DENGUE: LATEST ADVANCES IN TREATMENT AND PREVENTION

Dengue is a mosquito-borne viral infection affecting millions worldwide. The Aedes aegypti mosquito transmits dengue fever and is prevalent in tropical and subtropical regions. In rare cases, the virus may also be passed down via pregnancy, breast milk, blood transfusions, and organ transplants. Data suggest that 100-400 million people are infected with dengue yearly. While most cases of dengue are mild, some can progress to severe dengue, which can be life-threatening.

Four types of dengue viruses are known as serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. All four types can cause dengue fever; one type does not provide immunity against the others. DENV-2 is the most common type.

Roughly 1 in 4 people infected with dengue experience symptoms. In most cases, symptoms are mild, and those affected recover in 1-2 weeks.^[1]

Mild dengue symptoms include:

• High fever
• Severe headache
• Swollen glands
• Eye pressure and pain
• Joint and muscle pain
• Nausea
• Vomiting
• Rash

Repeat infections increase the risk of severe dengue, long-term complications, and possible mortality. 1 in 20 infected people go on to acquire severe dengue.^[2]

Symptoms of severe dengue occur after the fever dissipates and include:

• Abdominal pain
• Chronic vomiting
• Rapid breathing
• Bleeding from the gums, nose, vomit, or stools
• Excessive weakness and lethargy

If you have intense symptoms and suspect severe dengue, seek medical attention as soon as possible.

Severe dengue can lead to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), which can cause internal bleeding, steep drops in blood pressure, organ failure, and even death. DHF is more prevalent in children. There are about 20,000 to 25,000 dengue related deaths annually, primarily in children.

In severe dengue, long-term complications include:

• Post-dengue fatigue syndrome: Some people may experience fatigue and weakness for weeks or months after recovering from dengue.
• Neurological complications: In rare cases, dengue can lead to neurological complications such as encephalitis, meningitis, or Guillain-Barré syndrome.^[3]
• Cardiovascular complications: Dengue can also affect the heart, leading to myocarditis^[4], pericarditis, or cardiomyopathy.
• Liver damage: Severe dengue can cause liver damage, leading to jaundice and liver failure.
• Kidney damage: In rare cases, dengue can cause acute kidney injury, which can be life-threatening.

This article discusses the current treatment and management of dengue, prevention, what advances have been made, and where the future of dengue treatment is headed.

Current Treatment and Management of Severe Dengue

There is no specific treatment for dengue currently, and the standard approach is supportive care.

Supportive care includes rest, hydration, pain relief, maintaining nutrition and electrolyte balance, and addressing milder complications like secondary infections. Patients at home usually manage this type of care.

Managing severe dengue and its complications, such as bleeding, plasma leakage, organ failure, low platelet count, and shock, requires timely and appropriate interventions. These complications can rapidly progress and become life-threatening if not addressed promptly.

Patients with severe dengue may require medications for pain relief, fever reduction, and management of other symptoms. Ibuprofen, acetaminophen, and other NSAIDs (Non-steroidal anti-inflammatory drugs) help to thin the blood and lower pain, yet they may aggravate bleeding if not used with care.^[5]

Critical care interventions are crucial in managing severe dengue cases, including using the intensive care unit (ICU). ICU care allows for continuous monitoring and prompt intervention in case of any deterioration.

ICU admission may be necessary for:

• Close monitoring of vital signs
• Oxygen therapy and advanced respiratory support (if required)
• Fluid management
• Blood and platelet transfusions
• Specialized management of organ failure

It is worth noting that managing severe dengue demands a multidisciplinary strategy that involves healthcare professionals with expertise in critical care medicine, infectious diseases, and hematology. Individualized treatment based on the patient's condition and response to therapy is preferable.

Consult a healthcare professional for specific guidance and treatment options.

Dengue Treatment Updates

In recent years, advancements in the treatment of dengue including antiviral medications, immunomodulatory therapies, and the addition of plasmapheresis have improved the prognosis for those affected.

Antiviral Medications

Antiviral medications are drugs that specifically target and inhibit the replication of viruses. In the case of dengue, researchers are actively investigating small molecule inhibitors and nucleoside analogs to use against dengue fever.^[6]

• Small-molecule inhibitors aim to inhibit specific enzymes or proteins involved in the dengue virus replication. For example, in preclinical studies, inhibitors targeting viral enzymes NS3 and NS5 have shown promise.
• Nucleoside analogs mimic the nucleosides required for viral replication, thus interfering with viral RNA synthesis. Examples include compounds like sofosbuvir and BCX4430, which have shown activity against the dengue virus in laboratory studies.

Researchers are also exploring the use of multiple antiviral drugs in combination to enhance efficacy and reduce the likelihood of viral resistance.

While no specific antiviral medication for dengue exists, some drugs under development have shown promise in treating the disease.

