research work on dengue fever

• Research article
• Open access
• Published: 20 September 2021

A study on knowledge, attitudes and practices regarding dengue fever, its prevention and management among dengue patients presenting to a tertiary care hospital in Sri Lanka

• K. P. Jayawickreme   ORCID: orcid.org/0000-0001-9503-2854 1 ,
• D. K. Jayaweera 1 ,
• S. Weerasinghe 1 ,
• D. Warapitiya 1 &
• S. Subasinghe 1  

BMC Infectious Diseases volume  21 , Article number:  981 ( 2021 ) Cite this article

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The World Health Organization (WHO) has ranked dengue as one of the top ten threats to Global health in 2019. Sri Lanka faced a massive dengue epidemic in 2017, the largest outbreak in the country during the last three decades, consisting of 186,101 reported cases, and over 320 deaths. The epidemic was controlled by intense measures taken by the health sector. However, the reported dengue cases and dengue deaths in 2019 were significantly higher than that of 2018. Deaths were mostly due to delay in hospitalization of severe dengue patients. The mortality of dengue hemorrhagic fever is 2–5% if detected early and treated promptly, but is high as 20% if left untreated.

A descriptive cross-sectional study was done among patients with dengue fever presenting to the Sri Jayawardenepura General Hospital during October 2019. Data was collected using a questionnaire comprising 20 questions based on knowledge, attitudes and practices on dengue, which were categorized into questions on awareness of mortality and severity of dengue burden, prevention of dengue vector mosquito breeding and acquiring the infection, patient’s role in dengue management, and warning signs requiring prompt hospitalization.

The mean KAP score on all questions was 55%, while a majority of 65.2% patients scored moderate KAP scores (50–75%) on all questions, and only 7.6% had high KAP scores (> 75%). The highest categorical mean score of 62% was on awareness of dengue prevention, followed by 54% on awareness of dengue burden, and only 51% on dengue management. Only 5.3% patients scored high scores on awareness of dengue management, followed by 28.5%, and 40.9% patients scoring high scores on awareness of dengue burden, and awareness of prevention of dengue respectively. The mean KAP scores on all questions increased with increasing age category.

The population relatively has a better awareness of dengue prevention, as compared to awareness of dengue mortality and dengue management. The identified weak point is patient awareness of the patients’ role in dengue management, and identifying warning signs requiring prompt hospitalization. This results in delay in treatment, which is a major cause for increased mortality. There was a correlation between those who had good knowledge on dengue burden and those who were aware of patients’ role in dengue management. An action plan should be implemented to improve public awareness through education programs on the role of the public and patients in dengue management to drive a better outcome.

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The World Health Organization (WHO) has ranked dengue as one of the top ten threats to Global health in 2019 [ 1 ]. Brady et al. estimates a 3.9 billion prevalence of people, accounting to 40%-50% of the world’s population being at risk of infection. 128 countries worldwide are at risk of dengue infection, of which 70% of the global burden being in Asia [ 2 , 3 ]. The reported dengue cases to WHO increased from < 0.5 million in 2000 to > 3.34 million in 2016, characterized by a worldwide outbreak [ 4 ]. Although the world-wide numbers declined in 2017, there was a significant rise again in 2019 with 4.3 million cases worldwide. The highest number of dengue cases worldwide in 2019 in descending order were reported in Brazil, Philippines, Vietnam, Mexico, Nicaragua, Malaysia and India respectively, with Sri Lanka being placed in the 8th place worldwide, and in the 5th place in Asia [ 5 ]. Following a steady rise in annual dengue cases, Sri Lanka faced a massive dengue epidemic in 2017, which was the largest outbreak in the country during the last three decades, consisting of 186,101 reported cases, and over 320 deaths. The epidemic was controlled by intense measures taken by the health sector. However, the reported dengue cases rose again in 2019 reaching 102,746, being twice the number of reported cases of 51,659 in 2018, indicating re-emergence of an outbreak in 2019. A majority of cases being in the western province, with 20% in the Colombo district [ 6 ]. The dengue deaths in 2019 were 90; higher than the total dengue deaths in 2018 being 58, albeit with reduced mortality rate per overall cases [ 6 , 7 ]. The mortality of dengue fever is < 1%, and that of dengue hemorrhagic fever is 2–5% if detected early and treated promptly, but is high as 20% if dengue hemorrhagic fever is left untreated [ 8 ].

Dengue virus is a flavivirus transmitted by mosquito vectors, such as Aedes aegypti and Aedes albopictus. Dengue fever was first serologically confirmed in Sri Lanka in 1962 [ 9 ]. All four serotypes of dengue virus, DENV-1 to DENV-4 have been circulating in the country, and each serotype has many genotypes [ 9 ]. The most common cause for occurrence of new epidemics is the shift of the circulating serotype and genotype of the dengue virus, which is predisposed by increased foreign travel introducing new strains [ 9 ]. The dengue outbreak in 2003 was predominantly due to DENV-3 and DENV-4. The outbreaks in 2006, 2009 and 2010 was predominantly due to DENV-1 [ 9 ]. The predominant serotype in the 2017 epidemic was DENV-2 which was infrequent since 2009 [ 10 ]. The outbreak in 2019 was predominantly due to previously latent serotype DENV-3 [ 11 ].

The WHO published and implemented a “Global Strategy for Dengue Prevention And Control” targeting the years from 2012 to 2020, with the goals of improving dengue mortality, and morbidity by the year 2020, and estimating the true disease burden. The main elements of the global strategy were diagnosis and case management, integrated surveillance and outbreak preparedness, sustainable vector control, future vaccine implementation, basic operational and implementation research [ 12 ].This global strategy follows 10 priority areas for planning dengue emergency response, adapted from Rigau-Pérez and Clark in 2005, which also includes Engaging the community and relevant professional groups about dengue control as well as their participation in dengue prevention and control [ 13 ].

A recent study in Malaysia, showed that the population had only an average knowledge, and poor attitudes and practices on dengue prevention. They identified that a significant percentage had erroneous beliefs, such as fogging being the mainstay of dengue vector control. It had led them to a false sense of security, while evading actual measures that should be taken. They also identified that a proportion of people believed they had no responsibility in preventing dengue breeding, which needed urgent attention. They highlighted that it was impossible to reduce dengue prevalence without community participation, and concluded that measures were urgently required to educate the public to change their attitudes. The Communications for behavioral changes program on dengue prevention were subsequently implemented by Health departments of Malaysia to improve dengue awareness and prevention [ 14 ].

Although there had been a few studies on public awareness on dengue prevention, there was limited evidence focused on public awareness on their role in dengue prevention and management. It is therefore very important to take active measures to reduce the incidence and mortality of dengue, for which the responsibility lies not only with health professionals, but also with the general public. The purpose of this study is to identify the level of awareness in patients on preventing and managing dengue infection, and awareness of the patient’s role and responsibility in the above. Our goals were to identify areas in dengue control and management that need improvement, to implement policies that raise patient participation to deliver a better outcome of dengue infection, its complications and its management.

Study design

This is a descriptive cross-sectional study assessing the knowledge, attitudes, and practices on dengue fever, its prevention and the patient’s role in management, among the dengue patients presenting to a tertiary care hospital in Sri Lanka during the month of October 2019.

Study setting

The study was done among a random sample of 132 patients with dengue fever or dengue hemorrhagic fever who were admitted to adult medical wards for treatment at the Sri Jayawardenepura General Hospital during October 2019. These patients comprised people from draining areas of the western province of Sri Lanka.

Sample size

The number of patients who presented to the Sri Jayawardenepura General hospital in the month of October 2019 was 200. A sample size of 132 was calculated with a confidence interval of 95%, to match the population to assess a statistically significant result.

Participants

The study population was randomly selected among adult patients older than 13 years of age admitted with dengue infection to the medical wards of the Sri Jayawardenepura General Hospital during the month of October 2019.

Participants were not selected from the same family who would likely to be influenced by similar knowledge, to avoid bias of pseudo-replication.

Data collection

Data collection was commenced after obtaining the approval from the institutional Ethical Review committee of the Sri Jayawardenepura General Hospital and Postgraduate Training Centre (SJGH/20/ERC/017). Data was collected using a self-administered validated questionnaire regarding Knowledge, Attitudes, and Practices (KAP) on dengue in languages English, Sinhala, and Tamil which were translated and extensively reviewed for validation (Additional file 1 : Appendix S1, Additional file 2 : Appendix S2, Additional file 3 : Appendix S3).

Data was collected from randomly selected participants, only after informed written consent was obtained. The questionnaires were filled by the participants themselves using the validated questionnaire of the language convenient to them. The study investigators were with them while filling the questionnaire in case the participants needed to clarify any questions in order to ensure quality. The data was collected anonymously, while strict confidentiality of the responses and the results was maintained.

The questionnaire consisted of 20 questions which, comprised 5 questions on knowledge, 6 questions on attitudes, and 9 questions on practices on dengue fever and haemorrhagic fever, its prevention and patient’s role in management. Prior to analysis they were then re-categorized into questions on awareness of:

mortality and severity of dengue burden—5 questions

prevention of dengue vector mosquito breeding and acquiring the infection—5 questions

patient’s role in dengue management, and warning signs requiring prompt hospitalization—10 questions

The responses to each question was analyzed with percentage estimated of correct responses. The total marks scored by each participant to the whole questionnaire was estimated as a percentage, which has been defined as the “KAP score”. KAP score is an abbreviation used for the total score of the questions based on K nowledge, A ttitudes, and P ractices regarding dengue burden, dengue prevention and management in this study. The total results were categorized as “low” when KAP were < 50%, “moderate” when KAP scores were 50–75%, and “high” when KAP scores were > 75%.

Statistical methods

Data was analyzed using the SPSS (Statistical Package for the Social Sciences) software. All the questionnaire sheets were filled completely and none of the sheets were excluded. The mean of the KAP score of each category was calculated. The percentage of the population who scored low, moderate and high KAP scores was calculated separately. The responses to each of the 20 questions were analyzed separately to infer the areas which needed further improvement in awareness of the general public on dengue.

The study population comprised 61% males, and 39% females with a male: female ratio of 3:2. When categorizing by age, 42% of the study population was less than 30 years old, 36% were between 30 and 50 years old, and 22% were more than 50 years old. Of those who were between 30 and 50 years, 35% were graduates or diploma holders. Of those who were more than 50 years old, 21% were graduates or diploma holders. When categorizing by level of education, 10% of the population was currently schooling, 8% were adults educated up to less than ordinary level (O/L) at school who were not graduates or diploma holders, 18% were adults educated up to O/L at school who were not graduates or diploma holders, 34% were adults educated up to advanced level (A/L) at school who were not graduates or diploma holders, 24% were adults who had completed school education and were undergraduates, 6% were adults who had completed school education and were graduates or diploma holders (Table 1 ).

