Micro Viral Hemmorhagic Fevers

Dengue Fever is primarily transmitted by mosquitoes, and the Aedes genus is the main vector for this disease. Aedes mosquitoes, particularly Aedes aegypti and Aedes albopictus, are responsible for spreading the dengue virus to humans. These mosquitoes are commonly found in tropical and subtropical regions and are known for their ability to breed in urban areas, making them a significant threat for dengue transmission in densely populated areas.

Mosquitoes, sandflies and aerosols are vectors for Rift Valley HF virus.

Direct viral injury to myocytes might contribute to shock, as well as TNF- and nitric oxide produced by infected or activated Kupffer cells and splenic macrophages, through cell injury, oxygen radical production, and microvascular damage

Apoptosis and TNF- would be heavily involved in the increase of capillary vascular permeability
 Histamine release from infected mast cells might also contribute significantly to increased vascular permeability
 CCL2 (MCP-1) protein has been shown to reduce tight junctions of vascular endothelial cells in DHF/DSS patients

 Dengue virus non-structural protein 1 (NS1) – antibodies directed against NS1 also cross-react with platelets and endothelial cells (thrombocytic purpura)

2.2. Dengue
2.2.1. Etiology
• Dengue viruses types:
o Single-stranded positive-polarity (positive-sense) RNA
o Spherical
o Enveloped (sensitive to lipases, organic solvents and detergents)
o  50 nm in diameter
o Four types: DENV-1, DENV-2, DENV-3, and DENV-4
o Vectors: Mostly Aedes spp. mosquitoes
o Reservoir: Primates

2.2.2. Epidemiology
• In expansion [mostly due to A. aegypti and A. albopictus expansion (A. albopictus especially threatens to widen even more the distribution of dengue), as well as increasing population, uncontrolled urbanization and increased travel]
• More widely distributed than yellow fever; outbreaks and epidemics distributed worldwide in tropical regions (year round with peaks during the rainy season) and in some temperate regions (summer)
• Both jungle and urban dengue fever cycles exist, analogous to yellow fever; however, there is no jungle cycle in the Americas, as opposed to yellow fever. All involve Aedes spp. mosquitoes
• Primates serve as reservoir hosts
• Vertical transmission takes place
• Yearly incidence of 100 million infections with 500 000 cases of DHF/DSS
•Case fatality rates are lower than 1% to 5% (mostly DSS; see below)
2.2.3. Incubation period
• 2 to 7 days (up to 14 days)

2.2.4. Duration
• 5 to 9 days

2.2.5. Symptoms and course of disease
• Two forms of the infection exist:
o Classical dengue fever (DF)
o Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which are severe manifestations of dengue infection (mostly associated with DENV-2, followed by DENV-3, and DENV-1); usually in children ( • Classical dengue fever (DF):
o Viremic stage during which the patient is infectious and can serve as a source of infection for the vector; it is characterized by an abrupt onset of high fever (sustained or biphasic), chills, malaise, headache, retro-orbital pain, myalgias, arthralgias and deep bone pain (hence the nickname “breakbone fever”), lumbosacral pain, prostration, anorexia, nausea and vomiting, congestion of conjunctivae and face, puffy eyelids, relative bradycardia, along sometimes with respiratory symptoms (cough, sore throat, and rhinitis), especially in children; generalized macular or mottled rash (1st or 2nd day of infection), followed by a maculopapular or morbilliform rash upon defervescence (3rd to 5th days of infection), generalized lymphadenopathy, cutanous hyperesthesia, metallic taste sensation, petechiae, and epistaxis - Laboratory findings: Leucopenia with absolute neutropenia, and elevated levels of serum lactate dehydrogenase, AST and ALT
• Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS):
o DHF: Similar to classical dengue fever with gastrointestinal and respiratory symptoms (see DHF/DSS below) – Laboratory findings: Elevated hematocrit (increased by 20%), thrombocytopenia ( o DSS: Similar to DHF with weak pulse, hypotension or shock
o DHF/DSS: Classical dengue fever with prostration, restlessness, irritability, cold and clammy extremities, hemorrhagic manifestations, pleural effusions, and hepatosplenomegaly – Laboratory findings: Leukopenia (neutropenia), elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, reduced serum albumin, thrombocytopenia, depleted complement and fibrinogen
o Death or recovery within 24 hours (CFR is low with proper fluid management)
2.2.6. Diagnosis

