Dengue

A Case
Presentation and
Recap of Dengue
Zehdi Eydou
Intern House Officer
Dubai Health Authority

Outline
• Dengue Fever
• Introduction
• Epidemiology
• Presentation/Diagnosis
• Management
• Complications
• Hemophagocytic Lymphohistiocytosis
• Definition
• Types
• Diagnostic Criteria
• Treatment

Introduction to
Dengue
• Dengue viruses are arboviruses from the
Flaviviridae family capable of infecting
humans and causing disease.
• The spectrum of clinical presentation ranges
from no symptoms to hemorrhages with
severe shock.
• The majority of cases of dengue infection
present as dengue fever, which is a self-
limiting disease.
A Case Presentation and Recap of Dengue 4

Epidemiology
• Dengue is found in tropical and subtropical regions around
the world, predominantly in urban and semi-urban areas.
• About 3.9 billion people in 128 countries are at risk of
infection with dengue viruses.
• A recent estimate indicates 390 million dengue infections
per year, of which 96 manifest clinically with any severity of
the disease.
• The number of reported cases in 2015 was 3.2 million.
• Worldwide, annually about 500,000 people with DHF
require hospitalization. Approximately 90 percent of them
are children aged less than five years, and about 2.5
percent of those affected die.

Epidemiological Determinants
Agent Factors Vector Factors
Environmental
Factors

Dengue
Virus
DENV1
DENV2
DENV3
DENV4

Dengue Virus
• Infection with any one serotype confers
lifelong immunity to that virus serotype.
• They elicit cross-protection for only a few
months after infection by anyone of them.
• Secondary infection with dengue serotype
2 or multiple infections with different
serotypes lead to severe form dengue
DHF/DSS.

Antibody-Dependent Enhancement
Increase in the replication of the virus and a higher risk of severe dengue (immunological
catastrophe)
The antibodies help the virus infect monocytes more efficiently
The Ab–virus complex attaches to receptors called Fcγ receptors (FcγR) on circulating monocytes
The antibodies from the primary infection do not neutralize the virus
Subsequent infection with a different dengue virus serotype
Primary infection with dengue virus (sensitization)

Antibody-Dependent Enhancement

Epidemiological Determinants
Agent Factors Vector Factors
Environmental
Factors

Vector
• The two most important vectors are Aedes
aegypti and Aedes Albopictus
• Both carry high vectorial competency for
dengue virus: high susceptibility to
infecting virus, ability to replicate the virus,
and ability to transmit the virus to another
host

Environmental Factors
• The population of Ae. aegypti fluctuates
with rainfall and water storage.
• Its life span is influenced by temperature
and humidity, and survives best between
16°C- 30°C and relative humidity of 60-80
percent.
• It breeds in the containers in and around
the houses.

Community
A number of factors contribute to the initiation
and
maintenance of an epidemic of dengue
• The strain of the virus, which may influence
the magnitude and duration of the viremia in
humans
• The density, behaviour, and vectorial capacity
of the vector population
• The susceptibility of the human population
(both genetic factors and pre-existing immune
profile)
• The introduction of the virus into a receptive

Dengue virus
infection
Asymptomatic
(majority of cases)
Symptomatic
Undifferentiated
fever (viral
syndrome)
Dengue fever
With hemorrhage
Without
hemorrhage
Expanded dengue
syndrome/isolated
organopathy
(unusual
manifestation)
Dengue
hemorrhagic fever
(DHF) (with plasma
leakage)
DHF non-shock
DHF with dengue
shock syndrome
(DSS)

Undifferentiated
Fever
• Infants, children, and adults who have been infected
with the dengue virus, especially for the first time, may
develop a simple fever indistinguishable from other viral
infections.
• Maculopapular rashes may accompany the fever or
may appear during defervescence.
• Upper respiratory and gastrointestinal symptoms are
common.

Dengue Fever
• All ages and both sexes are susceptible to dengue
fever.
• Children usually have a milder disease than adults.
• The illness is characterized by an incubation period of 3
to 10 days (commonly 5-6 days).
• The onset is sudden, with chills and high fever, intense
headache, and muscle and joint pains, which prevent all
movement.
• Within 24 hours retroorbital pain, particularly on eye
movements or eye pressure and photophobia develops.
• Other common symptoms include extreme weakness,
anorexia, constipation, altered taste sensation, colicky
pain, abdominal tenderness, dragging pain in the
inguinal region, sore throat, and general depression.

Dengue Fever CONT
• Fever is usually between 39 °C and 40 °C, and it is
typically followed by a remission of a few hours to 2
days (biphasic curve).
• Fever lasts for about 5 days, rarely more than 7 days,
after which recovery is usually complete although
convalescence may be protracted.
• The case fatality is exceedingly low.