The mean KAP score of the sample population from the questionnaire was 55.04%. When categorizing the KAP scores as low (< 50%), moderate (50–75%), and high (> 75%), a majority of 65.2% of the population had moderate KAP scores. 27.3% had low KAP scores, and only 7.6% had high KAP scores (Fig. 1 ).

Percentage of the study population who scored under each KAP score level Category. When categorizing the KAP scores as low (< 50%), moderate (50–75%), and high (> 75%) scores, a majority of 65.2% of the population had moderate KAP scores. 27.3% had low KAP scores, and only 7.6% had high KAP scores

The KAP score achieved was higher with increasing age. The highest mean total KAP score of 57.86% was among those > 50 years of age, with those aged < 30 years having a mean KAP score of 53.48% and those aged 30–50 years having a mean KAP score of 55.21% (Fig. 2 ). The mean KAP score on awareness of dengue mortality and burden among the age categories < 30 years, 30–50 years, and > 50 years was 49.29, 56.88, and 58.57% respectively. The mean KAP score on awareness on prevention of dengue vector breeding and acquiring the infection among the age categories < 30 years, 30–50 years, and > 50 years was 63.57, 59.38, and 63.57% respectively. The mean KAP score on awareness of patients’ role in dengue management and warning signs requiring prompt hospital admission among the age categories < 30 years, 30–50 years, and > 50 years was 49.82, 52.08, and 51.79% respectively (Fig. 3 ).

The mean KAP score of each age category. The KAP score achieved was higher with increasing age. The highest mean KAP score of 57.86% was among those > 50 years of age, with those aged < 30 years having a mean KAP score of 53.48% and those aged 30–50 years having a mean KAP score of 55.21%

Comparison of the total KAP score, awareness on mortality and severity ofdengue burden, awareness on prevention of dengue vector breeding and acquiring the infection, and awareness on patient’s role in dengue management, and warning signs requiring prompt hospitalization under each age category

The mean KAP score was higher among those with higher educational qualification levels. The highest mean KAP score of 58.13% was among graduates and professional diploma holders of any field, and the lowest score of 49% was among adults educated in school up to below O/L. The mean total KAP score among those currently schooling was 54.62%. Adults who were not undergraduates, graduates, or diploma holders, who were out of school, but were educated at school up to O/L and those who had completed schooling after A/L had mean total KAP scores of 53.96 and 54.67% respectively. The mean KAP score on awareness of dengue mortality and severity of dengue burden among each of the age categories; schooling, adults educated less than O/L, adults educated up to O/L, adults educated up to A/L, under graduates, graduates or diploma holders were 50.77, 42, 60.83, 50.44, 58.75, and 55% respectively. The mean KAP scores on awareness on prevention of dengue vector breeding and acquiring the infection among each of the educational categories in above order were 60, 60, 60, 64, 60.94, 67.5% respectively. The mean KAP scores on awareness of the patient’s role in dengue management and warning signs requiring prompt hospital admission among each of the educational categories in above order were 53.85, 45, 44.58, 51.56, 55, 55% respectively (Fig. 4 ). The mean KAP score among females was 55.48%. and that of males was 54.75%.

Comparison of the total KAP score, awareness on mortality and severity of dengue burden, awareness on prevention of dengue vector breeding and acquiring the infection, and awareness on patient’s role in dengue management, and warning signs requiring prompt hospitalization under each educational category

When analyzing data by categorizing the questions by the awareness on the area assessed, the highest mean KAP score of 62.05% was on questions on awareness of prevention of dengue vector breeding and acquiring the infection, while the lowest mean KAP score of 51.06% was on questions on awareness of patient’s role in dengue management, and warning signs requiring prompt hospitalization. The mean KAP score on awareness of dengue mortality and severity of burden was 54.02% (Fig. 5 ). On analysis of questions related to awareness of dengue mortality and severity of burden, only 28.8% had high KAP scores, 40.9% had low KAP scores, and 30.3% had moderate KAP scores. On the analysis of questions related to awareness on dengue prevention, an equal percentage of 40.9% had low and high KAP scores respectively, and 18.2% had moderate KAP scores. Analysis of questions related to awareness on patient’s role in dengue management and warning signs prompting hospitalization showed, only 5.3% had high KAP scores, 62.9% had moderate KAP scores, and 31.8% had low KAP scores (Fig. 6 ).

Mean KAP score of each area assessed. 1. Mean KAP score on awareness of mortality and severity of dengue burden- 54%. 2. Mean KAP score on awareness of prevention of dengue breeding and acquiring the infection—62%. 3. Mean KAP score on awareness of patient’s role in dengue management, and warning signs requiring prompt hospitalization—51%

Comparison of percentage of the population who scored low (< 50%), moderate (50%-75%), and high (> 75%) KAP scores under each area assessed

There is no statistically significant correlation between the mean KAP scores on awareness of dengue mortality and severity of dengue burden, and the mean KAP scores on awareness on prevention of dengue vector breeding and acquiring infection according to the spearman’s test (p = 0.084). Although there is a statistically significant correlation between the mean KAP scores on awareness of dengue mortality and severity of dengue burden, and the mean KAP scores on awareness of patient’s role in dengue management and warning signs requiring prompt hospital admission according to the spearman’s test (p = 0.015).

The populations response to each individual question is shown in Table 2 . The percentage of the population who knew the correct answer for the questions on awareness of dengue burden and mortality were as follows: The number of reported dengue cases in Sri Lanka for the year during the outbreak in 2017 was close to 200,000 (42%), The number of reported dengue cases in the year 2019 is higher than that of 2018 (52%), Of 100 persons who get dengue fever only 1 or less persons would die per year when detected early and proper access to medical care (The mortality of dengue fever is < 1%) (60%), The mortality rate of dengue hemorrhagic fever is 2–5%, but is high as 20% if left untreated (60%), The WHO has ranked dengue as one of the top ten threats to Global health in 2019 (56%).

The percentage of the population who knew the correct answer for the questions on awareness of dengue prevention were as follows: all persons with dengue fever do not need to be notified to the Public Health Inspector (PHI) (39%), dengue vector mosquitoes breed in muddy water (52%), The peak biting times of the dengue mosquito is morning and evening (80%), If a person gets dengue fever once in their life, they will be immune to it and will not get dengue fever again (44%), discarded tires, coconut shells, and plastic containers collecting rain water in the garden should be destroyed to prevent dengue vector breeding (96%).

The percentage of the population who knew the correct answer to the questions on awareness of dengue management and warning signs which require prompt hospitalization were as follows: There is a special drug available to treat dengue fever (43%), papaya leaf juice increases the platelet count and thus helps treat dengue fever (33%), dengue patients with a platelet count < 150,000/mm 3 with a rapid drop are recommended to be admitted to hospital (85%), abdominal pain in a dengue patient is not an indication for hospital admission (32%), all pregnant mothers with dengue fever are recommended to be admitted in hospital irrespective of the platelet count (83%), NS1 antigen can be tested on any day since the onset of fever to diagnose dengue fever (23%), a negative report of dengue IgM antibody done on the second day since onset of fever means the patient does not have dengue fever (17%), When a dengue patient has a platelet count > 150,000/mm3 and does not meet criteria which require hospital admission, they should drink 2500 ml of oral fluids per day at home (40%), When a dengue patient has a platelet count > 150,000/mm3 and does not meet criteria which require hospital admission, they should check their Full blood count daily to assess the drop in platelet count (65%), dengue patients should avoid having red or brown drinks (89%).

Dengue virus has four serotypes. Acquisition of dengue infection due to one serotype does not give immunity against a subsequent infection with another serotype, though there is about a two years period of cross-protection [ 15 ]. All four serotypes share only 60–75% identity at amino acid level, and are thus considered as different viruses [ 14 ]. Infection from one serotype gives life-long immunity against that particular serotype [ 10 , 15 ]. Once the cross protection wanes off, secondary dengue infection is more severe than primary dengue infection [ 10 , 15 ]. However only 44% of the study population were aware that occurrence of dengue infection once, does not prevent occurrence of the disease again.

Dengue transmission increases during the rainy season in Sri Lanka, mostly in July, due to increasing dengue vector mosquito breeding places. Other causes for increase in the number of dengue cases is urbanization, climate change, and poor vector control and prevention of disease [ 10 ]. 96% of our cohort were aware of the need to destroy and clean water collecting areas, to prevent breeding of the dengue vector, while 84% of the cohort of a similar study done in the central province of Sri Lanka was aware of this same fact. This is probably because the latter study was done in 2015, prior to the dengue epidemic in 2017 [ 16 ]. Intense measures were taken in the country by which the epidemic in 2017 was controlled. This included clean-up campaigns, awareness programs, National dengue prevention and control, National Strategic framework (2016–2020) to align their action with the WHO Global strategy for dengue prevention and control (2012–2020), The Presidential Task Force on Dengue (PTF) and National dengue control unit of the Ministry of Health launched a rapid inter-sectoral program for prevention and control of dengue [ 7 ]. Awareness programs were held in rural and urban community gatherings, taught in school and institutions, shared on social media, television and radio [ 7 ]. However, data regarding the targeted population for these awareness programs was sparse. Dengue is ranked the third commonest notifiable disease in Sri Lanka, by which means the health sector can implement active vector control measures in the identified areas [ 17 ]. Only 39% of the study population was aware that all persons with dengue fever should be notified to the PHI. The low number of people who were aware of the importance of notifying dengue cases to the PHI, was probably due to the general public being unaware of the PHI’s role in dengue prevention, and lack of awareness of their responsibility in notifying cases, and it’s importance in vector control. Lack of notification of disease hinders action taken for vector control, which gives a falsely lower number of reported cases than the actual number. People should be educated on this to improve notification and vector control. Notification to the PHI of dengue patients managed at home or in the hospital should be made mandatory to avoid negligence in notification. This study population had a relatively good awareness about dengue breeding sites and biting times, probably due to awareness programs during the 2017 epidemic. Literature has shown the importance of improving knowledge on dengue prevention to control dengue outbreaks [ 18 ].

