Dr Shahjada SelimRegistrar (Medicine)

Shaheed Suhrawardy Medical College Hospital, Dhaka

Dengue The word dengue is derived from African

word denga: meaning fever with hemorrhage .

Is caused by virus transmitted of bites of

mosquito aedes.

Definition of Dengue Syndrome

Dengue Fever, a benign syndrome caused by several arthropod–borne viruses, is characterized by biphasic fever, Myalgia, or Arthralgia, rash, Leukopenia and lymphadenopathy.

HistoryOver the last two hundred years dengue

was known to the physician as a self limiting benign febrile condition.

The first outbreak that resembles a disease now recognized as dengue fever was that described by Benjamn Rush in Philadelphia, Pennsylvania in 1780.

HistoryEpidemics probably due to dengue were

common from the eighteenth to the twentieth centuries among the inhabitants of the Atlantic coast of the United States.

HistoryDengue viruses almost certainly were the

cause of the 5 and 7 day fevers that occurred among European Colonists in Tropical Asia.

In 1905 Aedes Aeggpti was identified as a dengue vector by Bancroft Ashburn and C raig.

HistoryIn 1956 Philippine hemorrhage fever was associated

with dengue when types 3 and 4 were recovered. It now has become endemic through out tropical Asia

since 1967 the term dengue hemorrhagic fever and DSS have come in to general use.

The Dengue VirusFlavivirusPositive senseSingle stranded RNA virus40 to 50 nanometersFour sero-sub typesType 1 to 4Arthropod borne

ETIOLOGY of VIRUS

Dengue virion are spherical particles approximately 50 nm in diameter.

contains a single plus strand of RNA. Surrounded by a lipid bilayer.

Mature virions are composed of 6% RNA, 9% carbohydrate, and 17% lipid.

Because of the lipid envelope, flavviviruses are readily inactivated by organic solvents and detergents.

ETIOLOGY VIRUS

ETIOLOGY VIRUS

Three viral proteins are associated with virions.

The E (envelop), M (membrane) and C (capsid) proteins.

VIRUSThe E protein is the major surface protein of the viral

particle probably interacts with viral receptors, and mediates virus-cell membrane fusion.

Antibodies that neutralize virus infectivity usually recognize this protein and mutations in E can affect virulence.

VIRUSM protein is a small proteolytic fragment which is

important for maturation of the virus into an infectious form.

C protein is a component nucleocapsid.

EtiologyTypesFour distinct antigenically related serotypes ( 1to 4) of

dengue virus of the family flaviviridae are etiologically responsible.

Infection in human by one serotypes produces life long immunity against re-infection by the same serotype.

subsequent infection with other serotypes may result in a severe illness ie., DHF or DSS

EtiologyDengue like feverThree other arthropod born viruses cause similar

febrile diseases with rash.

Chikungunya, Onyong-nyong and West Nile Fever

EtiologyDengue like fever Dengue like diseases may also occur in epidemics.

Epidemiological features depends on the vector and their geographic distribution.

EPIDOMIOLOGY Dengue outbreaks in urban areas infested with

A.aegypti may be explosive upto 70-80% of population may be involved.

During epidemic most disease occur in older children and adults because A.aegypti has a limited range spread, epidemic occurs mainly through viremic human beings and follows the main lines of transportation .

Where dengue is endemic children and susceptible foreigners may be the only persons to acquire overt disease adults having become immune.

EPIDOMIOLOGY VectorDengue viruses are transmitted by mosquitoes of the

stegomyia family. Acdes aegypti a day time biting mosquito is the

principal vector and all 4 types of virus have been recovered from it.

VectorAedes mosquitoes (Tiger mosquito): distinguished by

white stripes on black body. Important members aedes family:A. aegypty,

A.vittatus and A. albopictus. They are most abundent during rainy season.

VectorLays egg singly, and eggs are cigar shaped.Female mosquito acts as vector. They do not fly over long distance-

<100mts(110yards), this factor facilitates its eradication.

TransmissionIn most tropical areas A-aegypti is highly urbanized. They breed in fresh water like water stored for

drinking or bathing and in rain water collected in any container.

Dengue viruses have also been recovered from Aedes- Albopictus.

TransmissionOutbreaks in the Pacific area have been attributed to

several other Aedes species. These species breed in water trapped in vegetation.

The pathogenesis of severe disease is not well understood

Various mechanisms of severe disease have been suggested , including

1. Antibody –dependent enhancements2. Complement activation by virus- antibody

complex 3. T-cell mediated immuno pathology 4.Cytokine abundance

PathogenesisIn experimental studies of dengue virus infection in

rhesus monkeys, after subcutaneous inoculation, virus was disseminated rapidly to regional lymph nodes and then to lymphatic tissue through out the body.

PathogenesisEarly in the viremic period virus could be recovered

only from lymphonodes. 2-3 days later there will be evidence of dissemination

of skin and other tissuesVirus was recovred from skin, lymphonodes and

several leukocyte –rich tissues for up to 3 days after termination of Viremia.

PathogenesisThe number of sites of virus recovery greater as the

infection progresses. Intra cellular infection is terminated abruptly 2-3 days after viremia ceases.

Animals infected with dengue virus type, 1,3 & 4 and then infected with dengue virus type 2 circulated virus at higher titer than when the strain was inoculated on to susceptible animals.

PathogenesisEpidemiological , Clinical and virologic studies of

DHF / DSS in humans have shown a significant association between severe illness and infection in presence of circulating dengue antibody.

If tissue culture or suckling mice are used for virus recovery, dengue virus almost invariably is absent in tissues at the time of death. Tissue suspension contain large qualities of dengue neutralizing substances.

PathogenesisDHF / DSS occurred in children who were circulating

enhancing antibodies from a previous single dengue virus infection. But did not occur in children whose first infection left them with low levels of cross reactive Dengue virus type-2 neutralizing antibodies at the time of second dengue virus infections.

