Features of Singapore Dengue Fever Epidemics

Singapore has seen an increase in Dengue Fever cases in 2020, with on June 15th, 10,995 detected cases since January, double the number for the same period last year. Experts estimate that the 2020 figures should exceed the total of 16,000 cases registered in 2019.

Long confined to the intertropical zone, Dengue now has an almost worldwide distribution (1). With nearly 400 million people infected each year, Dengue is considered a "re-emerging" disease (2). Dengue is a viral disease, transmitted by vector mosquitoes. To date, there is no effective vaccine or specific treatment (1). The first Dengue epidemic recorded in Singapore dates back to 1901. The severe form of the disease appeared there in the 1960s. Dengue then began to rage on a regular basis in the City-State, where children were the main target, placing the pathology as a childhood illness (3,4). Dengue is considered “endemic” in Singapore, it is one of the infectious diseases legally notifiable (5). The Dengue control program launched in Singapore in the 1970s helps contain subsequent outbreaks. Gradually, the authorities note a decrease of Dengue cases; in parallel, they note a relative increase in severe cases, with primary infections delayed in adulthood, testifying of a loss of immunity among the population (3,6). This trend was confirmed in the 2000s, when Singapore recorded two unprecedented Dengue epidemics; 2 reversals of the predominant viral serotype in the country are observed during these 2 outbreaks (4). The figures recorded in 2019-2020 suggest the same scenario (7). In addition, among the cases detected over the last few months, the increased proportion of a 3rd serotype has been noted (8). How to explain such a turnaround? In an attempt to answer this question, lepetitjournal.com investigated the specifics of Dengue Fever, as well as the physiological and ecological processes behind the epidemics in Singapore.

The symptoms of Dengue

Dengue Fever (DF) is mild and is asymptomatic in 75% of cases. On average, 1% of cases progress to severe symptoms, called Dengue Haemorrhagic Fever (DHF), which can be accompanied by fatal shock syndrome (1,2). The symptoms of the 2 Dengue fevers are presented in Table 1.

Table n ° 1: Symptoms of Dengue Fever and Dengue Haemorrhagic Fever (1, 2)

The risk of developing DHF is increased for individuals over 50, of blood type A / B / AB, of male sex, suffering from chronic diseases including asthma, sickle cell anaemia, diabetes mellitus, or having already had a Dengue fever in the past (4). Finally, the pathology is likely to impact the development of in-utero babies (2).

Singapore Dengue epidemics

As a viral pathology transmitted by vector mosquitoes, Dengue affects several thousands of people each year in Singapore. Its transmission is horizontal, from man to mosquito and vice versa, and vertical, from a female mosquito to its offspring (9). In humans, the incubation period is 4 to 10 days after being bitten by a mosquito infected with a Dengue virus (2); it is shortened in case of hot weather (10). In Singapore, Dengue season generally runs from May to October. The figures presented in table 2 highlight 2 outbreaks over the past 16 years.

Table n ° 2: Dengue cases recorded in Singapore between 2004 and 2019 (4,7)

The epidemics of 2004-2007 and 2013-2016 were characterized by a peak of detected cases in years n1 and n2, followed by a lull in year n3, then a rebound in year n4. During the 2 outbreaks, 2 reversals of predominant serotype were noted (DENV-1 versus DENV-2). The highest number of infections was recorded in 2013 with 22,170 cases. The highest rate of DHF (2.7% of detected Dengue cases) was observed in 2005. The highest Case Fatality Ration (CFR) (0.32% of detected Dengue cases) was noted in 2006 (4). A new epidemic peak is observed in 2019 with nearly 16,000 cases, which represents 5 times more than in 2018, but remains lower than the annual figures reported in 2013 and 2014. As of June 15th, 2020, the amount of 10,995 cases detected in Singapore since January by the National Environment Agency (NEA) (Fig. 1), is higher than that of the same period in 2018 and 2019 (7).

