DENGUE

INTRODUCTION

Dengue is an arboviral disease of the Flavivirus genus that is transmitted between

human hosts by certain mosquitoes. There are four different strains of dengue fever, which
are antigenically different (DEN-1, DEN-2, DEN-3, DEN-4). Dengue infection is transmitted
through bites of Aedes aegypti, a diurnal, peridomestic and cosmopolitan species of
mosquito which thrives in congested and trash-ridden urban habitats.
Classical dengue is a self-limiting illness not much different from an ordinary bout of
influenza or common colds. Dengue fever, a benign syndrome caused by several arthropod-
borne viruses, is characterized by biphasic fever, myalgia or arthralgia, rash, leukopenia and
lymphadenopathy.

EPIDEMIOLOGY

Dengue is the most rapidly spreading mosquito-borne viral disease in the world. The
incidence has been increasing constantly in the last 50 years. Fifty million dengue infections
across approximately 100 countries are reported annually and an estimated of 2.5 million
people are at risk in dengue endemic countries.
Dengue may develop in any warm, moist climate where transmitting mosquitoes
exist. In recent years, it has occurred epidemically in Hawaii, Philippines, Thailand, Malaysia,
Vietnam, southwest Pacific region, Indonesia and Africa. The infectious febrile disease
caused by the dengue virus is highly incapacitating. In epidemics of hemorrhagic types 3
and 4, it may cause high morbidity and even high mortality, especially in children. This
flavivirus is contracted from bites of infected mosquitoes, usually Aedes aegypti, but
occasionally other Aedes species.

In 2010, the Philippines recorded a large number of dengue cases during the first six
months of the year. Between January 1 and July 10 of that year, 29,000 cases were reported,
a 34.7% increase from report in the preceding year. The highest numbers were recorded in
Region VII (3,600), Region XII (3,400), Region IV-A (3, 100) and the NCR (2, 777).
In 2011, the Philippines ranked 4th in the list of Association of Southeast Asian
Nations (ASEAN) member-countries tormented by dengue.
The most recent report regarding dengue by the National Epidemiology Center of the
Department of Health stated that a total of 6, 457 dengue cases was reported to different
sentinel hospitals nationwide from January 1 to February 2012 which is 52.93% lower
compared to the same time period last year. Most of the cases were from Region III
(28.59%), NCR (24.89%) and Region IV-A (16.6%). (Figure 3). There were thirty-five deaths
(CFR 0.54%) reported. Reported cases with CFR greater than 1 came from Regions II, VI, VII
and CARAGA.

ETIOLOGY

Dengue viruses are mosquito-borne viruses which exist in nature as four separate
serotypes types 1, 2, 3 and 4. These viruses are enveloped ribonucleic acid (RNA)
arboviruses belonging to the family Flaviviridae. All Flaviviruses share at least one common
antigen on the surface of the virus particle which serves to link these virus together as a
serological group
The Dengue virus is efficiently transmitted in an urban cycle which involves man and
Aedes aegypti, a day-biting species which often breeds in clean water stored in houses.
Other species such as Aedes albopictus has also been implicated.
Following an incubation period of 4 to 6 days, the virus is present in the blood of patients
during the acute phase of the disease and will become a reservoir of virus, accessible to
mosquitoes which may then transmit the disease.
TRANSMISSSION

The vectors of dengue in the Philippines include Aedes aegypti, which is associated
with urban dengue and Aedes albopictus, which is associated with rural dengue. There is a
widespread distribution of these vectors in the Philippines.

Aedes aegypti
This is primarily known as the tiger mosquito. It is black in color and small to
medium in size. It has characteristic lyre-shaped, silvery markings on its mesonotum. The
fore and mid-pairs of legs have white narrow bands at the base of the tarsi. The hind pair of
legs have five broad white bands, hence the name tiger mosquito.
This mosquito breeds in clear water collecting in indoor and outdoor containers such as old
tires, vases, jars and bottles.
The mosquito becomes infected only during the first 3 days of the patient's illness
and is not infective for man in until after an 11-day incubation period. However, the interval
can be as short as 8 days. Once the mosquito reaches the infective stage, it is infective until
it dies. The virus is found in all of its tissues, but human infection typically occurs when the
mosquito injects saliva into the skin.

