[03.12] Dengue and Chikungunya V2.2.pdf

Family Flaviviridae

What is the family of the Dengue virus?

Arboviruses

What is a common term for arthropod-borne viruses that is not a formal taxon?

Enveloped, icosahedral nucleocapsid, single-stranded, positive-sense RNA virus

Describe the structural characteristics of the Dengue virus belonging to the Genus Flavivirus.

Directly translated into proteins

Why can positive RNA strands immediately go to ribosomes?

Species Dengue virus (DENV)

What is the species of the virus that has adapted well enough to replicate in humans, causing its presence throughout the year?

"E" Envelope Protein Dimer

What surface protein of DENV is used to interfere with phospholipid bilayers of endosomes to enter the host cell cytoplasm?

"M" Membrane Protein and Capsid Protein

What structural proteins of DENV are synthesized in the membrane of the endoplasmic reticulum of the infected host cell and contain the viral RNA?

Non-structural Protein 1 (NS1)

What dengue protein is solubilized by the virus and can be detected as an antigen?

Polymerase Chain Reaction (PCR)

What is considered the gold standard for the detection of dengue, though often less accessible in the Philippines due to cost?

Serostatus

What is the state of having or not having detectable antigens, which can be used to diagnose dengue?

Obligate intracellular parasites

Why do viruses infect cells and need to use the host's cell machinery to replicate?

RNA virus

What type of virus is the Dengue virus based on its genetic material?

Immune cells

What type of host cells are primarily targeted by the dengue virus?

Cognate receptor

Which of the two cell surface receptor molecules is involved in normal dengue infection?

Fc receptor

Which of the two cell surface receptor molecules is involved in antibody-dependent enhancement in dengue infection?

Receptor-mediated endocytosis

What process internalizes the dengue virus into a bubble-like structure called an endosome after its envelope protein binds to the cognate receptor?

Lowering of pH

What happens to the interior of the endosome that triggers a change in the conformation of the virus's envelope proteins?

Hydrophobic spike-like structures

What forms on the dengue virus in response to the lowered pH in the endosome, allowing it to penetrate the endosome's membrane?

Capsid

What part of the dengue virus is released into the cytoplasm after the viral and endosomal membranes fuse?

Polyprotein chain

What is the whole viral genome translated into by the ribosome?

Host's peptidase enzyme

What enzyme activates the envelope protein and pre-membrane protein on the lumen side of the endoplasmic reticulum?

Viral protease enzyme

What viral protein in the cytoplasm activates all other proteins in the poly-protein chain to form the RNA replication complex?

Negative-sense copy

What is made using the virus's positive-sense RNA as a template during the first round of RNA synthesis?

Positive-sense strand

What is made using the negative-sense strand as a template in subsequent cycles of RNA synthesis, which can be translated or packaged into new viruses?

Endoplasmic reticulum

Where do envelope proteins aggregate in the lumen and capsid proteins on the cytoplasmic side during the assembly of new viruses?

Pre-membrane protein

What protein covers the tips of the envelope proteins in an immature dengue virus to prevent premature fusion back into the cell?

Golgi apparatus

Through what cellular organelle does the immature virus travel before becoming mature?

Female Aedes aegypti and Aedes albopictus

What are the known vectors of dengue in humans?

Through their saliva while feeding on human blood

How do Aedes mosquitoes infect humans with DENV?

Humans are not dead-end hosts

What characteristic distinguishes DENV from most arboviruses in relation to human infection and spread?

Yellow fever virus and Zika virus

What other flaviviruses, similar to DENV, can multiply in humans and infect uninfected mosquitoes?

Sylvatic cycle

What cycle maintains the population of the dengue virus in wild animals?

Urban cycle

What cycle of dengue transmission emerged due to human interaction with wildlife?

3-7 days (range: 3-14 days)

How long after an infected mosquito bite do dengue symptoms typically begin?

Saddleback or biphasic form

What pattern of fever is characteristic of dengue, with temperature subsiding around the 3rd day and rising again around the 5th-8th day?

Myalgia, arthralgia, and deep bone pain

What classical symptoms of dengue lead to its common name "breakbone fever"?

Severe headache and retro-orbital pain

What is a prominent clinical finding in dengue, especially in adults?

Blanching maculopapular rash (Herman's rash)

What type of rash may appear during the recovery phase of dengue and is described as "islands of white in a sea of red"?

Petechial rashes

What type of rash is a sign of bleeding and is associated with vascular plasma leakage in dengue?

Lymph nodes are frequently enlarged

What non-specific finding in dengue is due to the immune system actively fighting off infection?

Day 3 or 4

When is it advised to repeat a Complete Blood Count (CBC) if dengue is the top differential diagnosis?

Endemic areas

What did the new classification of dengue add emphasis on, concerning epidemiology?

Dehydration

What is a general threat in any febrile condition, including dengue?

Critical Phase

During which phase of dengue fever does the progression to more severe presentations occur, and thrombocytopenia and hemoconcentration become evident?

20, Figure 6

Thrombocytopenia and increased hematocrit (hemoconcentration)

What key changes in CBC should be expected during the critical period of dengue, especially after day 3?

Increased vascular permeability

What primarily characterizes Dengue Hemorrhagic Fever (DHF), leading to blood plasma leakage and sometimes overt bleeding?

Increased cytokine secretion, complement activation, platelet destruction, consumption of coagulation factors

What factors contribute to the endothelial damage causing increased vascular permeability in DHF?