• JNJ-1802: In the preclinical study conducted by Janssen^[7], the novel dengue antiviral JNJ-1802 demonstrated efficacy in inhibiting the replication of the dengue virus (DENV-1 and DENV-2) by inhibiting the viral proteins NS3 and NS4B. This finding highlights the potential of this antiviral for dengue treatment, offering hope for improved management.

Similar novel antiviral medications include Suramin, ST-60, Retrocyclin 1, AT-752, and many more.

Drug Repurposing. Additionally, research reveals that existing medications used for other purposes show efficacy against dengue.^[8]

A few medications currently under investigation for potential against dengue include:

• Eltrombopag: Originally approved for a blood disorder (thrombocytopenia)
• Ivermectin: Widely used as an anti-parasitic
• Doxycycline: Antibiotic
• Ketotifen: Primarily used as an antihistamine/allergy medication
• Montelukast: A leukotriene inhibitor for asthma
• Rupatadine: Primarily used for allergies
• Metformin: Mainly used for diabetes
• Oseltamivir: Antiviral medication (Tamiflu) for influenza
• Zanamivir: Antiviral for influenza

Immunomodulatory Therapies

These drugs modulate the immune system's response to an infection. In the case of dengue, these therapies aim to reduce the body's excessive immune response, which can lead to severe dengue.

Some examples of potential immunomodulatory therapies for dengue include

interferons, which are proteins naturally produced by the body in response to viral infections. In studies, synthetic interferons can treat dengue with some success.

Research reveals that dengue virus proteins (blocked by the novel antivirals under investigation) inhibit the body's ability to produce type I interferons^[9], including interferon-alpha. Interferon alpha activates various antiviral pathways within cells, inhibiting viral replication. It also limits excessive inflammation, reducing the severity of dengue symptoms.

A test-tube study suggests that interferon alpha therapy has potential as a treatment option for dengue fever by directly targeting the virus and modulating the immune response to control the infection.

Monoclonal antibodies: These are laboratory-produced antibodies that target specific components of the dengue virus. They have shown promise in treating dengue in clinical trials.

Monoclonal antibodies (mAbs) can work against dengue virus infection through various mechanisms.^[10]

1. Firstly, mAbs can neutralize the virus when binding to viral proteins, such as the envelope protein, preventing the virus from infecting host cells. This inhibits viral replication and spread.
2. Secondly, mAbs can bind to infected cells and trigger the immune system's response to eliminate these cells. This mechanism helps clear the virus from the body.

One promising monoclonal antibody includes 3G9, which targets a specific region on the dengue virus protein envelope (called a fusion loop epitope) that enables virus entry into host cells^[11].

Corticosteroids: These drugs block immune activity and reduce inflammation. Health authorities advise against their use for treating dengue fever^[12]. However, recent research suggests they may help with treating severe dengue.

One study suggests that corticosteroids may provide some benefits in reducing the duration of fever and hospital stay in children with dengue, yet as with NSAIDs, they can increase the risk of bleeding complications.^[13]

Further research is needed to understand better the optimal use and potential risks of corticosteroid therapy in children with dengue.

Plasmapheresis

Plasmapheresis is a procedure that concerns filtering blood plasma before returning it to the patient. This technique can treat severe dengue by removing the antibodies contributing to excessive immune response.

In a small sample of children with life-threatening kidney complications from dengue fever, plasma exchange improved the efficacy of kidney replacement therapy. It also lowered mortality rates by up to 50% compared to the control group (kidney replacement alone).

More research is needed to determine its effectiveness.

Innovations and New Technologies: The Future of Dengue Treatment

Due to recent advances, dengue treatment looks promising, with several innovations and new technologies under development to combat the disease. These include advancements in diagnostics, vector control, and vaccine development.

Diagnostic Innovations

Early and accurate diagnosis is crucial in the treatment of dengue. Current diagnostics include blood tests that can detect the virus or viral antibodies. However, these tests can be time-consuming and unavailable in all areas.

New diagnostic technologies are underway to provide faster and more accurate results. These include rapid diagnostic tests at the point of care, as well as new techniques that use artificial intelligence and data analysis to detect dengue.^[14]

Here are some key advancements in the field:

1. Point-of-care rapid diagnostic tests (RDTs): New RDTs offer speedy dengue diagnosis with accessible results at the point of care by detecting antigens or antibodies. For example, some cutting-edge biosensors can detect dengue virus in blood samples, screening for all four types in just 15 minutes, using advanced techniques.^[15]
2. Biomarker-based diagnostic approaches: Researchers have identified potential biomarkers for dengue infection, such as microRNAs, cytokines, and chemokines. These biomarkers can be detected and measured using advanced techniques, offering a more accurate and sensitive diagnostic approach.
3. Next-generation sequencing (NGS) for viral genome sequencing: NGS is a modern diagnostic technique that enhances viral genome sequencing, enabling in-depth analysis of dengue virus strains, genetic variations, and evolution, benefiting epidemiological investigations.

