Pathophysiology of Dengue Infection
Dengue is a mosquito-borne viral infection caused by one of four closely related but antigenically distinct serotypes of the dengue virus: DENV-1, DENV-2, DENV-3, and DENV-4. Dengue virus (DENV) is primarily transmitted by the bite of an infected ‘Aedes’ mosquito, particularly ‘Aedes aegypti’. Another important vector is ‘Aedes albopictus’, though it is generally less efficient in transmission. Dengue fever (DF) ranges from a mild febrile illness to severe forms of the disease, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which can be fatal if not treated promptly. Understanding the pathophysiology of dengue is essential in managing and preventing the spread of the disease.
Transmission and Vector
The ‘Aedes’ mosquito is the primary vector for dengue. Female mosquitoes require a blood meal for egg development, and during feeding on an infected host, they acquire the dengue virus. The virus replicates within the mosquito and, after an extrinsic incubation period of 8-12 days, can be transmitted to humans when the mosquito bites again. The mosquito remains infected for life, with a typical lifespan of 15-65 days. The mosquito does not suffer any ill effects from harboring the virus.
Humans are the primary reservoir for dengue, and the virus circulates in the blood of infected individuals. Transmission from human to mosquito occurs when the mosquito feeds on a person during the febrile phase, typically 1-2 days before symptoms appear and for up to 12 days afterward. Rare cases of vertical transmission from mother to child, sexual transmission, and needle-stick injuries have been documented but are uncommon.
Female ‘Aedes’ mosquitoes are well adapted to urban environments. They often breed in small collections of stagnant water, such as those found in discarded containers, tires, or even bottle caps. These mosquitoes are daytime feeders, usually biting on exposed areas such as the neck and ankles. A single infected mosquito can bite multiple people, making it an efficient vector for spreading dengue within households and communities, sometimes infecting entire families in a short span of time.
Viral Entry and Immune Response
Once the virus enters the human body through a mosquito bite, it undergoes an incubation period of 3 to 14 days, with an average of 4 to 7 days. During this period, the virus replicates in dendritic cells, macrophages, hepatocytes, and endothelial cells. These cells are part of the reticuloendothelial system, which plays a key role in immune defense. As viral replication progresses, the immune system responds by producing various mediators that modulate the immune response.
The infection triggers both innate and adaptive immune responses. Dendritic cells present viral antigens to T cells, stimulating the production of cytokines and antibodies. However, the immune response to dengue is complex and can sometimes contribute to disease severity. In primary infections, the body generates antibodies specific to the infecting serotype. These antibodies provide lifelong immunity against that serotype but only partial, short-term protection against other serotypes.
In cases of secondary infection with a different dengue serotype, the immune system’s response can exacerbate the disease through a process known as antibody-dependent enhancement (ADE). Pre-existing, non-neutralizing antibodies from the first infection bind to the new serotype without neutralizing the virus. These antibody-virus complexes are taken up by macrophages via Fc receptors, leading to increased viral replication and higher viral loads. This contributes to the heightened immune response, increased production of cytokines, and activation of the complement system, which together drive the severe forms of dengue, such as DHF and DSS.
Clinical Manifestations of Dengue Fever
Dengue fever presents with nonspecific symptoms similar to other viral infections, making it challenging to diagnose without laboratory tests. Patients typically develop a high fever (up to 41°C) around the third day of illness, which lasts for 5-7 days. Other symptoms include severe headache, retro-orbital pain, muscle and joint pain (hence the term "breakbone fever"), rash, and mild bleeding tendencies such as petechiae or gum bleeding. Leukopenia (low white blood cell count) and thrombocytopenia (low platelet count) are common findings during the febrile phase. The destruction of bone marrow precursor cells by the virus is believed to cause these hematologic changes.
Approximately one-third of patients with dengue fever may have mild hemorrhagic symptoms, such as easy bruising or a positive tourniquet test (more than 20 petechiae in a 2.5 x 2.5 cm area). Although the disease is rarely fatal, severe forms of dengue, including DHF and DSS, pose significant risks, especially during secondary infections.
Severe Dengue (Dengue Hemorrhagic Fever and Dengue Shock Syndrome)
Severe dengue, or dengue hemorrhagic fever, is less common than classic dengue fever but presents with more severe clinical features. DHF often begins similarly to dengue fever, with high fever, headache, and body aches. However, in severe cases, the fever may have a biphasic pattern, with an initial rise, followed by a brief defervescence, and then a second fever spike. This saddleback fever is a hallmark of severe dengue.
The critical feature of severe dengue is plasma leakage, which occurs due to increased capillary permeability. This leads to hemoconcentration (elevated hematocrit), pleural effusions, ascites, and shock. Progressive thrombocytopenia, rising hematocrit, and low albumin levels are early indicators of impending shock. Hemorrhagic manifestations, such as gastrointestinal bleeding or intracranial hemorrhage, can occur in severe cases, contributing to the high mortality rate if untreated.
The pathophysiology of DHF involves a complex interplay between viral factors, host immune responses, and vascular integrity. The release of vasoactive cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-2, increases vascular permeability, resulting in plasma leakage and shock. Liver involvement is also common, with elevated liver enzymes (ALT and AST) indicating hepatocyte damage. In severe cases, fulminant hepatic failure can occur, with widespread infection of hepatocytes and Kupffer cells.
Immunopathogenesis and Antibody-Dependent Enhancement (ADE)
The immunopathology of severe dengue is closely related to the phenomenon of antibody-dependent enhancement. During a secondary infection with a different serotype, non-neutralizing antibodies from the first infection facilitate viral entry into macrophages, increasing viral replication and the release of inflammatory mediators. This exaggerated immune response leads to increased vascular permeability, plasma leakage, and hemorrhage.
In addition to ADE, T-cell immunopathology may contribute to disease severity. Dengue infections activate T cells, leading to the release of cytokines such as interferon-gamma, TNF-alpha, and soluble IL-2 receptors. These cytokines are associated with the vascular leakage and shock seen in severe dengue.
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