DENGUEDENGUEAlso known as Also known as breakbone fever. breakbone fever. is an infectious is an infectious tropical disease. tropical disease.   caused by the dengue virus.caused by the dengue virus.There are four strains of the virus, There are four strains of the virus, which are called serotypes, and these which are called serotypes, and these are referred to as DENV-1, DENV-2, are referred to as DENV-1, DENV-2, DENV-3 and DENV-4. DENV-3 and DENV-4.

All four serotypes can cause the full All four serotypes can cause the full spectrum of disease.Infection with one spectrum of disease.Infection with one serotype is believed to produce lifelong serotype is believed to produce lifelong immunity to that serotype but only short immunity to that serotype but only short term protection against the others.term protection against the others.

The severe complications on secondary The severe complications on secondary infection occurs particularly if someone infection occurs particularly if someone previously exposed to one serotype then previously exposed to one serotype then contracts other serotype. contracts other serotype.

Dengue virus is primarily Dengue virus is primarily transmitted by transmitted by AedesAedes mosquitoes,  mosquitoes, particularly particularly A. aegypti.A. aegypti.

Other Other Aedes Aedes species that transmit species that transmit the disease include the disease include A. albopictusA. albopictus, , A. A. polynesiensis polynesiensis and and A. scutellaris.A. scutellaris.

Humans are the primary host of the Humans are the primary host of the virus, but it also circulates in virus, but it also circulates in nonhuman primates. nonhuman primates.

The VectorThe Vector AedesAedes aegypti aegypti mosquitomosquito

Distinct feature is Distinct feature is black and white black and white stripes on its stripes on its body and legsbody and legs

Bites during the day.Bites during the day.

Lays its eggs in Lays its eggs in clean, stagnant clean, stagnant water.water.

Potential breeding Potential breeding groundsgrounds

Replication and Transmission Replication and Transmission of Dengue Virusof Dengue Virus

1.1. Transmitted in salivaTransmitted in saliva

2.2. Replicates in white Replicates in white blood cells and blood cells and lymphatic tissueslymphatic tissues

3.3. Circulates in bloodCirculates in blood

4.4. Second mosquito Second mosquito ingests virus with bloodingests virus with blood

5.5. Replicates in mosquito Replicates in mosquito midgut, infects and midgut, infects and replicates in salivary replicates in salivary glandsglands  

Factors responsible for Factors responsible for resurgence of Dengueresurgence of Dengue

Population growth Population growth

Unplanned and uncontrolled Unplanned and uncontrolled urbanization urbanization

Inadequate & Interrupted water Inadequate & Interrupted water

supply- leading to storage of watersupply- leading to storage of water

Deficient waste water managementDeficient waste water management

Failure of effective mosquito control Failure of effective mosquito control measuresmeasures

Pathophysiology of DHF Pathophysiology of DHF and DSSand DSS

2 main pathophysiological 2 main pathophysiological changes: changes:

Increased vascular permeability Increased vascular permeability Haemostatic Disorder: Haemostatic Disorder:

Vascular ChangesVascular ChangesThrombocytopeniaThrombocytopeniaCoagulopathyCoagulopathy

Infected monocytesInfected monocytes

Vasoactive mediatorsVasoactive mediators

Increased vascular permeabilityIncreased vascular permeability

Hemorrhagic manifestations DHF, Hemorrhagic manifestations DHF, DSS DSS

Increased Vascular Permeability

ThrombocytopeniaThrombocytopenia

Infection of human haematopoietic Infection of human haematopoietic cellscells megakaryocytopoieses megakaryocytopoieses

Increased peripheral destruction of Increased peripheral destruction of antibody coated plateletsantibody coated platelets

Platelet destruction in the liver and Platelet destruction in the liver and spleen.spleen.

