DENGUE

FEVER
 Arboviruses

 The Arboviruses are also called as Arthropod

borne viruses, represent an ecological grounding
of viruses with complex transmission cycles
involving Arthropods
 These viruses have diverse physical and chemical
properties and are classified in several virus
families.
 Dengue infection is caused by Arboviruses
 History Dengue
 This disease was first described 1780, and the
virus was isolated by Sabin 1944. Dengue virus
infection is the most common arthropod-borne
disease worldwide with an increasing incidence
in the tropical regions of Asia, Africa, and
Central and South America. There are four
serotypes of the virus. All are transmitted by
mosquitoes, which are not affected by the
disease, although an infected mosquito may
infect others (not via man).
 Current Trends
 In the 1980s, DHF began a second expansion
into Asia when Sri Lanka, India, and the
Maldives Islands had their first major DHF
epidemics; Pakistan first reported an epidemic of
dengue fever in 1994. The epidemics in Sri
Lanka and India were associated with multiple
dengue virus serotypes, but DE N-3 was
predominant and was genetically distinct from
DEN-3 viruses previously isolated from infected
persons in those countries.
Prevalence of Dengue Infection
 Dengue Infection and
Implications
 Dengue virus (DENV) infects 50 million
(WHO) to 100 million (NIH) people annually.
Forty percent of the world’s population,
predominately in the tropics and sub-tropics, is
at risk for contracting dengue virus. DENV
infection can cause dengue fever, dengue
hemorrhagic fever, dengue shock syndrome, and
death.
 Dengue
Mosquito traanmitted Viral
Infection
 What causes Dengue
 Dengue (DF) and dengue hemorrhagic fever
(DHF) are caused by one of four closely related,
but antigenically distinct, virus serotypes
(DEN-1, DEN-2, DEN-3, and DEN-4), of the
genus Flavivirus. Infection with one of
these serotypes provides immunity to only
that serotype for life,
 Aedes aegypti – Vector

 Aedes aegypti, a domestic, day-biting mosquito

that prefers to feed on humans, is the most
common Aedes species. Infections produce a
spectrum of clinical illness ranging from a
nonspecific viral syndrome to severe and fatal
hemorrhagic disease. Other species of Aedes can
also transmit.
 Dengue Virus – A

Flavivirius
Flavivirius are spherical and
40- 60 mm in diameter.
Genome – Positive sense,
single sense RNA,11kb
size
in
Genome – RNA infectious
Enveloped virus
Three structural polypeptides
two are glycosylated
Replication in cytoplasam
How Mosquitos spread the infection

 The disease starts during the rainy season, when

vector Mosquito Aedes aegypti is abundant
 The Aedes breeds in the tropical or semitropical
climates in water holding receptacles or in plants close
to human dwellings
 A female Aedes acquires the infection feeding upon a
viremic human.
 After a period of 8 – 14 days mosquitoes are
infective and remain infective for life. ( 1- 3 )
months.
 Dengue - Endemics
 Persons living in a dengue-endemic area
can have more than one dengue infection
during their lifetime. DF and DHF are
diseases of tropical and sub tropical areas, and
primarily
the four different dengue serotypes are
maintained in a cycle that involves humans and
the Aedes mosquito.
 Clinical Manifestations
 Any or few of the following events can
occur.
 Fever,
 Severe head ache
 Muscle and joint pains
 Nausea, vomiting,
 Eye pain
 How Dengue Infection starts and
manifests
 Incubation period 4 – 7 days ( 3 – 14 days)
 Fever may start with, Malise,chills,head
 ache
Soon leads to severe back ache, joint pains, muscular pain, pain
 Temperature may persist for 3 -5 days.
in the eye ball.
 On some occasions once again raises in about 5 – 8 days ( Saddle
back fever )
 Myalgia may be severe with deep bone pain
( Break bone fever ) characteristic of the Disease
On majority of the occasions a self limited
condition, Subside on its own
Death is a rare event.
Dengue with Rashes
 Dengue Hemorrhagic
Fever
 Common in children.
 In children passively acquired contributed by
the maternal antibodies transferred to the fetus.
 In other ( Adults ) the presence of antibodies
due to previous infection with different
serotype
 Initially presents like classical Dengue infection
 But patients condition abruptly worsen s, an
important cause of morbidity and mortality in
Dengue
 Risk factor for
DHF
 Important risk factors for DHF include the
strain of the infecting virus, as well as the age,
and especially the prior dengue infection history
of the patient
Dengue Hemorrhagic Syndrome
 Chateresied by shock and hemoconcentration
 Contributed by circustantial evidence suggests
secondary infection with Dengue type 2
following type 1 infection in the past.
 Pathogenesis

