Pathophysiology: The Aedes Mosquito

Pathophysiology
Dengue fever is a mosquito-borne viral disease caused by 1 of 4 closely related but antigenically distinct
serotypes of dengue virus, serotypes DENV-1 through DEN-4. [10] Infection with one dengue serotype confers
lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can
eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic.
The Aedes mosquito

Dengue viruses are transmitted by the bite of an infected Aedes (subgenusStegomyia) mosquito.
[11]
Globally, Aedes aegypti is the predominant highly efficient mosquito vector for dengue infection, but the Asian
tiger mosquito, Aedes albopictus, and other Aedes species can also transmit dengue with varying degrees of
efficiency (see the images below).
Drawing of Aedes aegypti mosquito. Picture from

the Centers for Disease Control and Prevention (CDC) Web site.
Aedes aegypti mosquito. Picture from the

Centers for Disease Control and Prevention (CDC) Web site.
Aedes albopictus. From CDC Public Domain.
Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small
amounts of stagnant water found in old tires or other small containers discarded by humans. Humans are their
preferred hosts.
Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite, usually on the back of the neck
and the ankles, and are easily disturbed during a blood meal, causing them to move on to finish a meal on
another individual, making them efficient vectors. Not uncommonly, entire families develop infection within a 24to 36-hour period, presumably from the bites of a single infected mosquito.
Hosts for transmission

Humans serve as the primary reservoir for dengue. Certain nonhuman primates in Africa and Asia also serve
as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a
carrier of the virus. Persons with dengue viruses in their blood can transmit the viruses to the mosquito 1 day
before the onset of the febrile period. The patient can remain infectious for the next 6-7 days.
The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 812 days of viral replication in the mosquito's salivary glands (extrinsic incubation period). The virus does not
adversely affect the mosquito. The mosquito remains infected for the remainder of its life. The life span of A
aegypti is usually 21 days but ranges from 15 to 65 days. Vertical transmission of dengue virus in mosquitoes
has been documented.[12] The eggs of Aedesmosquitoes withstand long periods of desiccation, reportedly as
long as 1 year, but are killed by temperatures of less than 10C. Rare cases of vertical dengue transmission
have been reported. In addition, rare reports of human-to-human transmission via needle-stick injuries have
been published.[13]
Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 days) while
viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the
reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells, [14, 15, 16, 17] result in the
production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral
immune response to both the initial and subsequent virus infections. [14, 18, 19, 20, 21, 22, 23]
Dengue viral infections frequently are not apparent. In most cases, especially in children younger than 15
years, the patient is asymptomatic or has a mild undifferentiated febrile illness lasting 5-7 days. Classic dengue
fever primarily occurs in nonimmune, nonindigenous adults and children and is typically self-limiting. Recovery
is usually complete by 7-10 days. Dengue hemorrhagic fever and dengue shock syndrome usually occur
around the third to seventh day of illness during a second dengue infection in persons with preexisting actively
or passively (maternally) acquired immunity to a heterologous dengue virus serotype.
Dengue fever
Dengue presents in a nonspecific manner similarly to that of many other viral and bacterial illnesses. Fever
typically begins on the third day of illness and persists 5-7 days, abating with the cessation of viremia. Fever
may reach 41C. Occasionally, and more frequently in children, the fever abates for a day and recurs, a pattern
that is termed a saddleback fever; however, this pattern is more commonly seen in dengue hemorrhagic fever.
Leukopenia, lymphopenia near the end of the febrile phase, and thrombocytopenia are common findings in
dengue fever and are believed to be caused by direct destructive actions of the virus on bone marrow
precursor cells. The resulting active viral replication and cellular destruction in the bone marrow are believed to
cause the bone pain. Approximately one third of patients with dengue fever may have mild hemorrhagic
symptoms, including petechiae, gingival bleeding, and a positive tourniquet test (>20 petechiae in an area of
2.5 X 2.5 cm). Dengue fever is rarely fatal.
Dengue hemorrhagic fever