A study in Vietnam during the dengue epidemic in 2017 showed that 91% of the study population considered dengue to be dangerous to very dangerous [ 19 ]. Our study evaluated patients already being admitted for treatment of dengue at the Sri Jayawardenepura general hospital, comprising of patients from the western province, which has the highest dengue burden in the country. A similar study was done in the central province of Sri Lanka by Jayalath et al . among out patients visiting the Peradeniya hospital for reasons other than dengue. Jayalath et al. showed that 95% of their study population knew dengue was a severe disease [ 16 ]. 75% of the cohort of a similar study done among patients being admitted for treatment of dengue fever, in the northern province of Sri Lanka in 2017, knew that dengue was a severe disease [ 20 ]. Our study population had a moderate mean KAP score (54%) on questions on awareness on dengue severity and burden. 40.9% of the population had low awareness on severity and burden of dengue, and only 28.8% had high awareness on its severity and burden. This difference in evidence regarding awareness of severity of dengue in the above studies, could be because the questions by which awareness was evaluated was different in the three studies, and because our study, and the study in the northern province evaluated patients who had already acquired dengue fever and were admitted for treatment at that time. It could also be speculated that these populations acquired dengue infection due to their lack of awareness in prevention of disease.

This lack of awareness on the severity of dengue and it’s burden is probably due to most dengue patients uneventfully recovering from uncomplicated dengue fever, and due to successful dengue management by the healthcare system in the country. This study identified that those who had good awareness on the mortality and severity of the burden of dengue, also had a good awareness about their role in managing dengue, as well as warning signs requiring prompt hospital admission. It can be concluded that there is a strong correlation between those who have an appreciation of the gravity of the symptoms caused by dengue, and the likelihood of them educating themselves on dengue management and their active participation in it. Rozita et al. showed that people who were infected by dengue, or had a family member infected by the disease had better knowledge, attitudes and practices about dengue compared to those who did not [ 21 ]. A study in Singapore in 2017 after the country’s largest dengue epidemic showed that attitudes and practices regarding dengue among primary care physicians significantly improved after experiencing the epidemic [ 22 ]. Chanthalay S et al . showed that those who had better knowledge and attitudes regarding dengue are more likely to take precautions to prevent the disease [ 23 ]. Those who have good awareness will have a good understanding of the gravity and impact of the disease, will know the importance of preventing it, and will be aware of necessary preventive measures.

The mortality of dengue fever is < 1%, and that of dengue hemorrhagic fever is 2–5% if detected early and treated promptly, but is high as 20% if dengue hemorrhagic fever is left untreated [ 8 ]. In 2015 Malhi et al. reported that the presence of comorbidities like diabetes mellitus, hypertension, chronic kidney disease, allergies, asthma, ischemic heart disease and hepatic anomalies, as well as delay in identification and treatment were linked to increased mortality from dengue [ 24 ]. However, in 2017 a study by the same authors showed that 50% of dengue deaths were of previously healthy individuals with no comorbidities [ 25 ]. Therefore, the leading cause for dengue related complications and deaths is delayed identification and treatment of disease. This can be due to delays by the patient or health staff, mostly due to delayed patient presentation to the hospital [ 26 ].Studies have shown that late presentation of dengue fever to the hospital leads to increased development of dengue haemorrhagic fever, dengue shock syndrome, multi-organ involvement like acute kidney injury, and increased mortality [ 26 , 27 , 28 ]. According to the study findings, by identifying areas where the public has misconceptions and misunderstandings about dengue fever, its prevention and management, we can implement steps to improve those loop holes. By following correct practices, avoiding malpractices, and timely hospital admission, his will reduce dengue fatality, improve the outcome, and will also reduce the burden on the healthcare system.

The national Guidelines on dengue management indicates the need for hospital admission in a dengue patient if the platelet count is < 100,000, or platelet count between 100,000- 150,000 with a rapid drop in platelets, fever for three days with any warning signs such as abdominal pain, persistent vomiting, mucosal bleeding, lethargy and restlessness [ 29 ]. Irrespective of the above criteria, admission is required in dengue patients who are pregnant, elderly, obese, with comorbidities, or with adverse social circumstances [ 29 ]. In this study, 85 and 83% patients respectively were aware of the indication for admission as per the platelet count or if pregnant, but only 32% patients knew admission was indicated with warning signs like abdominal pain. Therefore, people need to be educated about warning signs of severe dengue infection. People who do not require admission must be educated about cautious self-management at home until they require admission [ 29 ]. By doing so there will be less likelihood to miss warning signs, will have improved outcome, and there will be less burden to hospital staff. Only 40% of patients knew about fluid management at home, but 89% knew to avoid red drinks.

Serological testing is important to confirm the diagnosis of dengue fever when the presentation is atypical or when unsure of the diagnosis. NS1 antigen is tested in the patient’s blood on the first few days of the disease and has a sensitivity of 60–90%. Dengue IgM antibody will be positive in the patient’s blood only after the 5th day of illness [ 29 ]. Therefore, patients should be educated about the ideal time to do each test to avoid false negatives being reported by doing the test at the wrong time of the illness. However, dengue infection cannot be excluded by a negative serological lab report. Few patients knew about the timing of testing, with only 23% and 17% being aware of the timing of testing, and sensitivity of NS1 antigen and dengue IgM respectively. It is important that health care professionals guide patients on the correct timing to do the serological tests. It would be prudent to do such serological tests only on request by a physician, to avoid patients testing at the wrong time, and getting a report which cannot be interpreted at that time of the illness. False negatives of serological testing can further be avoided by laboratory staff rechecking the patients’ day of the illness, and the physicians request form prior to drawing blood.

This study shows that people had misconceptions about dengue management. Only 43% knew there was no special drug to treat dengue fever. There is no particular drug to treat dengue, but is managed by careful monitoring and fluid tailoring resuscitation [ 29 ]. A tetravalent live attenuated dengue vaccine has been registered for use in several countries [ 15 ]. In sero-negative individuals it is believed that the vaccine mimics a silent natural infection, giving temporary cross-protection against all serotypes, and subsequently causing severe dengue infection when primarily infected [ 15 ]. However, its efficacy varies in different countries and is not currently recommended for use in Sri Lanka [ 15 ]. The use of papaya leaf juice in dengue management had recently gained interest, leading to many people consuming the juice assuming improvement of dengue infection. Research has shown papaya leaf juice to improve platelet counts, but has not shown to prevent or reduce fluid leaking in dengue hemorrhagic fever [ 30 ]. This can adversely cause early rise in platelet count masking the onset of fluid leaking, which can be detrimental in managing dengue hemorrhagic fever. 33% of our cohort believed papaya leaf juice helped treat dengue fever, while 13.4% of the cohort in a study done in Sri Lanka in 2015 believed the same to be true. This is probably because the concept of the effect of papaya leaf juice on platelet count came in to light only later on [ 16 ].

This study demonstrated an increasing trend in awareness on all categories, such as among people with a higher level of education, and maturity by age, indicating that education and maturity are important factors for improved awareness. Kumanan et al. showed a significant association between educational level and knowledge regarding dengue fever, and no significant association between educational level and preventive practices [ 20 ]. The trend in our study demonstrated on Fig. 3 suggests that responses in the awareness on dengue mortality and severity of dengue burden steadily increased with age, and strongly influence the mean total KAP scores. The highest awareness in all age categories was on dengue prevention and the lowest awareness in all categories was on patients’ role in dengue management and warning signs requiring prompt hospitalization (Fig. 3 ).

There was inadequate awareness among adults who dropped out of school prior to completion of the full school education up to advanced level even when they are older. This may demonstrate a population with lower level of understanding of the information given, and those who were not regularly educated at school regarding dengue infection as they dropped out. Those who drop out of school are also those who usually have a poor social background, and they may also have inadequate access to social media and electronic media to receive updates about dengue mortality, prevention and management. This highlights the need for any information to reach the people of all social backgrounds when implementing strategies to improve public awareness on dengue infection. Dissemination of information should be done in various ways targeting different populations of different levels of understanding. People with lower education levels should be the main target group requiring more advice and education regarding the patient’s role in dengue management.

This population has a relatively a better awareness on dengue prevention as compared to awareness of dengue mortality and dengue management. This is possibly due to prior media education of the public on prevention during the previous epidemic in 2017. The identified weak point is patient awareness on the patient’s role in dengue management, as well as identifying warning signs requiring prompt hospitalization. It causes delay in treatment, which is a major cause for increased mortality. The trend demonstrated on Fig. 5 suggests that responses in the dengue management and warning signs prompt hospitalization area strongly influence the total KAP scores. This indicates that patient awareness on the role of the public and patients on dengue management is critical in the outcome of dengue infection. An action plan should be implemented targeting improving public awareness by education programs on the role of the public and patients in dengue management, to improve outcome.

The general public play a major role in prevention and management of dengue fever, and influence the outcome. Jayalath et al. showed that 30% of their population believed the responsibility of dengue prevention lay with the public, while 66% believed both the public and the government were responsible [ 16 ]. In order to improve involvement of patients and the public in dengue prevention, control and management, attention should be paid on educating the public and patients on the disease.

Limitations and recommendations for future research

This study focused on 132 patients from one hospital. Therefore, the conclusions can be relevant only to draining areas in the vicinity of this hospital, and may not represent the knowledge, attitudes and practices in other parts of Sri Lanka. However, since majority of the dengue cases in the country are concentrated in the western province, of which a significant number of patients present to the Sri Jayawardenepura General Hospital, the findings of this study may represent the most dengue dense area in the country. Large scale future research from all parts of the country may be beneficial to infer the knowledge, attitudes, and practices of the country as whole.

The general public was educated about Dengue infection by various means, including messages on social media, electronic media, awareness programs at schools, and village meetings, posters and distribution of leaflets, during the dengue epidemic in 2017. This study did not extensively evaluate whether the study participants had been exposed to these prior teaching about Dengue infection, and if they did, by what means they were educated. However almost all the study participants had access to electronic and social media. This may not be the same when inferring on the population in some rural parts of Sri Lanka who may not have similar access to such media education. Awareness programs and active participation of the general public in dengue prevention and management should be implemented. We suggest future follow up research of the awareness on dengue infection among the public, before and after implementing formal dengue awareness strategies to assess the effectiveness of it. In addition to follow up research before and after implementing disease awareness steps, we also suggest future research to assess an association and comparison of dengue mortality and outcome before and after implementing practices to further educate the public, in order to identify its impact on dengue management and outcome.

The population has relatively a better awareness on dengue prevention, as compared to awareness of dengue mortality and dengue management. The identified weak point is patient awareness on the patient’s role in dengue management, and identifying warning signs requiring prompt hospitalization causing delay in treatment, which is a major cause for increased mortality. There was a correlation between those who had good knowledge on dengue burden and those who were aware of the patients’ role in dengue management. There is also an increasing trend in awareness on all categories, especially among people with a higher level of education, and maturity by age, indicating that education and maturity are important factors for improved awareness. An action plan should be implemented targeting improving public awareness on the role of the public and patients in dengue management to improve outcome.