•DF, DHF and DSS:
o Clinical and epidemiological
o Laboratory: RT-PCR, ELISA (4-fold increase in IgM on a single serum sample provides a presumptive diagnosis), dipstick dot blot immunoassay, immunochromatographic assay; older tests include hemagglutination inhibition, complement fixation, neutralization, and indirect immunofluorescence assays - prior dengue infection or cross-reactivity with YF and leptospirosis can render lab diagnosis confusing (e. g. antibody response to original type of dengue may far exceed the antibody response to the current infecting type, a clinical phenomenon referred to as the “original antigenic sin”)
o Epidemiology and research: Virus isolation and culture, and RT-PCR
• Differential diagnoses include: Flu, rubella, rubeola, malaria, scrub typhus, leptospirosis, and other arbovirus infections (Chikungunya, West Nile, Sindbis, O’nyong nyong, Mayaro, Edge Hill, Kokobera, Spondweni, Barmah Forest, and Ross River)
2.2.7. Pathogenesis
• DF:
o Poorly characterized due to the mostly self-limited nature of the illness
o Virus inoculated through mosquito bite and carried to draining lymph nodes by dendritic cells
o Viral replication in skin and lymph nodes (macrophages and dendritic cells are highly permissive to the dengue virus)
o Viral spread to other tissues through blood
o Genesis of systemic symptoms uncertain, but likely due to cytokine/chemokine production through mononuclear phagocyte insult and T lymphocyte activation
o Elevated levels of IFN-, IFN-, TNF-, IL-2 and IL-2R, IL-1, soluble CD4, CD8, and PAF (platelet-activating factor)
o Leukopenia likely due to bone marrow suppression
o Endothelial cell swelling, perivascular edema, and mononuclear cell infiltration in rash biopsies
• DHF/DSS:
o Usually found in children o Diffuse capillary leakage and hemorrhage
o Mostly mediated by cytokines leading to increased vascular permeability resulting in hemoconcentration, decreased effective blood volume, tissue hypoxia, lactic acidosis and shock
o Different hypotheses:
Antibody-mediated enhancement of infection of mononuclear phagocytes:
• Increased levels of viral immune complexes with non-neutralizing antibodies directed against the virus
• Uptake by and infection of mononuclear phagocytes (via FcR)
• Exacerbation of illness

Intervention of dengue-specific lymphocytes and release of cytokines and activation of complement:
• Serospecific and especially cross-reactive (poor avidity and more prone to apoptosis) CD4+ and CD8+ T-lymphocyte involvement leads to less than efficient virus clearance and increased levels of IFN-, TNF-/, IL-2 and IL-2R, IL-1, soluble CD4, CD8
• Apoptosis and TNF- would be heavily involved in the increase of capillary vascular permeability
• Histamine release from infected mast cells might also contribute significantly to increased vascular permeability
CCL2 (MCP-1) protein has been shown to reduce tight junctions of vascular endothelial cells in DHF/DSS patients
Dengue virus non-structural protein 1 (NS1) – antibodies directed against NS1 also cross-react with platelets and endothelial cells (thrombocytic purpura)
2.2.8. Immunology
• Cellular and humoral: Long-lasting immunity is achieved through neutralizing antibodies to homologous serotypes; potential risk for DHF/DSS upon infection with heterologous serotypes of dengue viruses
2.2.9. Complications
• Bacterial infections and sepsis

2.2.10. Treatment
• Supportive: Treatment is symptomatic with rest, oxygen (DHF/DSS) and fluid management especially (DHF/DSS); antipyretics and analgesics
• Salycilates are to be avoided

2.2.11. Prevention
• Vector control
• Personal protection: Use of long sleeves, insect repellents, and mosquito nets (the vectors are furtive feeders and tend to be diurnal)
• Sensitive to lipases, organic solvents, and detergents

2.2. Dengue
2.2.1. Etiology
 Dengue viruses types:
o Single-stranded positive-polarity (positive-sense) RNA
o Spherical
o Enveloped (sensitive to lipases, organic solvents and detergents)
o  50 nm in diameter
o Four types: DENV-1, DENV-2, DENV-3, and DENV-4
o Vectors: Mostly Aedes spp. mosquitoes
o Reservoir: Primates

2.1. Yellow fever-------NOT IN ASIA-- NOT IN ASIA--, NOT IN ASIA--
2.1.1. Etiology
 Yellow fever virus (YF or YFV):
o Single-stranded positive-polarity (positive-sense) RNA
o Spherical
o Enveloped (sensitive to lipases, organic solvents and detergents)
o  50 nm in diameter
o Two genotypes:
 Genotype I: East and central Africa
 Genotype II (with two sublineages): Genotype IIA in West Africa and genotype IIB in America
o Vectors: Mostly Aedes spp. mosquitoes
o Reservoir: Primates

During hemorrhagic fever infections, shock can occur due to vascular leakage. Vasoactive mediators are substances that can cause blood vessels to dilate or become more permeable, leading to fluid leakage. These mediators include histamine, prostaglandins, and cytokines. They are released by the immune system in response to the virus, and their effects can contribute to the development of shock and vascular leakage. Therefore, vasoactive mediators rank first as a cause of vascular leakage during hemorrhagic fever infections.