Aedes albopictus
The most important diagnostic characteristic of this mosquito is the presence of a
single, longitudinal, silvery stripe on the mesonotum.
This mosquito breeds in clear water collecting in indoor and outdoor containers such
as bamboo stumps, empty coconut shells, some artificial containers and tree holes. It is not
unusual, therefore, to see both Aedes species sharing a common both.

Man is the main reservoir of the virus. After feeding on a person whose blood
contains the virus, the female Aedesaegypti can transmit dengue either immediately, by a
change of host when its blood meal is interrupted or after an incubation period of 9 to 10
days, during which time the virus multiplies in the salivary glands.

The illustration at the left shows

infection of a mosquito vector by
the Dengue virus and inoculation
of the latter into the human body.
LIFE CYCLE OF THE MOSQUITO VECTOR

Female mosquitoes lay their eggs on the inner, wet walls of containers with water.
Larvae hatch when water inundates the eggs as a result of rains or the addition of water by
people. In the following days, the larvae will feed on microorganisms and particulate organic
matter, shedding their skins three times to be able to grow from first to fourth instars. When
the larva has acquired enough energy and size and is in the fourth instar, metamorphosis is
triggered, changing the larva into a pupa. Pupae do not feed; they just change in form until
the body of the adult, flying mosquito is formed. Then, the newly formed adult emerges from
the water after breaking the pupal skin (picture 4, inset). The entire life cycle lasts 8-10 days
at room temperature, depending on the level of feeding. Thus, there is an aquatic phase
(larvae, pupae) and a terrestrial phase (eggs, adults) in the Aedes aegypti life-cycle.
Their eggs can withstand desiccation for several months, which means that even if all
larvae, pupae, and adults were eliminated at some point in time, repopulation will occur as
soon as the eggs in the containers are flooded with water. Unfortunately, there is no
effective way to control the eggs in containers.

At the left is a concise

illustration of the stages that
occur in the life cycle of
Aedes aegypti with the
approximate number of days
to complete each stage.

PATHOGENESIS

The dengue virus probably penetrates into all tissues of the human body but has
special predilection for parynchymatous organs and the endothelium of blood capillaries. By
toxic action, it produces degenerative changes of the cells and hemorrhage.

CLINICAL MANIFESTATIONS

Manifestations vary with age and from patient to patient. In infants and young
children, the disease may be undifferentiated or characterized by a 1 5 days fever,
pharyngeal inflammation, rhinitis and mild cough.
After an incubation period of 1 7 days, there is sudden onset of fever, which rapidly
rises to 39.4 41.1C (103 - 106F), usually accompanied by frontal or retro-orbital
headache. Occasionally, back pain precedes the fever. A transient, macular, generalized
rash that blanches under pressure may be seen during the first 24 48 hours of fever. The
pulse rate may be slow relative to the degree of fever. Myalgia or arthralgia occurs soon
after the onset and increases in severity. From the 2nd 6th days of fever, nausea and
vomiting are apt to occur and generalized lymphadenopathy, cutaneous hyperesthesia or
hyperalgesia, taste aberrations and pronounced anorexia may develop.
One to 2 days after defervescence, a generalized, morbilliform, maculopapular rash
appears which spares the palms and soles. It disappears in 1 5 days; desquamation may
occur. Rarely, there is edema of the palms and soles. About the time the second rash
appears, the body temperature, which has previously fallen to normal, may become slightly
elevated and establish the biphasic temperature curve.
Epistaxis, petechiae and purpuric lesions are uncommon but may occur at any stage.
Swallowed blood from epistaxis, vomited or passed by rectum, may be erroneously
interpreted as gastrointestinal bleeding. In adults and possibly in children, underlying
conditions, together with a dengue-induced hemorrhagic diathesis, may lead to clinically
significant bleeding. Convulsions may occur during high fever.
Infrequently, after the febrile stage, prolonged asthenia, mental depression,
bradycardia and ventricular extrasystoles may occur in children.

DENGUE GRADING
The severity of DHF is categorized into four grades:
Grade I without overt bleeding but positive for tourniquet test
Grade II with clinical bleeding diathesis such as petechiae, epistaxis and
hematemesis.
Grade III circulatory failure manifested by a rapid and weak pulse with narrowing
pulse pressure (20mmHg) or hypotension, with the presence of cold clammy skin and
restlessness
Grade IV profound shock in which pulse and blood pressure are not detectable. It is
note-worthy that patients who are in threatened shock or shock stage, also known as
dengue shock syndrome, usually remain conscious.
Grade III and IV are considered to be Dengue Shock Syndrome.

DENGUE HEMORRHAGIC FEVER / DENGUE SHOCK SYNDROME

Individuals who were previously infected with a different serotype of the dengue virus
may acquire a more severe syndrome which is dengue hemorrhagic fever/dengue shock
syndrome (DHF/DSS). Affected individuals are usually children since they have less
developed immune defenses. Usually, initial symptoms simulate normal dengue and later in
the disease the patients condition worsens.

Induction of shock as well as vascular permeability in Dengue depends on the following

factors:
o Presence of enhancing and nonneutralizing antibodies- Transplacental maternal
antibody may be present in infants < 9 months old, or antibody elicited by previous
heterologous dengue infection may be present in older individuals. T cell reactivity is
also intimately involved.
o Age- susceptibility to DHF/DSS drops considerably after 12 years of age.
o Sex- females are more often affected than males.
o Race- Caucasians are more often affected than Blacks.
o Nutritional Status- Malnutrition is protective
o Sequence of Infection- Example, serotype 1 followed by serotype 2 seems to be more
dangerous than serotype 4 followed by serotype 2.
o Infecting serotype-Type 2 is more dangerous than other serotypes.

As mentioned, early symptoms of DHF/DSS are similar to those of Dengue fever, but
after several days the patient becomes irritable, restless, and sweaty. These symptoms are
followed by a shock-like state. Bleeding may appear as tiny spots of blood in the skin
(petechiae) and larger patches on the skin (ecchymoses). Shock may cause death and if the
patient survives, recovery begins after a one-day crisis period.

IMMUNITY

Dengue infection results in long-term immunity to the infecting virus serotype and
short-lasting immunity to heterologous serotypes.
Six months or more following infection with a single dengue serotype, humans are
fully susceptible to infections with a different serotype. Such infections are referred to as a
secondary infection. Secondary dengue infections are accompanied by a group-specific IgG
antibody response.

LABORATORY TESTS

There are virologic and serologic test methods for establishing a laboratory diagnosis
of dengue infections
Virologic tests include isolation of the virus and molecular technology using polymerase
chain reaction (PCR).
The following are the five basic serologic tests which are routinely used for
diagnosing of dengue infection:

Hemagglutination-inhibition (HI) most frequently used for routine serology; it is

sensitive, easy to perform, requires only minimal equipment, is very reliable if
properly done; best test for basic serology for flaviviruses
Complement fixation (CF) less widely used
Plaque reduction (NT) cannot be employed routinely by most laboratories
because of the expense and technical difficulty
IgM-capture enzyme-linked immunosorbent assay (MAC-ELISA) MAC-ELISA is
simple, rapid test that requires very little sophisticated equipment but is slightly less
sensitive than the HI
Indirect ELISA IgG-capture ELISA has also been developed but has not been very
useful in the diagnostic laboratory; it is a very insensitive test, primarily because of
competition of IgG binding sites by large quantities of nonspecific IgG

Recently, immunoblot test in the form of dengue blot has been developed as rapid
test
Using HI as the gold standard, validity testing showed that Dengue Blot is very sensitive in
the diagnosis of secondary dengue disease but has very low sensitivity in the diagnosis of
primary dengue infection. Therefore, this test cannot be relied upon if the patient has the
first dengue episode.

LABORATORY FINDINGS

Pancytopenia may occur on the 3rd to 4th days of illness; neutropenia may persist or
reappear during the latter stage of the disease and may continue into convalescence. White
cell counts as low as 2,000/mm3 has been recorded. Platelets rarely fall below 100,000 cells/
mm3. Venous clotting, bleeding and prothrombin times and plasma fibrinogen values are
within normal ranges. The tourniquet test infrequently is positive. Classic dengue
hemorrhagic fever-dengue shock syndrome may occur in infants born to dengue-immune
mothers.

MANAGEMENT
 Treatment is supportive. Bed rest is advised during the febrile period. Antipyretics or
cold sponging should be used to keep body temperature below 40C (104F). Analgesics or
mild sedation may be required to control pain. Because of its effects on hemostasis, aspirin
should not be used. Fluid and electrolyte replacement is required when there are deficits
caused by sweating, fasting, thirsting, vomiting or diarrhea.