Availability of data and materials

The raw data sets analyzed during the current study are available on reasonable request from the corresponding author.

Abbreviations

Dengue virus

Knowledge attitudes and practices

Ordinary level at school

Advanced level at school

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Acknowledgements

We all express our gratitude to all participants who consented to take part in this study.

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SS is a Consultant Physician [MBBS, MD, FRACP] Medical unit, Sri Jayawardenepura General Hospital. KPJ [MBBS], DKJ [MBBS] and DW [MBBS] are Registrars in Internal medicine, and SW is a Senior Registrar in Medicine at the Sri Jayawardenepura General Hospital.

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Data collection was done by KPJ, DKJ and DW. Analysis, interpretation of data, literature review and writing of the report was done by KPJ. SS and SW guided the study and corrected the final manuscript. All authors read and approved the final manuscript.

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Jayawickreme, K.P., Jayaweera, D.K., Weerasinghe, S. et al. A study on knowledge, attitudes and practices regarding dengue fever, its prevention and management among dengue patients presenting to a tertiary care hospital in Sri Lanka. BMC Infect Dis 21 , 981 (2021). https://doi.org/10.1186/s12879-021-06685-5

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• Dengue fever

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A Multi-Perspective Review on Dengue Research

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• DOI: 10.2174/1389450120666190724145937

Dengue fever is a disease which is caused by a family of viruses named Flaviviridae which are transmitted by female Aedes mosquitoes. Today, this is endemic in more than 100 nations in the World Health Organization's African, Americas, Eastern Mediterranean, South-East Asia and Western Pacific locales. The treatment of typical dengue is focused on relieving the symptoms and signs. Carica papaya is a very common plant whose leaf extract is used in the treatment of this disease. Despite extensive research on Dengue, not a single vaccine or anti-viral drug was available until 2016 (a partially effective Chimeric Yellow fever virus treated by DENV-Tetravalent Dengue Vaccine for dengue fever made by Sanofi Pasteur). This review highlights dengue fever's current situation and explains the importance of Natural chemical moieties like methionine-proline anilides, tetrapeptide aldehyde uncovered via Structure Activity Relationship studies. Also, we have reviewed the drug candidates currently in the clinical trials that have the potential to solve these issues. Important patents in the past 20 years have been outlined in this review. An in depth Protein Data Bank analysis of the different possible target proteins that can potentially have a major role in curing Dengue fever has been conducted.

Keywords: Dengue transmission; clinical studies; in silico work; non structural proteins; patent; protein data bank; structural proteins..

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Singapore’s 5 decades of dengue prevention and control—Implications for global dengue control

Contributed equally to this work with: Soon Hoe Ho, Jue Tao Lim

Roles Conceptualization, Data curation, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Environmental Health Institute, National Environment Agency, Singapore, Singapore

Roles Conceptualization, Supervision, Visualization, Writing – original draft, Writing – review & editing

Affiliations Environmental Health Institute, National Environment Agency, Singapore, Singapore, Lee Kong Chian School of Medicine, Nanyang Technological University Novena Campus, Singapore, Singapore

Roles Data curation, Visualization, Writing – original draft, Writing – review & editing

Roles Writing – original draft, Writing – review & editing

Roles Conceptualization, Supervision, Writing – original draft, Writing – review & editing

Affiliations Environmental Health Institute, National Environment Agency, Singapore, Singapore, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

• Soon Hoe Ho, 
• Jue Tao Lim, 
• Janet Ong, 
• Hapuarachchige Chanditha Hapuarachchi, 
• Shuzhen Sim, 
• Lee Ching Ng

Published: June 22, 2023

• https://doi.org/10.1371/journal.pntd.0011400
• Reader Comments

This paper summarises the lessons learnt in dengue epidemiology, risk factors, and prevention in Singapore over the last half a century, during which Singapore evolved from a city of 1.9 million people to a highly urban globalised city-state with a population of 5.6 million. Set in a tropical climate, urbanisation among green foliage has created ideal conditions for the proliferation of Aedes aegypti and Aedes albopictus , the mosquito vectors that transmit dengue. A vector control programme, largely for malaria, was initiated as early as 1921, but it was only in 1966 that the Vector Control Unit (VCU) was established to additionally tackle dengue haemorrhagic fever (DHF) that was first documented in the 1960s. Centred on source reduction and public education, and based on research into the bionomics and ecology of the vectors, the programme successfully reduced the Aedes House Index (HI) from 48% in 1966 to <5% in the 1970s. Further enhancement of the programme, including through legislation, suppressed the Aedes HI to around 1% from the 1990s. The current programme is characterised by 4 key features: (i) proactive inter-epidemic surveillance and control that is stepped up during outbreaks; (ii) risk-based prevention and intervention strategies based on advanced data analytics; (iii) coordinated inter-sectoral cooperation between the public, private, and people sectors; and (iv) evidence-based adoption of new tools and strategies. Dengue seroprevalence and force of infection (FOI) among residents have substantially and continuously declined over the 5 decades. This is consistent with the observation that dengue incidence has been delayed to adulthood, with severity highest among the elderly. Paradoxically, the number of reported dengue cases and outbreaks has increased since the 1990s with record-breaking epidemics. We propose that Singapore’s increased vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of new viral variants, expanding urban centres, and increasing human density. The growing magnitude of reported outbreaks could also be attributed to improved diagnostics and surveillance, which at least partially explains the discord between rising trend in cases and the continuous reduction in dengue seroprevalence. Changing global and local landscapes, including climate change, increasing urbanisation and global physical connectivity are expected to make dengue control even more challenging. The adoption of new vector surveillance and control tools, such as the Gravitrap and Wolbachia technology, is important to impede the growing threat of dengue and other Aedes -borne diseases.

Author summary

A densely populated, highly urban tropical city-state with long-established populations of Aedes aegypti and Ae . albopictus mosquitoes, plus travel and trade links to all corners of the world, Singapore is ideally suited for dengue transmission. Singapore’s experience and rich surveillance data provide important insights for an increasingly large number of territories at risk of dengue epidemics. Decades of vector control efforts, focused on source reduction and surveillance, have successfully lowered the vector population, with accompanying reductions in the resident population’s seroprevalence to dengue. We propose that Singapore’s vulnerability to outbreaks is due to low levels of immunity in the population, constant introduction of viral variants, expanding urban centres, and increasing human density. The discord between the rising trend in reported cases and falling seroprevalence could be at least partly attributed to improved diagnostics and surveillance. Singapore’s evidence-based vector-control programme, which involves strong partnership between the public and private sectors, will continue to adapt to future challenges in this space.

Citation: Ho SH, Lim JT, Ong J, Hapuarachchi HC, Sim S, Ng LC (2023) Singapore’s 5 decades of dengue prevention and control—Implications for global dengue control. PLoS Negl Trop Dis 17(6): e0011400. https://doi.org/10.1371/journal.pntd.0011400

Editor: Duane J. Gubler, Duke-NUS GMS, SINGAPORE

Copyright: © 2023 Ho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

1. Introduction

Dengue viruses (DENV) are hyperendemic in Singapore, with all 4 serotypes in co-circulation [ 1 , 2 ]. Aedes aegypti , the primary dengue vector, is well established in the tropical city-state, which has favourable conditions for breeding, including a year-round warm and humid climate and a highly urbanised population. In addition, the secondary vector, Ae . albopictus , is native to the country and thrives in the abundant foliage found throughout the island, including in built-up areas [ 3 ]. While Ae . albopictus is ubiquitous, Ae . aegypti is restricted to built-up areas. The geographical spread of dengue cases coincides with the spatial expansion of Ae . aegypti , and dengue cases were found to be associated with the percentage of Aedes breeding sites with presence of Ae . aegypti [ 3 ]. While Ae . aegypti was also the primary vector of a Zika outbreak in 2016 [ 4 ], Ae . albopictus played a key role in chikungunya transmission in Singapore in 2008 and 2013 [ 5 , 6 ]. Despite the 2 outbreaks, chikungunya seroprevalence remains low at 1% to 5% and showed a nonsignificant increase from 2009 to 2013 [ 5 ]. There has been no evidence of sustained transmission of chikungunya and Zika in Singapore since 2015 and 2018, respectively, though importations have been detected. However, given the presence of both vectors, Singapore remains vulnerable to chikungunya and Zika outbreaks.

This paper aims to outline and explain the dengue epidemiological situation in Singapore from the 1960s to the present. While anti-malarial control efforts had been in place since 1921 with the enforcement of the Destruction of Mosquitoes Ordinance [ 7 ], vector control efforts were greatly stepped up when the Vector Control Unit (VCU) was formed in 1966 to address the growing number of dengue haemorrhagic fever (DHF) cases. The first 2 decades following the start of active vector source reduction efforts led to large decreases in the vector population and reported dengue cases, but subsequent decades saw high rates of reported cases ( Fig 1A ) despite a successful vector control programme coupled with decreasing population seroprevalence to dengue ( Fig 1B ). Evidence suggests that the paradoxical situation is caused by a reduced population immunity, diverse array of virus lineages and improvements in case notifications and diagnosis rates, among other possible factors. We subsequently discuss the evolution of the country’s dengue prevention efforts over the preceding 5 decades and highlight some of the lessons learned.

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(a) Dengue FOI from [ 13 , 14 ] with associated 95% credible intervals plotted where available, together with the number of reported dengue cases from the 1960s to 2021. (b) Seroprevalence of dengue across adolescent and adult age groups over 2009, 2013, and 2017 [ 13 , 15 ]. (c) Aedes House Index from the 1960s to 2021 ([ 11 , 12 ] and NEA internal data). (d) Prevalence of serotype-specific neutralisation antibodies among 16–60 year olds in 2009 and 2013 [ 15 ]. DENV, dengue virus; FOI, force of infection; NEA, National Environment Agency.

https://doi.org/10.1371/journal.pntd.0011400.g001

1.1 Increased dengue cases amid declining Aedes house index and force of infection

Aedes House index (HI) sustained at low level While the earliest local epidemic of dengue fever (DF) was reported in 1901 [ 8 ] and sporadic epidemics were known to occur in Malaya and Singapore over the next 5 decades, it was only in the 1960s that the disease’s severity was recognised due to recurrent outbreaks of DHF [ 9 , 10 ]. The DHF outbreaks prompted the formation of the VCU in 1966 to tackle the high Aedes population in the country. From the outset, vector control centred on research to understand the bionomics and ecology of the vectors, which provided the basis for entomological surveillance, source reduction, and public education. At the same time, Singapore implemented infrastructural development and enhanced environmental management, with a public housing programme that improved the living conditions of the population, a holistic waste management programme, and regular campaigns to keep the city clean and mosquito-free. Together with the vector control programme, these efforts successfully reduced the Aedes HI from 48% in 1966 to <5% in the 1970s [ 11 , 12 ]. Further enhancement of the programme, including the passage of legislation that penalises homes found to have vector breeding habitats with immature larvae and pupae, has further suppressed the Aedes HI to around 1% since the 1990s ( Fig 1C ).