Dengue hemorrhagic fever occurs less frequently than dengue fever but has a more dramatic clinical
presentation. In most of Asia, where it first was described, dengue hemorrhagic fever is primarily a disease of
children. However, in the Americas, and more recently reported in Taiwan, dengue hemorrhagic fever has an
equal distribution in all ages.
Dengue hemorrhagic fever typically begins with the initial manifestations of dengue fever. The acute febrile
illness (temperatures 40C), like that of dengue fever, lasts approximately 2-7 days. However, in persons with
dengue hemorrhagic fever, the fever reappears, giving a biphasic or saddleback fever curve.
Along with biphasic fever, patients with dengue hemorrhagic fever have progressive thrombocytopenia,
increasing hematocrit (20% absolute rise from baseline) and low albumin (signs of hemoconcentration
preceding shock), more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test),
and progressive effusions (pleural or peritoneal). Lymphocytosis, often with atypical lymphocytes, commonly
develops before defervescence or the onset of shock. Transaminase levels may be mildly elevated or present
in the several thousands associated with hepatomegaly in those patients with acute hepatitis. Low fibrinogen
and elevated fibrin split products are signs of disseminated intravascular coagulation. Severe metabolic
acidosis and circulatory failure can occur.
The critical feature of dengue hemorrhagic fever is plasma leakage. Plasma leakage is caused by increased
capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites.
Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from
petechial skin hemorrhages to life-threatening gastrointestinal bleeding.
Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase,
low albumin levels, and deranged coagulation parameters (prothrombin time, partial thromboplastin time). [24, 25] In
persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer
cells with minimal cytokine response (tumor necrosis factor [TNF]alpha, interleukin [IL]2). This is similar to
that seen with fatal yellow fever and Ebola infections.[24]
As the term implies, dengue shock syndrome is essentially dengue hemorrhagic fever with progression into
circulatory failure, with ensuing hypotension, narrow pulse pressure (< 20 mm Hg), and, ultimately, shock and
death if left untreated. Death may occur 8-24 hours after onset of signs of circulatory failure. The most common
clinical findings in impending shock include hypothermia, abdominal pain, vomiting, and restlessness.
Secondary infection
The immunopathology of dengue hemorrhagic fever/dengue shock syndrome remains incompletely
understood. Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior
infection with one or more dengue serotypes. When an individual is infected with another serotype (ie,
secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1
of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and
monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody
complex.
This results in increased viral entry into macrophages bearing IgG receptors, allowing unchecked viral
replication with higher viral titers and increased cytokine production and complement activation, a phenomenon
called antibody-dependent enhancement.[26, 27]
The affected macrophages release vasoactive mediators that increase vascular permeability, leading to
vascular leakage, hypovolemia, and shock. This mechanism, along with individual host and viral genome
variations, plays an active role in pathogenesis. Infants born to mothers who have had dengue, as maternally
derived dengue neutralizing IgGs wane, are also thought to be at risk for enhanced disease. [26, 27]
Some researchers suggest that T-cell immunopathology may play a role, with increased T-cell activation and
apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during
symptomatic secondary dengue infections.[28] The activation of cytokines, including TNF-alpha, TNF receptors,
soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity.[14]
Cuban studies have shown that stored serum sample analysis demonstrated progressive loss of cross-reactive
neutralizing antibodies to DENV-2 as the interval since DENV-1 infection increased. [21] In addition, certain
dengue strains, particularly those of DENV-2, have been proposed to be more virulent, in part because more
epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.

Pathophysiology: The Aedes Mosquito

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Pathophysiology

The Aedes mosquito

Drawing of Aedes aegypti mosquito. Picture from

Aedes aegypti mosquito. Picture from the

Aedes albopictus. From CDC Public Domain.

Hosts for transmission

Dengue hemorrhagic fever

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