Dengue Fever CONT
• The skin eruptions appear in 80 percent of cases during the
remission or during the second febrile phase, which lasts for
1- 2 days.
• The rash may be diffuse flushing, mottling, or fleeting pin-point
eruptions on the face, neck, and chest during the first half of
the febrile period.
• In addition, a conspicuous rash, that may be maculopapular
or scarlatiniform on the 3rd or 4th day may appear.
• It starts on the chest and trunk and may spread to the
extremities and rarely to the face. It may be accompanied by
itching and hyperaesthesia.
• The rash lasts for 2 hours to several days and may be
followed by desquamation.

Criteria for DF Probable diagnosis
• Acute febrile illness with two or more of the
following;
• Headache,
• Retro-orbital pain,
• Myalgia,
• Arthralgia/bone pain,
• Rash,
• Hemorrhagic manifestations,
• Leukopenia(WBC ≤ 5000 cells/mm3),
• Thrombocytopenia (platelet count < 150,000
cells/mm3),
• Rising hematocrit (5-10%);
• And one of the following:
• Supportive serology on single serum sample:
titer ≥ 1280 with haemagglutination inhibition
test, comparable IgG titer with enzyme-linked
immunosorbent assay, or testing positive in IgM
antibody test, and
• An occurrence at the same location and time as
confirmed cases of dengue fever.
Criteria for DF Confirmed diagnosis
• Probable case with at least one of the following :
• Isolation of dengue virus from serum, CSF, or
autopsy samples
• Fourfold or greater increase in serum lgG (by
hemagglutination inhibition test) or increase in lgM
antibody specific to dengue virus.
• Detection of dengue virus or antigen in tissue,
serum, or cerebrospinal fluid by
immunohistochemistry, immunofluorescence. or
enzyme-linked immunosorbent assay.
• Detection of dengue virus genomic sequences by
reverse transcription-polymerase chain reaction.

Dengue virus
infection
Symptomatic
Undifferentiated
fever (viral
syndrome)
Dengue fever
With hemorrhage
Without
hemorrhage
Expanded dengue
syndrome/isolated
organopathy
(unusual
manifestation)
Dengue
hemorrhagic fever
(DHF) (with plasma
leakage)
DHF non-shock
DHF with dengue
shock syndrome
(DSS)
Asymptomatic
(majority of cases)

Dengue Hemorrhagic Fever (DHF)
Febrile
phase
Critical
phase
Recovery
phase

DHF Febrile Phase
• Following an incubation period of four to six days, the
illness commonly begins abruptly with a high fever (up
to 40°C to 41°C) accompanied by facial flushing and
headache.
• Commonly associated symptoms include Anorexia,
vomiting, epigastric discomfort, tenderness at the right
costal margin, and generalized abdominal pain.
• During the first few days the illness usually resembles
classical DF.
• A maculopapular rash, usually rubelliform type, is less
common.

DHF Febrile Phase
• Plasma leakage and abnormal haemostasis,
manifested by a rising haematocrit value and
moderate to marked thrombocytopenia, are
unique and constant features of DHF.
• These two clinical laboratory changes
determine the severity of the disease in DHF
and differentiate it from DF.
• A positive tourniquet test is the most common
haemorrhagic phenomenon.

Torniquet Test
• The test is performed by:
• inflating a blood pressure cuff to a midpoint
between systolic and diastolic pressure for 5
minutes
• The test is considered positive when 10 or more
petechiae per 2.5 x 2.5cm (1-inch square) are
observed.
• In DHF, the test is usually a definite positive with 20
petechiae or more.

Febrile
phase
Critical
phase
Recovery
phase

DHF Critical Phase
• Around the time of defervescence, usually in
days 3-7 of illness, an increase in capillary
permeability and hematocrit may occur.
• This marks the beginning of a period of
significant plasma leakage that usually lasts
24-48 hours (critical phase).
• Leukopenia and thrombocytopenia usually
precede plasma leakage.
• Pleural effusion and ascites may be clinically
detectable.

DHF Dengue Shock Syndrome
• Shock happens when a critical volume of
plasma is lost through leakage.
• With prolonged shock, organ hypoperfusion
occurs resulting in organ dysfunction,
metabolic acidosis, and DIC.
• The resultant severe hemorrhage causes the
hematocrit to decrease in this phase. The
WBC may also increase.