Dengue seroprevalence and force of infection maintained at reduced levels Concomitant with the decrease in Aedes HI, dengue seroprevalence among the resident population has also declined. The seroprevalence among youths between 15 and 19 years old plunged from 70% in the early 1980s to <20% since a survey in 1998 [ 15 ]. Current seroprevalence is significantly lower than the 39% to 92% found in the same age group in several endemic countries [ 16 – 19 ]. More recent local seroprevalence surveys conducted in 2009, 2013, and 2017 revealed continuing but more gradual decline in dengue seropositivity in all age groups, except among young adults between 21 and 25 years old ( Fig 1B ) [ 13 ]. The dengue force of infection (FOI) modelled using these data showed an approximate 10-fold decrease from >0.1 per year in the 1960s to about 0.01 since the 2010s ( Fig 1A ) [ 13 , 14 ]. This is consistent with the shifting of reported disease from predominantly paediatric cases in the 1960s to 1970s to young adults in recent decades [ 11 , 20 , 21 ]. Taken together, the evidence suggests that dengue incidence is substantially lower today compared to the 1960s, and not higher than the 1980s, contrasting with the trend observed among reported cases which has risen sharply since the 1990s with more frequent outbreaks ( Fig 1A ). The increase in reported dengue cases came against a backdrop of declining hospitalisation rate and continued low case fatality rate for dengue patients, which has been attributed to early diagnosis and improved management of patients by primary care physicians [ 22 ].

2. Potential factors contributing to the increase in reported dengue cases

Below, we delineate 6 potential factors that could have contributed to the increase in reported dengue cases against the backdrop of a suppressed vector population and reduced seroprevalence in Singapore.

Low level of immunity among the population Despite a suppressed Ae . aegypti population and an associated reduction in the force of infection ( Fig 1A and 1C ), Singapore remains vulnerable to outbreaks. A key driver is the low herd immunity of the population, evident from the continuous reduction in dengue seroprevalence across different age groups and the low prevalence of neutralising antibodies for each serotype among adults in Singapore ( Fig 1B and 1D ) [ 13 , 15 ]. Prevalence of antibodies against DENV1 and DENV2 are higher (at 35.8% and 36.4% for DENV1 and DEN2 among 16 to 60 year olds in 2013, compared to 15.4% and 7.7% for DENV3 and DENV4), consistent with these being the more common serotypes circulating in Singapore as determined by decades of virus surveillance [ 15 , 23 ]. Considering the high likelihood of cross-reactive antibodies across serotypes [ 24 ], actual immunity levels are likely to be lower than estimated. Paradoxically, the low human immunity to dengue caused by a suppressed vector population could counteract the reduced risk offered by the latter and could render the human population more sensitive to any increase in vector abundance and new virus strain introductions.

Increased viral diversity due to Singapore’s increasing connectivity As a highly globalised trade- and tourism-dependent country, a high number of DENV variant introductions is to be expected. Consequentially, Singapore’s highly diverse DENV population has been maintained over the years with fluctuations in overall composition [ 2 , 12 , 25 ]. The number of international visitor arrivals to Singapore grew over 10-fold from <100,000 in 1964 to >15 million in 2013 [ 26 ]. Prior to border restrictions due to the Coronavirus Disease 2019 (COVID-19) pandemic, the number of local residents (citizens and permanent residents) who travelled overseas rose from 520,000 (10% of population) in January 2011 to 760,000 (13% of population) in the same month in 2020 [ 27 ]. Border restrictions in 2020 and 2021 led to a decline in dengue viral diversity, as evidenced by the absence of DENV1 among serotyped samples from November 2020 to June 2022, a previously common serotype in constant circulation within Singapore over the preceding 3 decades. As intense serotyping was performed for an average of 30% of all reported cases each week during that period, the absence of DENV1 for 7 months suggests extinction of the serotype during border closure, after which DENV1 reemerged.

Multiple introductions offer ample opportunities for the selection of viruses with high epidemic potential. A DENV2 cosmopolitan clade replacement event in 2007 showed that small genetic shifts of 9 amino acid substitutions were associated with a local outbreak [ 1 , 28 ]. Infection studies revealed higher replication rates of the new clade in vector and mammalian cell lines [ 1 , 28 ], resulting in shortened extrinsic incubation period (EIP) in mosquitoes and possibly increase in viraemia levels in patients, respectively. Other examples of dengue epidemics following the introduction of novel viral genotypes include the 2009 epidemic in Sri Lanka [ 29 ] and the 2014 to 2015 epidemics in Taiwan [ 30 ].

Improved case ascertainment rate through diagnostic improvements While low population immunity and high viral diversity shed light on the vulnerability of Singapore to outbreaks, they do not explain the discord between a continuing reduction in seroprevalence and increasing dengue incidence rate. We propose that better case ascertainment and notification through improved surveillance and diagnostics likely contributed to the increase in reported incidence rates in the last 5 decades ( Table 1 ). While DHF was made legally notifiable in 1972, DF was in 1977 [ 20 ]. Though the case ascertainment rate was likely improved by law, it remained very limited as diagnosis was based on clinical assessment and most dengue cases had undifferentiated symptoms [ 31 ]. Dengue serology testing was made available globally in the 1980s [ 32 ] but usage in Singapore was limited to hospitals among the more severe cases. Even as late as 2006, 70% of dengue cases were reported by hospitals with the rest by primary healthcare [ 22 ]. Undifferentiated fever cases caused by dengue seen by primary healthcare could thus be underreported. To improve reporting, a programme was launched to make PCR-based early diagnostic tests available at a hospital in 2003 and at the Environmental Health Institute (EHI) in 2005 for private primary healthcare clinics [ 1 , 33 ]. However, capacity was only limited to a few laboratories. In 2008, a campaign encouraging clinical laboratories to use commercial dengue nonstructural protein 1 (NS1) rapid tests was launched and these tests have since become widely used by all clinical laboratories in Singapore [ 34 ]. These advances in dengue diagnostics and improvement in the healthcare system coincided with the progressive increase in reported dengue cases in Singapore, during which the FOI remained low at around 0.01. The estimated case-ascertainment rate rose from 1 in 14 infections from 2005 to 2009 to 1 in 6 infections in 2014 to 2017 [ 13 ].

https://doi.org/10.1371/journal.pntd.0011400.t001

This paradoxical trend highlights the limitations of a passive but changing case surveillance system to measure the long-term impact of dengue control programmes, a challenge shared by endemic countries globally. Case ascertainment helps to preempt and detect outbreaks and enables risk assessment and risk stratification for optimisation of dengue prevention efforts [ 35 ], thereby making surveillance a fundamental component of a vector control programme. However, using reported case counts to measure dengue burdens will be confounded by changing ascertainment rates, making periodic seroprevalence studies necessary for long-term impact assessment and triangulating the change in true transmission intensity over time.

Persistent presence of Aedes and climatic and spatial factors Singapore’s warm and humid climate year-round allows for favourable breeding and survival conditions for the Ae . aegypti vector. An increase in the ambient temperature between 25°C and 35°C accelerates the life cycle of mosquito vectors [ 40 ] and reduces the EIP of the dengue virus in the vector [ 41 ], thereby increasing the transmission potential of dengue virus [ 42 ]. For example, in Cairns, Australia, unseasonably warm temperatures above 30°C in late 2008 are believed to have shortened the EIP of DENV3 in Ae . aegypti and contributed to a 2008 to 2009 epidemic [ 43 ]. However, the relationship between mosquito survival and temperature is inverted U-shaped with optimum temperatures for Ae . aegypti and Ae . albopictus around 27.5°C and 21.5°C, respectively [ 44 ]. Extreme heat could thus be detrimental to dengue transmission through its inhibitory effect on vector survival [ 44 ]. This is supported by an analysis of recent dengue cases in Singapore that estimated that daily maximum temperatures above 31°C and heat waves (defined as weeks with 2 or more days exceeding the 90th percentile of maximum temperature) were associated with reduced dengue [ 45 ]. Singapore has warmed over the past decades, with the number of months per year with mean temperature above 27.5°C (the optimal temperature for the survival of Ae . aegypti ) exhibiting a positive trend between 1980 and 2021 (as measured at Changi meteorological station) [ 46 ]. With warming facilitated by climate change and urban heat island effect due to high urbanisation with large contiguous built-up areas, dengue transmission may be exacerbated [ 47 ]. However, given that extremely high temperature is detrimental to vector survival, if temperatures continue to rise, Singapore might experience a reversal of dengue seasonality where less transmission occurs in the middle of the year when the temperatures are too hot and heightened transmission at year’s end with lower, more conducive temperatures.

Relative humidity and rainfall are also associated with mosquito vector survival [ 44 , 48 ]. While rain is typically a risk factor for dengue [ 48 ], higher rainfall during the north-east monsoon could reduce dengue risk by flushing away outdoor habitats of the vectors [ 49 ]. In Singapore (Changi), precipitation from 1980 to 2021 remained nearly constant ( Fig 2C ) while the mean relative humidity had exhibited a downward trend since the 2010s ( Fig 2B ) [ 46 ], which might slightly attenuate the risk of dengue transmission at that location.

Recorded weather factors across time 1980 to 2022 including the mean, trend, and raw measurements for (a) temperature, (b) relative humidity, (c) rainfall at Changi Climate Station [ 46 ].

https://doi.org/10.1371/journal.pntd.0011400.g002

Increasing urbanisation and population density increases human–vector interactions Human population density in Singapore has increased from about 3,200 persons per km 2 in 1965 to 7,600 persons per km 2 in 2022 [ 50 ], with the population density reaching close to 50,000 people per km 2 in some areas [ 51 ]. With a highly dense population living in built-up areas and expansion of such areas, there are increasingly more breeding and biting opportunities for the anthropophilic Ae . aegypti , which breeds in man-made receptacles [ 52 ]. The risk is exacerbated by the aging of buildings and numerous construction activities, both of which have been shown to be risk factors for dengue transmission and/or Ae . aegypti abundance [ 53 , 54 ].

