Tracking Dengue Fever in China Dengue Fever

Dengue is a viral disease transmitted from host to host by mosquitoes (Shepherd, 2012, Background). Many tropical and subtropical regions of the world are currently combating this disease, including 112 countries in the Americas, Africa, Asia, and Australia. These regions are home to almost 3 billion people, therefore nearly half of the world's population is at risk for becoming infected with dengue. Currently, between 50 and 100 million people become infected with the virus each year.

Unfortunately, the number of reported cases of Dengue fever is increasing in many of these regions, including the Americas, South-East Asia, and the Western Pacific (Shepherd, 2012, Background). This report will review what is understood about this disease, its mode of transmission, ongoing efforts to control its spread, and how public health virologists track outbreaks.

Etiology

The virus that causes dengue fever is a single-stranded RNA virus, which is encoded by an 11-kilobase genome encased within an icosahedral nucleocapsid (Shepherd, 2012, Etiology). This capsid is in turn encapsulated by a lipid envelope. There are currently four main serotypes of dengue: DENV-1, DENV-2, DENV-3, and DENV-4. The serotypes are distinguished from each other using distinct antibodies and can be further divided into several genotypes. The different serotypes and genotypes are important because they seem to influence disease severity.

High-risk areas for dengue infection tend to be regions with a humid climate, because the primary vector for its transmission, Aedes aegypti, thrives in such environments (Shepherd, 2012, Etiology). These mosquitoes inhabit urban areas where there is poor sanitation, because discarded man-made waste, like old tires, will trap water, which then acts as a breeding ground for these mosquitoes (Shepherd, 2012, Background). Ae. aegypti can become infected with the dengue virus when it feeds on an infected human or primate, and once infected, the virus begins to replicate within the organs and body cavity of the insect. Ae. aegypti will remain infected for the duration of its lifespan, which averages 21 days; however, under desiccating conditions, infected Ae. aegypti eggs can represent a potential source for vertical transmission for as long as a year.

Pathophysiology

The incubation period of the virus is 3-14 days in a human host, with an average of a week or less (Shepherd, 2012, Pathophysiology). The virus targets dendritic cells, hepatocytes, and endothelial cells for infection and replication, which in turn activates an immune response to purge the body of the virus; however, most infected individuals will not develop symptoms. The people most susceptible to developing symptoms are those who have never encountered dengue before, such as recent tourists or immigrants to endemic regions. People who become symptomatic will suffer primarily from a fever that lasts about a week. Other symptoms can include severe headache, eye pain, severe joint and muscle pain, nausea and vomiting, and rash (NIAID, 2007). Full recovery occurs shortly thereafter, unless they develop hemorrhagic fever or dengue shock syndrome.

Children below the age of 15 are susceptible to developing hemorrhagic fever, although all ages are equally prone to developing this condition on the American continent and in Taiwan (Shepherd, 2012, Pathophysiology). Individuals who develop hemorrhagic fever will first develop a high fever lasting 2-7 days, followed by a period of remission. Infected individuals will again become febrile and develop hemorrhagic disease. This manifestation of dengue is potentially lethal because it can lead to plasma leaking, fluid accumulation, respiratory distress, severe bleeding, organ failure (WHO, 2012), and/or circulatory failure (Shepherd, 2012, Pathophysiology). One of the telltale signs, in addition to the biphasic fever, is bone pain, which is believed to result from the destruction of bone marrow precursors cells. Hemorrhagic fever will affect over half a million people each year, contributing to 25,000 yearly dengue-related deaths (reviewed by Jing et al., 2012).

The most dangerous form of this disease is dengue shock syndrome, which occurs primarily in children who are infected with the virus a second time (NIAID, 2007). In addition to the above symptoms, massive bleeding leads to hypotension and then shock. Unless medical care is available, this is frequently a fatal condition.

Control Measures

Dengue has become entrenched in over 100 countries around the world, making this disease both endemic to these countries and one of the most out of control diseases globally (TDR, 2011). A five-year study in five Asian countries investigated the efficacy of measures designed to bring this disease under control. The interventions included mechanical covers for water containers, chemical pesticides, biopesticides, introduction of mosquito larvae predators, and improved solid waste management.

