Dengue fever

from Wikipedia, the free encyclopedia
Classification according to ICD-10
A90 Dengue fever [classic dengue]
A91 Dengue hemorrhagic fever
ICD-10 online (WHO version 2019)
The typical rash in dengue fever

The dengue fever [ dɛŋge- ], including dengue , polka fever , bone crusher fever , seven-day fever and shortly Dengue is a disease whose cause is an infection with the dengue virus is. The virus is a 40 to 60  nm large, enveloped RNA virus with positive polarity from the flavivirus family .

The virus is transmitted by a mosquito bite and is common in tropical and subtropical areas. The only known hosts for the virus are primates and various mosquito species. There are four different serotypes (subgroups) of the virus, which most likely independently jumped from non-human primates to humans in Asia over the past 2000 years. Since the Second World War and the subsequent globalization , dengue fever has been on the advance, among other things due to the spread of its vector, and is often referred to as an emerging disease . Dengue is the fastest spreading, viral, mosquito-borne disease; the number of cases increased thirty-fold between 1960 and 2010.

The disease often manifests itself with unspecific symptoms or symptoms resembling severe flu ; internal bleeding can also occur. In a serious disease a so-called can "Hemorrhagic Dengue" (DHF) or dengue shock - syndrome (DSS) occur, both of which can lead to death. The WHO estimates that 50 to 100 million people fall ill every year, 500,000 people suffer from severe disease and 22,000 people die of dengue fever; most of the fatalities are children. Scientists from Oxford and Heidelberg reported in the journal Nature in April 2013 that, according to their research, around 390 million people were actually infected with the pathogen causing dengue fever each year.

For a long time there was no specific antiviral treatment for the disease. At the end of 2015, the first vaccine, " Dengvaxia ", was approved by Sanofi , which is supposed to be effective against all four variants of the virus and offer vaccine protection of 93%. However, later studies have shown that those who have never had dengue fever and were then vaccinated with Dengvaxia can later become infected and then develop even more severe symptoms than people who were not vaccinated. In Germany, Austria and Switzerland there is an obligation to report suspicion, illness, death, direct and indirect pathogen detection or hemorrhagic course of the disease.

Pathogen

Dengue virus under the microscope

Dengue fever is caused by one of the four serotypes (DENV-1 to DENV-4) of the dengue virus . It is a round, enveloped virus with a diameter of 40 to 60  nm from the flavivirus family . The viral genome (in contrast to the DNA used by all living things ) consists of ribonucleic acid (RNA). The genome is about 11,000 nucleotides long and is positive-stranded, so it can be read directly from ribosomes and with this information a protein (amino acid chain) can be formed. The genome only comprises an open reading frame that codes for a polyprotein (a long amino acid chain that has to be cut into the individual functional proteins afterwards).

During an infection, the viruses attach to the cell surface of a host cell via specific receptors and are taken up by a developing endosome vesicle . These vesicles are normally used to digest substances , but the virus uses them as a means of transport to get inside the cell. Inside the endosome, the acidic pH induces the fusion of the endosome membrane and the virus envelope , which allows the virus content to penetrate the cytosol . Thereafter, the viral genome in the rough endoplasmic reticulum (ER) and in so-called vesicle packets replicated and, after maturation in the Golgi apparatus arise infectious virus particles. These leave the cell and attack other host cells.

The four different serotypes occur either in demarcated or overlapping endemic zones . Phylogenetic analyzes make it possible to subdivide the individual serotypes into genotypes . DENV-1 and DENV-2 are divided into five genotypes, DENV-3 and DENV-4 each into four genotypes. Molecular biological investigations have shown that the endemic genotypes split off from the (silvatic) genotypes occurring in forests or in the jungle in the last 2000 years. DENV-2 then jumped over to humans about 1000 years ago, DENV-4 600 years ago and DENV-1 200 years ago (all data ± 50%). No silvatic strain has yet been isolated from DENV-3, and consequently no statement can be made about a possible point in time at which the virus was split off.

transmission

Egyptian tiger mosquito, Stegomyia aegypti , (formerly Aedes aegypti) at the blood meal

The most important vectors ( vectors ) of the dengue virus are the females of the yellow fever mosquito ( Aedes aegypti , also called Egyptian tiger mosquito or dengue mosquito, synonym Stegomyia aegypti ) and the Asian tiger mosquito ( Aedes albopicta ), which is also spreading in Europe , synonym Stegomyia albopicta . In certain regions there are other types of mosquitos as carriers of dengue fever. B. the Polynesian tiger mosquito ( Aedes (Stegomyia) polynesiensis ) in the southern Pacific or Aedes (Stegomyia) scutellaris in New Guinea . In other mosquito species, a suitability for the transmission of pathogens (vector competence) was also shown.

