DENGUE FEVER : Dr. HARISH DENGUE FEVER Introduction : Introduction Dengue - the most important mosquito-transmitted viral disease in terms of morbidity and mortality
Dengue fever is a acute febrile syndrome occurring in tropical regions
the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation (DIC) known as dengue hemorrhagic fever (DHF Slide 3: In 20-30% of DHF cases, the patient develops shock, known as the dengue shock syndrome (DSS).
Worldwide, children younger than 15 years comprise 90% of DHF subjects HISTORY : HISTORY Dengue is a homonym for the African ki denga pepo, which appeared in English literature during an 1827-28 Caribbean outbreak.
The earliest known documentation of denguelike symptoms was recorded in the Chinese Encyclopedia of Symptoms during the Chin Dynasty (AD 265-420)
The first definite clinical report of dengue is attributed to Benjamin Rush in 1789, but the viral etiology and its mode of transmission via mosquitos were not established until the early 20th century. Slide 5: The illness was called "the water poison" and was associated with flying insects near water
In 1779-1780, the first reported outbreak of dengue fever (DF) occurred almost simultaneously in Asia, North America, and Africa. This indicates that the virus and its vector have a worldwide distribution in the tropical regions of the world EPIDEMLOGY : EPIDEMLOGY Dengue virus causes about 100 million cases of acute febrile disease annually, including more than 500,000 reported cases of DHF/DSS.
Currently, dengue is endemic in 112 countries.
The world's largest known epidemic of DHF/DSS occurred in Cuba in 1981, with more than 116,000 persons hospitalized and as many as 11,000 cases reported in a single day PATHOPHYSIOLOGY : PATHOPHYSIOLOGY Dengue viral infections frequently are not apparent.
Classic dengue primarily occurs in nonimmune, nonindigenous adults and children.
Symptoms begin after a 5- to 10-day incubation period. DHF/DSS usually occurs during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype Slide 10: The pathologic process of dengue infection starts with an intimate relationship between the host and the vector that carries the virus.
Humans become infected with the virus after an infected mosquito feeds or probes on the susceptible human host
Rare reports of human-to-human transmission via needlestick injuries have also been published Slide 12: Typical dengue fever is a self-limiting, acute, febrile illness, which occurs after an incubation period of 4-7 days
In younger children, it may be accompanied by a maculopapular rash
In older patients, the disease may also be mild or it may be more incapacitating, with rapid onset of high fever, headache, retroorbital pain, diffuse body pain (both muscle and bone), weakness, vomiting, sore throat, altered taste sensation, and a centrifugal maculopapular rash Slide 13: This painful "breakbone" and febrile phase lasts 2-7 days and, afterward, most patients slowly improve.
Dengue virus disappears from the bloodstream at approximately the same time that the fever dissipates.
Leukopenia and thrombocytopenia--caused by direct destructive actions of the virus on bone marrow precursor cells
The resulting active viral replication and cellular destruction in the bone marrow are believed to cause the bone pain Slide 14: Approximately one third of patients with dengue fever may have mild hemorrhagic symptoms, including petechiae, gingival bleeding, and a positive tourniquet test (>20 petechiae in an area of 2.5 cm X 2.5 cm) Slide 15: plasma leakage
The critical feature of dengue hemorrhagic fever
This results from endothelial gaps in the peripheral vascular bed without necrotic or inflammatory changes in the endothelium Dengue hemorrhagic fever : Dengue hemorrhagic fever The acute febrile illness (temperatures ≤40°C), like that of dengue fever, lasts approximately 2-7 days
the fever reappears, giving a biphasic or "saddleback" fever curve that is not observed in individuals with dengue fever Slide 17: Along with this biphasic fever, patients with dengue hemorrhagic fever have progressive thrombocytopenia, increasing hematocrit (20% absolute rise from baseline) that leads to hemoconcentration, more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal). Slide 18: patients with dengue hemorrhagic fever may have circulatory failure and hepatomegaly.
The major pathologic difference between dengue fever and dengue hemorrhagic fever is that the marked vascular leakage, with resultant hemoconcentration and serous effusions, can lead to circulatory collapse (ie, dengue shock syndrome). Slide 19: The mechanism of progression from dengue fever to dengue hemorrhagic fever is not clearly understood.
immune enhancement is the most commonly accepted current explanation
hypothesis : individuals who have had a prior infection (ie, primary infection) with 1 of the 4 dengue virus serotypes have circulating nonneutralizing antiviral antibodies. Slide 20: When an individual is infected with another serotype (ie, secondary infection), these nonneutralizing antibodies recognize the dengue virus but do not neutralize or inhibit virus replication
the virus and antibody form an antigen-antibody complex.