Novel work arrangements associated with dengue epidemiological changes in 2020 In 2020, Singapore experienced an unprecedented approximately 35,000 case dengue outbreak, coinciding with the first year of the COVID-19 pandemic. A study showed that non-pharmaceutical interventions to reduce SARS-CoV-2 transmission, in particular, the partial lockdown from April to June 2020, was associated with an excess of dengue cases among working adults [ 55 ]. The study postulated that the outbreak was exacerbated by the working population spending prolonged periods of time in naturally ventilated homes rather than in air-conditioned offices or workplaces; this would have increased the chances of interaction with anthropophilic Ae . aegypti , which tends to breed and dwell in and around homes [ 55 , 56 ]. This shows the risk of home-based infection and contradicts an older hypothesis that dengue transmission in Singapore was more likely to occur outside homes [ 20 ]. In contrast, the same measures led to a decrease in dengue transmission among migrant workers who are largely employed in the local construction industry [ 56 ]. Confinement to dormitories during the lockdown, instead of working in construction sites, lowers the risk of dengue among workers—an observation that is consistent with evidence that showed higher dengue risk in construction sites [ 53 ].

Similar to the migrant worker population in Singapore, COVID-related lockdowns were associated with attenuated dengue transmission in Southeast Asia and Latin America [ 57 ]. This highlights differences in relative transmission risk between work and home locations across dengue endemic countries and populations and illustrates changing epidemiology through time and through work arrangements.

3. Evolution of Singapore’s dengue prevention efforts

To tackle the persistent challenge of dengue, Singapore has refined and strengthened its dengue prevention strategy since 1965 through the 2000s.

From its inception, Singapore’s dengue prevention programme has focused on environmental management and public education. In 1966, the first documented local pilot study in a township where a majority of the population lived in slums, thatched or zinc roofed houses, shophouses, or newly built public high-rise residential apartments showed the effectiveness of integrated source reduction and health education at reducing the Aedes population [ 36 , 58 ] ( Table 1 ). The pilot project successfully reduced the Aedes HI from a mean of 16% to 2% [ 36 ], leading to wider, national adoption. The subsequent passage of the Destruction of Disease Bearing Insects Act (DDBIA) in 1968 strengthened legal powers of vector control personnel to inspect premises for potential vector breeding [ 36 ]. The Keep Singapore Clean and Mosquito Free campaign was launched in 1969 to further mobilise public support for vector control efforts [ 36 ]. The transfer of the VCU from the jurisdiction of the Ministry of Health (MOH) to the newly formed Ministry of the Environment (ENV) in 1972 reflected the recognition of a need to align vector control with environmental management in dengue prevention [ 20 , 38 ].

The critical features driving Singapore’s more than 5 decades of dengue control efforts—source reduction, vector surveillance, community education, and legislation—were established within the first 5 years of the programme. The evidence-based approach adopted in the 1960s has continued till today where policies and operations are guided by scientific studies and data [ 59 , 60 ]. Through the years, the system development has been guided by 4 key principles that are consistent with those recommended by the World Health Organization [ 61 ]: (i) inter-epidemic surveillance and control; (ii) risk-based prevention and intervention; (iii) coordinated inter-sectoral cooperation; and (iv) development and adoption of science and technology.

Inter-epidemic surveillance and control enhanced by legislation Vector, virus, case, and environmental surveillance and control are integrated to mitigate dengue transmission in Singapore. The approach is proactive and preemptive rather than reactive as efforts continue regardless of whether the country is experiencing a dengue epidemic or not, although the frequency of inspection increases during epidemics. While the sustained surveillance provide data for outbreak alerts, risk stratification and prioritisation of resources, the sustained control between epidemics aims to moderate their intensity by reducing vector population and baseline of cases which would serve as a springboard for dengue transmission when dengue season approaches.

Case and virus surveillance by the healthcare system is supported by the Infectious Diseases Act (IDA) that mandates the reporting of all dengue cases by clinicians and diagnostics laboratories. Since 2005, greater advocacy and the setting up of a network of primary healthcare providers have enabled earlier case detection and higher ascertainment rates. Besides halving the average vector control response time (time taken from fever onset to initiation of vector control) from 7 days in 2004 to 3.5 days in 2010, the estimated ascertainment rate increased from 1 in 14 infections in 2005 to 2009 to 1 in 6 infections in 2014 to 2017 [ 13 ]. Circulating DENV populations are also monitored through a virus surveillance programme [ 1 ], where a subset of blood samples from suspected and test-positive dengue patients are subjected to serotype and genotype analyses on a weekly basis. This provides timely updates on the composition and distribution of DENV to facilitate resource allocation for dengue control operations and enables preemptive alerts in case of an outbreak signal such as a switch in the predominant serotype [ 1 ] and novel strains taking hold in the population which are associated with outbreaks in Singapore [ 12 ].

Vector surveillance and control is supported by the Control of Vectors and Pesticides Act (CVPA) [ 20 , 62 ] that legally empowers public health officers to conduct routine house inspections. Inspections and source reduction exercises form the bedrock of vector-based interventions in Singapore ( Table 1 ), and in recent years can total >1,000,000 annually [ 63 ]. These involve checking premises and their surrounding areas for receptacles that can collect water and breed mosquitoes. Checks are conducted year-round and intensify before the traditional dengue season approaches to detect and remove breeding, create community awareness, and identify potential breeding sites due to infrastructural defects for rectification [ 11 , 38 ]. Particular attention is paid to reducing the Aedes population and the number of dengue cases before the traditional dengue season between May and October [ 11 , 38 ]. Households averaging 3 inspections per annum were associated with reduced odds (adjusted odds ratio: 0.49 [95% CI: 0.38 to 0.63]) of mosquito larval habitat reports [ 63 ]. Together with the penalty imposed on premise owners found to harbour vector breeding, the inspection system motivates premises owners and occupiers to be more vigilant against mosquitoes breeding [ 63 ].

More recently, Gravitraps, developed by the EHI, a public health laboratory within the National Environment Agency (NEA) [ 64 ], have been mass-deployed for Aedes surveillance. The more than 70,000 trap network distributed island-wide covering about 80% of residences provides a 3D spatial picture of mosquito populations [ 65 ] that serves several objectives. The Gravitrap Aedes aegypti Index (GAI), based on the number of adult female Ae . aegypti caught per Gravitrap deployed in a locality, is a proxy for vector abundance and was found to be associated with dengue risk [ 59 ]. The index thus provides useful information on potential dengue risk to guide vector control operations [ 65 ], especially in inter-epidemic periods where reported dengue case counts are low and reduction in mosquito populations becomes the primary objective. Besides guiding vector control, the GAI is used to alert residents around areas with high vector abundance through the deployment of banners and visualisation of data on official applications and webpages. The GAI system also allows evaluation of control tools, such as the Wolbachia technology under pilot deployment in Singapore. By luring and removing gravid female Ae . aegypti mosquitoes, Gravitraps also play a role in reducing the Aedes population and were associated with an estimated 30% dengue risk reduction in the area of deployment [ 59 ].

Risk-based prevention and intervention through modelling and data analytics The adoption of data analytics tools allows for risk-based vector-control resource allocation. NEA has an integrated dengue alert surveillance system that combines information from clinical and laboratory diagnoses, circulating viral genotypes, Aedes population, and ecological parameters [ 66 ]. Dengue forecast models using machine learning and statistical methods that provide early warning of outbreaks to guide policymakers and NEA’s vector control operations up to 3 months in advance [ 60 , 67 ]. In case of an outbreak signal, stakeholders are alerted and national dengue campaign brought forward to collectively prepare for outbreaks and preemptively reduce Aedes population on the island. Annually, a spatial risk model is also built using information such as historical dengue burden, age of buildings, and amount of vegetation in an area to stratify transmission risk and guide resource allocation [ 68 ]. NEA has also adopted novel indices for dengue surveillance to better inform public health operations and channel resources to high-risk areas, such as estimating the effective reproduction number for dengue, which informs disease transmissibility in real time [ 42 ].

Coordinated inter-sectoral cooperation and adaptive communication strategies to reduce potential Ae . aegypti breeding With the dynamic urban landscape providing an array of breeding opportunities for Ae . aegypti , coupled with limited resources for vector control, it is critical to engage multiple stakeholders on good housekeeping and essential vector control measures to be conducted at their premises. Besides ensuring that the activities of stakeholders do not compromise source reduction and vector control efforts, this also encourages a ground-up, concerted, and proactive approach to protect more individuals against dengue.

Apart from the MOH, NEA works closely with other ministries and government agencies, academia, and the public to advance dengue prevention and control efforts [ 38 ]. First, the initiation of the Inter-Agency Dengue Task Force, which comprises Town Councils and key stakeholders from various government agencies, allows for regular situational dengue updates and sharing of vector control practices [ 38 ]. Also, as construction sites were estimated to have significantly higher risk of dengue transmission [ 53 ], NEA works closely with the Singapore Contractors Association to assist contractors in minimising mosquito breeding [ 38 ] and mandates the employment of environmental control officers to prevent environmental problems such as stagnant water for vector breeding [ 69 ]. A final example of inter-sectoral collaboration is NEA’s work with the Housing and Development Board (HDB) and the Building and Construction Authority (BCA) to re-design high-rise apartment blocks without roof gutters and replace cylindrical bamboo pole holders in older flats (where clothes are hung out to dry) with brackets, which helped to eliminate 2 key locations where rainwater tended to collect and allow vector breeding [ 38 , 62 ].

Public engagement to mobilise communities against mosquito breeding has also adapted to the changing population demographics. The original Keep Singapore Clean and Mosquito Free campaign of 1969 involved the distribution of leaflets and organisation of group competitions to educate the public about the sources of mosquito breeding [ 70 ]. Since then, public engagement has intensified through annual National Dengue Prevention Campaigns, with launches timed to precede the forecasted dengue peak each year [ 38 ]. Informational banners are colour-coded with traffic light signals to inform residents about the dengue risk level in their locality and posters incorporate graphic elements designed to attract public attention. Messages are short and sometimes accompanied by mnemonics to increase effectiveness [ 71 , 72 ].

To complement traditional media, social media is also leveraged to expand the reach of dengue prevention messages and target different audiences. NEA has accounts with Facebook, Instagram, Twitter, and TikTok, and uses these platforms to rapidly disseminate the latest information about the dengue situation. They also allow the tracking of user engagement of those posts, enabling fine-tuning of messages to suit targeted audiences. In 2011, NEA launched the myEnv mobile application that alerts users of dengue clusters and high Ae . aegypti populations so that the public can take the necessary precautions [ 73 ]. A newer version of the app was launched in 2021. These adaptations in public engagement have helped to increase communication efficiency and maximise the reach and impact of dengue prevention messages.

