DENGUE FEVER

Ppt by: BARIRA FAREED, PHARM D 4TH YR, 170512882007, SVCP.

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CONTENTS : Introduction Epidemiology Etiology Pathophysiology Classification Clinical presentation Diagnosis Management Prevention Vaccines

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INTRODUCTION

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Dengue fever is an acute infectious viral disease, also known as breakbone fever.

It is a arthropod-borne (arboviral ) illness in human . It is caused by infection with 1 of the 4 serotypes of dengue virus (DENV1,2,3,4), which is a Flavivirus (a genus of single-stranded nonsegmented RNA viruses).

Once affected persons acquire long-life serotype specific immunity.

Dengue is transmitted by mosquitoes of the genus Aedes and species aegypti and albopticus.

Dr Benjamin Rush a professor of chemistry and medical theory at the UPEN, during the Philadelphia epidemic 1779 -1780 , first described the dramatic symptoms of dengue as break bone fever.

A small percentage of persons who have previously been infected by one dengue serotype develop bleeding and endothelial leak up on infection with another dengue serotype. This syndrome is termed dengue hemorrhagic fever (DHF). Also been termed dengue vasculopathy.

Vascular leakage in these patients results in hemoconcentration and serious effusions and can lead to circulatory collapse.

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This, in conjunction with severe hemorrhagic complications, can lead to dengue shock syndrome(DSS), which poses a greater fatality risk than bleeding .

EPiDeMIOLOGY :

In India first outbreak of dengue was recorded in 1812.

A double peak hemorrhagic fever epidemic occurred in India for the first time in Calcutta between July 1963 & March 1964

In New Delhi, outbreaks of dengue fever reported in 1967,1970,1982, 1996, 2012& 2015

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An estimated 5,00,000 cases of DHF require hospitalization each year, of which a very large proportion are children. At least 2.5% of cases die without proper treatment.

A rapid rise in urban populations is bringing greater numbers of people into contact with this vector, especially in areas that are favorable for mosquito breeding, e.g. where household water storage is common and where solid waste disposal services are inadequate.

Increased worldwide distribution of disease seen after World War II 7

Etiology : Dengue infection is caused by dengue virus

(DENV), which is a single-stranded RNA virus (approximately 11 kilobases long) with an icosahedral nucleocapsid and covered by a lipid envelope. The virus is in the family Flaviviridae, genus Flavivirus, and the type-specific virus is yellow fever.

Transmission of dengue virus into the host is through the vectors AEDES EGYPTI AEDES ALBOPTICUS

http://www.cdc.gov/dengue/vector 8

Dengue is transmitted by infected female mosquito.

A.egypti is a primarily a daytime feeder. It lives around human habitation.

Lays eggs and produces larvae preferentially

in artificial containers . Only the female aedes mosquito bites as it needs the protein in blood to develop its eggs.

The mosquito becomes infective approximately 7 days after it has bitten a person carrying the virus.

This is the extrinsic incubation period, during which time the virus replicates in the mosquito and reaches the salivary glands.

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The mosquito remains infected for the remainder of its life. The life span of A aegypti is usually 21 days but ranges from 15 to 65 days.

The mosquito can lay eggs about 3 times in its lifetime, and about 100 eggs are produced each time.

The eggs can lie dormant in dry conditions for up to about 9 months, after which they can hatch if exposed to favourable conditions, i.e. water and food.

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Pathophysiology :

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The transmission cycle of dengue virus by the mosquito Aedes aegypti begins with a dengue-infected person. This person will have virus circulating in the blood—a viremia that lasts for about five days.

During the viremic period, an uninfected female Aedes aegypti mosquito bites the person and ingests blood that contains dengue virus.

Then, within the mosquito, the virus replicates during an extrinsic incubation period of eight to twelve days.

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The mosquito then bites a susceptible person and transmits the virus .

The virus then replicates in the second person and produces symptoms. The symptoms begin to appear an average of four to seven days after the mosquito bite—this is the intrinsic incubation period, within humans.

It can range from 3 to 14 days (average 4-7 days).

While viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells

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This result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections.

Fever typically begins on the third day of illness and persists 5-7 days, abating with the cessation of viremia. Fever may reach 41C°.

Occasionally, and more frequently in children, the fever abates for a day and recurs, a pattern that is termed a saddleback fever; however, this pattern is more commonly seen in dengue hemorrhagic fever.

15http://www.cdc.gov/dengue/

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There are actually four dengue clinical syndromes:• Undifferentiated fever;

• Classic dengue fever;

• Dengue hemorrhagic fever, or DHF; and

• Dengue shock syndrome, or DSS.

• Dengue shock syndrome is actually a severe form of DHF.

Dengue classification :

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Clinical presentation : Prodrome of chills, erythematous mottling of

the skin, and facial flushing (a sensitive and specific indicator of dengue fever). The prodrome may last for 2-3 days.

Children younger than 15 years usually have a nonspecific febrile syndrome, which may be accompanied by a maculopapular rash.

