Immune confusion -- disruption in the immune system -- is responsible for severe dengue fever in children, finds a study.
Most people infected with dengue virus have no symptoms, or a fever that quickly passes. However, 5 per cent of people progress to severe dengue, which can mean organ failure and even death within days of symptoms appearing.
The risk is particularly high for children, who experience the most severe reactions to dengue virus.
Until now, there was little understanding of why some patients have mild dengue, while others progress to serious disease.
The study, published in the journal Nature Immunology, showed that immune confusion could be used to diagnose at-risk patients and targeted with therapeutics.
The changes in patients' immune systems could also be targeted with therapeutics to prevent progression to severe dengue.
For example, clinicians could prescribe a drug that reactivates natural killer cells and T cells to fight the infection, said the researchers led by those from the University of New South Wales, Sydney.
For the study, they focused on children because they are at higher risk of severe dengue.
The study participants were 19 Colombian children who presented to health care settings with dengue virus infection in the early stages. Roughly half of this group progressed to severe disease. Four healthy children who presented for routine checkups or elective procedures were included as a control group.
The researchers analysed blood samples taken from the children on the first day that they presented with dengue. They used a technique called single cell RNA sequencing, which allowed them to study individual immune cells in the blood and how the cells were behaving.
In the children who progressed to severe dengue disease, the researchers identified three main changes in the immune cells in their blood.
Firstly, they found that antigen presenting cells were behaving differently. Normally, antigen presenting cells take up dengue virus particles, cut them up into smaller pieces, and show these virus fragments to the rest of the body as a warning of infection.
Secondly, B cells became heavily infected with dengue virus and had impaired ability to produce antibodies, which are one of the main weapons of the immune system to fight infections.
"The third element of the puzzle is that certain cells called natural killer cells, and their companion T cells, seem to be in a strange state of quiescence or exhaustion," said Dr. Fabio Zanini, from UNSW Medicine & Health.
"We expect them to be virus killing machines. Instead, they transform into couch potatoes that watch the action and wonder about whether they should do something or not," Zanini added.
This immune confusion means that the child's immune system doesn't protect them from the virus as it normally would, leading to severe dengue. By understanding what goes wrong early in dengue virus infection, we can design diagnostic tests to identify which patients are at risk of severe disease, the researchers said.