Platelet dysfunction(Qualitative Platelet dysfunction(Qualitative defect)defect)

Hemorrhage in Dengue Hemorrhage in Dengue

VasculopathyVasculopathyThrombocytopeniaThrombocytopeniaPlatelet dysfunction Platelet dysfunction DICDICCoagulopathyCoagulopathy

Clinical Manifestations of Clinical Manifestations of Dengue Virus InfectionDengue Virus Infection

Classic Dengue FeverClassic Dengue Fever is Dengue fever is Dengue fever without warning signswithout warning signs

Dengue Fever with unusual hemorrhageDengue Fever with unusual hemorrhage Dengue fever with warning signs Dengue fever with warning signs

DHF is Dengue fever with warning signs DHF is Dengue fever with warning signs DSS is Severe DengueDSS is Severe Dengue

But rather than separate entities, Now it But rather than separate entities, Now it is a continuum of the diseaseis a continuum of the disease

Dengue FeverDengue Fever is an acute febrile illness of is an acute febrile illness of 2-7 days duration(sometimes with two 2-7 days duration(sometimes with two peaks) with two or more of the following peaks) with two or more of the following manifestations:manifestations:

headacheheadache retro-orbital painretro-orbital pain myalgia/arthralgiamyalgia/arthralgia rashrash haemorrhagic manifestation (petechiae haemorrhagic manifestation (petechiae

and positive tourniquet test) and,and positive tourniquet test) and, leukopenialeukopenia

Dengue Haemorrhagic FeverDengue Haemorrhagic Fever is a is a probable case of dengue and probable case of dengue and haemorrhagic tendency evidenced by haemorrhagic tendency evidenced by one or more of the following:one or more of the following:

Positive tourniquet testPositive tourniquet test Petechiae, ecchymosis or purpuraPetechiae, ecchymosis or purpura Bleeding from mucosa (mostly Bleeding from mucosa (mostly

epistaxis or bleeding from gums), epistaxis or bleeding from gums), injection sites or other sitesinjection sites or other sites

Haematemesis or melenaHaematemesis or melena

Thrombocytopaenia (platelets 100,000/cu.mm Thrombocytopaenia (platelets 100,000/cu.mm or less) and or less) and

Evidence of plasma leakage due to increased Evidence of plasma leakage due to increased capillarycapillary

permeability manifested by one or more of permeability manifested by one or more of the following:the following:

– – A >20% rise in haemotocrit for age and sex A >20% rise in haemotocrit for age and sex – – A >20% drop in haemotocrit following A >20% drop in haemotocrit following

treatment with treatment with fluids as compared to baselinefluids as compared to baseline – – Signs of plasma leakage (pleural effusion, Signs of plasma leakage (pleural effusion,

ascites orascites or hypoproteinaemia).hypoproteinaemia).

Dengue Shock SyndromeDengue Shock Syndrome (DSS) All (DSS) All the above criteria of DHF plus signs the above criteria of DHF plus signs of circulatory failure manifested by;of circulatory failure manifested by;

rapid and weak pulse, rapid and weak pulse, narrow pulse pressure (< or equal to narrow pulse pressure (< or equal to

20 mm Hg);20 mm Hg); hypotension for age, hypotension for age, cold and clammy skin andcold and clammy skin and restlessnessrestlessness

Grading Of DHF/DSSGrading Of DHF/DSS Grade IGrade I:: Fever accompanied by non-specific constitutional Fever accompanied by non-specific constitutional

symptoms; the only haemorrhagic manifestation is a symptoms; the only haemorrhagic manifestation is a positive tourniquet test and/or easy bruising.positive tourniquet test and/or easy bruising.

Grade IIGrade II: : Spontaneous bleeding in addition to the Spontaneous bleeding in addition to the manifestations of Grade I patients, usually in the forms of manifestations of Grade I patients, usually in the forms of skin or other haemorrhages.skin or other haemorrhages.

Grade IIIGrade III: : Circulatory failure manifested by a rapid, weak Circulatory failure manifested by a rapid, weak pulse and narrowing of pulse pressure or hypotension, pulse and narrowing of pulse pressure or hypotension, with the presence of cold, clammy skin and restlessness.with the presence of cold, clammy skin and restlessness.

Grade IVGrade IV:: Profound shock with undetectable blood Profound shock with undetectable blood pressure or pulse.pressure or pulse.

