Dengue fever

Dengue fever
Classification and external resources
ICD-10 A90.
ICD-9 061
DiseasesDB 3564
MedlinePlus 001374
eMedicine med/528
MeSH C02.782.417.214
Dengue virus
A TEM micrograph showing Dengue virus virions (the cluster of dark dots near the center).
Virus classification
Group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Flavivirus
Species: Dengue virus

Dengue fever (pronounced UK: /ˈdɛŋɡeɪ/, US: /ˈdɛŋɡiː/) and dengue hemorrhagic fever (DHF) are acute febrile diseases which occur in the tropics, can be life-threatening, and are caused by four closely related virus serotypes of the genus Flavivirus, family Flaviviridae.[1] It is also known as breakbone fever, since it can be extremely painful. It occurs widely in the tropics, including northern Argentina, northern Australia, Bangladesh, Barbados, Bolivia,[2] Belize, Brazil, Cambodia, Colombia, Costa Rica, Cuba, Dominican Republic, French Polynesia, Guadeloupe, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, India, Indonesia, Jamaica, Laos, Malaysia, Melanesia, Mexico, Micronesia, Nicaragua, Pakistan, Panama, Paraguay,[3] The Philippines, Puerto Rico, Samoa,[4] Western Saudi Arabia, Singapore, Sri Lanka, Suriname, Taiwan, Thailand (ไข้เลือดออก khai lueat ok), Trinidad and Tobago, Venezuela and Vietnam, and increasingly in southern China.[5] Unlike malaria, dengue is just as prevalent in the urban districts of its range as in rural areas. Each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes (hyperendemicity) can occur. Dengue is transmitted to humans by the Aedes (Stegomyia) aegypti or more rarely the Aedes albopictus mosquito. The mosquitoes that spread dengue usually bite at dusk and dawn but may bite at any time during the day, especially indoors, in shady areas, or when the weather is cloudy.[6]

The WHO says some 2.5 billion people, two fifths of the world's population, are now at risk from dengue and estimates that there may be 50 million cases of dengue infection worldwide every year. The disease is now endemic in more than 100 countries.[7]

Contents

Signs and symptoms

The disease manifests as fever of sudden onset associated with headache, muscle and joint pains (myalgias and arthralgias—severe pain that gives it the nickname break-bone fever or bonecrusher disease), distinctive retro-orbital pain, and rash.[8] The classic dengue rash is a generalised maculopapular rash with islands of sparing. A hemorrhagic rash of characteristically bright red pinpoint spots, known as petechiae can occur later during the illness and is associated with thrombocytopenia. It usually appears first on the lower limbs and the chest; in some patients, it spreads to cover most of the body. There may also be severe retro-orbital pain, (a pain from behind the eyes that is distinctive to Dengue infections), and gastritis with some combination of associated abdominal pain, nausea, vomiting coffee-grounds-like congealed blood, or diarrhea. Some cases develop much milder symptoms which can be misdiagnosed as influenza or other viral infection when no rash or retro-orbital pain is present. Febrile travelers from tropical areas may transmit dengue inadvertently to previously Dengue free populations of Aedes (Stegomyia) Aegypti mosquitoes, having not been properly diagnosed for Dengue. Patients only transmit Dengue when they are febrile and bitten by Aedes (Stegomyia) Aegypti mosquitoes, or (much more unusually) via blood products. The classic dengue fever lasts about two to seven days, with a smaller peak of fever at the trailing end of the disease (the so-called "biphasic pattern"). Clinically, the platelet count will drop until after the patient's temperature is normal. Cases of DHF also show higher fever, variable hemorrhagic phenomena including bleeding from the eyes,nose,mouth and ear into the gut, and oozing blood from skin pores, thrombocytopenia, and hemoconcentration. When Dengue infections proceed to DHF symptoms, DHF causes vascular leak syndrome which includes fluid in the blood vessels leaking through the skin and into spaces around the lungs and belly. This fluid loss and severe bleeding can cause blood pressure to fall, then Dengue Shock Syndrome (DSS) sets in, which has a high mortality rate. Neurological manifestations such as encephalitis may also occur .[9]

Virology

Dengue fever is caused by Dengue virus (DENV), a mosquito-borne flavivirus. DENV is an ssRNA positive-strand virus of the family Flaviviridae; genus Flavivirus. There are four serotypes of DENV. The virus has a genome of about 11000 bases that codes for three structural proteins, C, prM, E; seven nonstructural proteins, NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5; and short non-coding regions on both the 5' and 3' ends.[10]