Adoption of science and technology to improve dengue control Given the already low Ae . aegypti population, attempts to achieve further reductions with conventional tools will yield diminishing returns, particularly against the backdrop of an increasingly conducive environment. Cost-effective advancement in dengue control thus requires a paradigm shift in strategy.

NEA has since 2016 been piloting the Wolbachia -based incompatible insect technique (IIT) [ 74 , 75 ], involving releases of Wolbachia- infected male Ae . aegypti mosquitoes to suppress urban vector populations. The potential of the technology, which has also garnered strong support from the community [ 76 , 77 ], was demonstrated by a 98% suppression of Ae . aegypti populations and 88% reduction of dengue incidences in pilot sites [ 75 ]. Automation solutions have been developed to ramp up rearing and releases of Wolbachia males; releases currently cover 50 km 2 of residential areas encompassing around 1 million residents, almost 20% of Singapore’s population [ 78 ]. A hypothetical national IIT programme was estimated to be cost-effective, at about $50,000 to $100,000 per disability-adjusted life year (DALY) averted in 2010 USD [ 79 ], and further automation enhancements are ongoing to improve cost-effectiveness. A randomised controlled trial is also underway to provide statistically robust data on the epidemiological impact of Wolbachia -based IIT in Singapore [ 80 ].

Wolbachia -based IIT, instead of the introgression approach (which seeks to gradually replace the wild-type Ae . aegypti population with a Wolbachia infected one and involves the release of male and female Wolbachia infected Ae . aegypti into the field), has been adopted as it harmonises with the focus on vector suppression in the country and has greater social acceptance as biting females are not released. The introgression approach may not be effective in Singapore as an uncontrolled increase in Wolbachia infected Ae . aegypti population will negate the partially reduced vector competence [ 81 ]. As Ae . aegypti population in Singapore is very low, such increase is very likely if the community slackens source reduction efforts. Viral evolution to resist Wolbachia -mediated blocking in female Ae . aegypti is also likely in the long term [ 82 ].

The successful translation of research and development into dengue control operations is facilitated by a dedicated research programme that is closely integrated with the control programme. Besides Wolbachia -based IIT, other examples include the Gravitrap Surveillance system, risk-based inspections, and the use of drones for inspection for mosquito breeding habitats [ 83 – 85 ].

4. Implications for the globe: Singapore’s dengue epidemiology illustrates the challenge of dengue control

Complex dengue viral dynamics and diversity are not unique to Singapore. Global connectivity has facilitated continuous introduction and exchange of dengue viruses across borders, with dengue transmission taking hold where the efficient vector Ae . aegypti thrives and environmental conditions are favourable [ 86 – 90 ]. Such introductions, coupled with in situ evolution, play key roles in shaping the local dengue epidemiological landscape and provide ample opportunities for the selection of viruses with high epidemic potential [ 2 , 25 ]. While the mosquito vector remains dengue’s primary driver of spread across small spatial scales, viral dynamics suggest that the high mobility of infected human hosts play a key role in driving outbreaks across countries and regions [ 86 , 88 , 91 ].

In the absence of an effective vaccine or antiviral, vector control remains the only means of moderating the impact of the disease. However, an epidemiologically effective vector control programme suppresses human population immunity towards the virus, which in turn demands further suppression of the vector population to arrive at a new equilibrium to prevent an outbreak. This feedback-looped relationship between vector population and human immunity highlights the paradoxical challenge of dengue control, which is expected to play out in any locale with decades of successful vector-based dengue control, including those using Wolbachia for vector population suppression or introgression [ 75 , 92 ]. This is consistent with a modelling study suggesting that reductions in dengue incidence, effected by successful vector control or modification, including Wolbachia introgression approach, would gradually be eroded unless the intervention is implemented at higher intensity [ 93 , 94 ].

Another implication is that successful vector control and low FOI tends to demographically shift dengue from a paediatric disease to one of young adults, thus reducing mortality and morbidity associated with infection of vulnerable paediatric populations. However, a further reduction of the FOI could shift dengue to primarily affect older adults, in whom preexisting medical conditions are common and may increase the risk of severe dengue, as experienced in Singapore [ 20 ].

Singapore’s experience highlights the global need for novel vector control tools that are more effective than classical approaches, as well as nonvector-based intervention tools such as tetravalent vaccines that raise population immunity, and antivirals which reduce the rate of transmission from infected hosts to vectors. Although the Dengvaxia vaccine has been approved by a number of regulatory authorities, its adoption is limited due to its potential to predispose immunologically naïve recipients to severe dengue [ 95 ]. Because of the lack of safety data among older adults, its utility is further limited by the contraindication for individuals >45 years old [ 95 , 96 ]—a group that would greatly benefit from protection due to higher prevalence of comorbidities and which, ironically, would be suitable for vaccination as they are more likely to be seropositive for dengue. In the pipeline are new vaccine candidates and antiviral candidates [ 97 – 99 ], the success of which is urgently needed to reduce the burden of dengue for all age groups, including paediatric and elderly populations.

The conflicting trends between reported case numbers and FOI in Singapore highlight the limits of passive surveillance, especially in programmes that are progressively enhanced. Progress in vector control often occurs hand-in-hand with improvements in dengue surveillance, and the impact of vector control could be masked by improvements in case ascertainment. It is, therefore, important that evaluation and monitoring of programmes, both at local and global levels, include more accurate measures such as seroprevalence.

Singapore’s experience and rich data provide important insights for an increasingly large number of territories at risk of dengue epidemics. We have witnessed the geographical expansion of locations favourable for Ae . aegypti populations driven by the growth and expansion of cities [ 3 ] and climate change [ 100 ]. Warmer weather and longer summers, coupled with the proliferation of breeding habitats among artificial containers and urban infrastructure, will continue to create more opportunities for Ae . aegypti to expand its range. This is further exacerbated by increasing human population densities and the constant inflow of dengue-susceptible individuals into cities as a result of global migrations from non-endemic areas to endemic cities [ 52 , 101 ]. These challenges underscore the importance of considering mosquito breeding prevention in urban planning and building codes [ 102 ]. Such environmental protection measures, together with community collaboration, will be essential to complement any vector control tool, classical or novel, in the control of dengue and other Ae . aegypti -borne viruses [ 52 , 103 ]. A concerted effort by all endemic territories to control dengue is required to reduce opportunities for viral mutation and exchanges and consequently large epidemics.

5. Conclusions

Singapore has since the 1960s put in place an effective dengue control and prevention programme, leading to a consistent decrease in dengue seroprevalence and FOI till the present day. Paradoxically, the resulting low herd immunity, in addition to other factors such as introduction of new serotypes/clades, increased urbanisation and globalisation, has today contributed to exacerbated dengue risk. Improvements in surveillance and diagnostics have also resulted in an uptick in reported dengue cases despite the maintenance of low Aedes HI. Through public-private-people partnerships and leveraging the latest scientific and technological expertise in vector control, Singapore’s dengue vector control programme aims to continue to adapt to future challenges. Singapore’s experience and data could provide valuable insights on dengue epidemiology and control for the global community.

Acknowledgments

The authors acknowledge the contributions of Swee Ling Low in generating the serotype-specific prevalence data.

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• Copy URL https://www.pbs.org/newshour/health/what-you-need-to-know-about-the-latest-outbreak-of-dengue-fever

What you need to know about the latest outbreak of dengue fever

Roughly 4.7 million people have been infected with dengue fever so far in 2024, an explosion of cases centered in Latin America and the Caribbean that experts warn could grow.

“We’re seeing a worrisome trend of expansion and increasing circulation of the virus at the global scale,” said Dr. Gonzalo Vazquez-Prokopec, a professor at Emory University who researches the intersection of ecology, epidemiology and global health.

Heavy precipitation from El Nino and the ongoing effects of human-driven climate change have fostered conditions in which mosquitoes that carry the disease can thrive. Populations in more regions of the world are being exposed to dengue as summers grow longer and hotter summers, especially in urban areas that are home to Aedes aegypti , the type of mosquito that transmits the virus, Vazquez-Prokopec said.

In late March, Puerto Rico issued a public health emergency after about 600 people were confirmed to have dengue fever, leading to hundreds of hospitalizations.

READ MORE : Puerto Rico has declared an epidemic following a sharp rise in dengue cases

People living in and traveling to these areas can take precautions to prevent exposure and further transmission. While vaccines exist to prevent the worst outcomes of dengue fever, there is no cure if someone gets sick.

How many cases have been identified in this outbreak?

So far in the first four months of 2024 alone, more than 4.6 million people in the Americas are estimated to have been infected with dengue fever, said Thais Dos Santos of Pan-American Health Organization (PAHO) . That amounts to more cases than were recorded during all of 2023, she said.

How is dengue fever transmitted?

The dengue virus is carried in the gut of female mosquitoes. When the insect bites an infected person and then feeds on someone else, it can spread the infection to that person.

People cannot directly spread dengue to each other.

Places with unreliable access to clean drinking water are particularly vulnerable in part because people may need to collect and store water in vessels, which become the perfect environment for mosquitoes to breed.

What are the symptoms of dengue fever?

Roughly two-thirds of people who are infected with dengue show no signs for disease, Dos Santos said.

But for those who do, symptoms typically develop within two weeks. People most commonly complain of sudden high fever and headache. The illness can be painful, and a person’s condition can deteriorate rapidly, Dos Santos said. Symptoms include muscle and joint pain, fatigue, nausea and vomiting.

Who is at risk of severe dengue infections?

There are four known serotypes, or strains, of the dengue virus. Infection with one strain typically leaves the person who was sick with lifelong immunity, but only from that strain, said Dr. Anna Durbin, who directs the Center for Immunization Research at Johns Hopkins University.

If the person gets infected again with a different strain, that can launch a process called antibody-dependent enhancement, where the immune system’s collection of antibodies “acts as a chaperone,” Durbin said, escorting the virus throughout the body. The person can become extremely ill and may require hospitalization.

Because first-time infections often result in undetected cases with no symptoms or mild ones, many people do not realize they have been exposed. It is upon the second bite and introduction of a different strain that people can get really sick, Vazquez-Prokopec said.

“If there's an outbreak going on, the best thing to prevent severe dengue is to go to the doctor as soon as you feel symptoms,” he said.

What treatment is available for dengue fever?

While there is no cure for dengue fever, people experiencing symptoms of infection can work with their health care provider to manage them. This may include taking medication to relieve pain, increasing fluid intake to prevent dehydration and getting plenty of rest.