These advances in diagnostics for dengue enable faster, more accurate, and accessible detection of the virus, aiding in timely patient management and control of dengue outbreaks.

Vector Control Advancements

Controlling the Aedes mosquito population is crucial in arresting the spread of the disease. Standard vector control methods, such as insecticides and larvicides, have shown limited effectiveness.

New technologies that can control the Aedes mosquito population more effectively are emerging. These include genetically modified mosquitoes that cannot transmit the dengue virus^[16] and Wolbachia-carrying mosquitoes that transmit bacteria that can sterilize and lower the mosquito population^[17]. Ongoing studies are testing these innovative control strategies.

Vaccine Landscape

Vaccines are among the most compelling ways to deter infectious diseases.

The FDA approved a vaccine known as Dengvaxia (CYD-TDV) in 2019, aimed at preventing the disease in children and adolescents between the ages of 9 and 16 with previous exposure to the virus. However, at present, there exists no vaccine for the broader public to avoid contracting the disease.

TAK-003, another dengue vaccine, shows promise in clinical studies and is currently approved for use in the EU, UK, and Indonesia in those over four years of age^[18]. It is currently under review for approval outside the EU.

Both TAK-003 and CYD-TDV are live-attenuated vaccines, which means they contain live strains of the virus to boost immunity.

Several other dengue vaccines target all four strains currently undergoing testing. These include^[19]:

• TV003/TV005 (another live-attenuated vaccine)
• WRAIR, GSK (non-live inactivated vaccine)
• V180 (viral sub-unit protein vaccine)

Artificial Intelligence and Data Analysis

Artificial intelligence (AI) data analysis can improve dengue prevention and control efforts. It can interpret large amounts of data to determine patterns and predict outbreaks, allowing for more targeted and effective interventions.

AI has helped uncover new insights into dengue transmission, host-virus interactions, and immune responses. For example^[20]:

• Algorithms have identified risk factors associated with transmission, such as climate conditions, population density, and socioeconomic factors.
• AI analyzes social media, climate, and health records to detect dengue outbreaks. It provides early warning for preventive actions.
• AI aids efficient medication and vaccine efficacy prediction, expediting clinical trials by interpreting vast datasets on host-virus interactions and immune responses.

Additionally, AI can potentially improve therapeutic strategies by enabling personalized medicine, predicting treatment outcomes, and identifying novel drug targets.

The use of AI in dengue research holds promise for more effective prevention, diagnosis, and treatment of the disease in the future.

Other Developments

Here are some technologies that may diagnose and treat dengue fever in the future:

• Stem cell therapy: Stem cells have shown promise in treating mice with dengue complications by reducing inflammation and promoting tissue repair^[21].
• Wearable biosensors: In the future, biosensors and point-of-care detection systems will become wearable. Wearable biosensors can detect early signs of dengue and allow for real-time monitoring of symptoms and complications.

Dengue Prevention

Prevention plays a vital role in combating dengue. Here are some key strategies individuals can take to prevent contracting dengue fever^[22]:

• Mosquito bite prevention: Wearing protective clothing, using insect repellents, and utilizing bed nets can reduce the risk of mosquito bites, especially during peak activity hours.
• Personal hygiene and environmental sanitation: Practicing good personal hygiene, such as routine handwashing and maintaining pristine living environments, can help minimize the breeding and presence of mosquitoes.
• Reducing breeding grounds around homes: Regularly removing stagnant water from containers, properly disposing of waste, and cleaning gutters can eliminate potential mosquito breeding sites.
• Early symptom recognition and prompt medical attention: Educating individuals about dengue's early signs and symptoms can enable timely diagnosis and treatment, reducing the risk of severe complications.
• Vaccines: Vaccination is a critical preventive measure against dengue. The availability and utilization of dengue vaccines contribute to reducing dengue cases and its impact on public health.

Countries and communities can look towards the following prevention measures:

• Awareness campaigns and vector control programs implemented by public health authorities are necessary to educate communities, promote prevention practices, and implement effective mosquito control measures.
• Engaging communities in clean-up drives and implementing effective waste management strategies can minimize potential mosquito breeding sites and reduce the mosquito population.
• Leveraging technology, such as geographic information systems (GIS), can enhance surveillance efforts to identify high-risk areas, track outbreaks, and facilitate targeted interventions.

By adopting these prevention strategies, individuals, communities, and global health authorities can work toward mitigating the transmission and impact of dengue.

Conclusion

Dengue is a significant public health concern. However, it can be controlled through the latest treatments, innovations, and management strategies. With continued research and advancements, we can hope for a future where dengue is no longer a threat to global health.