All of the mentioned viruses should be part of the differential because they can all cause symptoms similar to the ones described by the patient. Ebola virus, Crimean-Congo virus, Lassa fever virus, and Dengue virus are all known to cause hemorrhagic fever and can present with fever, malaise, prostration, diarrhea, nausea and vomiting, cough, chest pain, and a sore throat. Therefore, considering all of these viruses in the differential diagnosis is important in order to accurately diagnose and treat the patient.

 Dengue virus non-structural protein 1 (NS1) – antibodies directed against NS1 also cross-react with platelets and endothelial cells (thrombocytic purpura)

is is Arenavirus, which is found in Argentina and is called the Argentine hemorrhagic fever. It is a enveloped segmented ss(-)RNA and the reservoir is rodents.

Epidemiologically, yellow fever is the most likely due to the yearly incidence as compared with Rift Valley HF; so, the most likely answer is “C”. The biphasic presentation of this case also makes YF more likely.
2. FLAVIVIRIDAE
Yellow fever virus was the first human virus to be described (1901) and serves as the type species for the Flaviviridae, which contain several hemorrhagic fever (yellow fever, dengue, Omsk hemorrhagic fever, Kyanasur forest disease, and Alkhurma virus) and encephalitis viruses (Japanese encephalitis, West Nile encephalitis, St. Louis encephalitis, Russian spring-summer encephalitis, and Powassan encephalitis). Flaviviruses are small (50 nm), single-stranded positive-polarity (positive-sense) RNA viruses, and their distributions are restricted by vector and reservoir hosts. The remainder of the discussion on flaviviruses will focus on yellow fever and dengue, as these are by far the two most important diseases caused by this group.
2.1. Yellow fever
2.1.1. Etiology
• Yellow fever virus (YF or YFV):
o Single-stranded positive-polarity (positive-sense) RNA

o Spherical
o Enveloped (sensitive to lipases, organic solvents and detergents)
o  50 nm in diameter
o Two genotypes:
Genotype I: East and central Africa
Genotype II (with two sublineages): Genotype IIA in West Africa and genotype IIB in America
o Vectors: Mostly Aedes spp. mosquitoes
o Reservoir: Primates
2.1.2. Epidemiology
• Outbreaks and epidemics distributed in sub-Saharan Africa, central and South America, as well as the Caribbean
• Two types of transmission cycles: jungle (sylvatic) and urban
o Jungle yellow fever refers to the natural cycle in which the infection is spread from monkey to monkey via the mosquito bite (Aedes africanus, A. furcifer, A. luteocephalus, and other Aedes spp. in Africa, and Haemagogus and Sabethes spp. in the Americas); humans in this case get infected when they encroach this cycle
o Urban yellow fever refers to the human to human spread of the virus via the mosquito (A. aegypti) bite following the introduction of the virus into urban areas by sylvatically-infected individuals; most yellow fever outbreaks and epidemics are caused by the urban cycle

•Primates serve as reservoir hosts
• Yearly incidence of 200 000 infections, with 30 000 deaths
• Case fatality rates for individuals with late stage are variable, but approximate 20% (and as high as 50% during some epidemics)
2.1.3. Incubation period
• 3 to 6 days (can be as long as 14 days)

2.1.4. Duration
• 6 to 10 days (typically) or more

2.1.5. Symptoms and course of disease
• Non-specific febrile illness to life-threatening hemorrhagic fever
• Period of infection (usually lasts 3 days, can last up to several days): Viremic stage during which the patient is infectious and can serve as a source of infection for the vector; it is characterized by an abrupt onset of high fever, chills, malaise, headache, myalgias, lumbosacral pain, dizziness, anorexia, nausea and vomiting, along with congestion of conjunctivae and face, reddening of the tongue edges, Faget’s sign (heart rate does not increase with fever) - Laboratory findings: Leucopenia with relative neutropenia
• Abortive cases: The patient recovers fully with no further signs or symptoms (most common presentation)

