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Pathogenesis and Pathophysiology of Deng PDF
Pathogenesis and Pathophysiology of Deng PDF
Dengue Hemorrhagic
Hemorrhagic Fever
Fever
Host factors
Immunity Prior dengue infection
Age Adult
Nutrition Malnourished
Genetics Black
Risk factors Ö DHF
• Virus
– Serotype and virulence of the infecting virus
• Demography
– Age, sex
• Case fatality and hospitalization rate highest in infants and
elderly
• More severe among females
– Genetic background of the host
• Immune status
– Malnutrition appears to be uncommon in DHF
– DHF more common among in patients with chronic illnesses
(eq. asthma and diabetic)
Primary
Antigen antibody
Virus uptake complex
Reseptor Fc
• DHF patients have higher level TNF-α, IL-6, IL-13, IL-18 and
cytotoxic factor than DF
– These cytokines Ö implicated in causing increased vascular
permeability and shock
• Level of cytotoxic factor (from CD4+ T cells) ≈ diseases severity
• IL-8 higher in severe infections, may have important role in
pathogenesis
• IFN-α and IFN-γ were produced by lymphocytes infected by
DenV, not related to grading of disease; IFN-γ is produced
early, with peak on or before day of defervescence ≈
disappearance or viraemia
1. Chaturvedi UC. Elbishbishi EA, Agarwal R et al. Cytotoxic factor autoantibodies; possible
role in the pathogenesis of DHF. FEMS Immunol Med Microbiol 2001;30:181-6
2. Jufrie M, van der Meer, Hack CE et al. Inlamatory mediators in dengue virus infections In
children; interleukin-8 and its relationship to neutrophil degranulation. Infect Immun
2000;68:702-7
Secondary heterologous dengue infection
Complex virus-antibody
Complemen activation
Complemen È
Anafilatoxin (C3a, C5a)
Urine Histamin Ç
Capillary permeability increase
Ht increase
30% shock Plasma leakage Natrium
decrease
Hipovolemia Intra serous
fluid
Anoxia Acidosis
Shock
Death
Secondary heterologous dengue infection
Platelet Endothelial
Endothelial disturbances
disturbances Complement
Complement activation
activation
Platelet agregation
agregation
Hageman
Hageman factor
factor activation
activation Anafilatoxin
Anafilatoxin
Platelet
Platelet destruction
destruction Coagulation
Coagulation
by
by RES
RES activation
activation
Releasing
Releasing factor
factor III
III
platelet
platelet
Kinin
Kinin system
system
Thrombocytopenia
Thrombocytopenia Capillary
Capillary
Consumptive
Consumptive coagulopathy
coagulopathy Kinin
Kinin permeability
permeability
increase
increase
FDP
FDP increasing
increasing
Platelet
Platelet function
function Decreasing
Decreasing coagulation
coagulation function
function
disturbances
disturbances
• DenV :
– Vary and change genetically by selection
pressure as they replicate in human /
mosquitoes Ö some strain have greater
epidemic potential
– Phenotypic expression of genetic changes
in the virus genome Ö increased replication
and viremia, severity of disease
1. Scott B. Halstead. Pathophysiology and pathogenesis of Dengue Hemorrhagic Fever.
Monograph on Dengue / Dengue Hemorrhagic Fever. P. Thongcharoen. Ed. WHO,
SEARO, New Delhi, 1993. p80-103.
2. Duane J. Gubler. Dengue and Dengue Hemorrhagic Fever. Clinical Microbiology
Reviews, 1998:480-96
Pathophysiology changes
• Thrombocytopenia
– IgM type of anti-platelet antibody
• Antiplatelet antibodies + complements → lysis of
platelets
– Dengue viral specific antibodies
– Bone marrow hypercellularity
– Destruction of platelet in the liver and spleen
• Atypical lymphocyte
Lin CF, Lei HY, Liu CC. Generation of IgM anti-platelet autoantibody
In dengue patients. J Med Virol 2001;63:143-9
Immune-pathogenesis of dengue virus (DV) infections.
Lei HY, Yeh TM, Liu HS, Lin YS, Chen SH and Liu CC, J
Biomed Sci 2001;8:377-88.
Relationship Cytokine Plasma Relationships between DHF and
level chemical substances
Directly related
TNF‐ α Ï Endothelium destruction, ↑ cap
permeability, early stage
IL‐ 1 Î Endothelium, stimulate PAF and
prostaglandin
IL‐ 2 Ï Same level in DF and DHF
Indirectly IFN‐γ Ï ↑ infected cells, T cells activation
related
IL‐ 6 Ï ↑ in convalescence, feedback TNF‐ α &
endotoxin
IL‐ 4,5,10 Ï Appear later
IL‐ 13,18 Ï DSS
Others PAF Ï ↑ cap permeability, complement
activation
C3a,C5a Ï ↑ cap permeability, related to disease
severity
Histamine Ï
Endotoxin Ï DSS with prolonged shock
Summary of pathogenesis