1.1.1. Dengue in Asia and the Pacific

Some 1.8 billion (more than 70%) of the population at risk for dengue worldwide live in member states of the WHO South-East Asia Region and Western Pacific Region, which bear nearly 75% of the current global disease burden due to dengue. The Asia Pacific Dengue Strategic Plan for both regions (2008–2015) has been prepared in consultation with member countries and development partners in response to the increasing threat from dengue, which is spreading to new geographical areas and causing high mortality during the early phase of outbreaks. The strategic plan aims to aid countries to reverse the rising trend of dengue by enhancing their preparedness to detect, characterize and contain outbreaks rapidly and to stop the spread to new areas.

1.1.2. Dengue in the Americas

Interruption of dengue transmission in much the WHO Region of the Americas resulted from the Ae. aegypti eradication campaign in the Americas, mainly during the 1960s and early 1970s. However, vector surveillance and control measures were not sustained and there were subsequent reinfestations of the mosquito, followed by outbreaks in the Caribbean, and in Central and South America (7). Dengue fever has since spread with cyclical outbreaks occurring every 3–5 years. The biggest outbreak occurred in 2002 with more than 1 million reported cases.

From 2001 to 2007, more than 30 countries of the Americas notified a total of 4 332 731 cases of dengue (8). The number of cases of dengue haemorrhagic fever (DHF) in the same period was 106 037. The total number of dengue deaths from 2001 to 2007 was 1299, with a DHF case fatality rate of 1.2%. The four serotypes of the dengue virus (DEN-1, DEN-2, DEN-3 and DEN-4) circulate in the region. In Barbados, Colombia, Dominican Republic, El Salvador, Guatemala, French Guyana, Mexico, Peru, Puerto Rico and Venezuela, all four serotypes were simultaneously identified in one year during this period.

By subregion of the Americas, dengue is characterized as described below. All data are from the Pan American Health Organization (PAHO) (8).

1.1.3. Dengue in the WHO African Region

Although dengue exists in the WHO African Region, surveillance data are poor. Outbreak reports exist, although they are not complete, and there is evidence that dengue outbreaks are increasing in size and frequency (16). Dengue is not officially reported to WHO by countries in the region. Dengue-like illness has been recorded in Africa though usually without laboratory confirmation and could be due to infection with dengue virus or with viruses such as chikungunya that produce similar clinical symptoms.

Dengue has mostly been documented in Africa from published reports of serosurveys or from diagnosis in travellers returning from Africa, and dengue cases from countries in Sub-Saharan Africa. A serosurvey (17) suggests that dengue existed in Africa as far back as 1926–1927, when the disease caused an epidemic in Durban, South Africa. Cases of dengue imported from India were detected in the 1980s (18).

For eastern Africa, the available evidence so far indicates that DEN-1, -2 and -3 appear to be common ca;uses of acute fever. Examples of this are outbreaks in the Comoros in various years (1948, 1984 and 1993, DEN-1 and -2) (19) and Mozambique (1984-1985, DEN-3) (20).

In western Africa in the 1960s, DEN-1, -2 and -3 were isolated for the first time from samples taken from humans in Nigeria (21). Subsequent dengue outbreaks have been reported from different countries, as for example from Burkina Faso (1982, DEN-2) (22) and Senegal (1999, DEN-2) (23). Also DEN-2 and DEN-3 cases were confirmed in Côte d'Ivoire in 2006 and 2008.

Despite poor surveillance for dengue in Africa, it is clear that epidemic dengue fever caused by all four dengue serotypes has increased dramatically since 1980, with most epidemics occurring in eastern Africa, and to a smaller extent in western Africa, though this situation may be changing in 2008.

While dengue may not appear to be a major public health problem in Africa compared to the widespread incidence of malaria and HIV/AIDS, the increasing frequency and severity of dengue epidemics worldwide calls for a better understanding of the epidemiology of dengue infections with regard to the susceptibility of African populations to dengue and the interference between dengue and the other major communicable diseases of the continent.

1.1.4. Dengue in the WHO Eastern Mediterranean Region

(Figure 1.3)

Figure 1.3

Outbreaks of dengue fever in the WHO Eastern Mediterranean Region, 1994–2005.

Outbreaks of dengue have been documented in the Eastern Mediterranean Region possibly as early as 1799 in Egypt (24). The frequency of reported outbreaks continue to increase, with outbreaks for example in Sudan (1985, DEN-1 and -2) (25) and in Djibouti (1991, DEN-2) (26).