Molecular...

Primates continue to represent the primary reservoir for the dengue virus, because the virus can amplify without causing disease (Weaver and Vasilakis, 2009).
The genetic differences between the four main serotypes are significant for several reasons. The first infection with the virus will confer life-long immunity against the offending serotype, but not against the other three (Weaver and Vasilakis, 2009). In addition, the increased risk of developing hemorrhagic disease or dengue shock when reinfected with the virus is consistent with the possibility that some serotypes produce more severe disease. For example, DENV-4 has been correlated with more severe disease in children, and to a lesser extent in adults, after secondary infection (reviewed by Jing et al., 2012). DENV-4 occurs most frequently as a secondary infection and is responsible for 10% of hemorrhagic disease in Thai children.

A DENV-4 outbreak was first identified in Guangzhou, China in 1978, and subsequent outbreaks occurred in 1990 and 2010 (reviewed by Jing et al., 2012). Guangzhou is a large metropolitan area with a subtropical, humid climate, where all four serotypes have emerged in the past. To determine whether the 2010 outbreak represented a reemergence of the 1990 DENV-4 strain, the genotypes and phylogenetic relationships between viruses involved in the individual dengue cases were investigated.

The primary vector for dengue transmission in Guangzhou is Aedes albopictus (Jing et al., 2012). Larval surveys indicated a high prevalence of this arthropod at the time of the 2010 outbreak. A total of 19 dengue fever cases were identified, of which one was determined to be imported from Bangkok, Thailand. The person suspected of importing dengue returned to the Jingtai Street district in Guangzhou on September 2, 2010, after beginning to experience symptoms on the evening of August 31. The indigenous cases occurred between September 6 and October 29, 2010 and all cases were confined to the Jingtai Street community. Hospitalization was required in 16 of the cases, which is consistent with a more severe form of the disease. The timing of the cases, the limited geographic distribution, and the uniform disease severity, suggests that the Guangzhou 2010 outbreak was introduced from Thailand.

Viral isolates were available for five cases and all were determined to be DENV-4 (Jing et al., 2012). Sequencing of the envelope gene, the prototypical reference sequence for dengue genotyping, indicated 99.9% to 100% homology between all five cases. Sequence comparisons with GenBank data base entries indicated Thailand was the most likely source.

When compared to another DENV-4 sequence isolated from Guangzhou in 2010, which had been deposited in GenBank previously, both were found to be identical phylogenetically (Jing et al., 2012). Both belong to the same clade and the DENV-4 genotype II; however, comparison with reference sequence from the 1990 DENV-4 outbreak did not reveal strong homology. A phylogenetic comparison to a Thailand strain isolated from a 2002 outbreak revealed strong homology, consistent with this representing the parent strain. These results suggest there was no phylogenetic relationship between the Guangzhou DENV-4 outbreaks in 1990 and 2010; therefore, the 2010 outbreak represented an introduced strain rather than a reemergence.

Discussion

Jing and colleagues (2012) investigated the genetic and phylogenetic relationships between DENV-4 outbreaks in 1990 and 2010, to determine whether the recent outbreak represented a reemergence of the 1990 strain or one that was recently introduced. Several lines of evidence were relied upon to make this judgment, including patient case histories, timelines, geographical information, symptom severity, genotyping, and phylogenetic analysis. The evidence from all of these different sources of information provided consistent, and thus sufficient, support for concluding that the 2010 DENV-4 outbreak represented an introduced strain from Thailand.

This finding is consistent with what is known about past outbreaks and the geographic distribution of DENV-4 (Jing et al., 2012). DENV-4 is endemic to Thailand, where several dengue epidemics have occurred over the past several decades. In contrast, dengue cases in China are thought to originate from outside the country. In addition, the arthropod vector in Guangzhou, Ae. Albopictus, functions primarily as a maintenance vector for the dengue virus (DVBD, 2011). In other words, the virus will survive for only a short period inside the mosquito and feeding on human blood rarely leads to an infection. This would explain the limited size of the outbreak. In summary, a number of different findings consistently support concluding that the Guangzhou 2010 dengue outbreak was the result of…