Clinical courseClinical course

Disease CourseDisease Course Febrile phase Febrile phase lasts 2-7 days lasts 2-7 days

Look for warning signs Look for warning signs Mild hemorrhagic manifestations may occurMild hemorrhagic manifestations may occur

Critical phaseCritical phase Begins after the fever improvesBegins after the fever improves

usually on days 3–7 of illnessusually on days 3–7 of illness lasts 24–48 hourslasts 24–48 hours Progressive leucopenia , thrombocytopenia Progressive leucopenia , thrombocytopenia

and plasma leakageand plasma leakage Recovery phaseRecovery phase: :

Gradual reabsorption of fluid in 48-72hrsGradual reabsorption of fluid in 48-72hrs

The course of infection is divided The course of infection is divided into three phases: febrile, critical, into three phases: febrile, critical, and recovery and recovery

The febrile phase involves high The febrile phase involves high fever, often over 40 °C (104 °F), and fever, often over 40 °C (104 °F), and is associated with generalized pain is associated with generalized pain and a headache; this usually lasts and a headache; this usually lasts two to seven days two to seven days

The disease proceeds to a critical phase, The disease proceeds to a critical phase, which follows the resolution of the high which follows the resolution of the high fever and typically lasts one to two days. fever and typically lasts one to two days. 

During this phase there may be significant During this phase there may be significant fluidaccumulation in thefluidaccumulation in the chest and chest and abdominal cavity due to increased abdominal cavity due to increased capillary permeability and leakage. This capillary permeability and leakage. This leads to depletion of fluid from the leads to depletion of fluid from the circulation and decreased blood supply to circulation and decreased blood supply to vital organs.During this phase, organ vital organs.During this phase, organ dysfunction and severe bleeding, typically dysfunction and severe bleeding, typically from the gastrointestinal tract, may from the gastrointestinal tract, may occur. occur. 

The recovery phase occurs next, with The recovery phase occurs next, with resorption of the leaked fluid into the resorption of the leaked fluid into the bloodstream bloodstream

This usually lasts two to three days This usually lasts two to three days During this stage, a fluid overload state During this stage, a fluid overload state

may occur; if it affects the brain, it may may occur; if it affects the brain, it may cause a reduced level of consciousness cause a reduced level of consciousness or seizures.A feeling of fatigue may last or seizures.A feeling of fatigue may last for weeks afterwards.for weeks afterwards.

Unusual Manifestations Unusual Manifestations of Dengueof Dengue

Acute liver failure and Acute liver failure and encephalopathy which may be encephalopathy which may be present even in the absence of present even in the absence of plasma leakageplasma leakage

Cardiomyopathy and myocarditis Cardiomyopathy and myocarditis Encephalitis and rarely AIDPEncephalitis and rarely AIDP Severe gastrointestinal Severe gastrointestinal

hemorrhagehemorrhage

Clinical Evaluation in Clinical Evaluation in Dengue FeverDengue Fever

Blood Pressure including pulse Blood Pressure including pulse pressurepressure

Pulse ratePulse rate Hydration statusHydration status Capillary refill time Capillary refill time E/O petechiae, purpura and echymosisE/O petechiae, purpura and echymosis E/O increased vascular permeabilityE/O increased vascular permeability

Pleural effusion, ascitesPleural effusion, ascitesTourniquet testTourniquet test

Differential Diagnosis: Differential Diagnosis: Conditions that Conditions that mimic the febrile phase of dengue mimic the febrile phase of dengue

infectioninfectionFlu-like syndromesFlu-like syndromes Influenza, measles, Influenza, measles,

Chikungunya, infectious Chikungunya, infectious mononucleosis , HIV mononucleosis , HIV seroconversion illnessseroconversion illness

Illnesses with a rashIllnesses with a rash Rubella, measles, scarlet Rubella, measles, scarlet fever, meningococcal fever, meningococcal infection, Leptospirosis, infection, Leptospirosis, Chikungunya, drug Chikungunya, drug reactionsreactions

Diarrhoeal diseasesDiarrhoeal diseases Rotavirus, other enteric Rotavirus, other enteric infectionsinfections