Recent outbreaks of suspected dengue have been recorded in Pakistan, Saudi Arabia, Sudan and Yemen, 2005–2006 (24). In Pakistan, the first confirmed outbreak of DHF occurred in 1994. A DEN-3 epidemic with DHF was first reported in 2005 (27). Since then, the expansion of dengue infections with increasing frequency and severity has been reported from large cities in Pakistan as far north as the North-West Frontier Province in 2008. Dengue is now a reportable disease in Pakistan. A pertinent issue for this region is the need to better understand the epidemiological situation of dengue in areas that are endemic for Crimean-Congo haemorrhagic fever and co-infections of these pathogens.

Yemen is also affected by the increasing frequency and geographic spread of epidemic dengue, and the number of cases has risen since the major DEN-3 epidemic that occurred in the western al-Hudeidah governorate in 2005. In 2008 dengue affected the southern province of Shabwa.

Since the first case of DHF died in Jeddah in 1993, Saudi Arabia has reported three major epidemics: a DEN-2 epidemic in 1994 with 469 cases of dengue, 23 cases of DHF, two cases of dengue shock syndrome (DSS) and two deaths; a DEN-1 epidemic in 2006 with 1269 cases of dengue, 27 cases of DHF, 12 cases of DSS and six deaths; and a DEN-3 epidemic in 2008 with 775 cases of dengue, nine cases of DHF, four cases of DSS and four deaths. A pertinent issue for the IHR is that Jeddah is a Haj entry point – as well as being the largest commercial port in the country, and the largest city with the busiest airport in the western region – with large numbers of people coming from high-burden dengue countries such as Indonesia, Malaysia and Thailand, in addition to the dengue-affected countries of the region.

1.1.5. Dengue in other regions

As described above, dengue is now endemic in all WHO regions except the WHO European Region. Data available for the European region (http://data.euro.who.int/cisid/) indicate that most cases in the region have been reported by European Union member states, either as incidents in overseas territories or importations from endemic countries. [See also a report from the European Centre for Disease Prevention and Control (28)]. However, in the past, dengue has been endemic in some Balkan and Mediterranean countries of the region, and imported cases in the presence of known mosquito vectors (e.g. Aedes albopictus) cannot exclude future disease spread.

Globally, reporting on dengue cases shows cyclical variation with high epidemic years and non-epidemic years. Dengue often presents in the form of large outbreaks. There is, however, also a seasonality of dengue, with outbreaks occurring in different periods of the year. This seasonality is determined by peak transmission of the disease, influenced by characteristics of the host, the vector and the agent.

1.1.6. Dengue case classification

Dengue has a wide spectrum of clinical presentations, often with unpredictable clinical evolution and outcome. While most patients recover following a self-limiting non-severe clinical course, a small proportion progress to severe disease, mostly characterized by plasma leakage with or without haemorrhage. Intravenous rehydration is the therapy of choice; this intervention can reduce the case fatality rate to less than 1% of severe cases. The group progressing from non-severe to severe disease is difficult to define, but this is an important concern since appropriate treatment may prevent these patients from developing more severe clinical conditions.

Triage, appropriate treatment, and the decision as to where this treatment should be given (in a health care facility or at home) are influenced by the case classification for dengue. This is even more the case during the frequent dengue outbreaks worldwide, where health services need to be adapted to cope with the sudden surge in demand.

Changes in the epidemiology of dengue, as described in the previous sections, lead to problems with the use of the existing WHO classification. Symptomatic dengue virus infections were grouped into three categories: undifferentiated fever, dengue fever (DF) and dengue haemorrhagic fever (DHF). DHF was further classified into four severity grades, with grades III and IV being defined as dengue shock syndrome (DSS) (29). There have been many reports of difficulties in the use of this classification (30–32), which were summarized in a systematic literature review (33). Difficulties in applying the criteria for DHF in the clinical situation, together with the increase in clinically severe dengue cases which did not fulfil the strict criteria of DHF, led to the request for the classification to be reconsidered. Currently the classification into DF/DHF/DSS continues to be widely used. (29)

A WHO/TDR-supported prospective clinical multicentre study across dengue-endemic regions was set up to collect evidence about criteria for classifying dengue into levels of severity. The study findings confirmed that, by using a set of clinical and/or laboratory parameters, one sees a clear-cut difference between patients with severe dengue and those with non-severe dengue. However, for practical reasons it was desirable to split the large group of patients with non-severe dengue into two subgroups – patients with warning signs and those without them. Criteria for diagnosing dengue (with or without warning signs) and severe dengue are presented in Figure 1.4. It must be kept in mind that even dengue patients without warning signs may develop severe dengue.

