What is dengue fever?

Causes and Symptoms

Although dengue fever is primarily confined to the tropics, each year it causes nearly four hundred million infections worldwide. Dengue is caused by the dengue virus (DENV) that belongs to the Flaviviridae family. This viral family includes several other members, such as the yellow fever
virus and the West Nile
encephalitis
virus, all of which have emerged as serious public health concerns over the years. All four serotypes of dengue virus (DENV-1 through DENV-4) are capable of causing the full spectrum of clinical manifestations, from asymptomatic presentation to dengue fever to the more severe dengue hemorrhagic fever or dengue shock syndrome. These forms are primarily found in hyperendemic areas that have all four serotypes of dengue virus.

Dengue virus enters the human host via the bite of an infected Aedes mosquito, primarily A. aegypti and occasionally A. albopictus. These vector populations are difficult to control because they are highly invasive and over time have accumulated adaptations that make them extremely resilient. Once inside the Aedes mosquito, having entered it via a blood meal, the dengue virus needs to incubate for about eight to twelve days in the mosquito before it can initiate another round of infection in a healthy host. An Aedes mosquito that has acquired the dengue virus will forever act as a vector.

After being bitten by the infected Aedes mosquito, a human host will typically start showing symptoms anywhere between four to seven days; symptoms last for as long as three to ten days. Once inside the human body, the dengue virus first replicates inside the dendritic cells. The replicated virus then infects macrophages and lymphocytes before entering the patient’s bloodstream. Dengue fever patients can show a variety of symptoms, from mild feverishness to high fever of abrupt onset along with severe headache, pain behind the eyes (retro-orbital pain), flushing of the face, malaise, generalized joint and muscle pains, nausea, vomiting, and rash.

In dengue hemorrhagic fever and dengue shock syndrome, the more severe forms of dengue, clinical manifestations include fever, hemorrhage (diagnosed with a tourniquet test), low platelet count (thrombocytopenia), and increased vascular permeability. Some signs of hemorrhage seen in dengue hemorrhagic fever patients include pinpoint-sized red dots (petechiae), fragile capillaries that could lead to passage of blood from the ruptured blood vessels into subcutaneous tissue (purpura), and blood stains in vomit and stool (melena). The severity of dengue hemorrhagic fever depends on the extent of plasma leakage (detected by a rise in hematocrit level) from the capillaries that results in hypovolemia. As plasma continues to leak into the interstitial spaces, the patient can go into hypovolemic shock, a situation that can be fatal. These symptoms are typically accompanied by liver failure and increase in liver size (hepatomegaly). Concomitantly, as one would expect, viremia titers (indicating the presence of virus in the bloodstream) are much more pronounced in cases of dengue hemorrhagic fever and dengue shock syndrome as compared to dengue fever.

Clinical diagnosis of dengue virus infection is based on signs of leukopenia (low white blood cell count), thrombocytopenia, and high serum transaminase levels in blood tests. Since rash is a common component of dengue fever, often the extent, nature, and location of the rash is used in the diagnostic process—for example, dengue rash is usually seen on the trunk and inner surfaces of the thighs and arms. With an increase in number of dengue cases, some unusual neurological complications, such as convulsions, spasticity, and encephalopathy (resulting from water intoxication), have also been reported. To date, the exact molecular mechanism that underlies the pathogenesis seen in dengue hemorrhagic fever and dengue shock syndrome is not very well understood and is still under investigation.

Treatment and Therapy

Patients who have been diagnosed with dengue virus infection are required to maintain adequate hydration levels. Often, the key to successful management of a patient with dengue hemorrhagic fever or dengue shock syndrome involves a careful monitoring of the patient’s fluid level and replenishing any deficits with isotonic solution administered intravenously. Antipyretics such as acetaminophen are used for pain and fever management; patients are advised to avoid using aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), since they may accentuate the bleeding problem associated with certain types of dengue infection. Blood transfusions and oxygen therapy may also be used to treat dengue hemorrhagic fever.

The adaptive immune response of the patient plays an important role in clearing of the infection as well as providing immunity against reinfection. Infection with a DENV serotype (1–4) protects the individual only against reinfection by the same serotype. Since there are four serotypes of dengue virus, in theory, a person can get dengue as many as four times during his or her lifetime. Efforts are underway to design a vaccine; the ideal vaccine would provide lifelong protection against all four DENV serotypes. Dengue vaccine candidates that are currently being investigated include live attenuated vaccines, inactivated virus vaccines, recombinant subunit vaccines, and deoxyribonucleic acid (DNA) vaccines.

Perspective and Prospects

Dengue is considered an emerging infectious disease. As with the Ebola virus, the four serotypes are believed to have originated in monkeys in Africa or Southeast Asia and then mutated to move on to the human host several hundred years ago. Until the mid-twentieth century, dengue was largely a localized infection, primarily affecting populations in Southeast Asia. It is believed that the spread of the Aedes mosquito vector, and thus the dengue virus pathogen, via cargo ships to different parts of the world contributed to the global threat that the world is currently experiencing. Approximately 3.9 billion people in 128 countries are now at risk of infection with the dengue virus. Nearly 2.4 million cases are reported annually, but the disease is thought to be underreported, and the actual number is estimated to be closer to 390 million. In 2010, local transmission of the dengue virus within Europe was reported for the first time, and in 2012 there was an outbreak on the Madeira islands of Portugal that resulted in a number of cases being imported to mainland Portugal and elsewhere in Europe. In 2013 there was an outbreak in Laos and an increase in cases in Singapore, and several South American countries, primarily Costa Rica, Honduras, and Mexico, were badly affected by the virus. Cases were also reported in Florida that year. In 2014 cases increased throughout the Pacific Islands and in China, and Japan recorded its first cases of dengue in over seventy years. Countries particularly affected in 2015 include Brazil, Fiji, Tonga, and French Polynesia. In addition, cases increased 35 percent in Taiwan between 2014 and 2015, and India had its worst outbreak in years.

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