 Presence of existing Dengue antibody,

associated with fresh viral infection with new
serotype complexes and forms within few days
of the second dengue infection.
 Non neutralizing enhancing antibodies
promote infection of higher number of
Mononu clear cells.
Dengue hemorraghigic
Syndrome
DHS is caused due to release of,
1 Release of cytokines
2 Vasoactive mediators.
3 Procoagulants
Manifest with
disseminated
intravascular coagulation
 Risk of Hemorrhagic Fever
 The risk of hemorrhagic fever syndrome is about
0.2% during the first attack
 The second attack with different serotype increases the
risk to ten fold
 The fatality rate with dengue hemorrhagic fever can
reach 15% but proper medical care and symptomatic
mangement can reduce mortality to less than 1%
 On few occasions patients condition abruptly worsens
into Dengue shock syndrome, a more severe form of
disease characterized by shock and
hemoconcentration.
 Diagnosis
In resource rich establishments
1 Reverse transcriptase polymerase chain
reaction methods help rapid identification
2 Isolation of virus is difficult
3The current favored approach is inoculation of
mosquito cell line with patient serum coupled
with nucleic acid assay to identify a recovered
virus.
 Dengue Serology
 The serology is limited with cross reactivity of
IgG antibodies to heterologus Flavivirius antigens
 Most commonly used methods are

Viral protein specific capture IgM or IgG by ELISA

IgM antibodies develop within few days of illness
Neutralizing anti Hemagglutination inhibiting antibodies
appear within a week after onset of Dengue fever
Importance of paired sample testing
in Serology

 Testing one sample for serum and reporting a

negative test is fallacious
 Analysis of paired acute and
convalescent sera to show significant
rise in antibody titer is the most
reliable evidence of an active dengue
infection.
 Newer Diagnostic Methods
RT - PCR

 RT PCR is a highly
sensitive tool in
Diagnosis, with
established high
sensitivity in Diagnosis in
Puzzles
 Developing world lacks
resources to
implement and utilize
the Scientific advances
 Immunology Dengue

 Four serotypes exist distinguished by Molecular

basis and Nt tests
 Infection confers life long immunity
 But cross protection between serotypes is of
short duration.
 Reinfection with different serotype after primary
attack is more dangerous causes Dengue
hemorrhagic fever.
 Treatment
 No Anti viral therapy available
 Symptomatic management in Majority of
cases
 Dengue Hemorrhagic fever to be treated
with suitable fluid replacement
 No Vaccine available, difficult in view of four
serotypes.
 Control of Dengue
 Control of Mosquito breeding places.
 Anti mosquito measures
 Use of Insecticides.
 Screened windows and doors can reduce
exposure to vectors.
 Epidemiology - Dengue
 Dengue virus are distributed world wide in
tropical regions.
 Where the Aedes vectors exist, are endemic
areas
 Changing and increasing incidences are
associated with rapid urban population
growth, over crowding and lax mosquito
control measures
Dengue a Reemerging Infection

 Dengue in 2005 identified as the most important

mosquito borne viral disease
 An estimated 50 million or more cases occur
annually worldwide
 400,000 cases of dengue hemorrhagic fever.
 Asian counties report major cases of childhood
deaths
 Malaria

The word “malaria” comes from the Italian mala

aria, meaning “bad air.” When the term was
coined, it was commonly believed that malaria was
caused by breathing in bad air.
 Malaria

Malaria is a mosquito-borne parasitic disease

caused by genus Plasmodium, affecting over 100
countries of the tropical and subtropical regions of
the world.
Around 400-900 million people are affected
At least 2.7 million deaths annually.
It is one of the major public health concerns
 Epidemiology
Around 300-500 million clinical cases of malaria
are reported every year, of which more than a
million die of severe and complicated cases of
malaria.
 Malaria is known to kill one child every 30 sec,
3000 children per day under the age of 5 years.
 Malaria ranks third among the major infectious
diseases in causing deaths after pneumococcal
acute respiratory infections and tuberculosis, and
accounts for approximately 2.6% of the total
disease burden of the world.
 Epidemiology

It mainly occurs throughout tropical regions

515 million clinical cases per year
An estimated 655,000 people died from malaria
in 2010
with two-thirds of these occurring in sub-
Saharan Africa
especially amongst children and pregnant women
the incidence of malaria was greatly reduced
between 1950 and 1960
but since 1970 there has been resurgence.
 People at risk

Most people who get malaria are travelers or

people who live in an area with malaria
transmission.
 Young children and pregnant women.
 Poor people that live in rural areas who lack
knowledge, money and the access to health care.
 Causative Agent

Malaria is caused by species of Plasmodium. The

genus Plasmodiumcontains over 200 species  at
least 11 species infect humans. Most important are:
 Plasmodium falciparum  Plasmodium
malariae  Plasmodium ovale  Plasmodium
vivax  Plasmodium knowlesi
 Causative Agent

Plasmodiumparasites are highly specific with

female Anopheles mosquitoes
Causative Agent
Female mosquitos of genus Anopheles are
primary hosts and transmission vectors.
There are approximately 460 recognized species
Over 100 can transmit human malaria
Only 30–40 commonly transmit parasites of the
genus Plasmodium
Anopheles gambiae is one of the best known
which transmits Plasmodium falciparum Vector
 Life Cycle & Pathogenesis
Inside the vector (sexual reproduction):  Young female mosquitoes
ingest the malaria parasite by takinga blood meal from aninfected
human carrier  The ingested gametocytes will differentiate into
male and female gametes and then unite to form a zygote (ookinete)
in the mosquito’s gut  The resulting ookinete penetrates the gut
lining to form an oocyst in the gut wall  The oocyst ruptures to
release sporozoites that migrate in the mosquito’s body to the
salivary glands and are ready toinfect new human hosts
Life Cycle & Pathogenesis

Inside humans: Malaria develops via two phases: 
Exoerythrocytic: involves infection of liver  Erythrocytic phase:
involves infection of RBC (erythrocytes)
Life Cycle & Pathogenesis
 Life Cycle & Pathogenesis

Inside humans: Malaria develops via two phases:

 Exoerythrocytic: involves infection of liver 
Erythrocytic phase: involves infection of RBC
(erythrocytes)
 Life Cycle & Pathogenesis

A mosquito infects a person by taking a blood meal. First,

sporozoites enter the bloodstream, and migrate to the liver. They
infect liver cells (hepatocytes), where they multiply into merozoites,
rupture the liver cells, and escape back into the bloodstream.
Then, the merozoites infect red blood cells, where they develop
into ring forms, trophozoites and schizonts which in turn produce
further merozoites. Sexual forms (gametocytes) are also produced,
which, if taken up by a mosquito, will infect the insect and continue
the life cycle.


 Clinical Features

P. falciparum (malignant tertian): It is the most dangerous of the

malarias Onset is insidious, with malaise, headache and
vomiting… commonly mistaken for influenza The fever has no
particular pattern. Jaundice is common due to hemolysis &
hepatic dysfunction There is hepatosplenomegaly Anemia
develops rapidly
P. falciparum complications:  Cerebral Malaria: the most grave
complication, causing either confusion or coma without localizing
signs.  Convulsions  Hypoglycemia  Acute pulmonary edema 
Acure renal failure (Blackwater fever )  Metabolic acidosis 
Aspiration pneumonia  Severe anemia 
Coagulopathy/Spontaneous bleeding
 Causes of severe malaria