Febrile
phase
Critical
phase
Recovery
phase

Recovery Phase
• A gradual reabsorption of fluid from the
extravascular compartment occurs in the 48-
72 hours after defervescence if the patient
survives the critical phase.
• The symptoms and general well-being
improve.
• Bradycardia and ECG changes are common
and generalized pruritis may develop.
• The hematocrit stabilizes and WBC starts to
rise before platelets.
• Excessive fluid therapy may precipitate CHF
or pleural effusions.

• All of the following:
• Acute onset of fever of two to seven days duration
• Hemorrhagic manifestations, shown by any of the
following: positive tourniquet test, petechiae, ecchymoses,
purpura, or bleeding from the mucosa, gastrointestinal
tract, injection sites, or other locations
• Platelet count ≤ 100,000 cells/mm3
• Objective evidence of plasma leakage due to increased
vascular permeability shown by any of the following:
• Rising hematocrit/hemoconcentration ≥ 20% from
baseline
• Evidence of plasma leakage such as pleural effusion,
ascites or hypoproteinemia/albuminemia
DHF Criteria

• Criteria for DHF as above with signs of shock
including :
• Tachycardia, cool extremities, delayed capillary
refill, weak pulse, lethargy, or restlessness, which
may be a sign of reduced brain perfusion
• Pulse pressure ≤ 20 mmHg with increased
diastolic pressure, e.g. 100/80 mmHg
• Hypotension by age, defined as systolic pressure
<80 mmHg for those aged <5 years, or 80 to 90
mmHg for older children and adults
DSS Criteria

Laboratory Diagnosis
Detection of the
virus/viral
components
Serological
response
• Viral isolation: mosquito/mosquito cell
culture inoculation
• Nucleic acid detection (RT-PCR and real
time RT-PCR)
• Antigen detection (NS1 Ag rapid tests and
ELISA)
• Paired sera (acute serum days 1-5 and
second serum days 15-21): IgM or IgG
seroconversion by ELISA,
hemagglutination assay, or neutralization
• Serum after day 5 (IgM or IgG detection):
ELISA, rapid tests, or hemagglutination
assay

Management:
Grading the Severity
of Dengue Infection
35
A Case Presentation and Recap of Dengue

DF
•Fever with two or more of
the following: headache,
retro-orbital pain, myalgia,
arthralgia, rash, or
hemorrhagic
manifestations and no
evidence of plasma
leakage
Labs: leukopenia (≤ 5000
cells/mm3)
thrombocytopenia
(<150,000 cells/mm3),
and/or rising hematocrit
(5-10 percent)
WHO Grade I (DHF)
Above criteria and
hemorrhagic
manifestations plus
positive tourniquet test
and evidence of plasma
leakage
Labs: thrombocytopenia
(< 100,000) and
hematocrit rise 20% or
more
WHO Grade II (DHF)
Above criteria plus some
evidence of spontaneous
bleeding in skin or other
organs (black tarry stools,
epistaxis, bleeding from
gums, etc) and abdominal
pain
Labs: as above
WHO Grade III (DHF with DSS)
Above criteria plus
circulatory failure (weak
rapid pulse, pulse
pressure: 20 mmHg, or
high diastolic pressure,
hypotension with the
presence of cold clammy
skin, and restlessness)
Labs: as above
WHO Grade IV (DHF
with DSS)
Above criteria plus
profound shock with
undetectable blood
pressure or pulse
Labs: as above

Management
Dengue
Fever
DHF
Grades
I and II
DHF
Grades
III and IV

Tolerating oral intake of fluids, passing urine q6hr, and no
warning signs
Stable hematocrit:
send home
Encourage
ORS/fruit juices
Give paracetamol
PRN q6hr
Avoid ibuprofen and
other NSAIDs due
to risk of gastritis
and bleeding
Bring back if any of
the following occur:
• No clinical improvement
• Deterioration around the
time of defervescence,
severe abdominal pain
• Persistent vomiting,
• Cold and clammy
extremities, lethargy, or
irritability/restlessness
• Bleeding (e.g. black
stools or coffee-ground
vomiting)
• Not passing urine for
more than 4-6 hours.