Illnesses with Illnesses with neurological neurological manifestationsmanifestations

Meningo/encephalitisMeningo/encephalitisFebrile seizuresFebrile seizures

Differential Diagnosis: Conditions Differential Diagnosis: Conditions that mimic the critical phase of that mimic the critical phase of

dengue infectiondengue infectionInfectiousInfectious Acute gastroenteritis, Acute gastroenteritis,

malaria, leptospirosis, malaria, leptospirosis, typhoid, typhus, viral typhoid, typhus, viral hepatitis, acute HIV hepatitis, acute HIV seroconversion illness, seroconversion illness, bacterial sepsis, septic bacterial sepsis, septic shockshock

Other ConditionsOther Conditions Acute abdomenAcute abdomenDiabetic ketoacidosisDiabetic ketoacidosisPlatelet disordersPlatelet disordersRenal failureRenal failure

Laboratory Laboratory Manifestations Manifestations

Hematocrit/ Packed cell volume:Hematocrit/ Packed cell volume: Crude estimated Hb× 3Crude estimated Hb× 3 May be altered by bleeding/volume May be altered by bleeding/volume

replacementreplacement

Increase in Hct by 20% Increase in Hct by 20% DHF or plasma DHF or plasma leakageleakage

When previous value NAWhen previous value NA > 45% is > 45% is significantsignificant

Other Manifestations Other Manifestations

Peripheral Smear and TLCPeripheral Smear and TLC Normal, LeukocytosisNormal, Leukocytosis

Leukopenia Leukopenia Lymphocytosis and Atypical Lymphocytosis and Atypical

lymphocyteslymphocytes Thrombocytopenia Thrombocytopenia

Other Manifestations Other Manifestations

Hypoalbuminemia Hypoalbuminemia Hyponatremia Hyponatremia Mild increase in AST, ALT upto 200-250Mild increase in AST, ALT upto 200-250

> 250> 250 Hepatic involvement and severe Hepatic involvement and severe DengueDengue

↑ ↑ PT, APTTPT, APTT ↑ ↑ BUNBUN Mild albuminuria Mild albuminuria Reduced Serum Complement Reduced Serum Complement

Laboratory criteria for Laboratory criteria for confirmation of dengue confirmation of dengue

feverfever Isolation of the dengue virus from Isolation of the dengue virus from

serum or autopsy samplesserum or autopsy samples Demonstration of a fourfold or Demonstration of a fourfold or

greater change in reciprocal IgG or greater change in reciprocal IgG or IgM antibody titres to one or more IgM antibody titres to one or more dengue virus antigens in paired dengue virus antigens in paired serum samplesserum samples

Dengue NS-1 Antigen Dengue NS-1 Antigen NS-1 is a non structural protein NS-1 is a non structural protein

associated with intracellular organalles associated with intracellular organalles and transported to the surface by and transported to the surface by secretory pathways.secretory pathways.

Soluble hexameric form found to Soluble hexameric form found to circulate in the blood of patients with circulate in the blood of patients with acute dengueacute dengue

ELISA has been developed for specific ELISA has been developed for specific detection of Dengue Type NS-1 detection of Dengue Type NS-1 AntigenAntigen. .

TreatmentTreatment Management is relatively simple, inexpensive Management is relatively simple, inexpensive

and very effective in saving lives so long as and very effective in saving lives so long as correct and timely interventions are instituted.correct and timely interventions are instituted.

Main Pathological Abnormality Main Pathological Abnormality is LOSS OF is LOSS OF PLASMA VOLUME FROM THE VASCULAR PLASMA VOLUME FROM THE VASCULAR COMPARTMENTCOMPARTMENT because of increased because of increased capillary permeability. capillary permeability.