E protein

The DENV E (envelope) protein, found on the viral surface, is important in the initial attachment of the viral particle to the host cell. Several molecules which interact with the viral E protein (ICAM3-grabbing non-integrin.,[11]CD209 ,[12] Rab 5 ,[13] GRP 78 ,[14] and The Mannose Receptor [15])have been shown to be important factors mediating attachment and viral entry.[16]

prM/M protein

The DENV prM (membrane) protein, which is important in the formation and maturation of the viral particle, consists of seven antiparallel β-strands stabilized by three disulphide bonds.[16]

The glycoprotein shell of the mature DENV virion consists of 180 copies each of the E protein and M protein. The immature virion starts out with the E and prM proteins forming 90 heretodimers that give a spiky exterior to the viral particle. This immature viral particle buds into the endoplasmic reticulum and eventually travels via the secretory pathway to the golgi apparatus. As the virion passes through the TGN it is exposed to low pH. This acidic environment causes a conformational change in the E protein which disassociates it from the prM protein and causes it to form E homodimers. These homodimers lay flat against the viral surface giving the maturing virion a smooth appearance. During this maturation pr peptide is cleaved from the M peptide by the host protease, furin. The M protein then acts as a transmembrane protein under the E-protein shell of the mature virion. The pr peptide stays associated with the E protein until the viral particle is released into the extracellular environment. This pr peptide acts like a cap, covering the hydrophobic fusion loop of the E protein until the viral particle has exited the cell.[16]

NS3 protein

The DENV NS3 is a serine protease, as well as an RNA helicase and RTPase/NTPase. The protease domain consists of six β-strands arranged into two β-barrels formed by residues 1-180 of the protein. The catalytic triad (His-51, Asp-75 and Ser-135), is found between these two β-barrels, and its activity is dependent on the presence of the NS2B cofactor. This cofactor wraps around the NS3 protease domain and becomes part of the active site. The remaining NS3 residues (180-618), form the three subdomains of the DENV helicase. A six-stranded parallel β-sheet surrounded by four α-helices make up subdomains I and II, and subdomain III is composed of 4 α-helices surrounded by three shorter α-helices and two antiparallel β-strands.[16]

NS5 protein

The DENV NS5 protein is a 900 residue peptide with a methyltransferase domain at its N-terminal end (residues 1-296) and a RNA-dependent RNA polymerase at its C-terminal end (residues 320–900). The methyltransferase domain is comprised of an α/β/β sandwich flanked by N-and C-terminal subdomains. The DENV RNA-dependent RNA polymerase is similar to other to other RdRps containing palm, finger, and thumb subdomains and a GDD motif for incorporating nucleotides.[16]

The potential factors causing hemorrhagic fever are varied. The most suspected factors are human's cross-serotypic immune response and membrane fusion process.

Human antibodies produced in response to the virus actually increase the infection.[17]

Diagnosis

The diagnosis of dengue is usually made clinically. The classic picture is high fever with no localising source of infection, a rash with thrombocytopenia and relative leukopenia - low platelet and white blood cell count. Dengue infection can affect many organs and thus may present unusually as liver dysfunction, renal impairment, meningo-encephalitis or gastroenteritis.

  1. Fever, headaches, eye pain, severe dizziness and loss of appetite.
  2. Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
  3. Thrombocytopenia (<100,000 platelets per mm³ or estimated as less than 3 platelets per high power field)
  4. Evidence of plasma leakage (hematocrit more than 20% higher than expected, or drop in hematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)
  5. Encephalitic occurrences.

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

Dependable, immediate diagnosis of dengue can be performed in rural areas by the use of Rapid Diagnostic Test kits, which also differentiate between primary and secondary dengue infections.[18] Serology and polymerase chain reaction (PCR) studies are available to confirm the diagnosis of dengue if clinically indicated. Dengue can be a life threatening fever.

Prevention

There is no tested and approved vaccine for the dengue flavivirus. There are many ongoing vaccine development programs. Among them is the Pediatric Dengue Vaccine Initiative set up in 2003 with the aim of accelerating the development and introduction of dengue vaccine(s) that are affordable and accessible to poor children in endemic countries.[19] Thai researchers are testing a dengue fever vaccine on 3,000–5,000 human volunteers after having successfully conducted tests on animals and a small group of human volunteers.[20] A number of other vaccine candidates are entering phase I or II testing.[21] As of July 2010, the National Institutes of Health reported on their ClinicalTrials.Gov Web site that there were 19 vaccines undergoing testing or recruiting for participants.[22] Because exposure to one of dengue's 4 serotypes provides no immunity against infection by the other types, and may make the patient susceptible to more severe disease symptoms, testing vaccines must be performed carefully, and usually not in areas where the disease is endemic for fear that even attenuated virus vaccines may cause severe reactions.[23]

In 1998, scientists from the Queensland Institute of Medical Research (QIMR) in Australia and Vietnam's Ministry of Health introduced a scheme that encouraged children to place a water bug, the crustacean Mesocyclops, in water tanks and discarded containers where the Aedes aegypti mosquito was known to thrive.[24] This method is viewed as being more cost-effective and more environmentally friendly than pesticides, though not as effective, and requires the continuing participation of the community.[25]

Even though this method of mosquito control was successful in rural provinces, not much is known about how effective it could be if applied to cities and urban areas. The Mesocyclops can survive and breed in large water containers but would not be able to do so in small containers that most urban dwellers have in their homes. Also, Mesocyclops are hosts for the guinea worm, a pathogen that causes a parasite infection, and so this method of mosquito control cannot be used in countries that are still susceptible to the guinea worm. The biggest dilemma with Mesocyclops is that its success depends on the participation of the community. This idea of a possible parasite-bearing creature in household water containers dissuades people from continuing the process of inoculation and, without the support and work of everyone living in the city, this method will not be successful.[26]

Treatment

The mainstay of treatment is timely supportive therapy to tackle circulatory shock due to hemoconcentration and bleeding. Close monitoring of vital signs in the critical period (up to 2 days after defervescence - the departure or subsiding of a fever) is critical. Oral rehydration therapy is recommended to prevent dehydration in moderate to severe cases. Supplementation with intravenous fluids may be necessary to prevent dehydration and significant concentration of the blood if the patient is unable to maintain oral intake. A platelet transfusion may be indicated if the platelet level drops significantly (below 20,000) or if there is significant bleeding. The presence of melena may indicate internal gastrointestinal bleeding requiring platelet and/or red blood cell transfusion.

Aspirin and non-steroidal anti-inflammatory drugs should be avoided as these drugs may worsen the bleeding tendency associated with some of these infections. Patients may receive paracetamol, acetaminophen, preparations to deal with these symptoms if dengue is suspected.[27]

Epidemiology

Disability-adjusted life year for dengue fever per 100,000 inhabitants in 2002.
     no data      < 15      15-30      30-45      45-60      60-75      75-90
     90-105      105-120      120-135      135-150      150-250      > 250
Worldwide dengue distribution, 2006. Red: Epidemic dengue. Blue: Aedes aegypti.
Worldwide dengue distribution, 2000.

Dengue is transmitted by Aedes mosquitoes, particularly A. aegypti and A. albopictus.

The first recognized Dengue epidemics occurred almost simultaneously in Asia, Africa, and North America in the 1780s, shortly after the identification and naming of the disease in 1779. A pandemic began in Southeast Asia in the 1950s, and by 1975 DHF had become a leading cause of death among children in the region. Epidemic dengue has become more common since the 1980s. By the late 1990s, dengue was the most important mosquito-borne disease affecting humans after malaria, with around 40 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever each year. Significant outbreaks of dengue fever tend to occur every five or six months. The cyclical rise and fall in numbers of dengue cases is thought to be the result of seasonal cycles interacting with a short-lived cross-immunity for all four strains in people who have had dengue. When the cross-immunity wears off the population is more susceptible to transmission whenever the next seasonal peak occurs. Thus over time there remain large numbers of susceptible people in affected populations despite previous outbreaks due to the four different serotypes of dengue virus and the presence of unexposed individuals from childbirth or immigration.

There is significant evidence, originally suggested by S.B. Halstead in the 1970s, that dengue hemorrhagic fever is more likely to occur in patients who have secondary infections by another one of dengue fever's four serotypes. One model to explain this process is known as antibody-dependent enhancement (ADE), which allows for increased uptake and virion replication during a secondary infection with a different strain. Through an immunological phenomenon, known as original antigenic sin, the immune system is not able to adequately respond to the stronger infection, and the secondary infection becomes far more serious.[28]

Reported cases of dengue are an under-representation of all cases when accounting for subclinical cases and cases where the patient did receive medical treatment.

There was a serious outbreak in Rio de Janeiro in February 2002 affecting around one million people and killing sixteen. On March 20, 2008, the secretary of health of the state of Rio de Janeiro, Sérgio Côrtes, announced that 23,555 cases of dengue, including 30 deaths, had been recorded in the state in less than three months. Côrtes said, "I am treating this as an epidemic because the number of cases is extremely high." Federal Minister of Health, José Gomes Temporão also announced that he was forming a panel to respond to the situation. Cesar Maia, mayor of the city of Rio de Janeiro, denied that there was serious cause for concern, saying that the incidence of cases was in fact declining from a peak at the beginning of February.[29] By April 3, 2008, the number of cases reported rose to 55,000 [30]

In Singapore, there are 4,000–5,000 reported cases of dengue fever or dengue haemorrhagic fever every year. In the year 2004, there were seven deaths from dengue shock syndrome.[31]

Recent outbreaks

An outbreak of dengue fever was declared in Cairns, located in the tropical north of Queensland, Australia on 1 December 2008. As of 3 March 2009 there were 503 confirmed cases of dengue fever, in a residential population of 152,137. Outbreaks were subsequently declared the neighbouring cities and towns of Townsville (outbreak declared 5 January 2009), Port Douglas (6 February 2009), Yarrabah (19 February 2009), Injinoo (24 February 2009), Innisfail (27 February 2009) and Rockhampton (10 March 2009). There have been occurrences of dengue types one, two, three, and four in the region. On March 4, 2009, Queensland Health had confirmed an elderly woman had died from dengue fever in Cairns, in the first fatality since the epidemic began last year. The statement said that although the woman had other health problems, she tested positive for dengue and the disease probably contributed to her death.

An epidemic broke out in Bolivia in early 2009, in which 18 people have died and 31,000 infected.

In 2009, in Argentina, a dengue outbreak was declared the northern provinces of Chaco, Catamarca, Salta, Jujuy, and Corrientes, with over 9673 cases reported as of April 11, 2009 by the Health Ministry [3]. Some travelers from the affected zones have spread the fever as far south as Buenos Aires [4]. Major efforts to control the epidemic in Argentina are focused on preventing its vector (the Aedes mosquitoes) from reproducing. This is addressed by asking people to dry out all possible water reservoirs from where mosquitoes could proliferate (which is, in other countries, known as "descacharrado"). There have also been information campaigns concerning prevention of the dengue fever; and the government is fumigating with insecticide in order to control the mosquito population.[32]

The first cases of dengue fever have recently been reported on the island nation of Mauritius in the Indian Ocean. One of the South Asian countries still suffering highly from this problem is Sri Lanka.[33]

2010 Outbreak table

Country/Region Reported Cases Dengue
(Cumulative)		 Reported Deaths
(Cumulative)		 Compared with previous year Figures as of**
 World (sum of all regions) 280,133 998
 Philippines 62,503 465 up 88% end Aug[34]
 Thailand 57,940 70 up 94% Aug 20[35]
 Honduras 54,000 60 N/A end Aug[36]
 Malaysia 32,688 103 up 88% end Aug[37]
 Sri Lanka 26,824 192 mid Jul[38]
 Costa Rica 21,000 N/A 3,326 end Aug[39]
 Puerto Rico 11,000 18, 14 suspected - end Aug[40]
 Dominican Republic 9,000 41 3,000 end aug[40]
Delhi,  India 1,370 4 3,000 sep 5[41]
 Singapore 2,608 41 3,050 end aug[42]
 Trinidad and Tobago 1,200 4 N/A end aug[40]

Blood transfusion

Dengue may also be transmitted via infected blood products (blood transfusions, plasma, and platelets),[43][44] and in countries such as Singapore, where dengue is endemic, the risk was estimated to be between 1.6 and 6 per 10,000 blood transfusions.[45]

History

Etymology

The origins of the word dengue are not clear, but one theory is that it is derived from the Swahili phrase "Ka-dinga pepo", which describes the disease as being caused by an evil spirit.[46] The Swahili word "dinga" may possibly have its origin in the Spanish word "dengue" meaning fastidious or careful, which would describe the gait of a person suffering the bone pain of dengue fever.[47] Alternatively, the use of the Spanish word may derive from the similar-sounding Swahili.[48]

Literature

Slaves in the West Indies who contracted dengue were said to have the posture and gait of a dandy, and the disease was known as "Dandy Fever".[49] The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (265–420 AD) which referred to a “water poison” associated with flying insects.[48] The first confirmed case report dates from 1789 and is by Benjamin Rush, who coined the term "breakbone fever" because of the symptoms of myalgia and arthralgia.[50] The viral etiology and the transmission by mosquitoes were discovered in the 20th century by Sir John Burton Cleland.

Population movements during World War II spread the disease globally. A pandemic of dengue began in Southeast Asia after World War II and has spread around the globe since then.[51]

Society and culture

Use as a biological weapon

Dengue fever was one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program.[52]

Research

Emerging evidence suggests that mycophenolic acid and ribavirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug.[53] In vivo studies, however, have not yet been done. Unlike HIV therapy, lack of adequate global interest and funding greatly hampers the development of a treatment regime.

Management

Singapore has managed to reduce the cases of not only dengue, but chikungunya and malaria by introducing an Integrated Vector Management System. Cases fell from 7,500 to 4,500 in 2008[54], the 2,608 cases this year so far until aug 19, lower rate than preceeding years[55] For chikungunya results are dramatic, cases fell from 720 in 2008 to only 22 cases this year so far.[54]

Wolbachia

In 2009, scientists from the School of Integrative Biology at The University of Queensland revealed that by infecting Aedes mosquitos with the bacterium Wolbachia, the adult lifespan was reduced by half.[56] In the study, super-fine needles were used to inject 10,000 mosquito embryos with the bacterium. Once an insect was infected, the bacterium would spread via its eggs to the next generation. A pilot release of infected mosquitoes could begin in Vietnam within three years. If no problems are discovered, a full-scale biological attack against the insects could be launched within five years.[57]

Antiviral approaches

Dengue virus belongs to the family Flaviviridae, which includes the hepatitis C virus, West Nile and Yellow fever viruses among others. Possible laboratory modification of the yellow fever vaccine YF-17D to target the dengue virus via chimeric replacement has been discussed extensively in scientific literature,[58] but as of 2009 no full scale studies have been conducted.[59]

In 2006 a group of Argentine scientists discovered the molecular replication mechanism of the virus, which could be specifically attacked by disrupting the viral RNA polymerase.[60] In cell culture[61] and murine experiments[62][63] morpholino antisense oligomers have shown specific activity against Dengue virus.

Sterile insect technique

The sterile insect technique, a form of biological control, has long proved difficult with mosquitos because of the fragility of the males.[64] However, a transgenic strain of Aedes aegypti was announced in 2010 which might alleviate this problem: the strain produces females that are flightless due to a mis-development of their wings,[65] and so can neither mate nor bite. The genetic defect only causes effects in females, so that males can act as silent carriers.[64]