Pathogenesis

In vitro studies of dengue virus type-2 demonstrated enhanced growth in cultures of human mononuclear phagocytes that were supplemented with very small qualities of dengue antibodies.

It has been proposed that the number of infected mono nuclear phagocytes in individuals with naturally or passively acquired antibody may exceed that in non immune individuals.

PathogenesisIncrease production of infected cells may contribute

to shock, possibly through the release of cytokines, themselves the products of the immune elimination of virus infected, mononuclear phagocytes through cell mediated mechanisms.

PathogenesisIt is thought that the reduced risk to DHF / DSS of

protein – calorie malnourished children is consistent with hypothesis that a competent immune elimination system generates the cytokines that produce DHF / DSS.

PathogenesisEarly in the acute stage of secondary dengue virus

infection, there is rapid activation of the complement system.

During shock : Blood levels of C1q, C3, C4, C5, C6, C7, C8 and C3

proactivator are depressed. C3 catabolic rates elevated. The blood clotting and fibrinolytic system are

activated.

Pathogenesis Recent studies suggest a role for tumor

necrosis factor and interferon gamma. As yet neither the mediator of vascular

permiability nor complete mechanism of bleeding has been identified.

PathogenesisCapillary damage allows fluid electrolytes, protein,

and in some instances red blood cell to leak in to intra vascular spaces. This internal redistribution of fluid together with deficit due to fasting, thirsting and vomiting results in hemo concentration, hypovolemia, increased cardiac work, tissue hypoxia, metabolic acidosis and hyponatremia.

PathogenesisA mild degree of DIC plus liver damage and

thrombocytopenia Could contribute additively to produce haemorrhage.

PathologyPathologic examination there usually are no gross or

microscopic lesions found that might account for death. In rare instances death may be due to gastro intestinal or

intra cranial hemorrhages. Haemorrhages are seen in: Upper GI tract intra

ventricular septum of heart, on the pericardium. And on the subserosal surfaces of major viscera.

PathologyFocal hemorrhages occasionally seen in the lungs,

liver, adrenals, sub arachniod space. The liver is usually is enlarged often with fatty

changes. Yellow watery at times blood tinged effusions are

present in serous cavities in about ¾ of patient and retro peritoneal tissues are markedly edematous.

PathologyMicroscopyPerivascular edema in the soft tissues and wide

spread of diapedesis of RBC. There may be maturational arrest of megakaryocytes

in the bone marrow and increased numbers of them are seen in capillaries of lungs, in renal grlomeruli and in sinusoids of the liver and spleen.

PathologyMicroscopyProliferation of lymphoid and plasma cytoid cells,

lymphocytolysis and lymphophagocytosis occurs in the spleen and lymphonodes.

In the spleen malpighian corpuscle germinal centres are necrotic there is a depletion of lymphocytes in the thymus.

PathologyMicroscopy Liver: there are varying degrees of Falty metamorphosis, Focal midzonal necrosis Hyperplasia of the Kupffer Cells. Non nucleated cells with vacuolated

acidophilic cytoplasm resembling councilmanbodies are seen in the sinusoids.

PathologyMicroscopyKidney:There is a mild proliferative glamerulo

nephritis .Skin: Biopsies of the rash reveal swelling and minimal

necrosis of endothelial cells. Subcutaneous deposits of fibrinogen and in a few cases dengue antigen in extra vascular mononuclear cells and on blood vessel walls.

DengueClassification

Dengue feverDengue haemorrhagic feverDengue shock syndromeExpanded dengue syndrome

Classification Dengue fever Dengue fever is an acute febrile viral illness

presenting with Headache, bone (break bone fever), or joint (chikungunya or o-nyony-nyong) and muscular pains, rash and leucopenia caused by arthropod borne viruses.

Age & sex distribution

1

7

9

32

4

8

4

0

2

4

6

8

10

<1 yr 1-5 yrs 5-10 yrs >10 yrs

Male

Female

Population distribution

11

6

22

0

5

10

15

20

25

Rural

UrbanslumUrban

Manifestations

16

9

20

0

10

20

30

Dengue fever

DHF

DSS

Fever

14 15

7 7

0

5

10

15

20

<5 days

5-10 days

>10 days

Biphasic

Symptoms - Typical

11

12

10.5

11

11.5

12

12.5

Flushing

Rashes

Natural course of illness2.1. Undifferentiated fever Those who have been infected with dengue

virus,especially for the first time (i.e. primary dengue infection), may develop a simple feverindistinguishable from other viral infections.

2.2. Dengue fever (DF)It is generally an acute febrile illness, with severe headache, myalgia,

arthralgia and rashes. Leucopenia and thrombocytopenia may also beobserved. Although DF may be benign, it could be an incapacitatingdisease with severe headache, muscle and joint and bone pains (breakboneFever). Occasionally unusual haemorrhage such as gastrointestinalbleeding, hypermenorrhea and massive epistaxis may occur.

Dengue haemorrhagic fever (DHF)DHF is characterized by the acute onset of high fever and is associatedwith signs and symptoms similar to DF in the early febrile phase. Plasmaleakage is the hallmark of DHF which occurs soon after the end of thefebrile phase. There is a tendency to develop hypovolemic shock (dengueshock syndrome) due to plasma leakage.

High-risk patientsInfant and the elderlyObesity pregnant womenPUD Women who have menstruation or abnormal vaginal

bleedingHemolytic diseaseCongenital heart diseaseChronic disease such as DM, HTN,CRF,IHD,

Asthama, Liver cirrhosisPatient on steroid or NSAID treatment

Warning signsNo clinical improvement or worsening of the

situation just before or during the transition to afebrile phase or the disease progresses .

Persistent vomiting . Severe abdominal pain .Lethargy and / or restlessness ,sudden behavioral

change .Bleeding : Epistaxis, black stool, haematemesis,

excessive menstrual bleeding , dark coloured urine (haemoglobinuria)or haematuria.