Management
Dengue
Fever
DHF
Grades
I and II
DHF
Grades
III and IV

Management
DHF Grades I
and II
Dengue
Fever
DHF
Grades
III and IV

Initiate IV crystalloids 6
mL/kg/hr for 1-2 hr and
check Hct
Improvement: continue
IVF for 2-4 hr
Reduce to 3 mL/kg/hr for
2-4 hr
Reduce to 1.5-3 mL/kg/hr
for 2-4 hr
Stop IVF with further
improvement
No improvement
Hct rises
Increase IV to 10
mL/kg/hr for 2 hr
Check Hct
Hct falls: suspect internal
hemorrhage
Blood transfusion of 10
mL/kg whole blood or 5
mL/kg pRBC
IVF with crystalloids
reducing the flow from 10
to 3 mL/kg/hr and
discontinuation after 24-
48 hr

Management
DHF Grades I
and II
Dengue
Fever
DHF
Grades
III and IV

Management
DHF Grades
III and IV
DHF
Grades
I and II
Dengue
Fever

Compensated
shock
IV crystalloids 10-
20 mL/kg/h for 1
hr
Improvement
Reduce IVF over
5-10 hr to reach
1.5-3 mL/hr
Discontinue IVF
with further
improvement
No improvement Check Hct
Rising or >45% Continue IVF
Falling: suspect
bleeding
Blood
transfusion/ABCS
/IV inotropes

Profound shock
IV crystalloid
bolus 10-20
mL/kg over 15-30
min
Improvement
Reduce IVF over
5-10 hr to reach
1.5-3 mL/hr
Discontinue IVF
with further
improvement
No improvement
Repeat IV
crystalloids/colloid
s bolus; check Hct
Hct rising or
>45%
Continue IVF
Hct falling:
suspect bleeding
Blood
transfusion/ABCS
/IV inotropes

Complications:
Hemophagocytic
Lymphohistiocytosis
46
A Case Presentation and Recap of Dengue

Definition
• A rare but potentially fatal disease of normal
but overactive histiocytes and lymphocytes
that commonly appears in infancy
• The pathologic hallmark is the aggressive
proliferation of activated macrophages and
histiocytes, which phagocytose RBCs, WBCs,
and platelets, leading to the clinical symptoms
• Rapid diagnosis and early treatment are
crucial

Types
• Primary HLH is an inherited form, which is a
heterogeneous autosomal recessive disorder
• Secondary (acquired) HLH occurs after strong
immunologic activation, such as that which
can occur with systemic infection,
immunodeficiency, or underlying malignancy
• Both forms are characterized by the
overwhelming activation of normal T
lymphocytes and macrophages, invariably
leading to clinical and hematologic alterations
and death in the absence of treatment

Secondary HLH
• Epstein-Barr virus is the pathogen that most
commonly triggers infection-associated HLH
• Although unusual, HLH may be a complication
of dengue and scrub typhus

Histiocyte
Society
Diagnostic
Criteria for
HLH
•Fever: seven or more days of a
temperature as high as 38.5°C
(101.3°F)
•Splenomegaly: a palpable spleen
greater than 3 cm below the costal
margin
•Cytopenia: counts below the specified
range in at least 2 of the following cell
lineages
•ANC < 1000/µL
•Platelet count < 100,000/µL
•Hgb < 9.0 g/dL
•Hypofibrinogenemia or
hypertriglyceridemia
•Fibrinogen < 1.5 g/L or > 3 SDs below the
age-adjusted reference range
•Fasting triglycerides > 2 mmol/L or > 3 SDs
above the age-adjusted reference range
•Hemophagocytosis: must have tissue
demonstration from lymph node,
spleen, or bone marrow without
evidence of malignancy

Other Labs
• Ferritin may be observed as a marker for HLH,
with the serum levels paralleling the course of
the disease.
• Liver damage may also occur, as evidenced
by hyperbilirubinemia, hypoalbuminemia, and
elevated findings on liver function tests
including AST and ALT.

Treatment
• Initial therapy in patients consists of etoposide
and dexamethasone for 8 weeks in varying
doses
• Antineoplastic agents: etoposide and
methotrexate
• Corticosteroids: dexamethasone
• Immunosuppressants: cyclosporin
• Immunomodulators: emapalumab
• IV immunoglobulins

References
• Park K. Arthropod-borne infections. In: Parks Textbook of Preventive
and Social Medicine. 25th edn. Jabalpur: M/S Banarsidas Bhanot
Publishers. 2014. Pp. 269–279.
• Scriptable by Nature Education. Host Response to the Dengue Virus.
2014. Available from: https://www.nature.com/scitable/topicpage/host-
response-to-the-dengue-virus-22402106/ [accessed 20 Sep 2022].
• Schwartz RA. Lymphohistiocytosis (Hemophagocytic
Lymphohistiocytosis). In Coppes MJ (ed), Medscape. 2021. Available
from: https://emedicine.medscape.com/article/986458-overview
[accessed 20 Sep 2022].
• Pal P, Giri PP, Ramanan AV. Dengue Associated Hemophagocytic
Lymphohistiocytosis: A Case Series. Indian Pediatrics. 15:469-467.
2014.

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Editor's Notes