As with other mosquito-borne arboviruses , dengue virus is ingested by a female mosquito who suckles the blood of an infected person. The viruses get into the mosquito's stomach and if the virus concentration is high enough, the virions can attack the gastric epithelial cells and multiply there. From there they get into the haemocoil (the mosquito's blood system) and on to the salivary glands . The next time the mosquito sucks blood, it injects its saliva into the wound, bringing the virus into the bloodstream of the stung primate. There is also evidence of a vertical infection of the dengue virus, i.e. the transmission from the female mosquito to her clutch and thus the larvae . This infection of the vectors without a previous blood meal appears to play a role in maintaining a reservoir of virus between outbreaks.

There are two epidemiologically distinguishable infection cycles in which the virus is transmitted from mosquitoes to humans or other primates . The yellow fever mosquito and the Asian tiger mosquito are involved in the so-called urban cycle, which are well adapted to large urban centers and transmit other diseases in addition to dengue fever.

In addition to the urban cycle, there is a silvatic cycle (forest cycle or jungle cycle) in both Africa and Asia, but very likely not in America , in which the mosquitoes Aedes (Diceromyia) furcifer and Aedes ( Stegomyia) luteocephala serve as vectors. Mainly non-human primates are infected in the jungle. While DENV-2 only circulates silvatically in Africa, in Asia this is very likely the case with all four serotypes. There is no evidence that the Silvatic cycle was involved in past dengue epidemics, but it is known that the pathogens of the Silvatic cycle can also infect humans.

distribution

Occurrence of the pathogen in 2006, red: epidemic occurrence, blue: Aedes aegypti (formerly Stegomyia aegypti )

Dengue fever is endemic to tropical and subtropical areas with 75% of global dengue cases occurring in the Asia / Pacific region. The main distribution areas include Latin America , Central Africa , India , Southeast Asia , parts of the Pacific (including New Caledonia and Hawaii ) and the southern United States .

Around half of the world's people live in endemic areas , and WHO's official estimates are between 50 and 100 million diseases, 500,000 serious disease courses and 22,000 deaths annually. In Asia, children account for over 90% of serious illnesses. According to the WHO , the number of illnesses roughly doubled between 2000 and 2010. Laos and the Philippines are particularly hard hit by this development.

Dengue is not endemic in Europe, with the spread of the vector mosquitoes Aedes aegypti and especially Ae. albopictus increases the risk of locally (autochthonously) transmitted infections that originate from imported cases. Between September 2012 and March 2013, for example, a dengue outbreak occurred on the Portuguese Atlantic island of Madeira with 1,080 proven cases. There were no major clinical and no deaths. The vector mosquito was Aedes aegypti , which was introduced to the island in 2005. The Asian tiger mosquito Aedes albopictus is now widespread in southern Europe and continues to expand its settlement area. In 2010, the first indigenous dengue fever cases occurred in southern France and Croatia . In 2013, another locally transmitted dengue infection was detected near Aix-en-Provence (southern France). In August 2015, two autochthonously acquired cases of dengue were discovered in Nîmes in the south of France . In October 2018, another five autochthonously acquired cases in Saint-Laurent-du-Var became known.

Symptoms

Dengue is transmitted by a mosquito bite and has an incubation period of three to 14 days. Most cases are mild ("oligosymptomatic", that is, accompanied by few symptoms), as is often observed with a flu-like infection . Symptoms include fever (up to 40 ° C) with chills and severe pain in the head, muscles, and limbs. Together with a rash ( exanthema ), these symptoms are also known as denguetrias. Diffuse hair loss can occur as a late manifestation up to two months after the onset of the disease.

In most patients, the disease resolves after 3 to 7 days. In about 2-4% of cases, however, the disease becomes severe and dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) can occur. These severe courses end fatally in 1–5% of all cases, but the mortality rate in individual epidemics can also reach 15%.