Giddiness Pale, cold and clammy hands and feet .Less /no urine output for 4-6 hours .Liver enlargement >2cm.Haematocrit>20%.

Tourniquet Test

Inflate blood pressure cuff to a pointmidway between systolic and diastolicpressure for 5 minutes

Positive test: 20 or more petechiaeper 1 inch² (6.25 cm²)

Tourniquet Test

Atypical manifestationNeurolgical:

•Febrile seizures in young children

•Encephalopathy

•Encephalitis/aseptic meningitis

•Subdural effusions

•Mononeuropathies/polyneuropathies/guilane-barre syndrome

•Transverse myelities

Gastrointestinal/hepatic:

Hepatitis/fulminant hepatic failure

Acalculous cholecystitis

Acute pancreatitis

Hyperplasia of peyer’s patches

Acuteparotitis

Renal:

Acute renal failure

Hemolytic uremic syndrome

Cardiac:

Conduction abnormalities

myocarditis

pericarditis

Respiratory

Acute respiratory syndrome

Pulmonary haemorrhage

Musculoskeletal

Myositis with raised creative phosphokinase

Rhabdomyolysis

Lymphoreticular/ bonemarrow :

Infection associated haemophagocytic syndrome

ITP

Spontaneous splenic rupture

Lymph node infarction

Eye

Macular haemorrhage

Impaired visual acuity

Optic neuritis

Others

Post-infectious fatigue syndrome, depression, hallucinations, psychosis, alopecia

Expanded dengue syndrome / Isolated organopathy ( unusual manifestation )patients with dengue illness can sometimes develop

unusual manifestations such as involvement of liver ,kidneys ,brain or heart with or without evidence of fluid leakage and therefore do not necessarily fall into the category of DHF. These conditions are very rare and management is symptomatic . Such unusual manifestations may be associated with coinfections and comorbidities. However , these manifestations if seen in DHF patients are mostly a result of prolonged shock leading to organ failure .

Lab investigations for diagnosis management Dengue virus infection creates a broad spectrum of

symptoms , several of which are non – specific . Thus ,a clinical diagnosis based on only symptoms is untrustworthy .Early laboratory confirmation of clinical diagnosis may be important because some patients progress within a short period from mild to severe disease and sometimes to death . Early intervention may be life –saving. The management of DS is based on clinical judgment rather than laboratory evaluations alone . However , few indirect tests may be suggestive of DS from the outset . The following tests may be done .

Lab tests for diagnosis and monitoring :CBC: including Total Leucocyte Count, Total Platelet

Count and Hct should be done on first consultation of the patient to have the baseline :

Recommendations: All febrile patients at the first visit . All patients with warning signs . All patients with fever >3 days .Leucopenia is common in both adults and children

with DF and has an important diagnostic implication in early period . The change in total white cell count (<_5ooo cells /mm3) and ratio of neutrophils to lymphocyte (neutrophils< lymphocytes ) is useful to

predict the critical period of plasma leakage . This finding precedes thrombocytopenia or rising haematocrit. This changes seen in DF and DHF both .

Thrombocytopenia is observed in some patients with DF Mild thrombocytopenia (100,000-150,000 cells /mm3)is common and about half of all DF patients have platelet count below 100,000 cells /mm3; A sudden drop In platelet count to below 100,000 occurs before the onset of shock or subsidence of fever . The level of platelet count is correlated with severity of DHF. Severe thrombocytopenia (<100,000/mm3) usually precedes / accompanies overt plasma leakage .

Hct : A slight increase may be due to high fever , anorexia and vomiting (10%). A sudden rise in haematocrit is observed simultaneously or shortly after the drop in platelet count.Haemoconcentration or rising haematocrit by 20% from the baseline , e.g. from haematocrit of 35% to >_42% is objective evidence of leakage of plasma .1 of haematocrit may be affected by early volume replacement and by bleeding .

Serum AST(SGOT) and ALT(SGPT):AST and ALT levels are frequently elevated in both adults and children with DF and DHF; -- Levels are significantly higher (5-15 times the upper limit of normal )in patients with DHF.

Other findings are hypoproteinemia/ albuminaemia (as a consequence of plasma leakage ), hyponatremia, Albuminuria.

Occult blood is often found in the stool .In DSS cases , assays of coagulation and

fibrinolytic factors show reduction . Partial thromboplastin time and prothrombin time are prolonged in about half and one third of DHF cases respectively . Thrombin time is also prolonged in severe cas.

Dengue Diagnostic TestDetection of antigen: NS1 antigen (non-

structural protein 1):NS1 antigen rapid test –positive within minutes of

starting symptoms .The ELISA NS1 antigen will be positive on first day of

illness .This test becomes negative from day 4-5 of illness .Commercial kits for the detection of NS1 antigen are

now available in ELISA or rapid test format .

Detection of Antibody(Anti dengue

antibody test )Dengue lgM/lgG test (MAC ELISA or Rapid ICT) Anti –dengue lgM specific antibodies can be detected

3-5 days after the onset of fever . lgM is detected and which increase to 95-98%, by day

6-10. It can be detected in low level up to 1-3 months after

fever . In primary dengue infection –IgM will be more than

lg G early period and increased lg G at 9 or 10th day of fever . Level of this lgG may persist at low levels for decades , indicating past dengue infection .

Detection of antibody(cont..)In secondary dengue infection – higher elevation of

anti- dengue specific lgG antibodies and lower levels of lgM. The higher lgG levels remain for 30-40 days .

Rapid ICT test provides result within 15-20 minutes .

Dengue virus isolation Dengue virus isolation from serum ,plasma and leukocytes is the most definitive test for dengue infection ,which can be accomplished in majority of cases if the sample is taken in the few days of illness .

