Pathogenesis of DHF/DSS


Risk Factors Reported for DHF

 Most cases of dengue fever are self-limited in their course and never progress to dengue hemorrhagic fever. So what are the factors associated with the occurrence of DHF?

  • Virus strain: DHF can occur in primary infection with certain genetic strains of virus.
  • Pre-existing anti-dengue antibody, either caused by previous infection or to maternal antibodies passed to infants.
  • Host genetics—for example, race seems to be a factor: data from Cuba suggest that whites may be at greater risk, and blacks at lower risk. And
  • Age—in Southeast Asia, children are most affected, though in the Americas, all age- groups are affected.

For individuals, there is a higher risk for DHF in secondary infections. There is also higher risk in locations with two or more serotypes circulating simultaneously at high levels—this is called hyperendemic transmission. The most widely accepted hypothesis for the increased risk of DHF in secondary infections is called antibody-dependent enhancement of viral infections. This hypothesis will be explained in a moment.


Increased Probability of DHF 



There are two general pathways through which hyperendemicity may increase the probability of DHF:

  • First, as we see on the left, in a situation of hyperendemicity, where several virus serotypes are circulating at high levels, the probability of virulent strains occurring is increased, which increases the probability of DHF.
  • In addition, as is presented on the right, in a situation of hyperendemic transmission, the probability that an individual will experience a secondary infection is increased, which increases the likelihood of immune enhancement and DHF.


Hypothesis on Pathogenesis of DHF 


1.Homologous Antibodies Form Non-Infectious Complexes



A  graphic depiction of the development of homologous antibodies. When an individual is infected with any dengue serotype—here called dengue type A, to indicate that the infection may be with DEN-1, 2, 3 or 4—the immune system responds by producing anti-A antibodies. These anti-A antibodies form homologous complexes with the type A virus, which results in the neutralization of the virus.


2.Heterologous Antibodies Form Infectious Complexes 



Antibody-dependent enhancement, dengue type B represents the new serotype. The anti-A antibodies produced in response to the original infection can form complexes with the new serotype, as we see here. However, the new virus serotype is not neutralized by these heterologous antibodies. The virus retains its capacity to become active and replicate.


3.Heterologous Complexes Enter More Monocytes, Where Virus Replicates

 Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with these non-neutralizing antibodies, can enter a greater proportion of the mononuclear cells where the virus replicates unchecked, thus increasing virus production and producing a massive infection.

The heterologous antibody-virus complexes can enter a greater proportion of monocytes than the virus alone. The greater proportion of infected cells results in greater virus production.


4.Infected monocytes release vasoactive mediators 

 It has been hypothesized that the infected monocytes release vasoactive mediators, resulting in the increased vascular permeability and hemorrhagic manifestations that characterize dengue hemorrhagic fever or dengue shock syndrome. It should be noted, however, that to date there are no data from viremia studies to confirm this hypothesis.


Conclusion of pathogenesis

1.Antibody – enhanced infection or Immune enhancement mechanism

                                                Common Ag >>>>>>Ab ( homologous ) 1º

                                                                            ( heterologous )  >>>>>Enhancing Ab         2º

                        DHF ( 87 – 98 % = 2º )

                        DSS  ( 95 – 99 % = 2º )

2.Immune complex mechanism >>>>> activate complement

3.Immune elimination mechanismmonokines>>>>>>activate complement 

4.Virus type  : 1 & 3 > 2 & 4 in 1º


6.Subsequent infection of dengue type  :  2º, type 2, 3, 4

 Dengue hemorrhagic fever most often occurs in second infections with dengue virus, but the phenomenon seems to be mostly restricted to infections with certain dengue virus strains, or genotypes, first identified in Southeast Asia. The potential for these strains to produce DHF epidemics may be related to their ability to produce greater concentrations of circulating virus in the blood (level of viremia), or their ability to produce infection in both the human and mosquito hosts. Cohort studies in Southeast Asia have shown that secondary (repeat) infections in which DEN-2 is the infective serotype have greater probability of producing DHF than infections with other serotypes, followed closely by DEN-3. The risk is less when the second infecting virus is DEN-4 or DEN-1 (in that order).

Immune Response to Dengue Infection

Primary dengue immune response

Long term immunity only to the infecting serotype.


–      produced by 5th day after symptoms appear.

–      rises for 1-3 weeks and persists for 30-60 days (or even up to 90 days).


–      appears by 14 days after onset of symptoms and persists for life.

Secondary dengue immune response

•IgM –may not be produced until 20 days after onset of infection. –may be produced at low levels or for shorter period than in a 1º infection.

•IgG –rises rapidly 1-2 days after onset of symptoms. –reaches levels above those found in 1º or past infection.persists at high levels for 30-40 days, then declines to levels found in 1º or past infection

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