The hemorrhagic dengue (DHF) is an acute shock syndrome with haemorrhages , the permeability (in the course of permeability ) of the blood vessel walls becomes larger and, therefore, uncontrolled bleeding occur. The hemorrhagic form begins like normal dengue fever, but the condition of the sick worsens dramatically after two to six days. The blood circuit breaks down and it comes to the redness of the face, to the (inner) bleeding, fluid loss, brain-related (cerebral) seizures, coma , bleeding gums, hematemesis, melena , swelling of the liver and the general signs of shock ( tachycardia , hypotension , clammy Skin, pallor). In addition, disseminated petechiae can occur in this phase . These are microcircular hemorrhages on the skin that appear as red spots.

If the infection survives, there is brief immunity against all serotypes and lifelong immunity against the infecting strain.

Infection-enhancing antibodies

During infection with one of the four dengue serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) only antibodies against this particular serotype are produced. The infected person remains vulnerable to viruses of a different serotype.

In the event of a second infection by a virus of a different serotype, the antibodies - which can be acquired through a previous illness or transmitted from mothers to their children - against the first serotype are not able to neutralize the new virions . Instead, antibody-virus complexes are formed which are absorbed by macrophages , but are not destroyed by them, but allow the viruses to continue to multiply. In the case of a second infection, this leads to a higher viral load than in the case of a first infection (these ineffective antibodies are referred to as infection-enhancing antibodies or ADE for Antibody-dependent enhancement of infection ). At the molecular level, it has been observed that cells with Fcγ receptors or complement receptors are particularly susceptible to the virus at low antibody concentrations. This explains why children whose protective maternal antibody concentration is currently decreasing are particularly often affected by DHF. Furthermore, it is assumed that the antibodies against a certain virus strain bind a second strain with reduced avidity and therefore also lead to ADE. One possible explanation for this phenomenon is that the antibodies cause the virus to bind to the cell more efficiently.

This hypothesis is considered very likely, as the following example from Cuba shows: In 1977 a DENV-1 epidemic had struck the island and infected 44% of the population, with only mild symptoms being observed. In 1981 a DENV-2 epidemic was registered with more than 10,000 cases of DSS / DHF. The death rate of children aged 3-14 years was almost 15 times higher than that of adults. In 2001, a DENV-3 epidemic broke out in Havana . Only adults were affected by DSS / DHF because the children were too young to have seen the DENV-2 epidemic of 1981.

diagnosis

The clinical diagnosis is difficult because of the large number of possible pathogens for infectious diseases with similar initial symptoms. Sporadic and only mild courses can only be reliably recognized by a virological examination.

If an infection is suspected, the dengue virus can be detected using the reverse transcriptase polymerase chain reaction (RT-PCR), in which the genetic material of the virus is duplicated and thus detected directly. The direct detection of the pathogen can also be carried out via virus isolation by culturing in cell culture, whereby this process can take one to four weeks. Both procedures are carried out with blood plasma , the PCR also with blood serum . Serologically , an enzyme-linked immunosorbent test in the acute phase cannot usually detect any dengue-specific IgM antibodies , but if it is positive it can confirm the diagnosis after the symptoms have subsided. The specific IgG - titer can distinguish between an initial infection or a secondary infection (at a initial infection occur in the first 8 days no IgG antibodies). A four-fold increase in the specific antibody titer compared to a preliminary sample is considered reliable evidence. Since the serological test methods often cross-react with other flaviviruses , these indirect methods are never conclusive for an infection.

Antigen tests based on the direct detection of the NS1 protein (which is highly conserved within the four serotypes) are also commercially available. They are characterized by their easy handling (no laboratory required), but are significantly less sensitive and specific than more complex test methods.

The handling of all test material from the patient, especially blood, is subject to strict safety regulations and may only be carried out in laboratories of protection level 3 .

Differential diagnosis

If dengue fever is suspected, other viral ( influenza , measles , rubella , chikungunya , yellow fever and Japanese encephalitis ) and bacterial ( typhoid , leptospirosis , sepsis , meningococci and rickettsial diseases) and malaria should be excluded.

According to the WHO recommendations, the blood of a patient suspected of having dengue fever should be tested for antibodies against the chikungunya virus whenever an infection with dengue virus cannot be detected and the patient has been in an area where the chikungunya fever occurs.

Reporting requirement

In Austria, dengue fever is notifiable in the event of illness or death in accordance with Section 1, Paragraph 1, Number 1, Epidemic Act 1950 . Doctors and laboratories, among others, are obliged to report this ( Section 3 Epidemics Act).