Isolation of dengue virus from serum ,CSF or autopsy sample

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 sequence by reverse transcription –polymerase chain reaction.

Nucleic Acid Detection The reverse transcriptase ploymerase chain reaction

(RT-PCR)-confirm diagnosis (<5 days of illness ).The amplified DNA viral RNAs can be detected by

tradition or real time PCR.The test is expensive and available only in referral

centers.

Case definitions

Purpose

Case definitions are developed as aid tools for Early Diagnosis and Promote Treatment ,Epidemiological surveillance and Reporting .But this should not supersede the good clinical judgment in individualized situation .The purpose is as follows :

1. For uniformity in clinical case management at both outpatient and inpatient setups .

2. For uniform reporting of the cases to designed appropriate health authority .

Dengue fever Suspected DengueActual febrile illness with two or more of following :

Headache Retro-orbital pain MyalgiaRash Haemorrhagic manifestations Leucopenia (wbc<_5000 cells \mm3)Thrombocytopenia(platelet count<150000 cells/mm3)Rising haematocrit(5-10%)AndHigh index of suspicion based on period ,population & place .AndAbsence of convincing evidence of any other febrile illness .

Probable dengue

Suspected dengue and at least one of following :Supportive serology on single serum sample : titre

>_1280 with haemagglutination inhabition test ,comparable IgG titre with enzyme –linked immunosorbent assay, or testing positive in IgM antibody test .

Confirmed dengue Probable dengue and at least one of the following :

Isolation of dengue virus from serum ,CSF or autopsy samples .

Fourfold or greater increase in serum lgG (by haemagglutination inhalation 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 sequence by reverse transcription –polymerase chain reaction .

Therefore suspected DF and DHF patients should be closely monitored to identify patients with DHF.For efficient management of DHF it is important to understand its natural history and its dynamic nature. Clinical course of DHF is stereotypic and consists of three stages

Febrile phaseCritical phase (leakage phase)Convalescent phase

Febrile phaseFebrile phase is characterized by continuing high fever lasting for 2-7days. Other features seen in the febrile phase include facialflushing/diffuse blanching erythema of the skin, myalgia, arthralgia,headache, nausea and vomiting. Some patients may have sore throat,injected pharynx, conjunctival injection and diarrhoea. Mild haemorrhagicmanifestations can occur. Leucopenia (WBC<5000 mm3) and mildthrombocytopenia (<150,000 /mm3) are common in the late febrile phase.Above features are usually indistinguishable between DF and DHF duringthe febrile phase. However, the presence of tender hepatomegaly favoursthe diagnosis of DHF.

Critical phase (leakage phase)The critical phase is heralded by the onset of plasma leakage. Thisusually occurs towards the late febrile phase, often after the 3rd day offever, usually around the 5th or 6th day of illness with defervescence(settling of fever). However some patients may enter the critical phasewhile having high fever.

Plasma leakage is due to increased capillary permeability. Plasma leakage

in DHF is selective and transient and usually lasts f o r 24-48 hours.

Increased capillary permeability is the result of immune mediators and is

not a result of destruction of capillaries. Though the disease is systemic,

plasma leakage occurs selectively into the peritoneal and pleural spaces.

Pericardial effusion, if there is any, is rather minimal. Generalized or facial

oedema, if seen, is more likely to be due to fluid overload rather than due to

plasma leakage.

With the leakage of plasma there will be haemo-concentration which will

manifest as an increase in HCT. A 20% rise of HCT from the baseline is

indicative of significant plasma leakage. (A smaller rise in HCT which may

be seen in the early phase of the disease is usually due to dehydration). A

rise in HCT less than 20% can be found in patients who received excess

oral/I.V. fluids or in patients with bleeding.Other evidence of plasma leakage are a decrease in serum

albumin(<3.5g/dl) and non-fasting serum cholesterol (<100

mg/dl).

Convalescent phase (recovery phase)This starts after the end of the critical phase and usually lasts 2-5 days.There will be reabsorption of extravasated fluid during this period.Features which would suggest that the patient has reached theconvalescent phase are: Improved general wellbeing and improved appetite Appearance of convalescent rash Generalized itching (more intense in palms and soles) Haemodynamic stability Bradycardia (seen in some patients) Diuresis Stabilization of Haematocrit (HCT) may even be lower than baselinedue to reabsorption of extravasated fluid) Rise in white cell count followed by a rise in the platelet count

Dengue haemorrhagic fever

Suspected DHF

Probable DHF

Suspected DHF and at least one of following :Supportive serology on single serum sample : titre

>_1280 with haemagglutination inhabition test ,comparable IgG titre with enzyme –linked immunosorbent assay, or testing positive in IgM antibody test .

Confirmed DHFProbable 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 haemagglutination inhalation 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 sequence by reverse transcription –polymerase chain reaction .

DHFApproximately 20-30% of cases of dengue H.F. are

complicated by shock (DSS)Fewer than 10% of patients have gross echymosis or

gastro intestinal bleeding usually after a period of corrected shock.

DHFAfter a 24 to 36 hrs period of crisis, convalescence is

fairly rapid in children who recover.The temperature may return to normal before or

during the stage of shock.Bradycardia and ventricular extrasystoles are

common during convalescence.

Dengue shock syndrome Dengue shock syndrome is a presentation of Dengue

syndromes when a case of DHF manifests circulatory failure with one or more of the following features :

Criteria for dengue haemorrhagic fever as above with signs of shock including :

o Tachycardia ,cool extremities ,delayed capillary refill ,weak pulse ,lethargy or restlessness ,which may be a sign of reduced brain perfusion .

o Pulse pressure _< 20mmHg with increased diastolic pressure ,e.g. 100/80mmHg.

o Hypotension by age ,defined as systolic pressure .

Severity grading of dengue syndrome

DF /DHF Grade

Symptoms Laboratory

DF Fever with two or more of the following signs; headache, retro-orbital pain, Myalgia, arthralgia.