Loss of plasma volume varies = 5-20%Loss of plasma volume varies = 5-20% Early and effective replacement of plasma Early and effective replacement of plasma

losses with plasma expander or fluid and losses with plasma expander or fluid and electrolyte solution results in a favorable electrolyte solution results in a favorable outcome in most casesoutcome in most cases

Management Decisions Management Decisions

Depending on the clinical Depending on the clinical manifestations and other manifestations and other circumstances, patients may be circumstances, patients may be sentsent

Group A : Sent Home Group A : Sent Home Group B: In-hospital managementGroup B: In-hospital management Group C: Require emergency Group C: Require emergency

treatment treatment

Group AGroup A Outpatient treatment Outpatient treatment

Who?Who?

Able to take orallyAble to take orally

Pass urine adequately once every 6 hrsPass urine adequately once every 6 hrs

No warning signs particularly atdefervescence of No warning signs particularly atdefervescence of feverfever

What to doWhat to do

Review daily for disease progression ( TLC, Hct Review daily for disease progression ( TLC, Hct and warning signs)and warning signs)

ORS, juice and other fluidsORS, juice and other fluids

Paracetamol ( max 4/day)Paracetamol ( max 4/day)

Instruct to come back in case of warning signs or Instruct to come back in case of warning signs or decreasing urine outputdecreasing urine output

Group BGroup B In hospital In hospital

managementmanagement Warning SignsWarning Signs

Abdominal pain or Abdominal pain or tendernesstenderness

Persistent vomitingPersistent vomiting Clinical fluid Clinical fluid

accumulation: PE, ascitesaccumulation: PE, ascites Mucosal bleedMucosal bleed Lethargy, restlessnessLethargy, restlessness Liver enlargement >2 cmLiver enlargement >2 cm

Co-existing ConditionsCo-existing Conditions Pregnancy, Diabetes, Pregnancy, Diabetes,

renal failure, renal failure, infancy, old infancy, old age, obesity, chronic age, obesity, chronic haemolytic diseaseshaemolytic diseases

Social CircumstancesSocial Circumstances

Dengue without warning Dengue without warning signssigns

Encourage oral fluids

Start NS or RL at maintenance rate

If not tolerated

Give minimum volume required to maintain good perfusion

and urine output

IV fluids for few hrs switch to oral fluids as

soon as possibleContinue IV fluid

No warning signs patient improving

Warning signs or î Hct

3–5 ml/kg/hr for 2–4 hr

isotonic solutions such as NS or RL

5–7 ml/kg/hr for 1-2 hrs

Obtain Hct

2–3 ml/kg/hr

Obtain Hct and reassess clinically

Hct same or rising minimally

2–3 ml/kg/hr for 2-4 hrs

minimum IVF required to maintain good perfusion and urine output =0.5 ml/kg/hr.

Reduce IV fluid as Hct decreases and patient improves IV Fluid for 24-48hrs

Vital signs worseningHct rising

MonitoringMonitoring Vital signs and peripheral perfusionVital signs and peripheral perfusion 1–4 1–4

hourlyhourly

Urine outputUrine output 4–6 hourly 4–6 hourly Hematocrit Hematocrit before and after fluid before and after fluid

replacement, then 6–12 hourlyreplacement, then 6–12 hourly

Blood glucose, and other organ functions as Blood glucose, and other organ functions as

indicatedindicated

Till the patient is out of critical periodTill the patient is out of critical period

Group C: require urgent Group C: require urgent treatment in a treatment in a high dependency high dependency

unitunit Early presentation with shock (on days 2 Early presentation with shock (on days 2

or 3 of illness)or 3 of illness) Severe plasma leakage and/or shockSevere plasma leakage and/or shock Undetectable pulse and blood pressureUndetectable pulse and blood pressure Severe bleedingSevere bleeding Fluid overloadFluid overload Organ impairment (such as hepatic Organ impairment (such as hepatic

damage, cardiomyopathy, damage, cardiomyopathy, encephalopathy, encephalitis)encephalopathy, encephalitis)

Compensated vs hypotensive Compensated vs hypotensive shockshock

ParameterParameter Compensated Compensated shockshock

Hypotensive shockHypotensive shock

Fluid lossFluid loss 10-15%10-15% >15-20%>15-20%

Mental statusMental status Clear and lucidClear and lucid Change of mental stateChange of mental state

