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Dengue fever, the neglected infectious disease

Dengue fever is the most common infectious disease transmitted by mosquitoes. The disease is spreading in Europe and Germany, an upward trend that is due to increased long-distance travel. There are no specific drugs or vaccine for dengue, which is why an international research network has been established to improve the management of the disease. The consortium is coordinated by the Department of Tropical Medicine at Heidelberg University.

Dengue fever is the number one infectious disease transmitted by mosquitoes, followed by malaria, which is the second most frequent mosquito-borne infectious disease. The International Research Consortium on Dengue Risk Assessment, Management and Surveillance (IDAMS) found that true disease incidence is about three times as high as the World Health Organisation (WHO) believes.

Every year, 390 million people are infected with the disease. Although its name is barely known in Germany, there is an upward trend in imported dengue fever infections in Germany due to the larger number of people travelling to tropical and subtropical countries. Only minimal funding is available for research into the medical treatment of dengue fever, far less compared to the funding provided for research into the ‘big three’ infectious diseases (HIV/AIDS, malaria, tuberculosis). The WHO therefore counts dengue fever among the neglected tropical diseases.

Heidelberg – centre for dengue research

Dr. Thomas Jaenisch and Dr. Bridget Wills (Oxford University Clinical Research Unit) in the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam, discussing the patient file of a child with severe dengue fever. © Jaenisch, University Hospital Heidelberg

The EU-funded project IDAMS is coordinated by the Section of Clinical Tropical Medicine in the Department of Infectiology led by Dr. Thomas Jaenisch at Heidelberg University Hospital. The Heidelberg department has become an internationally recognised hub in dengue research. A large multinational study analysed more than 8,000 dengue fever reports that were compiled over the last 50 years and identified areas that are likely to be at risk of dengue outbreaks. The projections are based on social and environmental factors such as poverty, population density, infrastructure and climate. Such strategies could help prevent outbreaks and reduce morbidity and mortality from dengue. 

Dengue fever emerged as a public health burden in South and Southeast Asia where around 70 percent of all dengue fever infections occur. It has spread to tropical America and Africa and from there to Europe; direct dengue fever infections have been registered in southern Europe for around three years now. In autumn 2012, a dengue fever outbreak occurred on the Portuguese archipelago of Madeira with more than 2,100 people infected. This was the first sustained transmission of dengue fever in europe since 1927 when around one million people in Greece were infected.

Over the last few months, fourteen Germans returning from holidays on Madeira were diagnosed with the infection. Dr. Schmidt-Chanasit, a virologist at the Bernhard Nocht Institute for Tropical Medicine assumes that around 90% of all dengue fever infections remain undiagnosed as the initial infection only leads to mild symptoms with adults experiencing flu-like symptoms such as fever, headache and pain in the limbs. Doctors do not usually associate these symptoms with the infection. The diagnosis of dengue fever is confirmed with laboratory blood tests.

Dengue virus is a single positive-stranded RNA virus and there are four dengue serotypes. It belongs to the genus Flavivirus and is closely related to the yellow fever virus and the West Nile virus. Professor Dr. Ralf Bartenschlager and his Molecular Virology team in the Department of Infectiology at Heidelberg University Hospital were involved in the elucidation of the molecular properties of the dengue virus, its genome organisation, the expression of the viral proteins and the viral replication cycle.

The spread of Aedes mosquitoes

Biting Aedes aegypti on human skin. © IDAMS

Most dengue infections are relatively mild, but in some cases complications occur. Severe infections can lead to haemorrhagic bleeding and shock (dengue shock syndrome). It is usually secondary infections with a different strain of dengue virus that lead to haemorrhagic fever and dengue shock syndrome. Children in tropical countries carry a particularly high risk of infection. According to information supplied by the WHO, dengue fever is a leading cause of serious illness and death among children in some Asian and Latin American countries.

Since 2011, IDAMS has been carrying out a study in several Asian and Latin American countries, including Vietnam and Brazil, whose results are being pooled and analysed in Heidelberg. Jaenisch hopes that this study will provide the consortium with information that will help lead to the recognition of the seriousness of dengue fever and an assessment of disease progression.

Dengue virus is primarily transmitted by mosquitoes, particularly the Asian Aedes albopictus and the Egyptian yellow fever mosquito (Aedes aegypti). They belong to Stegomyia, an Aedes subgenus which some experts regard as an own genus; therefore, Aedes mosquitoes are also known as Stegomyia albopicta and Stegomyia aegypti. Both species can also lead to other serious viral diseases such as yellow fever and chikungunya, which are not as common as dengue fever. The tremendous increase in international travel and expanding commodity market facilitates the spread of the mosquitoes. A. aegypti populations have established themselves around the Black Sea and have even been discovered in Holland, transported on used car tyres imported from the southern states of the USA. Yellow fever mosquitoes have been known on Madeira for quite some time. It is assumed that the latest dengue outbreak was caused by infected travellers from Brazil who were bitten by the mosquitoes on Madeira. The mosquitoes ingested the virus and were able to transmit it to other people. The first specimen of Asian A. albopictus, which also occurs in Northern China and tolerates cool temperatures quite well, was discovered in the Upper Rhine area in Baden-Württemberg some years ago. Last year, A. albopictus mosquitoes were discovered in numerous locations in southern Germany and Austria.

Most effective protection: avoid being bitten

“Todos contra a Dengue“, a public service campaign teaching people measures to prevent dengue and yellow fever. © Dep. Saúde, Brazil

There are no specific antiviral drugs for dengue. A number of large pharmaceutical companies, including GlaxoSmithKline, Sanofi Pasteur and Merck, have announced that they are working on dengue virus vaccines, but little progress has been made. Sanofi Pasteur opened a vaccine production plant in Mexico in 2010 and announced that the first dengue vaccine would be available by 2015, “possibly even earlier”. However, the vaccine was far less effective than hoped. In summer 2012, the company announced that a clinical study involving four thousand Thai children had only been 30.2 percent effective. The vaccine was effective against three of the four dengue serotypes, but failed to protect against the DENV-2 type.

The best way to protect oneself against dengue is to avoid being bitten. This is the conclusion of public information campaigns in Brazil, where the disease has already become a huge economic burden although the mosquitoes were only introduced around 25 years ago. Mosquito nets, anti-insect sprays and protective clothing seem at present to be the most effective methods against female mosquitoes that bite and spread the dengue virus further. Efforts to develop an effective dengue vaccine are ongoing in the hope that one will soon be available.

Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GRW, Simmons CP, Scott TW, Farrar JJ, Hay SI: The global distribution and burden of dengue. Nature, online 7 April 2013. Doi: 10.1038/nature12060

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