PROGNOSIS

Primary infections - usually self-limited and benign. Complications in infants and young
children are fluid and electrolyte losses, hyperpyrexia and febrile convulsions. For the large
majority of people infected, the prognosis is excellent, although they are likely to feel very ill
during the first one or two weeks of the acute illness and weak for about one month. Also,
people who have been infected by one dengue viral serovar are still able to be infected by
the remaining three serovars; a second infection increases the possibility that complications
will develop so patients with second-time dengue fever have a less optimal prognosis.
DHF and DSS have about 50% fatality rate if untreated but about a 3% rate if treated
with supportive measures. Overall fatality rate is 1% of all dengue fever infections.
500,000 to 1 million people die each year from dengue fever. This is a concern
worldwide because case numbers and outbreaks are increasing.

PREVENTION AND CONTROL

The greatest concern is the development of an ideal dengue vaccine:

tetravalent
acceptable immunogenicity and cold chain maintenance
inexpensive especially for the developing countries
Under study are live attenuated vaccine, live vectored vaccine, protein subunit vaccine
and killed whole-virus vaccine.
Meanwhile, focus should be sustained on the mosquito vector and its control.
Emergency control measures are based on insecticide applications. This is a weak
approach to vector control. It is essential to monitor vector susceptibility to insecticides
widely used for control operations as there have been reports of resistance and tolerance.

Long-term control should be based on health education and community participation:

Standing water in the household and premises should be properly drained. Flower
vases, empty tine, old tires and other receptacles in the yard are good breeding
places of mosquitoes.
Participate by undertaking the disposal of all unused objects that may collect water
and by routinely changing the water in containers.
Water jars and drums that cannot be disposed should be adequately covered to
prevent egg-laying by mosquitoes or cleaned and scrubbed weekly.

Prophylaxis:
use of insecticides, repellants, body covering with clothing, screening of houses and
destruction of Aedes aegypti breeding sites.
Water storage use a tight-fitting lid or a thin layer of oil may prevent egg laying or
hatching.
A larvicide, such as Abate [O,O (thiodi-p-phenylene) O,O,O,O
tetramethylphosphorothiote], available as a 1% sand-granule formation and effective
at concentration of 1 part/million may be added safely to drinking water.
Only personal mosquito measures are effective against mosquitoes in the field, forest
or jungle.

UPDATE
 There is currently no vaccine to protect against dengue, and efforts to develop one have been hampered by
the fact that dengue is not caused by a single virus, but rather four different related viruses (known as DENV 1, 2, 3
and 4), making development of an effective vaccine considerably more complicated than for some viral diseases.
Furthermore, the disease appears to be unique to humans, meaning that scientists cannot use animal models to test
prospective vaccine candidates.
Researchers based in France and Thailand tested the effectiveness of a vaccine candidate called CYD-TDV
on a group of 4002 schoolchildren in Thailand, aged from four to eleven years old. The trial took place in Thailand
because dengue is known to be endemic in this area, and local residents have a good awareness of the disease and
its symptoms.
2669 children were given the CYD-TDV vaccine, and 1333 given a placebo. Overall, there was no
statistically significant difference between the number of dengue cases recorded in the vaccine (76 cases or 2.8% of
the vaccine group) and control groups (58 cases or 4.4% of the control group). However, secondary tests showed
that the vaccine was effective against DENV 1, 3 and 4 (in the range of 60 to 90%), with only DENV 2 appearing to
be resistant to the effects of the vaccine in this trial. Furthermore, CYD-TDV appears to be safe and well-tolerated,
with no vaccine-related serious adverse events being reported in the group who received it.
While the scientists point out that the phase 2b trial is limited by the fact that it was conducted in a single
geographical area, the results nonetheless represent a substantial advance in the development of a vaccine for
dengue. Further trials of CYD-TDV are currently underway in a number of different countries.
Dr Scott Halstead of the International Vaccine Institute in Seoul, said: "Results from this vaccine trial provide
hard evidence of protection against DENV 1, 3 and 4 mild disease but insufficient data to calculate vaccine efficacy
rates for severe disease.
References:
Books

Journal
http://medicalxpress.com/news/2012-09-scientists-dengue-vaccine-
breakthrough.html