Classic dengue fever begins with sudden onset of fever, chills, and severe (termed breakbone) aching of the head, back, and extremities, as well as other symptoms. The fever lasts 2-7 days and may reach 41°C. Fever that lasts longer than 10 days is probably not due to dengue.

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According to the Pan American Health Organization (PAHO), the clinical description of dengue fever is an acute febrile illness of 2-7 days duration associated with 2 or more of the following:

• Severe and generalized headache• Retro-orbital pain• Severe myalgia's, especially of the lower

back, arms, and legs• Arthralgia's, usually of the knees and

shoulders• Characteristic rash (maculopapular)• Hemorrhagic manifestations(eg, petechiae,

bleeding gums, epistaxis, menorrhagia, hematuria)

• Thrombocytopenia• Leukopenia.

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Additional findings may include the following:

Injected conjunctivae Facial flushing, a sensitive and specific

predictor of dengue infection Inflamed pharynx, lymphadenopathy ,

hepatic injury Nausea and vomiting, nonproductive cough ,

sore throat Tachycardia, bradycardia, and conduction

defects,anorexia Increasing hematocrit (20% absolute rise

from baseline) and low albumin (signs of hemoconcentration preceding shock), more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal)

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Fever typically abates with the cessation of viremia. Occasionally, and more commonly in children, the fever abates for a day and then returns, a pattern that has been called saddleback fever.

Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence.

Abdominal pain in conjunction with restlessness, change in mental status, hypothermia, and a drop in the platelet count presages the development of dengue hemorrhagic fever.

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If left untreated, dengue hemorrhagic fever most likely progresses to dengue shock syndrome. Common symptoms in impending shock include abdominal pain, vomiting, and restlessness. Patients also may have symptoms related to circulatory failure.

https://en.wikipedia.org/wiki/Dengue_fever

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25WHO: Guidelines for diagnosis, treatment, prevention and control Geneva 2009

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Diagnosis : Based on clinical signs , travel history , ruling

out other diseases (such as malaria, typhoid fever, rubella, measles, acute febrile syndrome)

Diagnostic tests

Direct – detection of viral components :

• RT- PCR• NS-1 AG detection by ELISA or lateral flow

rapid test

Indirect by serology

28WHO: Guidelines for diagnosis, treatment, prevention and control Geneva 2009

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NS- 1 Ag : Structural protein secreted by all flaviviridae Detectable upto 10 days after onset of

illness Disappear once seroconversion has occurred ELISA/rapid test lat flow serology NS-1

specific IgM, IgG Many commercial rapid test :15mn Not FDA approved Sensitivity in first 5 days – febrile phase,

>90% for primary infection, 60-80% for secondary infection.

Cross reactivity due to other flaviviridae. Lateral flow test : IgG, IgM, NS-1 Ag ( not

available in US)

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DENV-1 TO 4 RT-PCR : Useful for first five days of symptoms 80-90% sens, >90% specificity Better sensitivity when combined with

serology follow FDA approved in 2012 for diagnostic use in

USA Kits were available for distribution july, 2012.IgM capture ELISA (MAC ELISA) : Detected as early as 4 days after the onset

of fever False positive sec to cross reactivity within

other faviviridae (recent vaccines) Sensitivity 61.5-99% FDA approved MAC -ELISA in april 2011 If negative even then repeated within 6 days

—> PCR or NS-1 Ag

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Viral cell culture : Its confirmatory , identifies serotype . Needs acute serum sample(first 5 days) Does not differentiate between primary and

secondary Can be done only at research lab PRNT : Plaque reduction and neutralisation assay,

it’s a most specific serology tool . Measures titer and neutralising antibodies Labor intensive, requires maintenance of

very specific cell lines Limited to research lab.

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Management :General approach :

Dengue fever is usually a self-limited illness. There is no specific antiviral treatment

currently available for dengue fever. Supportive care with analgesics, fluid

replacement, and bed rest is usually sufficient. Aspirin, nonsteroidal anti-inflammatory drugs

(NSAIDs), and corticosteroids should be avoided.

Management of severe dengue requires careful attention to fluid management and proactive treatment of hemorrhage.

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The Novartis Institute for Tropical Diseases (NITD) in Singapore is carrying out research to find inhibitors of dengue viral target proteins to reduce the viral load during active infection.GOALS :

Reduce mortality rate Decrease the progression of disease state Maintain hydration , platelet levels ,

hematocrit levels Decrease the viral load in the body To reduce the complications associated with

dengue (cardiomyopathy , hepatic injury, seizures, pneumonia etc.)

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Factors that affect disease severity and prognosis include the following:

Patient age Pregnancy Nutritional status Ethnicity Sequence of infection with different dengue

serotypes Virus genotype Quality and extent of available medical care

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NON PHARMACOLOGICAL :BED REST FOR

DHF/DSS

FLUID INTAKE

VECTOR CONTRO

L METHOD

S

MOSQUITO REPELLEN

TS

MAINTAIN HYGEINE

PATIENT EDUCATION

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Vector Control Methods:1.Biological and Environmental Control2.Biological control . Largely experimental . Option: place fish in containers to eat larvae . Environmental control Elimination of larval habitats . Most likely method to be effective in the long term3.Chemical Control: . Larvicides may be used to kill immature aquatic stages

. Ultra-low volume fumigation against adult mosquitoes . Mosquitoes may have resistance to commercial aerosol sprays

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PHARMACOLOGICAL : Supportive only as there is no antiviral

against DENV

Oral rehydration therapy is recommended for patients with moderate dehydration caused by high fever and vomiting. Antipyretic (acetaminophen 325-600mg Q4hr) to be given to reduce fever .

Patients with known or suspected dengue fever should have their platelet count and hematocrit measured daily from the third day of illness until 1-2 days after defervescence.

Patients who develop signs of dengue hemorrhagic fever warrant closer observation(ICU).

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Activities at the first level of care should focus on: – recognizing that the febrile patient could have dengue; – notifying early to the public health authorities that the patient is a suspected case of dengue;

– managing patients in the early febrile phase of dengue; – recognizing the early stage of plasma leakage or critical phase and initiating fluid therapy;

– recognizing patients with warning signs who need to be referred for admission and/or intravenous fluid therapy to a secondary health care facility;

– recognizing and managing severe plasma leakage and shock, severe bleeding and severe organ impairment promptly and adequately

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Admission for intravenous fluid administration is indicated for patients who develop signs of dehydration, such as the following:

Tachycardia Prolonged capillary refill time Cool or mottled skin Diminished pulse amplitude Altered mental status Decreased urine output Rising hematocrit (polycythemia) Narrowed pulse pressure Hypotension

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In DHF , blood transfusion is required (if significant bleeding)

Intravascular volume deficits should be corrected with isotonic fluids such as Ringer lactate solution. Boluses of 10-20 mL/kg should be given over 20 minutes and may be repeated.

If this fails to correct the deficit, the hematocrit value should be determined. If it is rising, limited clinical information suggests that a plasma expander may be administered. Starch, dextran 40, or albumin 5% at a dose of 10-20 mL/kg may be used.

Patients with internal or gastrointestinal bleeding may require transfusion, and patients with coagulopathy may require fresh frozen plasma.

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After patients with dehydration are stabilized, they usually require intravenous fluids for no more than 24-48 hours. Intravenous fluids should be stopped when the hematocrit falls below 40% and adequate intravascular volume is present.

Patients with dengue hemorrhagic fever or dengue shock syndrome may be discharged from the hospital when they meet the following criteria: Afebrile for 24 hours without antipyretics Good appetite, clinically improved condition Adequate urine output, stable hematocrit

level At least 48 hours since recovery from shock No respiratory distress, platelet count greater

than 50,000 cells/μL

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Special population :Pregnancy : Dengue in pregnancy must be carefully

differentiated from preeclampsia. An overlap of signs and symptoms, including

thrombocytopenia, capillary leak, impaired liver function, ascites, and decreased urine output may make this clinically challenging.

Pregnant women with dengue fever respond well to the usual therapy of fluids, rest, and antipyretics.

If the mother acquires infection in the peripartum period, newborns should be evaluated for dengue with serial platelet counts and serological studies

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Monitoring parameters : Body temperature Respiratory rate Heart rate Blood pressure Pulse pressure/ volume Capillary refill time Abdominal pain Bleeding Vomiting

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Prevention : The only way to prevent dengue virus

acquisition is to avoid being bitten by a vector mosquito.

Wear N,N-diethyl-3-methylbenzamide (DEET)–containing mosquito repellant

Wear protective clothing, preferably impregnated with permethrin insecticide

Remain in well-screened or air-conditioned places

The use of mosquito netting is of limited benefit, as Aedes are day-biting mosquitoes

Eliminate the mosquito vector using indoor sprays

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Vaccines : No vaccine is currently approved for the

prevention of dengue infection. Because immunity to a single dengue strain

is the major risk factor for dengue hemorrhagic fever and dengue shock syndrome, a vaccine must provide high levels of immunity to all 4 dengue strains to be clinically useful.

Tetravalent LA dengue virus strains based on yellow fever –dengue virus [CYD-TDV]

Future directions : TV003 a single dose of LATV – induced a trivalent or greater Nab response in 90% of flavivirus-naive adults

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References : Wagner D, de With K, Huzly D, Hufert F,

Weidmann M, Breisinger S, et al. Nosocomial acquisition of dengue. Emerg Infect Dis. 2004 Oct. 10(10):1872-3

www.cdc.gov/dengue/

"Travelers' Health Outbreak Notice". Centers for Disease Control and Prevention. 2 June 2010.

Center for Disease Control and Prevention.

"Chapter 5 – dengue fever (DF) and dengue hemorrhagic fever (DHF)“

WHO : Guidelines for diagnosis, treatment, prevention and control, World health organisation new edition GENEVA 2009.

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ACTION AGAINST DENGUE Dengue Day Campaigns Across Asia. World Health Organization. 2011

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