In Switzerland, doctors, hospitals, etc., or the laboratory investigating , are obliged to report positive laboratory analysis results for the disease dengue fever or the pathogen dengue virus . This results from the Epidemics Act (EpG) in conjunction with the Epidemics Ordinance and Annex 1 or Annex 3 of the Ordinance of the FDHA on the reporting of observations of communicable diseases in humans .

In Germany, according to Section 6 of the Infection Protection Act (IfSG) , dengue fever must be reported by name if a virus- related hemorrhagic fever is suspected or, according to Section 7 IfSG, if the pathogen dengue virus is detected by the doctor or the laboratory . In the second case, it is primarily the heads of the laboratories, etc., and only in the case of hemorrhagic fever also the diagnosing doctor ( Section 8 IfSG) that are required to report .

treatment

As for all diseases caused by flaviviruses , there is no causal therapy for dengue fever . In severe cases, admission to a hospital (hospitalization) must be carried out and, due to the rapidly deteriorating condition of the disease in some cases, intensive medical supervision is advisable. Symptomatic treatment includes measures to replenish fluids ( rehydration ) and administration of agents such as paracetamol to relieve pain. On acetylsalicylic acid (. Eg aspirin ) should be avoided because of their anticoagulant effect, as this in the case of internal bleeding, which can occur in dengue fever, has devastating consequences for the patient. Furthermore, the early intravenous administration of fluids can be of decisive importance.

prevention

Unlocked water containers and small amounts of stagnant water that collects in buckets, cans, bottles, car tires or plastic sheeting are sufficient as larval biotopes. In addition, the eggs of the tiger mosquitoes are drought-resistant and can therefore survive dry periods. All of this makes it difficult to control the mosquitoes.

Personal precautions against dengue include avoiding mosquito bites in areas where dengue is endemic. Institutional measures to prevent dengue fever include measures to control the disease-transmitting mosquitoes.

Personal Prevention

Bites can be avoided in particular by wearing suitable clothing and repellants such as mosquito- repellent sprays. Since the adult tiger mosquitoes are diurnal, you can only protect yourself to a limited extent with bed nets, which are effective against malaria , for example . Mosquito repellent sprays with a high DEET content can further reduce the risk of a bite.

vaccination

Strategic prevention

Information campaign on the prevention of dengue and yellow fever in Paraguay .
Spraying insecticides in East Timor to combat dengue vectors (2019)

Although the first vaccine against dengue viruses has been available since the end of 2015, combating vector mosquitoes continues to play a central role. The yellow fever mosquito Stegomyia aegypti prefers to breed in pools of water that were created by residents in areas with problematic drinking water supplies or that accumulate in household waste; especially in tires , but also in old cans and plastic containers. These conditions are particularly common in the vicinity of urban centers in developing countries and form an excellent habitat for the yellow fever mosquito. Two strategies are followed in combating the mosquito:

  • Control of the developing larvae. One of the most important strategies at the moment is based on the most comprehensive disposal of larval waters supported by the general public. In addition to measures to reduce larval waters, chemical larvicides as well as larval- eating fish and copepods are used, which directly reduce the number of larvae and thus indirectly the number of mosquitoes that transmit disease. In Vietnam, copepods of the genus Mesocyclops have been used to combat dengue fever for several years , with the implementation of the measures being checked monthly. As a result, no more cases of dengue fever occurred in the affected areas between 2002 and 2005. Pyriproxyfen is mainly recommended as a chemical larvicide because it is safe for humans and effective even in small amounts.
  • Control of adult yellow fever mosquitoes. Curtains and covers of water tanks are treated with insecticide . They kill female mosquitoes which are dormant or looking for egg-laying waters. Furthermore, insecticide can be sprayed indoors, but this is not recommended by the WHO. A newer method is the use of special traps with an attractant mixture that have been optimized for catching tiger mosquitoes .

Other approaches are:

  • the spread of mosquitoes immunized against the virus by wMel Wolbachia (bacteria of the genus Wolbachia ).
  • the release of genetically modified males of the yellow fever mosquito There have been and still are numerous concerns about the release of around 10 million genetically modified male mosquitoes in Brazil.
  • a parasitic fungus ( Beauveria bassiana ) that kills or weakens mosquitoes.

history

The origin of the name dengue is not clear. An early name for it was dandy fever ; later the Spanish name dengue came up, which indicates a pain-related, noticeably peculiar change in posture and behavior in sick people. According to other sources, dengue comes from the African language area ( Swahili : dinga ) and stands for a seizure that is triggered by an evil spirit.