See also

References

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  2. ↑ "Dengue fever outbreak in Bolivia". BBC. 2009-02-03. http://news.bbc.co.uk/2/hi/americas/7866908.stm. Retrieved 2009-02-26. 
  3. ↑ Reuters, "Dengue Fever Hits Paraguay", New York Times" (March 4, 2007)
  4. ↑ http://www.samoalivenews.com/Health/Dengue-Fever-Outbreak-Confirmed-In-Samoa.html
  5. ↑ "Zhuhai reports outbreak of dengue fever". China Daily. 200-09-06. http://www.chinadaily.com.cn/china/2007-09/06/content_6087035.htm. Retrieved 2009-11-18. 
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  7. ↑ Dengue epidemic threatens India's capital
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  9. ↑ http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2010;volume=58;issue=4;spage=585;epage=591;aulast=Varatharaj
  10. ↑ Hanley, K.A. and Weaver, S.C. (editors) (2010). Frontiers in Dengue Virus Research. Caister Academic Press. ISBN 978-1-904455-50-9. 
  11. ↑ ,Navarro-Sanchez E, et al. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep 2003;4:723–728.
  12. ↑ ,Tassaneetrithep, B et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 2003;197:823–829.
  13. ↑ ,Krishnan, MN et al. Rab 5 is required for the cellular entry of dengue and West Nile viruses. J Virol 2007;81:4881–4885.
  14. ↑ ,Jindadamrongwech, S et al. Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Arch Virol 2004;149:915–927.
  15. ↑ , Miller, JL et al. The Mannose Receptor Mediates Dengue Virus Infection of Macrophages. PLoS Pathog 2008;4:e17.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 ,Perera, Rushika and Kuhn, Richard J. Structural Proteomics of Dengue Virus. Curr Opin Microbiol. 2008 August ; 11(4): 369–377.
  17. ↑ doi:10.1126/science.1185181
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  18. ↑ Such a diagnostic kit may consist of a "test cassette" or other device. One type is described as follows: "Dengue fever rapid test devices, also known as one-step dengue tests, are a solid phase immuno-chromatographic assay for the rapid, qualitative and differential detection of dengue IgG and IgM antibodies to dengue fever virus in human serum, plasma or whole blood." Atlas Link Biotech co. Ltd (2008)Dengue Fever Rapid Test Kits. Accessed: 27/06/09. Available at: http://www.ivdpretest.com/Dengue-Rapid-Tests.html
  19. ↑ "Pediatric Dengue Vaccine Initiative". 2008. http://www.pdvi.org/. Retrieved 2008-10-05. 
  20. ↑ "Thailand to test Mahidol-developed dengue vaccine prototype". People's Daily Online. 2005-09-05. http://english.people.com.cn/200509/05/eng20050905_206569.html. Retrieved 2006-10-08. 
  21. ↑ Edelman R (July 2007). "Dengue vaccines approach the finish line". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 45 Suppl 1: S56–60. doi:10.1086/518148. PMID 17582571. http://www.journals.uchicago.edu/doi/abs/10.1086/518148?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov. 
  22. ↑ [1]
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  25. ↑ "Water bug aids dengue fever fight". BBC News. 2005-02-11. http://news.bbc.co.uk/1/hi/health/4257935.stm. Retrieved 2008-10-05. 
    Kay B, Vu SN (2005). "New strategy against Aedes aegypti in Vietnam". Lancet 365 (9459): 613–7. doi:10.1016/S0140-6736(05)17913-6. PMID 15708107. 
  26. ↑ "Control of aedes vectors of dengue in three provinces of Vietnam by use of Mesocyclops (Copepoda) and community-based methods validated by entomologic, clinical, and serological surveillance". The American Society of Tropical Medicine and Hygiene. 2002. http://www.ajtmh.org/cgi/content/abstract/66/1/40. Retrieved 2009-02-18. 
  27. ↑ "Dengue & DHF: Information for Health Care Practitioners". Dengue Fever. CDC Division of Vector-Borne Infectious Diseases (DVBID). 2007-10-22. http://www.cdc.gov/NCIDOD/dvbid/dengue/dengue-hcp.htm. Retrieved 2008-10-05. 
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  29. ↑ Fernanda Pontes (20 March 2008). "Secretário estadual de Saúde Sérgio Côrtes admite que estado vive epidemia de dengue" (in Portuguese). O Globo Online. http://oglobo.globo.com/rio/mat/2008/03/20/secretario_estadual_de_saude_sergio_cortes_admite_que_estado_vive_epidemia_de_dengue-426368388.asp. .
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  33. ↑ Sri Lanka
  34. ↑ http://www.abs-cbnnews.com/lifestyle/09/02/10/can-tawa-tawa-cure-dengue
  35. ↑ http://www.thehindu.com/news/international/article589763.ece
  36. ↑ http://news.xinhuanet.com/english2010/health/2010-09/01/c_13473175.htm
  37. ↑ http://health.asiaone.com/Health/News/Story/A1Story20100903-235340.html
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  39. ↑ http://www.insidecostarica.com/dailynews/2010/september/03/costarica10090304.htm
  40. ↑ 40.0 40.1 40.2 http://www.etaiwannews.com/etn/news_content.php?id=1365772&lang=eng_news
  41. ↑ http://www.dnaindia.com/india/report_fourth-dengue-death-in-delhi-breeding-checkers-on-strike_1434342
  42. ↑ http://wildsingaporenews.blogspot.com/2010/08/surge-in-dengue-cases-in-singapore.html
  43. ↑ Wilder-Smith A, Chen LH, Massad E, Wilson ME (2009). "Threat of dengue to blood safety in dengue-endemic countries". Emerg Infect Dis 15 (1): 8–11. doi:10.3201/eid1501.071097. PMID 19116042. 
  44. ↑ Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KR, Dodd RY (2009). "Emerging infectious disease agents and their potential threat to transfusion safety.". Transfusion 49 (Suppl 2): 1–29. doi:10.1111/j.1537-2995.2008.02019.x. PMID 19686562. 
  45. ↑ Teo D, Ng LC, Lam S (2009). "Is dengue a threat to the blood supply?". Transfus Med 19 (2): 66–77. doi:10.1111/j.1365-3148.2009.00916.x. PMID 19392949. 
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