This complex is recognized by receptors on macrophages, which then internalize the immune complex and allow the virus to replicate unchecked (ie, immune enhancement). Slide 21: The affected macrophages release vasoactive mediators that increase vascular permeability
leading to vascular leakage, hypovolemia, and shock
Recent research demonstrated that this mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis. Slide 22: Cascades activation after virus infecting
Suppressor T cell cascade:
DV-specifi c antibody cascade:
Helper T cell cascade,
Cytotoxic cascade, Slide 23: Suppressor T cell cascade: Cascade 1: SYMPTOMS : SYMPTOMS Fever
Abrupt onset, rising to 39.5-41.4°C
Accompanied by frontal or retro-orbital headache
Lasts 1-7 days, then defervesces for 1-2 days
Biphasic, recurring with second rash but not as high Slide 27: Rash
Initial rash transient, generalized, macular, and blanching; occurs in first 1-2 days of fever
Second rash occurring within 1-2 days of defervescence, lasting 1-5 days
Second rash morbilliform, maculopapular, sparing palms and soles
Occasionally desquamates Slide 28: Bone pain
Absent in dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS)
After onset of fever
Increases in severity
Not associated with fractures
May last several weeks
Most common in legs, joints, and lumbar spine OTHER : OTHER Nausea and vomiting
Abdominal pain (severe in DHF/DSS) WHO CLASSIFICATION : WHO CLASSIFICATION Grade 1 : fever with constitutional symptoms, with positive tourniquet test or scattered petechiae
Grade 2: same as grade 1 but spontaneous hemorrhagic manifestation
Grade 3 : circulatory failure – rapid,weak pulse,narrowing of pulse pressure or hypotension Slide 31: Grade 4 ; profound shock with undetectable pulse and blood pressure SYNDROMS : SYNDROMS Classic dengue fever (DF)
Children younger than 15 years usually have a nonspecific febrile syndrome, which may be accompanied by a maculopapular rash.
The febrile and painful breakbone phase lasts approximately 2-7 days and is followed by a period of slow but complete recovery. The convalescent phase may last for 2 weeks. Slide 33: Patients present with fever and any combination of the following symptoms:- Headache,Retroorbital pain,General body pain (arthralgias, myalgias),Vomiting,Centrifugal maculopapular rash, Weakness,Altered taste sensation,Anorexia,Sore throat,Mild hemorrhagic manifestations (eg, petechiae, bleeding gums, epistaxis, menorrhagia, hematuria,lymphadenopathy Dengue hemorrhagic fever : Dengue hemorrhagic fever Initial phase is similar to that of dengue fever and other febrile viral illnesses.
then the fever breaks, after 2-7 days, signs of plasma leakage appear, suggesting the diagnosis of dengue hemorrhagic fever (usually within 24 h before or after fever resolution) Slide 35: The World Health Organization (WHO) has 4 minimal criteria to make the diagnosis of dengue hemorrhagic fever:
Hemorrhagic manifestations (eg, hemoconcentration, thrombocytopenia, positive tourniquet test)
Circulatory failure, such as signs of vascular permeability (eg, hypoproteinemia, effusions)
Hepatomegaly Slide 36: Dengue shock syndrome (DSS)
Untreated, dengue hemorrhagic fever mostly 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. Physical findings : Physical findings Dengue fever
Hemorrhagic findings (petechiae, purpura, bleeding gums, epistaxis, menorrhagia, positive tourniquet test, hematuria) Dengue hemorrhagic fever : Dengue hemorrhagic fever Findings for dengue hemorrhagic fever are similar to dengue fever and also include the following
Biphasic fever curve
Hemorrhagic findings more pronounced than in dengue fever
Signs of peritoneal effusion, pleural effusion, or both Dengue shock syndrome : Dengue shock syndrome Hypotension
Bradycardia (paradoxical) or tachycardia associated with hypovolemic shock
Narrow pulse pressure (<20 mm Hg)
Signs of decreased peripheral perfusion VIRUS : VIRUS dengue is known to be caused by 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 (of the genus Flavivirus), and the type-specific virus is yellow fever.
The dengue virus has 4 closely related but distinct serotypes, DEN1-DEN4 Slide 41: the nucleocapsid or core (C) protein, a membrane-associated(M) protein, an enveloped (E) glycoprotein and seven nonstructural(NS) proteins.
Anti-E antibodies neutralize DV infectivity in vitro and protect from DV challenge on passive transfer and show a variable degree of cross-reactivity among the DV serotypes. Slide 42: Antibodies against NS1 can trigger complement-mediated lysis of DV-infected cells in vitro
These antibodies may cross-react with endothelial cells leading to their activation and expression of cytokine, chemokine, and adhesion molecules resulting in cell damage. Slide 43: NS3 protein is the main antigen that stimulates DV-reactive CD4+ and CD8+ T cells that produce high levels of IFN-γ as well as TNF-α, TNF-β, and chemokines including macrophage inhibitory protein-1β upon interaction with DV-infected antigen presenting cells, and are effi cient at lysis of DV-infected cells in vitro Causes : Causes Living in endemic area,moist temp helps to grow mosquito
Poorly planned urbanization combined with explosive global population growth brings the mosquito and the human host into close proximity.
Increased air travel easily transports infectious diseases between populations Slide 45: Ineffective control of mosquito control
Poor sanitation and poor refuse control provide excellent conditions for mosquito larvae to grow
Lack of immunity to the virus serotypes contributes to infection rates in a population.
