus you were infected with. But it only gives temporary protection against the other three types.
Need for Tetravalent Vaccines: Experts want vaccines that protect against all four types of dengue virus because getting one type doesn’t protect you from getting sick with the other types, and all four types can cause severe dengue.
Cross-reactivity and Antibodies: Some vaccines might cause a problem where the antibodies your body makes to fight dengue can also make you more likely to get sick if you get infected later. So, scientists are working on vaccines that don’t have this problem.
Preventing Dengue Infections: People traveling to areas where dengue is common should avoid getting bitten by mosquitoes, especially Aedes aegypti, which spread dengue. Most travelers from places where dengue isn’t common are at low risk because they haven’t been exposed to the virus before.

Vaccinating against dengue can shield your patients:

The U.S. Food and Drug Administration (FDA) authorized Dengvaxia in May 2019 for use in children 9 to 16 years old who have laboratory-confirmed prior dengue virus infection and who reside in an endemic area (where dengue occurs regularly or continuously). The use of Dengvaxia was advised by the Advisory Committee on Immunization Practices (ACIP) in June 2021 as a preventative measure against dengue in children aged 9 to 16 who have a laboratory-confirmed history of dengue virus infection and reside in dengue-endemic areas.

Contraindication:

The use of aspirin, nonsteroidal anti-inflammatory drugs and anticoagulants is contraindicated in dengue as it causes severe bleeding.

Conclusion:

The emergence of dengue as a global threat demands urgent attention and coordinated action from governments, pharmaceutical industries, healthcare sectors, and individuals alike. While significant strides have been made in developing new strategies for diagnosis and treatment, the true challenge lies in their effective implementation. Additionally, there is a critical need to raise global awareness and promote preventive measures to impact the incidence of dengue. It is only through combined efforts and collective commitment that we can effectively address the growing threat of dengue and mitigate its impact on communities across the globe.

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