•Remission 2 to 24 hours
• Late stage (also referred to as the intoxication period; typically lasts 3 to 5 days): Recurrence of the symptoms with epigastric pain, onset of jaundice, renal dysfunction, oliguria, hypotension, and hemorrhagic diathesis [hematemesis, melena, metrorrhagia, petechiae, ecchymoses, epistaxis, bleeding of the mucous membranes (gums, nose, eyes, rectum)] – Laboratory findings: Increased bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, albuminuria, azotemia, thrombocytopenia, prolonged clotting and prothrombin times, global reduction in clotting factors
• At this stage, the patient can still recover
• Preterminal events: Include hypothermia, delirium, hypoglycemia, hyperkalemia, stupor and coma
• Death usually occurs after 7 to 10 days after the onset of the disease
2.1.6. Diagnosis
• Often clinical (and epidemiologic)
• Laboratory: Mostly RT-PCR and ELISA (4-fold increase in IgM on a single serum sample provides a presumptive diagnosis); paired acute- and convalescent-phase samples provide confirmation; these tests are not commercially available and have to be done by specialized laboratories; older tests include hemagglutination inhibition, complement fixation, neutralization, and indirect immunofluorescence assays
• Epidemiology and research: Virus isolation and culture, and RT-PCR
• Differential diagnoses include: Viral hepatitis (especially hepatitis D, and hepatitis E in pregnant women), leptospirosis, dengue hemorrhagic fever, West Nile hepatitis, Rift Valley fever, Congo-Crimean hemorrhagic fever, severe malaria, Q fever, and typhoid fever; other viral hemorrhagic fevers are usually not associated with jaundice
2.1.7. Pathogenesis
• Virus inoculation through mosquito bite
• Viral replication in draining lymph nodes
• Viral spread to other tissues (liver, spleen, bone marrow, heart, and skeletal muscle) through blood
• Viral infection is directly involved in hepatocellular damage; Kupffer cells are infected first, followed by hepatocytes
• Renal failure (acute tubular necrosis) as a consequence of lower blood volume (shock)
• Direct viral injury to myocytes might contribute to shock, as well as TNF- and nitric oxide produced by infected or activated Kupffer cells and splenic macrophages, through cell injury, oxygen radical production, and microvascular damage

2.1.8. Immunology
• Yellow fever infection recovery provides life-long immunity to yellow fever virus (in the form of neutralizing antibodies)
2.1.9. Complications
• Superimposed bacterial pneumonia and sepsis

2.1.10. Treatment
• Supportive: Treatment is symptomatic with rest, fluid, electrolyte, and acid base management; non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or acetaminophen
• Salycilates are to be avoided

2.1.11. Prevention
• Vaccination: A relatively safe and effective vaccine is available (Yellow fever virus 17D strain), which affords protective immunity (neutralizing antibodies) in 10 (90%) to 30 (99%) days; the vaccine, which is good for 10 years, probably provides life-long immunity and is a legal requirement for entry in certain countries. Severe adverse reactions (neurological and visceral) to the vaccine, although rare, are to be considered prior to undertake attempts to achieve herd immunity
• Vector control, especially of A. aegypti
• Personal protection: Use of long sleeves, insect repellents, and mosquito nets (the vectors are furtive feeders and tend to be diurnal)
• Sensitive to lipases, organic solvents, and detergents

The correct answer is rats. The patient's symptoms and the positive serum test for an enveloped, segmented (-) ssRNA virus suggest that the patient has contracted a viral hemorrhagic fever. Rats are known to be reservoir hosts for several hemorrhagic fever viruses, including Lassa fever virus and Seoul virus. These viruses can be transmitted to humans through contact with rat urine, feces, or saliva. Therefore, rats are the likely reservoir host for the virus responsible for this patient's disease.

Technically, rodent is the reservoir and the vector is aerosolized urine, feces or saliva; but these options are not offered so that the best answer still remains “C”. Just thought it would be good practice for technically incorrect questions. Technically incorrect questions will arise sometimes and, although the true right answer may not be there, just go for the best one and do not overthink it; the question is bad and imprecise, there’s nothing you can do about it, just move on to the next question. Choosing the best answer is always what you should be doing anyway, especially since you are now starting to get questions that have multiple right answers (from us, but your gateway exams will have a lot of them); so the right answer is the most likely, the most important, or the most common etc., which most of us state in the question anyway. Therefore, even though there may be multiple right answers, this usually ensures that there is only one best answer. That’s the one you have to go for! And that should be your frame of mind when approaching COMP or STEP exams; it may not be stated in the question for these exams (I think it is stated in the preamble of the tests, but I am not 100% sure…), but many questions provide many correct answers of which you have to choose the most accurate one. We try our best to avoid incorrect questions like the previous one (and so this question would never be found on one of our exams), but we do slip up sometimes… Anyhow, the take home message is that you will have some of these later (COMP, STEPs) for sure and you cannot grieve these. So again just pick the best, imperfect answer and move right on to the next question. Last thing, having to choose the best answer out of two, three, or more right answers (even if you have a mix of right and wrong answers) is a good and valid question; a question that does not have a right answer is an invalid one.