The first mention of the disease is seen by some in the Chinese Jin dynasty (265–420) and later in the 1st millennium of our era. The next reports of dengue fever came from Panama (1635, 1699), Jakarta (1779–1788), Cairo (1881, 1883), Philadelphia (1789) and Spain (1881) and show the widespread spread of the disease at that time.

1927–1929 a dengue epidemic raged in Greece with more than a million infected people - the last epidemic before the eradication of the yellow fever mosquito ( Stegomyia aegypti ) in the Mediterranean area and the disappearance of dengue from this area. The mobility of troops during the Second World War led to major dengue epidemics between 1941 and 1945. As early as the 1960s, the spread of the virus increased sharply and the four serotypes were circulating in Asia. In the 1990s the global spread of dengue was complete, caused in particular by the abandonment of vector control programs, increased urbanization and globalization (individual mobility ). In 1998 a global pandemic was registered with more than 1.2 million cases in 56 countries. Dengue is on the rise and is known as the emerging disease .

Through a policy of vector control, dengue case numbers declined on the American continent during the 1960s and 1970s. Since the 1980s, however, the number of dengue fever cases in South America has risen again and the yellow fever mosquito has returned to the urban centers in South America, partly because the vector control programs were abandoned. On the American continent, major outbreaks of dengue fever followed in Brazil (2002, 2007), Paraguay (2007) and Mexico (2007). In some countries, a series of epidemics can be observed in which the serotypes alternate. There were outbreaks in Cuba in 1977 (DENV-1), 1981 (DENV-2) and 2001 (DENV-3), and in Brazil there were outbreaks in 1986 (DENV-1), 1990/1998 (DENV-2) , 2002–2005 (DENV-3) and 2007/2008 (DENV-2).

In 2019, Brazil, Mexico, Nicaragua, Colombia and Honduras were hardest hit in South and Central America.

research

In the 20th century the first steps to identify and control the causative agent of the disease were taken. After the successful scientific investigation of yellow fever virus by Finlay , Reed, and others, attention was drawn to dengue fever. Percy M. Ashburn and Charles F. Craig showed in 1907 that dengue fever is caused by a non-filterable factor, a virus just like yellow fever. Stegomyia aegypti was identified as a vector by Joseph Franklin Siler, Milton W. Hall, and Arthur Parker Hitchens in 1926.

In the late 1960s and early 1970s put Scott B. Halstead his hypothesis about infection-enhancing antibodies , which states that a second infection may be more dangerous than an initial infection. In 1970, the isolation of a virus from a human confirmed the hypothesis that silvatic pathogens can also infect humans.

Dengue fever has been studied by the US government as a potential biological weapon . This program was officially discontinued in 1970. Still, the United States was accused of being responsible for the dengue outbreak in Cuba in 1981 .

The so-called Pediatric Dengue Vaccine Initiative , financed by private and public bodies, is trying to develop a safe dengue virus vaccine . Various vaccine strains are already successfully in clinical test phases I, II and III. The French pharmaceutical company Sanofi Pasteur MSD announced in October 2010 that it would develop a vaccine by 2015. This tetravalent vaccine against all four known subtypes of dengue has already been successfully tested in a phase III study. Other researchers tried to stop the transmission with the help of Wolbachia .

literature

Selected free scientific review articles

About vaccinations

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About history

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  • G. Kuno: Emergence of the severe syndrome and mortality associated with dengue and dengue-like illness: historical records (1890 to 1950) and their compatibility with current hypotheses on the shift of disease manifestation . In: Clin. Microbiol. Rev. Band 22 , no. 2 , April 2009, p. 186-201 , doi : 10.1128 / CMR.00052-08 , PMID 19366911 , PMC 2668235 (free full text).
  • N. Vasilakis, SC Weaver: The history and evolution of human dengue emergence . In: Adv. Virus Res. Band 72 , 2008, p. 1-76 , doi : 10.1016 / S0065-3527 (08) 00401-6 , PMID 19081488 .

About infection-enhancing antibodies

Web links

Commons : Dengue fever  - collection of images, videos and audio files
Wiktionary: Dengue fever  - explanations of meanings, word origins, synonyms, translations

Individual evidence

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