Hurricanes and other natural disasters increase the habitat for mosquito growth in urban areas by increasing rubble and garbage, which act as water reservoirs. VECTOR : VECTOR Dengue virus types 1-4Aedes aegypti mosquito vector
Found in tropical regions, especially Southeast Asia Differential Diagnoses : Differential Diagnoses Slide 52: Other Problems to Be Considered
Typhoid feverRiver VirusChikungunyaWest Nile encephalitisRoseola infantumScarlet feverIdiopathic thrombocytopenic purpura Other causes of viral hemorrhagic fever Laboratory Studies : Laboratory Studies Hematologic and chemistry studies may reveal hemorrhagic or organ dysfunction.
CBC count to evaluate for leukopenia, thrombocytopenia (<100 X 109/L), and increasing hematocrit levels (increase of 20% indicates hemoconcentration; serial hematocrit levels needed every 4 h)
Chemistry panel to evaluate for imbalances
Serum protein and albumin levels
Liver function tests
Disseminated intravascular coagulation (DIC) panel Slide 54: Urinalysis identifies hematuria.
Type and crossmatch.
Dengue can be identified by using virus isolation (ie, growing sample in a cell line) or serologic identification, using enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin (Ig) G or IgM.
A reverse-transcriptase polymerase chain reaction (PCR) test Imaging Studies : Imaging Studies Chest radiography
Head CT scan without contrast
For altered level of consciousness
Cerebral edema Treatment : Treatment Prehospital Care
Initiate supportive therapy
Intravenous (IV) crystalloids, as needed to keep systolic blood pressure above 90 mm Hg
O2, empirically Slide 57: Supportive therapy
IV access, O2, and monitoring are helpful.
IV crystalloids may be necessary for hypotension; central line may be needed.
Correction of electrolyte abnormalities and acidemia.
Implement therapy for DIC if indicated.
Corticosteroids are not helpful.
No antiviral therapy is available. Slide 58: supportive care by administering isotonic NS solution intravenously to maintain adequate BP and adequate urine output.
Strict monitoring of urine output Slide 59: the plasma leakage period is short (24-48 h), and intravenous fluids may be reduced if the patient maintains adequate oral hydration.
When the plasma leakage phase starts to resolve, the hematocrit level begins to fall,
making identification of significant occult hemorrhage difficult.
Administer blood transfusion if significant hemorrhage ensues. (GI bleeding may be profound.) Slide 60: Administer fresh frozen plasma or platelets if disseminated intravascular coagulation (DIC) is extensive.
Administer acetaminophen for fever control (not salicylates or ibuprofen, which can further hinder platelet function and increase bleeding complications). Slide 61: Antipyretic agents
They reduce fever. They inhibit central synthesis and the release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus and, thus, promote the return of the set-point temperature to normal. Complications : Complications Complications are rare but may include the following:
Brain damage from prolonged shock or intracranial hemorrhage
Liver failure Issues to be addressed in dengue control : Issues to be addressed in dengue control Ever increasing use of non-bio degradable plastics, polythene and other containers with poor disposal systems
Lack of co-ordination and co-operation among public health authorities and local government institutions
Poor response & participation of the community initially to keep their compounds free of mosquito breeding places
Rapid urbanization with poor adherence to health concerns in building construction, refuse disposal and other sanitary measures Prevention : Prevention Reduce A aegypti vector populations.Reduce exposure to A aegypti.Use insect repellent.
Sleep under a mosquito net in affected areas.
Wear protective clothing.
Vaccines against all 4 serotypes are currently under development. While this is challenging due to the complex immune response, vaccines may ultimately be the most effective control strategy, since vector control programs have been largely unsuccessful and of only short-term local benefit. Vaccine : Vaccine Mutation rates in RNA viruses are exponentially greater than agents with DNA genomes due to the lack of proof reading mechanisms in the RNA dependant RNA polymerases of the former.
leads to the development of antigenic diversity because of varying levels of inter-virus genetic recombination
Tetravalent vaccine needed for control Slide 66: Recently the carboxy-terminal region of the major dengue virion envelope (E) protein, known as domain III (ED III), has emerged as a significant sub-unit vaccine candidate
purified recombinant domain EDIII that refolds in vitro and protects cells in cultureagainst DV-2 infection by blocking the virus from binding to host cells. Slide 67: Recombinant adenovirus capable of expressing the EDIII of DV-2
Combination with plasmid encoding same domain
a recombinant,replication-defective Ad (rAd) vector encoding a chimeric antigen made of in-frame linked EDIIIs of DV serotypes 2 and 4. Prognosis : Prognosis Mortality/Morbidity
Treated DHF/DSS is associated with a 3% mortality rate.
Untreated DHF/DSS is associated with a 50% mortality rate.
Convalescence may be prolonged, with weakness and mental depression.Continued bone pain, bradycardia, and premature ventricular contractions (PVCs) are common. Survival is related directly to early hospitalization and aggressive supportive care.Dengue fever is not contagious through person-to-person contact. THANK YOU : THANK YOU Slide 70: 2003 : The programme has been renamed as National Vector Borne Disease Control Programme and all vector borne diseases like malaria, Filariasis, dengue etc. have been brought under the ambit of this programme.