Fever, signs of bleeding or hemorrhage, thrombocytopenia (<100,000/mm3), and evidence of plasma leakage (pleural effusion, ascites, hemoconcentration)

What are the diagnostic criteria for Dengue Hemorrhagic Fever?

Plasma leakage

What is the most important presentation of dengue, often leading to bleeding, and distinguishes dengue from severe dengue?

Antigen presenting cells (APCs)

What cells take up viral particles released by an infected mosquito when its proboscis is inserted into the epidermis?

Proinflammatory cytokines (e.g., TNF-alpha, IFN-gamma, IL-6, IL-8)

What do activated T cells react and secrete in a dengue patient, which are significantly higher in severe dengue and may play a role in plasma leakage?

Endothelial surface glycocalyx and cell-to-cell junctions

What structures maintain the integrity of blood vessels?

Glycocalyx

What network of proteoglycans and glycoproteins projects from the surface of endothelial cells and acts as the primary barrier against leakage of proteins and fluid?

Reactive oxygen species, enzymes, and pro-inflammatory molecules

What evidence suggests the breakdown of the glycocalyx layer, allowing plasma to leak into tissues?

Red blood cells (RBCs)

What component of blood is generally too large to pass into the tissue during plasma leakage, leading to an increase in hematocrit?

20% or more increase in hematocrit levels compared to baselines

What increase in hematocrit levels is indicative of severe plasma leakage?

Hypovolemic shock

What can severe plasma leakage result in, potentially leading to dengue shock syndrome?

Brain

What organ is prioritized for blood perfusion during shock, leading to blood redirection from other organs?

Kidney failure, liver failure

What are examples of organ failures that may result from blood redirection during shock?

Pleural effusions and ascites

What can plasma leakage cause that may result in respiratory problems?

Isotonic intravenous fluids and colloids

What supportive treatment is administered to replace plasma during plasma leakage?

Pulmonary edema and respiratory failure

What can excessive IV fluid therapy lead to if not carefully monitored?

T-cells (releasing pro-inflammatory cytokines)

What is the primary source of the signaling that causes plasma leakage in dengue, coming from the host's immune system?

Host-pathogen relationship

What factor is integral in the varied clinical presentation of dengue, as the pathogen alone is not always the sole cause of severe symptoms?

Personalized medicine

What approach is needed in managing dengue due to individual differences in immune system reactions, patient characteristics, and comorbidities?

Severe plasma leakage leading to shock, fluid accumulation with respiratory distress, severe bleeding, and severe end-organ damage

What are the important clinical findings that classify a patient with Severe Dengue (formerly DSS)?

30, Table C

AST/ALT >1000

What specific laboratory finding indicates severe liver impairment in severe dengue?

30, Table C

Seizures, impaired consciousness

What neurological manifestations indicate CNS impairment in severe dengue?

30, Table C

Myocarditis

What cardiac condition indicates heart impairment in severe dengue?

30, Table C

Renal failure

What kidney condition indicates renal impairment in severe dengue?

30, Table C

Fluid overload

What problem can arise during the recovery phase if fluid correction is not careful, due to extravasated fluid returning to the intravascular compartment?

Five

How many serotypes does dengue have, including those in the sylvatic cycle?

Reinfection with a different serotype

What scenario is more apt to result in a severe presentation of dengue after a primary attack?

No

Can an individual who has recovered from an infection with a basic pathogen virus be reinfected by the same strain of the virus?

Adaptive immune system (humoral and cell-mediated immune responses)

What system develops a response, including specific antibodies, to a pathogen in an immunocompetent person?

Mutation into a different strain

How can viruses bypass long-term immunity, leading to recurrent infections like the common cold?

Serologically distinguishable strains of a microorganism

What are serotypes?

Polyclonal antibodies

What type of antibodies can the human immune system produce as long as it has encountered the pathogen?

Four times

How many times can a person potentially get dengue due to the four serotypes in the urban cycle?

Second exposure

When do patients typically seek medical attention for dengue, often mistaking the first infection for a common cold?

Lifelong protection against the specific Dengue virus serotype

What type of protection does infection with a specific Dengue virus serotype confer?

Antibody Dependent Enhancement (ADE)

What phenomenon occurs when pre-existing antibodies against a primary DENV infection are not protective against a new serotype and can worsen the clinical presentation?

Pre-existing non-neutralizing or sub-neutralizing heterologous Dengue antibodies

What type of antibodies facilitate infection of host cells in ADE?

Fc receptor

What host receptor does the dengue virus use to facilitate its internalization when subpar antibodies are present in ADE?

Block of viral replication

What is the outcome if effective, neutralizing antibodies are directed to the correct dengue serotype?

500-fold risk in severity

According to epidemiology data, what is the increased risk of severity if a patient had serotype 1 followed by serotype 2?

Protection against all serotypes

What is the key to preventing Antibody Dependent Enhancement?

Tetravalent vaccine

What type of vaccine is required for dengue to provide protection against all serotypes and prevent ADE?

Seropositive patient

Dengvaxia was found to be protective only for what type of patient?

Simulated primary infection

What did Dengvaxia do for seronegative patients, which caused problems upon subsequent infection with a different serotype?

Manifest severe presentations

What happens if a seronegative person who received Dengvaxia contracts another serotype?

Test for seropositivity

What should have been done before administering the Dengvaxia vaccine to determine if a patient had antibodies against dengue?

Banned in the country

What is the current status of Dengvaxia in the Philippines due to the controversy surrounding its use in seronegative individuals?

Singapore, US, European Union

What countries still use Dengvaxia despite its ban in the Philippines?