Luecopenia occasionally Thromocytopenia may be present, no evidence of plasma leakage.

DHF I Above signs plus positive tourniquet test.

Thrombocytopenia <100,000 HCt rise>20%

DHF II Above signs plus spontaneous bleeding

Thrombocytopenia <100,000, HCt rise>20%.

DHF III Above signs plus circulatory failure (rapid weak pulse, pressure, cold clammy skin, restlessness and capillary refill time >3sec)

Thrombocytopenia <100,000, Het rise >20%

DHF IV Profound shock with undectable blood pressure and pulse

Thrombocytopenia <100,000, rise >20%.

DiagnosisD.FClinical diagnosis (High suspicion)Knowledge of the geographic distribution. Environmental cycles of causal viruses.The term dengue like disease should be used until a

specific diagnosis is established.

DiagnosisD.H.FWHO Criteria For DHF : Fever, Minor or Major Hemorrhagic manifestations.Thrombocytopenia ( < 100000 / mn3)Objective evidence of increased capillary permeability

(hematocrit increased > 20%) X-ray pleural effusionHypoalbuminemia.DSS : Above mentioned criteria plus hypo tension and

narrow pulse pressure ( < 20 mm of Hg)

DiagnosisD.H.FVirologic diagnosis can be established by serologic tests

or by isolation of the virus from blood leukocytes or serum.

Both in primary and second dengue infections, there is relatively transient appearance of anti dengue immunoglobulin IgM antibodies. These antibodies disappear after 6-12 weeks which can be used to time a dengue infection.

DiagnosisD.H.FIn secondary infection most antibody is of the IgG

class.Serological diagnosis depends on a four fold or

greater increase in IgG antibody titer in paired sera

By: Hemaglutination inhibition. Complement fixation Enzyme immunoassay Neutralization tests

DiagnosisD.H.FCarefully standardized immunoglobulin IgM, and IgG

capture enzyme immuno assays are now to identify the acute phase antibodies from patients with primary or secondary dengue infections in single serum samples. (IgG antibody concentrations are abundant in secondary but minimum in primary) usually such samples should be collected not earlier than 5 days nor later than 6 weeks after onset.

D/DD.FThe DDS of DF includes viral respiratory and

influenza like diseases. Early stages of Malaria , mild yellow fever, scrub typhus, viral hepatitis and leptospirosis.

Four arboviral diseases have dengue like courses but without rash – Colorado Tick fever, sand fly fever, Rift valley fever and Ross river

D/DD.H.FMeningo Cocccemia , Yellow Fever other viral

hemorrhagic fevers, many in rickettsial diseases and other severe illneses caused by a variety of agents may produce clinical picture similar to DHF.

Management of those who do not need AdmissionFollowing treatment measures are recommended: Ensure adequate oral fluid intake of around 2500 ml for

24 hours(if the body weight is less than 50kg give fluids as 50ml/kg

for 24hours). This should consist of oral rehydration fluid, coconutwater, other fruit juices, kanji or soup rather than plain

water.Exclude red and brown drinks which could cause confusion

withhaematemesis or coffee ground vomitus.commercial

carbonated drinks that exceed the isotonic level should be avoided.

Adequate physical rest Tepid sponging for fever Paracetamol not exceeding 2 tablets six hourly (reduce

dose forpatients with lower body weights). Warn the patient that

the fevermay not fully settle with paracetamol and advice not to

takeexcess. A nti-emetics and H2 receptor blockers if necessary Avoid all NSAIDS and steroids Withhold Aspirin, Clopidogrel & Dipyridamole in

patients who takethese on long term basis

Advise immediate return for review if any of the following occur:

Clinical deterioration with settling of fever Inability to tolerate oral fluids Severe abdominal pain Cold and clammy extremities Lethargy or irritability/restlessness Bleeding tendency including inter-menstrual

bleeding ormenorrhagia Not passing urine for more than 6 hours

Management Indications of hospitalizations

Restlessness or lethargy frequent vomiting one or two days of febrile illness.

Cold extremities or circumoral cyanosis. Bleeding in any form. Rapid and weak pulse. Capillary refill time > 3 seconds. Narrowing of pulse pressure (<20 mm Hg) or Hypo tension. Hematocrit of 40 or rising hematocrit. Platelet count of < 1,00000/ mm3 Acute abdominal pain Evidence of Plasma leakage. Eg. Pleural effusion /Ascities

Management Dengue fever There is no specific anti viral treatment and The management is essentially supportive and

symptomatic (Bedrest) The key to success is frequent monitoring and

changing strategies depending on clinical and laboratory evaluations.

Management Dengue fever The management of dengue fever is symptomatic

and supportive. Bed rest is advisable during the acute febrile phase. Antipyretics or cold sponging should be used to

keep the body temperature < 400C. Analgesics and mild sedation may be required to

control pain

Management Dengue fever Fluids and electrolyte replacement therapy is

required when there are deficits due to sweating/ fasting / thirsting / vomiting or diarrhea.

Because of the dengue hemorrhageic diathesis aspirin should not be given to reduce fever or control pain.

Management DHFElectrolyte and dextrose Solution ( as used in

diarrhea disease) or Fruit Juice or both are preferable to plain water.

With high fever there is a risk of convulsion and antipyretic drugs may be indicated.

Management DHFAcetaminophen is preferable at the following

doses younger than year of age 60mg / dose, 1-3 years 60-120mg/dose, 3-6 years – 120 mg/dose, 6-12 years 240mg /dose children should be observed closely for early signs of shock. The critical period is the transition from febrile to afebrile phase.

A rise in hematocrit value indicates significant plasma loss and a need for parenteral fluid therapy.

Management DHFIn grade I and II volume replacement can be given in

a period of 12-24 hours.Patients with any signs of bleeding and persistently

high hematocrit values dispite being given volume replacement should be admitted to hospital.