Figure n ° 1: Annual evolution of Dengue cases detected in Singapore since 2016 (source: NEA)

The Dengue virus

The pathogen causing Dengue is the DENV virus (Fig. 2), an Arthropod-Borne Virus (arbovirus) (1). It is known as 5 serotypes, with high mutation rates, allowing it to adapt very quickly to ecological disturbances. In particular, increased temperatures accelerate its replication speed (6,10). DENV-2 has been the predominant strain in Singapore since 2016 (8). DENV-1 remains however very present, while DENV-3 and DENV-4 coexist in smaller proportions. However, Singapore has recently seen a significant increase in the proportion of DENV-3, reaching 48% of the serotypes identified in February 2020, almost double the number of DENV-2. This figure is of concern because there has not been any DENV-3 epidemic in Singapore over the past 30 years (10). On the other hand, a new form of DENV was detected in humans in 2007, in Malaysia. A series of scientific tests confirmed in October 2013 that it was a new serotype, DENV-5. This strain is mainly transmitted in non-human primate populations, it is a sylvatic form of the virus. The low intensity human epidemic observed in 2007 in the Serawak forest suggests that DENV-5 has a low transmission rate; its main known vector is the Aedes nivalis mosquito (11).

Figure n ° 2: DENV-2 serotype (x 123,000) (source: University of NSW, Australia)

A deleterious immune phenomenon

Catching Dengue a second time can sometimes lead to DHF, due to an immune phenomenon that facilitates viral infection. What does it consist of? Any infection with DENV induces in Humans (host) the production of homotypic antibodies (immunoglobulins) Ig G, providing long-term immunity, as well as heterotypic Ig G, providing cross-immunity against other serotypes of DENV. Heterotypic Ig G provide protection that lasts several months to several years. While heterotypic Ig G decrease over time (4 to 20 years), homotypic Ig G levels increase. Below a threshold concentration, heterotypic Ig G only provide partial or no protection at all (12). When the body is infected with another DENV serotype, the host's heterotypic Ig G bind to the surface antigens of the virus but do not always succeed in neutralizing it. The Antibody-Virus complex then acts like a Trojan horse: it is absorbed by the host’s macrophages, target of DENV, where it can replicate itself without being detected. This phenomenon, called Antibodies-Dependent Enhancement (ADE), promotes the onset of severe symptoms after a second infection by a different serotype (13). This would explain the trends observed in Table 2.

Singapore Dengue vectors

In Singapore, Dengue is transmitted by Aedes aegypti and Aedes albopictus mosquitoes (4). These can also be vectors of other arboviruses, such as those of Yellow Fever, Chikungunya and Zika, diseases also under surveillance in the City-State (5). A.aegypti is present in majority in Singapore, while A. albopictus is the main vector of DENV-3. The 2 insects have a daytime activity, they bite at dawn or at dusk, mainly outdoors. (1). They usually settle in cool, shaded and humid places (14).

Figure 5 (top) : Aedes aegypti; Figure n ° 6 (bottom): Aedes albopictus (source: wikipedia)

A. aegypti (Fig. 5) is a small mosquito about 5mm long, with white markings on the legs and a lyre-shaped design on the thorax; A. albopictus (Fig. 6), the "tiger mosquito", has a broad white longitudinal line on the thorax and its colour is darker (15). Their development occurs in 4 phases (metamorphosis): egg, larva, pupa and adult. The first 3 are aquatic, while the adult is a flying insect. The female lives 2 to 3 weeks (16) while the male lives a little shorter. Both sexes feed on plant juices and nectars (14). The characteristic buzzing of mosquitoes is only emitted by the female, it allows the male to spot her (2). Once fertilized, the female requires several blood meals to lay fertile eggs, she is anautogenic (15). She is attracted to her hosts via parameters such as their temperature, the smell of their perspiration, the carbon dioxide they emit, the humidity of their skin. The brooder can lay up to 300 eggs at a time, every 3 days, in a volume of water no bigger than a 20-cent piece (16). After laying, the eggs hatch within 24 hours (14). The complete metamorphosis can last between 7 and 14 days; it is accelerated by temperatures increase (9).

A combination of pre-determining factors

For several years, the region has witnessed global warming, deforestation, urban construction sites proliferation and population densities increase. These act as many epigenetic factors which disturb living things ecological niches. These changes tend to favour mosquito and arbovirus (human or wild) adaptation processes to urban environments (17,18). In addition, international trade and individual mobility increase allow the DENV to be easily transported from one country to another, where potential vectors can transmit it locally (1). In Singapore, eradication programs effectiveness has clearly led to a drop in the population’s natural immunity, making it more susceptible to the country's prevalent serotypes. On the other hand, due to the increasing prevalence of the DENV-3 serotype and the deleterious ADE immune phenomenon, the population is all the more vulnerable (10, 12, 13). Finally, following the recent COVID-19 epidemic, the confinement of the population in dwellings created a daytime mosquitoes hosts concentration, residential areas being favourable for their development (7). Indeed, during the 2 months of circuit-breaker, NEA agents detected 5 times more A. aegypti larvae near residential premises, than over the 2 previous months.

Dengue prevention is more than ever a priority in Singapore. In case of suspicious symptoms, a virus detection test (NS1 test kit) can be performed in most General Practitioners clinics in Singapore.

To know NEA recommendations on anti-Dengue prevention, click here.

To follow the evolution of the Dengue epidemic in Singapore, click here.

To know where are located Dengue clusters in Singapore, click here.

Leslie Colin

French version published on lepetitjoutnal.com/singapour, on June 16th, 2020.

References :

1) Institut Pasteur. Disease sheets. Dengue.

2) World Health Organization. Health theme. Dengue [accessed June 8, 2020]. Available here.

3) Channel News Asia [online]. Commentary: The lower immunity behind the current dengue outbreak [published July 24, 2019].

4) Rajarethinam J. and al. Dengue in Singapore from 2004 to 2006: cyclical epidemic patterns dominated by serotypes 1 and 2. American Journal of Tropical Medicine and Hygiene, July 2018, 99 (1): 204-210.

5) Ministry of Health (MOH). List of infectious diseases legally notifiable under the infectious diseases act.

6) Channel News Asia [online]. More mosquitos or mutating virus? Experts have different views on dengue spike [published July 16, 2019].

7) National Environment Agency (NEA). Dengue and Zika. Dengue [accessed June 12, 2020].

8) The Straits times [online]. Singapore faces dengue threat from emergence of little-seen strain [published January 15, 2020].

9) Wu Y. et al. Mining weather information in dengue outbreak, Predicting future cases based on Wavelet, SVM and GA. Agency for Science, Technology and Research, Institute of High Performance Computing, Singapore.

10) Channel News Asia [online]. More than 4000 dengue cases in Singapore since start of 2020 as virus strain re-emerges [published on March 22, 2020].

11) Mustafa M.S. and al. Discovery of fifth serotype of dengue virus (DENV-5): a new public health dilemma dengue control. Medical Journal Armed Forces India, January 2015; 71 (1): 67-70.

12) Wikipedia, the free encyclopedia. Antibody-dependent enhancement [accessed June 8, 2020].

13) Dengue Virus Net .com. Antibody-dependent enhancement [accessed June 8, 2020].

14) 1880-No Pests [online]. Mosquito pest control and treatment methods [accessed June 8, 2020].

15) Wikipedia, the free encyclopedia. Aedes aegypti [accessed June 8, 2020].

16) Institute for Research for Development (IRD). Dengue in the French departments of America, Chapter 1: Bio-ecology and vector competence of Aedes aegypti [published in 2003].

17) Naciri M. Wolbachia bacteria block mosquitoes from different human pathogens. Medicine / Sciences, June-July 2019, vol 35, numbers 6-7: 584-585.

18) Kamgang B and al. Notes on the blood-feeding behavior of Aedes albopictus (Diptera: Culicidae) in Cameroon. Parasites & Vectors, 2012, 5: 57.