is is Arenavirus, which is found in Argentina and is called the Argentine hemorrhagic fever. It is a enveloped segmented ss(-)RNA and the reservoir is rodents.

5. ARENAVIRIDAE
5.1. Etiologies
 Arenavirus spp.:
o Segmented, single-stranded negative-polarity (negative-sense) RNA
o Spherical
o Enveloped
o 60 nm to 300 nm in diameter
o Two serologic groups: Old and New World
 Lassa virus - Old World (Africa)
 Argentine hemorrhagic fever virus (Junin)

 South American hemorrhagic fevers:
o Insidious onset of fever, malaise, and myalgias
o Intensification of initial symptoms, accompanied by dizziness, headache, gastrointestinal manifestations (nausea, vomiting, diarrhea, meteorism, constipation), flushing, hypotension, and tachycardia
o Full blown manifestations: Prostration, hyperesthesia, confusion, tremors, bleeding (petechiae, mucosal membranes), seizures, coma, shock
o Laboratory findings: Thrombocytopenia, leucopenia, and proteinuria

Mosquitoes are commonly found in urban areas due to the availability of stagnant water sources such as puddles, drains, and containers. Urban areas often have a higher concentration of human population, providing ample opportunities for mosquitoes to find hosts for blood meals. Additionally, urban areas tend to have more artificial structures and vegetation, which create ideal breeding grounds for mosquitoes. Therefore, it is most likely that this population of mosquitoes would be found in urban areas.

 Filoviruses:
o Single-stranded negative-polarity (negative-sense) RNA
o Filamentous and pleiomorphic
o Enveloped
o 80 nm in diameter and 800 nm to 14 000 nm in length
o Two species:
 Marburg
 Ebola (with four subspecies):
 Zaire (Democratic Republic of the Congo)
 Sudan
 Côte d’Ivoire
 Reston (not known to be pathogenic in humans)
o Transmission:
 Direct contact with body fluids from infected hosts
 Aerosols (Ebola Reston, and others in laboratory conditions such as centrifugation)
o Reservoir: Bats
3.2. Epidemiology
 Natural infections: Democratic Republic of the Congo (Zaire), Sudan, Gabon, Kenya, South Africa, and the Ivory Coast
 Unknown initial infection (probably contact with infected bats)
 Transmitted from person to person by contact with body fluids
 Bats serve as reservoir hosts
 Case fatality rates often exceed 50% (except for Ebola Reston)

Lassa fever is caused by the Lassa virus, a member of the Arenaviridae family; it is an enveloped, single-stranded, bisegmented RNA virus.[2]
Replication for Lassa virus is very rapid, while also demonstrating temporal control in replication. There are two genome segments. The first replication step is transcription of mRNA copies of the negative- or minus-sense genome. This ensures an adequate supply of viral proteins for subsequent steps of replication, as proteins known as N and L are translated from the mRNA. The positive- or plus-sense genome then makes viral complementary RNA (vcRNA) copies of itself, which are + sense. The vcRNA is a template for producing − sense progeny but mRNA is also synthesized from it. The mRNA synthesized from vcRNA are translated to make the G (spike) proteins and Z proteins. Thus, with this temporal control, the spike proteins, which are on the outside of the virus particle, are produced last, making the infection more difficult for the host immune system to detect.
Nucleotide studies of the genome have shown that Lassa has four lineages: three found in Nigeria and the fourth in Guinea, Liberia, and Sierra Leone. The Nigerian strains seem likely to have been ancestral to the others but additional work is required to confirm this.[
Lassa virus is zoonotic (transmitted from animals), in that it spreads to man from rodents, specifically multi-mammate rats (Mastomys natalensis). This is probably the most common rodent in equatorial Africa, ubiquitous in human households and eaten as a delicacy in some areas
Infection in humans typically occurs via exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infective material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infective material. Transmission from person to person has also been established, presenting a disease risk for healthcare workers. Frequency of transmission via sexual contact has not been established.