Dengue fever
Dengue fever is a mosquito-borne disease caused by dengue virus, prevalent in tropical and subtropical areas. Most cases of dengue fever are either asymptomatic or manifest mild symptoms. Symptoms typically begin 3 to 14 days after infection. They may include a high fever, headache, vomiting, muscle and joint pains, and a characteristic skin itching and skin rash. Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue with bleeding, low levels of blood platelets, blood plasma leakage, and dangerously low blood pressure.
Dengue is spread by several species of female mosquitoes of the Aedes genus, principally Aedes aegypti. The virus has four confirmed serotypes; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications, so-called antibody-dependent enhancement. The symptoms may resemble those of malaria, influenza, or Zika. Blood tests to confirm the diagnosis including detecting viral RNA, or specific antibodies.
Infection can be prevented by mosquito elimination and the prevention of mosquito bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016, but it is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. Treatment is symptomatic, as there is no specific treatment for dengue fever. In mild cases, treatment focuses on treating pain. Severe cases of dengue require hospitalisation; treatment of acute dengue is supportive and includes giving fluid either by mouth or intravenously.
The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease. During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported.
Signs and symptoms
Typically, people infected with dengue virus are asymptomatic or have only mild symptoms such as an uncomplicated fever. Others have more severe illness, and in a small proportion it is life-threatening. The incubation period ranges from 3 to 14 days, but most often it is 4 to 7 days.The characteristic symptoms of mild dengue are sudden-onset fever, headache, muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness.
Clinical course
The course of infection is divided into three phases: febrile, critical, and recovery.The febrile phase involves high fever, and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints.
Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue. Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools.
During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets. This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs.
The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate.
Severe dengue
The World Health Organization's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated clinically with severe plasma leakage, severe bleeding, or severe organ dysfunction.Severe dengue can develop suddenly, sometimes after a few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock; patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen, insufficient protein in the blood, or thickening of the blood. Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death.
Complications
following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage, low birth weight, and premature birth.Children and older individuals are at a risk of developing complications from dengue fever compared to other age groups; young children typically suffer from more intense symptoms. Concurrent infections with tropical diseases like the Zika virus can worsen symptoms and make recovery more challenging.
Cause
Virology
Dengue virus is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same genus include yellow fever virus, West Nile virus, and Zika virus.Dengue virus genome contains about 11,000 nucleotide bases, which code for the three structural protein molecules that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes, referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity.
Transmission
Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti. They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus, but it also circulates in nonhuman primates, and can infect other mammals. An infection can be acquired via a single bite.For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles. A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life.
Dengue can also be transmitted via infected blood products and through organ donation. Vertical transmission during pregnancy or at birth has been reported.
Risk factors
The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent.Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe dengue include female sex, older age, younger age, and high body mass index.
Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to a phenomenon known as antibody-dependent enhancement. The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself.
Mechanism of infection
When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells. The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.The white blood cells respond by producing several signaling proteins, such as cytokines and interferons, which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability. As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever.