Understanding Dengue: Causes, Prevention, and Treatment

Dengue

• Dengue is a common mosquito-borne illness in tropical and subtropical areas.
• Globally, there are around 100 to 400 million cases each year.
• The disease is endemic in areas such as Africa, Eastern Mediterranean, the Americas, Southeast Asia, and the Western Pacific.
• Asia accounts for approximately 70% of the global disease burden.
• Key factors contributing to dengue transmission include rapid urbanization, poor infrastructure, inefficient vector management, population susceptibility, temperature, rainfall, humidity, and human mobility.
• Disease determinant factors in the epidemiologic cycle of dengue are addressed through epidemiology.
• Vector control, management, diagnosis, and treatment are all vital aspects.
• Philippines is facing the tropical and sub-tropical climates with is why the disease is common.
• As of August 12, 2023, there have been around 101,778 dengue cases reported in the Philippines, a 25% decrease from 2022.
• From January 1 to August 12, 2023, 382 deaths were recorded, lower than the 516 in the same period of 2022.
• Due to warm temperature and humidity there are rising dengue outbreaks.
• The dengue virus (DENV) causes dengue.
• Rapid spread, high morbidity, and general population susceptibility mark the disease.
• Severe cases can result in high mortality rates.
• Mild symptoms include fever, pain, or rash, with the most prevalent being fever along with nausea, vomiting, rash, and pain.
• Severe symptoms include severe abdominal pain, persistent vomiting, respiratory distress, severe hemorrhage, and organ swelling.
• Has a high fatality rate of 20%.
• The country is hyperendemic, with all four strains in circulation, making it one of the most well-known and dreaded tropical infectious diseases.
• A dengue epidemic was first documented in Southeast Asia in Manila in 1954.

Dengue: Continued Concerns

• The largest number of dengue cases reported globally occurred in 2019.
• Asia reported a high number of cases.
• The Philippines reported 437,563 cases, the highest number ever reported.
• Clinical manifestations include dengue with or without warning signs, and severe dengue.
• Probable dengue is indicated of travel to dengue endemic area, Fever and 2 of the following criteria: Nausea, vomiting, Rash, Aches and pains, Tourniquet test positive, Leukopenia.
• Warning signs include abdominal pain, consistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, and rapid blood test increase and decrease in platelets.
• Leading to shock, severe bleeding and organ impairment, Severe plasma leakage is hallmark.

Vector & Virus

• Dengue is transmitted through mosquitoes of Aedes aegypti or Aedes albopictus.
• The virus replicates and spreads to the mosquito's secondary tissue after a mosquito feeds on a DENV-infected person.
• The external incubation period is 8-14 days and is affected by ambient temperature, virus genotype and concentration.
• Throughout the mosquito's life, the virus is spread once ingested.
• Transmission also can happen from Mother-to-child, Blood Transfusion, Organ Transplantation and Occupational exposure.
• The Dengue Virus belongs to Flaviviridae
• It is an enveloped virus, with Structural Proteins like Capsid (C), Envelope protein (E) and Membrane Bound Protein (M).
• Possesses Single Stranded RNA
• Protein C: Specific Antigen Determinant
• Immune system uses these epitopes to distinguish between antigens

Infection Response & Transmission

• The immune system uses antigens/epitopes to recognize, but single-stranded RNAs serve at triggers (PAMPs) detected by TLR-7 and TLR-3 (PRRs)
• Structural proteins are vital virus components: Capsid helps in packaging coded RNA, Envelope aids host receptor, and Membrane for structure.
• Dengue has Non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) for virus genome regulation, replication, and evading host immune defenses.
• NS1 interacts with TLR4, activates macrophages, and disrupts endothelial barriers for plasma.
• NS3 and NS2B are proteases for dengue polyprotein replication.
• Envelope-like proteins attach to cell receptors for host cells, leading to viral replication in the brain.
• Dengue process enters Febrile phase (1 week), then progresses to a Critical phase (1-2 days) with various immune responses and symptoms.
• Fever is triggered by pathogen (PRRs), immune response or inflammatories the immune cells proinflammatory bloodstream cytokines or BBB.
• Endothelial dysfunction via proinflammatory cytokines and reactive species contributes to plasma leakage during infection.
• NS2B and NS3 proteins form a functional complex that exerts proteolytic effects. NS3 helps in the viral's synthesis.