Figure 1.4

Suggested dengue case classification and levels of severity. * (requiring strict observation and medical intervention)

Expert consensus groups in Latin America (Havana, Cuba, 2007), South-East Asia (Kuala Lumpur, Malaysia, 2007), and at WHO headquarters in Geneva, Switzerland in 2008 agreed that:

“dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome”;

the classification into levels of severity has a high potential for being of practical use in the clinicians' decision as to where and how intensively the patient should be observed and treated (i.e. triage, which is particularly useful in outbreaks), in more consistent reporting in the national and international surveillance system, and as an end-point measure in dengue vaccine and drug trials.

This model for classifying dengue has been suggested by an expert group (Geneva, Switzerland, 2008) and is currently being tested in 18 countries by comparing its performance in practical settings to the existing WHO case classification. The process will be finalized in 2010. For practical reasons this guide adapts the distinction between dengue and severe dengue.

Additionally the guide uses three categories for case management (A, B, C) (Chapter 2).

1.4.1. The virus

Dengue virus (DEN) is a small single-stranded RNA virus comprising four distinct serotypes (DEN-1 to -4). These closely related serotypes of the dengue virus belong to the genus Flavivirus, family Flaviviridae.

The mature particle of the dengue virus is spherical with a diameter of 50nm containing multiple copies of the three structural proteins, a host-derived membrane bilayer and a single copy of a positive-sense, single-stranded RNA genome. The genome is cleaved by host and viral proteases in three structural proteins (capsid, C, prM, the precursor of membrane, M, protein and envelope, E) and seven nonstructural proteins (NS).

Distinct genotypes or lineages (viruses highly related in nucleotide sequence) have been identified within each serotype, highlighting the extensive genetic variability of the dengue serotypes. Purifying selection appears to be a dominant theme in dengue viral evolution, however, such that only viruses that are “fit” for both human and vector are maintained. Among them, “Asian” genotypes of DEN-2 and DEN-3 are frequently associated with severe disease accompanying secondary dengue infections (43–45). Intra-host viral diversity (quasispecies) has also been described in human hosts.

1.4.2. The vectors

The various serotypes of the dengue virus are transmitted to humans through the bites of infected Aedes mosquitoes, principally Ae. aegypti. This mosquito is a tropical and subtropical species widely distributed around the world, mostly between latitudes 35 °N and 35 °S. These geographical limits correspond approximately to a winter isotherm of 10 °C. Ae. aegypti has been found as far north as 45 °N, but such invasions have occurred during warmer months and the mosquitoes have not survived the winters. Also, because of lower temperatures, Ae. aegypti is relatively uncommon above 1000 metres. The immature stages are found in water-filled habitats, mostly in artificial containers closely associated with human dwellings and often indoors. Studies suggest that most female Ae. aegypti may spend their lifetime in or around the houses where they emerge as adults. This means that people, rather than mosquitoes, rapidly move the virus within and between communities. Dengue outbreaks have also been attributed to Aedes albopictus, Aedes polynesiensis and several species of the Aedes scutellaris complex. Each of these species has a particular ecology, behaviour and geographical distribution. In recent decades Aedes albopictus has spread from Asia to Africa, the Americas and Europe, notably aided by the international trade in used tyres in which eggs are deposited when they contain rainwater. The eggs can remain viable for many months in the absence of water (Chapter 3).

1.4.2. The host

After an incubation period of 4–10 days, infection by any of the four virus serotypes can produce a wide spectrum of illness, although most infections are asymptomatic or subclinical (Chapter 2). Primary infection is thought to induce lifelong protective immunity to the infecting serotype (46). Individuals suffering an infection are protected from clinical illness with a different serotype within 2–3 months of the primary infection but with no long-term cross-protective immunity.

Individual risk factors determine the severity of disease and include secondary infection, age, ethnicity and possibly chronic diseases (bronchial asthma, sickle cell anaemia and diabetes mellitus). Young children in particular may be less able than adults to compensate for capillary leakage and are consequently at greater risk of dengue shock.