Management DHFThe volume and type of fluid should be similar to that

used in the treatment of diarrhea with moderate isotonic dehydration but the rate should be carefully titrated. The required volume should be charted on a 2 – 3 hours basis and the rate of administration adjusted throughout the 24 – 48 hours period of leakage.

6.5.3 When the patient is in the critical phase (leakage phase)

The fluid requirement, both oral and intravenous, in critical phase (48

hours) is calculated as M+5% (maintenance + 5% deficit). Maintenance

(M) is calculated as follows: For the 1st 10 kg -100 ml/kg For the 2nd 10 kg - 50 ml/kg From 20 kg and above up to 50 kg - 20 ml/kg 5% deficit is calculated as 50 ml/kg up to 50kg

Management DHFSerial haemetocrit determination every 4 – 6 hours

and frequent recording of vital signs are recorded for adjusting the fluid replacement. In order to assume adequate volume replacement and avoid over transfusion.

DHFFluid Management

DHFFluid Management Formula ml / hr = (drop / min) x 3The fluid replacement should be the minimum

volume i.e. sufficient to maintain effective circulation during the period of leakage.

Excessive replacement will cause respiratory distress (from massive pleural effusion and ascites). Pulmonary congestion and edema

D H F Fluid managementThe type of fluid used are 1) Crystalloid and 2)

Colloidal I. Crystalloid 1/3 to ½ of the total fluid as physiologic saline

solution (NS)½ to 2/3 of the remainder as 5% glucose in water. For acidosis ¼ of the total fluid should be 1/6

molar sodium bicarbonate.

D H F Fluid management 5% dextrose in ringer lactate solution 5% dextrose in ringer acetate solution 5% dextrose in half strength NS. 5% dextrose in NS solution.

Fluid management Colloids Dextran 40 and plasma Management of Shock :DSS is a medical emergency that requires prompt

and vigorous volume replacement therapy.There are also electrolytes (sodium) and acid base

disturbances it must be consider that there is a high potential for developing DIC. And stagnant acidemia. Blood will promote and or enhance DIC which may lead to sever hemorrhage and or irreversible shock.

The replacement of plasma loss Immediate replacement of plasma loss with isotonic

salt solution (5% dextrose in ringer acetate solution or 5% dextrose in NS) at the rate of 10-20ml / kg body weight are in case of profound shock (grade-4) as a bolus of 10ml/kg body weight (1-2 times) should take place.

ABCSIf the patient is not responding to two boluses of crystalloid, contributorycauses for shock other than plasma leakage should be considered. Theseare,

Acidosis check venous blood gas (if present, check liver and renal profiles)

Bleeding check HCTCalcium and other electrolytes (sodium and

potassium) - check serumSugar check random capillary blood sugar

It is important to correct these conditions as quickly as possible. If the

patient is clinically acidotic one dose of 50 ml of 8.4% sodium bicarbonate

may be given empirically if blood gas cannot be assessed.Empirical treatment with 10% calcium gluconate 10 ml over 10

minutes is justifiable if a patient is in shock and is not responding to

adequate fluid replacement, this may be continued six hourly. IV calcium

gluconate maybe used in patients who show evidence of myocardial involvement

as well,as hypocalcaemia is common in DHF patients and calcium may

improve the myocardial contractility in such patients

If the blood g l u c o s e l e v e l i s less than 7 0 mg/dl correct it by giving

15 – 20g glucose orally or intravenously. At the time of shock, use

30–40 ml of 50% Dextrose (15-20g) intravenously. Re-check capillary

blood sugar in 15 minutes and if it is less than 7 0 mg/dl repeat 30-

40ml of 50% Dextrose intravenously.

The replacement of plasma lossIn case of continued or propound shock (with high

haematocrit values) colloidal fluid (dextran or medium molecular weight in NSS or plasma) should be given the following initial fluid at a rate of 10-20ml/kg body weight / hour.

Blood transfusion is indicated in cases with profound and persistent shock dispite declining hematocrit values after initial fluid replacement

The replacement of plasma lossWhen improvement is apparent the rate of I/V fluid

replacement should be reduced and adjusted 1-2 hourly throughout the 24 hours period.

Colloidal fluid is indicated in cases with massive leakage and to whom a large volume of crystalloid fluid as been given.

The replacement of plasma lossIn small children 5% dextrose in a half strength

normal saline solution (5% dextrose / ½ NSS ) initial resuscitation and 5% dextrose in ½ NSS may be used in infants under 1 year age. If the serum sodium is normal.

D H F Discontinuation of IV fluids WHEN:The hematocrit reading drops to around 40% Vital signs are stable. A good urine out flow indicates sufficient circulate

renal volume. A return of appetite and diuresis are signs of recovery

D H F Discontinuation of IV fluidsIt is extremely important to emphasize that a drop in

heamatocrit reading at this stage should not be interpreted as a sign of internal hemorrhage.

Strong pulse, BP with wide pulse pressure and diuresis are good vital signs during this re-absorption phase.

D H F Management (contd) Sedations are needed in some cases because of

marked agitation. Hepatotoxic drugs should be avoided. Chloral hydrate orally or rectally recommended in a

dose of 30 – 50 mg/kg as a single hypotonic dose (maximum dose 1gram).

D H F Management (contd) In cases without pulmonary complications

paraldehyde 0.1ml/kg I.M. (maximum dose 10ml) also be use.

Oxygen therapy should be given to all patients in shock. The oxygen mask or tent may increase apprehension.

Management of fluid overload Review the total intravenous fluid therapy and

clinical course and check and correct for abcs.All hypotonic solution should be stopped . Switch from crystalloid to colloid solutions as bolus

fluid .Dextran 40 is effective as 10 ml/kg bolus infusion , but

the dose is restricted to 30ml/kg/day because of its renal effects .

ManagementBlood transfusion Transfusion with fresh whole blood is preferable and

the amount to given should be such that normal RBC concentration is not exceeded.