P. falciparum-infected erythrocytes sequester in blood vessels,

creating blockages.
 Infected erythrocytes also “stick to endothelium, platelets, and
other erythrocytes”  Rosetting-- cohesion of erythrocytes
 Leads to immune evasion because of lack of circulation through
the spleen.
 Aids in the progression of the severity of malaria
 Clinical Features

P. vivax & P. ovale (benign tertian): In many cases the illness starts
with several days of continued fever before the development of
classical bouts of fever on alternate days. Fever starts with a rigor.
The patient feels cold and the temperature rises to about 40 C. After
an hour hot or flush phase begins. It lasts several hours and gives
way to profuse perspiration and a gradual fall in temperature. The
cycle is repeated 48 hours later. Anemia develops slowly
 Clinical Features

P. malariae infection (quartan): This is usually

associated with mild symptoms and bouts of fever every
third day. Parasitemia may persist for many years with the
occasional recurrence of fever, or without producing any
symptoms.
 Hypnozoites

It is the round or oval, uninucleate, dormant

form of Plasmodium seen inside the liver cells
during the intrahepatic (exoerythrocytic) stage of
the parasite’s life cycle; it is believe to be the true
latent stage associated with relapse in malaria.
Hypnozoites are seen in:  Plasmodium vivax 
Plasmodium ovale
 Diagnosis

Clinical  Fever, sweat, chills, headache and muscle pain  Serology

 PCR  ELISA  Blood Film (gold standard)  Banana-shaped
intraerythrocyticgametocytes identify P. falciparum  Enlarged
erythrocytes with Schuffner’sdots are characteristics of P. vivax 
Schuffner’sdots in ovale-shaped red blood cells are characteristic of
P. ovale  Band-form trophozoitesare seen in P. malariae
 Prevention

Medications (will be mentioned in treatment)

Vector control Mosquito nets and bedclothes
Immunity (natural & vaccines) Education
 Vector Control

Efforts to eradicate malaria by eliminating mosquitoes have been

successful in some areas. Malaria was once common in the United
States and southern Europe, but vector control programs, in
conjunction with the monitoring and treatment of infected humans,
eliminated it from those regions. Malaria was eliminated from
most parts of the USA in the early 20th century by use of the
pesticide DDT.
 Mosquito nets

 Mosquito nets help keep mosquitoes away from people

and greatly reduce the infection and transmission of
malaria. The nets are not a perfect barrier and they are
often treated with an insecticide designed to kill the
mosquito before it has time to search for a way past the
net. Insecticide-treated nets (ITNs) are estimated to be
twice as effective as untreated nets and offer greater than
70% protection compared with no net. Since the
Anopheles mosquitoes feed at night, the preferred method
is to hang a large "bed net" above the center of a bed such
that it drapes down and covers the bed completely.
 Treatment

When properly treated, a patient with malaria can expect a

complete recovery. The treatment of malaria depends on the severity
of the disease; whether patients can take oral drugs or must be
admitted depends on the assessmentand the experience of the
clinician.  Uncomplicated malaria is treated with oral drugs. The
most effective strategy for P. falciparum infection recommended by
WHO is the use of artemisinins in combination with other
antimalarials artemisinincombination therapy, ACT, to avoid the
development of drug resistance against artemisinin-based therapies.
 Treatment

Severe malaria requires the parenteral administration of

antimalarial drugs. Until recently the most used treatment for severe
malaria was quinine but artesunate has been shown to be superior to
quinine in both children and adults. Treatment of severe malaria
also involves supportive measures.
 Infection with P. vivax, P. ovale or P. malariae is usually treated
on an outpatient basis. Treatment of P. vivax requires both
treatment of blood stages (with chloroquine or ACT) as well as
clearance of liver forms with primaquine.
Chemoprophylaxis
Antimalarial tablets Adult prophylactic Regimen
dose

Melloquine 250mg weekly Started 2-3 weeks before

travel and continued until
4 weeks after
or Doxycycline l00mg daily Started 1 week before and
continued until 4 weeks
after travel
Or Malarone 1 tablet daily From 1—2 days before
travel until 1 week after
return

Chloroquine 300mg base weekly Started 1 week before &

and proguanil 100-200mg daily continued until 4 weeks
after travel