Seroepidemiological studies in Cuba and Thailand consistently support the role of secondary heterotypic infection as a risk factor for severe dengue, although there are a few reports of severe cases associated with primary infection (47–50). The time interval between infections and the particular viral sequence of infections may also be of importance. For instance, a higher case fatality rate was observed in Cuba when DEN-2 infection followed a DEN-1 infection after an interval of 20 years compared to an interval of four years. Severe dengue is also regularly observed during primary infection of infants born to dengue-immune mothers. Antibody-dependent enhancement (ADE) of infection has been hypothesized (51,52) as a mechanism to explain severe dengue in the course of a secondary infection and in infants with primary infections. In this model, non-neutralizing, cross-reactive antibodies raised during a primary infection, or acquired passively at birth, bind to epitopes on the surface of a heterologous infecting virus and facilitate virus entry into Fc-receptor-bearing cells. The increased number of infected cells is predicted to result in a higher viral burden and induction of a robust host immune response that includes inflammatory cytokines and mediators, some of which may contribute to capillary leakage. During a secondary infection, cross-reactive memory T cells are also rapidly activated, proliferate, express cytokines and die by apoptosis in a manner that generally correlates with overall disease severity. Host genetic determinants might influence the clinical outcome of infection (53,54), though most studies have been unable to adequately address this issue. Studies in the American region show the rates of severe dengue to be lower in individuals of African ancestry than those in other ethnic groups. (54)

The dengue virus enters via the skin while an infected mosquito is taking a bloodmeal. During the acute phase of illness the virus is present in the blood and its clearance from this compartment generally coincides with defervescence. Humoral and cellular immune responses are considered to contribute to virus clearance via the generation of neutralizing antibodies and the activation of CD4⁺ and CD8⁺ T lymphocytes. In addition, innate host defence may limit infection by the virus. After infection, serotype-specific and cross-reactive antibodies and CD4⁺ and CD8⁺ T cells remain measurable for years.

Plasma leakage, haemoconcentration and abnormalities in homeostasis characterize severe dengue. The mechanisms leading to severe illness are not well defined but the immune response, the genetic background of the individual and the virus characteristics may all contribute to severe dengue.

Recent data suggest that endothelial cell activation could mediate plasma leakage (55,56). Plasma leakage is thought to be associated with functional rather than destructive effects on endothelial cells. Activation of infected monocytes and T cells, the complement system and the production of mediators, monokines, cytokines and soluble receptors may also be involved in endothelial cell dysfunction.

Thrombocytopenia may be associated with alterations in megakaryocytopoieses by the infection of human haematopoietic cells and impaired progenitor cell growth, resulting in platelet dysfunction (platelet activation and aggregation), increased destruction or consumption (peripheral sequestration and consumption). Haemorrhage may be a consequence of the thrombocytopenia and associated platelet dysfunction or disseminated intravascular coagulation. In summary, a transient and reversible imbalance of inflammatory mediators, cytokines and chemokines occurs during severe dengue, probably driven by a high early viral burden, and leading to dysfunction of vascular endothelial cells, derangement of the haemocoagulation system then to plasma leakage, shock and bleeding.

1.4.4. Transmission of the dengue virus

Humans are the main amplifying host of the virus. Dengue virus circulating in the blood of viraemic humans is ingested by female mosquitoes during feeding. The virus then infects the mosquito mid-gut and subsequently spreads systemically over a period of 8–12 days. After this extrinsic incubation period, the virus can be transmitted to other humans during subsequent probing or feeding. The extrinsic incubation period is influenced in part by environmental conditions, especially ambient temperature. Thereafter the mosquito remains infective for the rest of its life. Ae. aegypti is one of the most efficient vectors for arboviruses because it is highly anthropophilic, frequently bites several times before completing oogenesis, and thrives in close proximity to humans. Vertical transmission (transovarial transmission) of dengue virus has been demonstrated in the laboratory but rarely in the field. The significance of vertical transmission for maintenance of the virus is not well understood. Sylvatic dengue strains in some parts of Africa and Asia may also lead to human infection, causing mild illness. Several factors can influence the dynamics of virus transmission – including environmental and climate factors, host-pathogen interactions and population immunological factors. Climate directly influences the biology of the vectors and thereby their abundance and distribution; it is consequently an important determinant of vector-borne disease epidemics.