Fresh Frozen Plasma (FFP) may be indicated in cases where consumptive coagulopathy causes massive bleeding. DIC is usual in sever shock and may play an important part in the development of massive bleeding or lethal shock.

ManagementPlatelet transfusionPlatelet transfusion in cases of DHF / DSS is also

surrounded with controversies. Mild reductions in platelet counts are usually not associated with significant bleeding.

Secondly thrombocytopenia in DHF / DSS is a short lived phenomenon with platelets returning to normal by 7 to 9 days.

Management Platelet transfusionPlatelet transfusions are recommended only for

children with platelet count of 50,000 / mm3 and having significant bleeding manifestations.

Prophylactic platelet concentrate is indicated when platelet count is less than 10000-20000 / mm3 (10 to 20ml / kg of platelet).

PolyserositiesNeed the insertion of intercostal tube or ascitic drainage

respectively. Caution must be taken before drainage as the chances of

sever hemorrhages are high.Patients should be haematologically stabilized first with use

of fresh whole blood, FFP or platelet concentrates and drainage of these fluids should be done slowly to prevent sudden circulatory collapse.

PolyserositiesLarge pleural effusions during the recovery phase

after 48 hours may need small doses of frusemide (0.25 to 0.5 mg / kg B/w 6th hourly) with these method it may possible to avoid insertion of intercostal drains.

Generally steroids do not shorten the duration of disease or improve the prognosis in children receiving careful supportive therapy.

Management of Hepatic Encephalopathy in DHF Maintain adequate airway and oxygenation Infuse minimal intravenous fluids sufficient to maintain

intravascular volume (80% of maintenance) Use hyper-oncotic colloid solution early if HCT is increased Infuse Mannitol to reduce intracranial pressure if renal

functions are normal Take measures to maintain serum sodium in-between 145-155

meq/L. (3% hypertonic saline may be of use if Mannitol cannot be used, and if serum sodium is very low)

Maintain blood sugar above 60 mg/dl Give a single dose of Vitamin K 10 mg IV Give Lactulose to maintain 3-4 bowel motions per day. However,

lactulose commonly causes gaseous abdominal distension and this may interfere with respiration in these patients and may even cause aspiration

Treat with broad spectrum antibiotics, which are not excreted through liver, if secondary bacterial infection is suspected (Cefotaxime is preferred)

Oral Metronidazole may be used (supportive evidence is limited)

Ventilate (IPPV) early, if the features of encephalopathy are getting worse

Fresh Frozen Plasma (FFP) should not be used routinely, but may be

used if there is active bleeding or prior to invasive procedures.

(However, be aware of possible fluid overload with FFP)

Bowel washes and enemas should be avoidedThere is no evidence to support the use of L-

Arginine L-Ornithine (LOLA)or N-Acetyl Cysteine (NAC) in these patients and

therefore, use of which isnot recommended

Dengue in Co-morbid ConditionsLiver Disease:Baseline liver function tests (LFT) including prothrombin time

(PT) is ofvalue when dengue is suspected in patients with chronic liver

disease. IfAST/ALT is very high the patient is likely to develop neurologicalinvolvement (Hepatic Encephalopathy) especially in those with

gastrointestinal(GI) bleeding. In such patients liver failure regime should beused early . If baseline albumin level is low these patientsmay have more plasma leakage.

Managing these patients with theminimum amount of IV fluids to maintain intravascular

volume in order toprevent respiratory distress (acute pulmonary oedema)

and/or heartfailure is crucial. Prolonged PT or INR (>1.3) indicates

that these patientshave a tendency for more bleeding and therefore Vitamin

K1 IV isrecommended. In addition, assessment of the degree of

bleeding andtransfusing adequate amount of blood and blood

components areimportant considerations.

Heart Disease:The key consideration in patients with heart diseases would be

to identifythe underlying heart disease and the current medication.

These patientsshould be observed carefully with close and continuous

monitoringpreferably echocardiography especially during the critical

phase. Carefuladjustment of IV fluid is the key to success and to prevent

complications.Those who are on anti-platelet or anti-coagulation therapy arerecommended to stop the medication for a few days especially

during thecritical phase.

Myocardial Involvement in DengueGlobal dysfunction of myocardial contractility may be seen

in DHF patientswho are in prolonged shock and the most likely reason is

metabolicacidosis. However hypocalcaemia (which is a common

finding in DHFpatients with moderate to large pleural effusion / ascites)

should beconsidered as well.Hence, if there is evidence of cardiac dysfunction,

acidosis andhypocalcaemia should be corrected quickly

Empirical treatment with calcium is justifiable if clinically indicated.

Myocarditis is an uncommon finding in Dengue and is very unlikely to

cause death in a patient with DHF. However, such a patient could easily

develop pulmonary oedema with fluid overload.Therefore, if myocardial Involvement is

suspected fluid should begiven very carefullyTreatment of myocardial Involvement is

symptomatic.

Diabetes Mellitus:Frequent monitoring of blood sugar is important from

the time the patientsare admitted to hospital. All anti-diabetic drugs have to

be switched toinsulin in order to keep blood sugar level preferably

below 150-200mg/dl.Closely monitor the patient and look for the possible

development ofDiabetic Ketoacidosis where patient will need more IV

fluid, IV insulin asan infusion and monitoring of central venous pressure if

possible. Managethe commonly associated conditions with DM, e.g.

hypertension

Renal Disease:The baseline renal function tests (Blood Urea, Creatinine), electrolytes,acid-base balance, GFR, urine output per day and urine analysis shouldbe performed during the early febrile phase and regularly tested during

thecourse of the illness. Close monitoring of fluid intake and urine output

isvery important. Fluid overload during convalescent phase is the mostimportant cause of death among these patients. Early consultation

with aNephrologist and early planning of any renal replacement therapy in

thosepatients who are oliguric with signs and symptoms of fluid overload isimportant.