DENV: Prevention & Evasion

• Dengue virus life cycle includes these steps:
• Virus fuses after attaching to host cell via host cell receptors, and is releases viral components (Nucleocapsids)
• Translated proteins form 3 structural (CEM) and 7 nonstructural proteins. Nonstructural creates a replication process with methylated ends that mimics mRNA
• In a structural level, this allows stabilization, cleavage and the synthesis in cell membranes while replication and assembly are being formed
• Dengue can't be contracted during the Viremia phase(virus in the blood), indicated by fever and changing platelets/WBC count where infection requires a blood transfusion
• DENV evades innate immune system through IFN suppression and modulates host response. CD8 directly kills infected cells and CD4 is recognized.
• The complement system hinders virus in early stages via C3A and B. But DENV counters this using NS1.

Treatment & Diagnosis

• The DENV life cycle includes Entry, Genome Uncoating, Translation, Nucleocapsid Formation, Virus assembly,
• Virus Maturation and its own Viral Release, ultimately completing the replication.
• To diagnosis the virus is Enzyme Linked Immunoassay, costly but fast
• Febrile stage can use Immunochromatographic assays
• Plasma leakage can happen due to immune response to DENV, and causes reactive factors to break cells

Management

• Intensive Supportive Therapy, with no cure to blood loss with transfusions. Blood is given questionable.
• Currently Vaccines arent avail in the PH.
• Drug Resistance can occur. In all types, protection will require immunity, but effectiveness can vary, like lower efficacy in the past but proven safe in recent studies.
• The development is Live Attenuated Vaccines with the highest development. Live requires balanced immunity with tetravalent formations as strains can be more severe than others.

Tuberculosis Introduction

• Mycobacterium tuberculosis causes TB, predominantly affecting the lungs and spreads through air by cough. It's a global health concern, recently overtaking COVID-19 as the deadliest infectious disease
• TB can be Multidrug-resistant & the Philippines have highest burden of TB around the globe, DOTS are free to avail and BCG vaccinations are given.
• MTB is initiated by bacilli inhaling into the lungs, later alveolar macrophages engulf and it and induces actions or chemokines. ESX1 is a main contributor to survival as it evades and protects fusion for Mtb.
• Primed immune cells kill Mtb or become reactivated leading to T-cells migrating by chemokines (15 to 18 days). TB cases can also progress more readily to immunecompromised people or sustain

Pathophysiology

• This process is also how tubercle bacilli can evade Phagolysosome and pH balance. They regulate, recruit or degrade components
• This is cruicial for inter cellular persistence. Granulomas or Dormant Mtb contain the infection but is prone for risk or reactivation with lipin content.
• The breakdown of the granuloma leads to rapid infection. Granulomas are the histopathological hallmark of TB.
• This process forms inflammation, promotes T-cell priming, and matures cells (CD8+). This creates a mixture or combination of marophage activity and it all results in the Granuloma.

Symptoms & Diagnostics

• Symptoms such as Hemoptysis or Phlegm is caused Mucus secretion, Tissue damage/Granulomas during Phagocytosis or vascular dmg
• Symptoms such as Weight loss Cytokines/Hypothalamic regulation which alter the metabolic state and cause Leptin dysregulation. As well as other factors
• Lymph nodes and subtle fevers are symptoms of tb. But its asymptomatic is because they suppress Mtb and dont promote immune cell action.
• A few diagnostic tools is Nucleic acid amplification and Line Probe testing in which they identify and can also assesss drug effectiveness and resistance. These are WHO approved with emerging field portability
• Next generation sequencing helps identify all across TB with all drugs , good for field suitability
• LAMP increases at constant temperature without cycling through. And CRISPR acts a ultrasensitive reporter.