Capillary refill Capillary refill timetime

Prolonged (>2 Prolonged (>2 sec)sec)

Very prolonged, Very prolonged, mottled skinmottled skin

ExtremitiesExtremities Cool peripheriesCool peripheries Cold, clammy Cold, clammy extremitiesextremities

Pulse volumePulse volume Weak and Weak and threadythready

Feeble or absentFeeble or absent

Heart rateHeart rate 100-120100-120 >120>120

Blood Blood pressurepressure

SBP=N, DBP î, PP SBP=N, DBP î, PP decreased, decreased, Postural Postural hypotensionhypotension

Hypotension, Hypotension, Unrecordable blood Unrecordable blood pressure, Pulse pressure, Pulse Pressure<20mmHgPressure<20mmHg

Respiratory Respiratory raterate

20-3020-30 >30>30

IV Isotonic Crystalloid @10ml/kg/hr for 1 hr

Reassess vitals, CRT, Hct, urine output

improvementYes

IV crystalloid 5–7ml/kg/hr for 1–2hrs3–5 ml/kg/hr for 2–4hrs2–3 ml/kg/hr for 2–4hrs

Hct î fluid

bolusesHct decreases consider BT

Patient improves, Hct stable,↓IVF to maintenance level stop after 48hrs

No

Hct↑ or > 50%

10–20 ml/kg/hr for 1

hrimprovement

Yes

NoHct low (<45 in males, <40 in females or ↓ from baseline

Consider occult/ significant bleed BT

Management plan of Management plan of compensated shockcompensated shock

Hypotensive Shock

isotonic crystalloid or colloid 20 ml/kg for 15 min

Clinical ImprovementYES

Crystalloid/colloid 10 ml/kg/hr for 1 hour

IV crystalloid 5–7ml/kg/hr for 1–2hrs3–5 ml/kg/hr for 2–4hrs2–3 ml/kg/hr for 2–4hrs

Patient improves, Hct stable,↓IVF to maintenance level stop after 48hrs

Monitor Hct 6 hrly

NO

Review 1st HCT

HCT ↑or high

2nd Bolus: Colloid 10-20ml/kg over 1hr

Improvement

NO

Repeat 2nd HCT

HCT ↑or high

3rd Bolus: Colloid 10-20ml/kg over 1hr

Consider occult/ significant bleed BT

HCT ↓

HCT ↓

Repeat Hct

NO

Criteria for Platelet Criteria for Platelet Transfusion Transfusion

Platelet counts of dengue patients Platelet counts of dengue patients fluctuate in an unpredictable manner fluctuate in an unpredictable manner despite platelet transfusiondespite platelet transfusion

Stable patients with Platelet Count Stable patients with Platelet Count <10000/cc<10000/cc

Patients with Platelet Count < 20000/cc with Patients with Platelet Count < 20000/cc with minor bleedingminor bleeding

Patients with Platelet Count < 50000/cc with Patients with Platelet Count < 50000/cc with significant bleedingsignificant bleeding

Role of FFP in Dengue Role of FFP in Dengue associated thrombocytopeniaassociated thrombocytopenia

Antibody concentrates in FFPAntibody concentrates in FFP

block immune mediated platelet destructionblock immune mediated platelet destruction

reduction in peripheral platelet destructionreduction in peripheral platelet destruction

an increase in the platelet countan increase in the platelet counto Thrombopoeitin activator in FFP directly Thrombopoeitin activator in FFP directly

stimulates thrombopoeitin in BMstimulates thrombopoeitin in BM

Criteria for discharging inpatientsCriteria for discharging inpatients Absence of fever for at least 24 hours without the use Absence of fever for at least 24 hours without the use

of antifever therapyof antifever therapy Return of appetite·Return of appetite· Visible clinical improvementVisible clinical improvement Good urine outputGood urine output Stable haematocritStable haematocrit Passing of at least 2 days after recovery from shockPassing of at least 2 days after recovery from shock No respiratory distress from pleural effusion or ascitesNo respiratory distress from pleural effusion or ascites Platelet count >50 000 per mm3.Platelet count >50 000 per mm3.