Management of Pregnant patients with DF/DHF close to delivery

Risk of bleeding is at its highest during the period of plasma leakage therefore ,

Unless to save mothers life, avoid Lower segment caesarean section during the critical ( plasma leakage ) phase.

Obstetric procedure should be avoided . If obstetric procedure are to be undertaken ,Maintain the platelet count above 50,000/mm3. Single donor platelet transfusion is preferred , if

available , if platelet transfusion is necessary .

If patient goes into spontaneous labor during critical phase take steps to prevent vaginal tears by performing an episiotomy.

Increase of fetal compromise priority should be given to the mothers life .

MonitoringPatients should be monitored constantly until there is

a reasonable certainly that the danger as passed in practice.

Pulse, BP, RR & Temp. be taken every 15 to 30 minutes are more often until the shock resolves.

Monitoring Hematocrit or Hb studies should be performed

every two hours for the first six hours then every four hours thereafter until the patient is stable.

Accurate record of intake and output including the type of fluid given should be made.

Management of Epidemic Dengue Hemorrhagic Fever During epidemics, outpatient and inpatient facilities

may be overwhelmed. It is essential that only children requiring hospital

care be admitted. A recently elevated body temperature and positive

tourniquet test are sufficient to suggest DHF

Management of Epidemic Dengue Hemorrhagic FeverWhen possible, a microhematocrit and platelet count

should be done in the outpatient department. Patients with thrombocytopenia and elevated

hematocrit counts should be sent to a rehydration ward or, if hematocrit does not fall or rises in the face of fluid therapy, admitted to hospital.

Management of Epidemic Dengue Hemorrhagic Fever. If a patient lives a long distance from the hospital

and nearby accommodations are not available, admission for observation may be necessary.

Regulatory Measures Dengue diseases are not subject to international

surveillance regulations. An intensive and effective voluntary reporting system has been devised by the regional offices of the World Health Organization.

Prognosis Children who develop profound shock rapidly with

no detectable diastolic pressure or with unobtainable blood pressure.

Children in shock with delayed admission to hospital.

Children in shock with gastrointestinal hemorrhage have a poor prognosis.

Mortality rates may exceed 50 per cent in these groups.

Discharge criteria

PREVENTION Tissue culture-based vaccines for dengue virus

types 1, 2, 3 and 4 are immunogenic but not available for general use.

Prophylaxis depends on use of insecticides, repellents, body protective clothing, and screening of houses to avoid the bite of the mosquito.

Destruction of A. aegypti breeding sites also is effective.

PREVENTION If water storage is mandatory, a light-fitting lid or a

thin layer of oil may prevent egg deposits or hatching.

A larvicide, such as Abate, available as a 1% sand granule formulation and effective at a concentration of 1 part per million, may be added safely to drinking water.

EPIDEMIC MEASURES

World Health Organization recommendations are as follow :

On the basis of epidemiologic and entomologic information, the size of the area that requires adult mosquito abatement should be determined.

With technical malathion or fenitrothion at 438 ml/ha, two adulticidal treatments at a 10-day interval should be made by use of a vehicle-mounted or portable ultra-low-volume aerosol generator or mist blower.

EPIDEMIC MEASURESCities of moderate size should stockpile at least one

vehicle-mounted aerosol generator, five mist blowers, 10 swing fog machines, and 1000 liters of ultra-low-volume insecticides to be prepared to carry out adulticidal operations over a 20-km2 area rapidly.

EPIDEMIC MEASURES With limited funds, such equipment and

insecticides can be stockpiled centrally for rapid transportation where required. Priority areas for launching ground applications are those having a concentration of cases.

EPIDEMIC MEASURES Special attention should be focused on areas where

people congregate during daylight hours, for example, hospitals and schools. If necessary, ultra-low-volume insecticides may be applied from aircraft. C47 or similar aircraft, smaller agricultural spray planes, and helicopters have been used to make aerial applications.

During the early stages of epidemics, ultra-low-volume spray of 4 % malathion in diesel oil or kerosene may be used to spray all houses within a 100-m radius of the residence of DHF patients.

Eradication and Control A. aegypti was eradicated from countries and whole

continents with use of the techniques pioneered by the Rockefeller Foundation.

With time, the species successfully reestablished itself in much of its former range.

Eradication and ControlAn eradication campaign in the United States was

abandoned and was replaced by a program of disease surveillance and containment of introduced virus.

Eradication and Control Mosquito control or eradication programs require

the simultaneous use of two approaches: Reduction in breeding sites Application of larvicides Alternatively, a significant reduction in population

may be effected by closely spaced application of adulticides.

Reduction in breeding sitesSource reduction campaigns should be well

organized, supervised, and evaluated. Includes proper disposal of discarded cans, bottles,

tires, and other potential breeding sites not used for storage of drinking or bathing water.

Drinking and bathing water storage containers and flower vases should be emptied completely once weekly.

Reduction in breeding sites

Water containers that can not be emptied should be treated with Abate 1% sand granules at dosage of 1 ppm (e.g., 10 g of sand to 100 L of water).

Treatments should be repeated at intervals of 2 to 3 months.

Application of larvicides

Vehicles-mounted or portable ultra-low-volume aerosol generators or mist blowers can be used to apply technical grade malathion or fenitrothion at 438 mL/ha.

Three applications made at 1-week intervals can suppress. A aegypti populations for about 2 months.

Health Education A. aegypti control has been maintained effectively

in some tropical areas through the simple expedient of emptying water containers once a week.

During the yellow fever campaigns, strong sanitary laws made the breeding of mosquitoes on premises a crime punishable by fine or jail

Health Education In the modern era, Singapore and Cuba have

adopted these measures successfully. Health education through mass media or through

the schools has been attempted in Burma, Thailand, Malaysia, and Indonesia without spectacular success.