What can be done to prevent dengue fever?

Use mosquito repellant and wear long-sleeved shirts and long pants in areas where dengue is spreading, Vazquez-Prokopec said. Mosquitoes that transmit dengue are day biters, so mosquito nets over beds are a less effective prevention measure (although these fine-mesh nets are recommended to slow the spread of other mosquito-borne illnesses, such as malaria ).

“Make sure you don't accumulate standing water in or around your house,” Dos Santos said.

In addition to removing standing water when possible, Vazquez-Prokopec said it is important that communities spray for mosquitoes and households use mosquito-repellent coils to deter the insects from feeding on residents.

He added that when traveling to an area where dengue fever is endemic, it’s a good idea to wear mosquito repellant for the next three or four days after returning home to prevent introduction of the disease to your community.

One prevention method that has gained attention is the introduction of male mosquitoes infected with the bacteria Wolbachia . When those mosquitoes mate with female mosquitoes, the resulting eggs do not hatch, thus stopping the possible spread of any diseases the insects may carry.

“We cannot give up on vector control,” Vazquez-Prokopec said.

Why is this recent outbreak so widespread?

Dengue cases declined between 2016 and 2018 but began an uptick before the COVID pandemic, Durbin said. COVID lockdowns prevented people (and the virus) from circulating, meaning fewer people were getting bitten or had a chance to develop immunity.

But a recent surge of global travel, coinciding with an El Nino year, has translated to a dramatic increase in confirmed and suspected dengue infections, Durbin said.

“In the past two years, it's exploded,” she said.

More than 5 million people have developed dengue fever since early 2023, according to estimates released by the World Health Organization in January, and the Americas “reported the largest proportion of the global burden.” Confirmed and suspected cases in the Western Hemisphere have more than quadrupled over the last five years.

Will the continental U.S. experience a significant outbreak?

For now, most people in the continental U.S. do not need to be concerned about dengue fever, Dos Santos said. During warm weather, a lot of people spend time inside screened-in houses with air conditioning, she said. When they are thirsty, they turn a faucet for water and generally do not need to store rainwater. But that type of infrastructure is not guaranteed in parts of the world that struggle more regularly with dengue fever, she said.

Laura Santhanam is the Health Reporter and Coordinating Producer for Polling for the PBS NewsHour, where she has also worked as the Data Producer. Follow @LauraSanthanam

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Dengue Vaccination: What Everyone Should Know

Sanofi-Pasteur will stop manufacturing its dengue vaccine for children. The manufacturer is discontinuing the vaccine citing a lack of demand in the global market to continue production of this vaccine. CDC, in collaboration with the Puerto Rico Department of Health, will continue alerting health professionals about the discontinuation of Dengvaxia and the use of this vaccine as recommended by the Advisory Committee on Immunization Practices (ACIP). Dengvaxia is safe and effective when administered as recommended. There are two other dengue vaccines either approved or in late stages of development. However, they are not currently available in the United States. People can continue to protect themselves and their families from dengue by preventing mosquito bites  and  controlling mosquitoes  in and around their homes.

Who Should Get a Dengue Vaccine?

Where does dengue commonly occur, who should not get a dengue vaccine, what type of dengue vaccine is available, how well do these vaccines work, what are the possible side effects of the dengue vaccine, where can i find this vaccine, how can i get help paying for this vaccine.

One type of dengue vaccine is available for use in areas with risk of dengue in the United States:

• Dengvaxia® dengue vaccine

CDC recommends dengue vaccination for children 9 through 16 years old, but only when they have been previously infected with dengue and living in areas where dengue is common.  This previous infection should be confirmed by laboratory testing.  This vaccine is different from other vaccines in that it is only recommended for people who have already been infected with dengue virus.  The reason is that children without previous dengue infection are at increased risk for severe dengue disease and hospitalization if they get dengue after they are vaccinated with Dengvaxia.  Therefore, healthcare providers should check for evidence of a laboratory-confirmed previous dengue infection before vaccination.

Dengue is common in the U.S. territories of American Samoa, Puerto Rico, and the U.S. Virgin Islands, and the freely associated states, including the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.

Children 9 Through 16 Years Old

• The dengue vaccine is approved for use in children 9 through 16 years of age of who have a previous history of laboratory-confirmed dengue infection.
• Only children with laboratory-confirmed evidence of previous dengue infection should be vaccinated.
• Children must also be living in areas where dengue occurs frequently or continuously, which include American Samoa, Puerto Rico, and the U.S. Virgin Islands, and the freely associated states of the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.

Special Populations

Pregnant people were not specifically enrolled and studied in the vaccine trials. Although no significant differences in adverse pregnancy outcomes between vaccinated and unvaccinated people were found, the number of pregnant people enrolled was too small to determine the effect of Dengvaxia on pregnancy.

Vaccine providers should consider the risk of dengue virus infection when making a recommendation for vaccination for pregnant people. Pregnant people are at increased risk of dengue-related complications.

No data are available to evaluate Dengvaxia and breastfeeding.

Vaccine providers should consider the developmental and health benefits of breastfeeding as well as the risk of dengue virus infection to the breastfeeding person and infant.

The vaccine should not be administered to

• Children under 9 years of age are less likely to have had a prior dengue infection. For this reason, if your child is under the age of 9, they are not eligible for dengue vaccination.
• The dengue vaccine is not licensed for people over 16. There is not enough data to show how well the vaccine works in that population.
• Children who have not had a prior dengue infection.
• Children with weakened immune systems (immunocompromised)
• Children who have had a severe (life-threatening) allergic reaction to a previous dose of the vaccine.
• Children who have a severe (life-threatening) allergy to any ingredient in this vaccine.
• Travelers and non-residents of areas where dengue is common. The FDA has not approved dengue vaccine for use in travelers.

One type of dengue vaccine is available in the United States. The Dengvaxia vaccine will be available starting in 2022 for use in children 9 through 16 years old with laboratory-confirmed evidence of a previous dengue virus infection and living in areas where dengue is common (occurs frequently or continuously). Dengue is common in the U.S. territories of American Samoa, Puerto Rico, and the U.S. Virgin Islands, and freely associated states, including the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau.

Dengvaxia Vaccine

Dengvaxia : Vaccine providers give three doses administered subcutaneously and each dose given 6 months apart (at 0, 6, and 12 months) for full protection.

Overall, Dengvaxia protects children from dengue illness, hospitalizations, and severe dengue 8 out of 10 times (80%) in children who had dengue before vaccination. The vaccine protects against all four dengue virus types: dengue 1, 2, 3, and 4.

The vaccine provides years of protection

• We are still learning about how long the vaccine protects children. To date, we know that the vaccine can provide protection against dengue for at least 6 years.
• Over time, we will learn more about how long vaccine protection lasts.

While the vaccine is highly effective, there is a low risk that some vaccinated people can still get infected with dengue. This is called vaccine breakthrough.

For children who HAVE already had dengue

• The most common side effects include soreness, itchiness, or pain in the injection site, headaches, lack of energy, and general discomfort. These side effects are normal signs that the body is building protection, and the side effects should go away within a few days.
• People sometimes faint after medical procedures, including vaccination. Tell your provider if you feel dizzy or have vision changes or ringing in the ears.
• As with any medicine, there is a very remote chance of a vaccine causing a severe allergic reaction, other serious injury, or death.

Problems that Could Happen After Getting Any Vaccine

• People sometimes faint after medical procedures, including vaccination. Sitting or lying down for about 15 minutes can help prevent fainting, and injuries caused by a fall. Tell the provider if you or your child feel dizzy, have vision changes, or have ringing in the ears.

Your child’s healthcare provider is usually the best person to discuss recommended vaccines for your child. These vaccines are part of the routine childhood immunization schedule. Vaccines for children and teens are available at:

• Community health clinics

If your healthcare provider does not have these vaccines for children, ask for a referral.

Vaccines may also be available at:

• Health departments
• Other community locations, such as schools and religious centers

You can also contact the health department in your U.S. territory or freely associated state to learn more about where to get vaccines in your community.

When receiving any vaccine, ask the provider to record the vaccine in the state or local vaccine registry, if available. This helps providers at future visits know what vaccines you or your child have already received.

Most health insurance plans cover routine vaccinations. The Vaccines for Children (VFC) program also provides vaccines for children 18 years and younger who are uninsured, underinsured, Medicaid-eligible, American Indian, or Alaska Native.

• CDC’s Dengue Website

Immunization Schedules

• Childhood and Adolescent Immunization Schedule

Dengvaxia Vaccine Information Statement

• Dengue Vaccine VIS

Vaccine Safety

• CDC’s Vaccine Safety Website
• Dengue Vaccine: Vaccine Safety & Efficacy Data
• Vaccines & Immunizations

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• Perspective
• Open access
• Published: 15 April 2023

Is new dengue vaccine efficacy data a relief or cause for concern?

• Stephen J. Thomas   ORCID: orcid.org/0000-0002-8368-7682 1  

npj Vaccines volume  8 , Article number:  55 ( 2023 ) Cite this article

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• Drug development

Dengue is a major global public health problem requiring a safe and efficacious vaccine as the foundation of a comprehensive countermeasure strategy. Despite decades of attempts, the world has a single dengue vaccine licensed in numerous countries, but restrictions and conditions of its use have deterred uptake. Recently, clinical efficacy data has been revealed for two additional dengue vaccine candidates and the data appears encouraging. In this perspective I discuss dengue, the complexities of dengue vaccine development, early development setbacks, and how the latest data from the field may be cause for measured optimism. Finally, I provide some perspectives on evaluating dengue vaccine performance and how the pursuit of the perfect dengue vaccine may prevent advancement of vaccines which are good enough.

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Introduction.

Dengue is caused by infection with any of the four dengue viruses (DENV-1–4) and represents a significant global public health burden 1 . Dengue not only causes morbidity and mortality in the infected but also consumes scarce resources for infection prevention, caring for the ill, and missed work and school 2 , 3 . The DENVs are transmitted in tropical and subtropical regions by infected Aedes mosquito species as they take a blood meal from a susceptible host. Hundreds of millions of people are infected every year and an estimated 96 million infections are clinically apparent 4 , 5 .

Clinically relevant dengue is characterized by fever, headache, bone and muscle pain, eye discomfort, fatigue, and the development of rash. Gastrointestinal and respiratory complaints may also be common depending on the age of the infected individual 6 , 7 . Severe dengue manifests with plasma leakage, intravascular volume depletion, and reduced organ perfusion (shock). Disruption of coagulation is also possible and may result in significant hemorrhage contributing to shock 8 .

Individuals are at greatest risk for severe dengue when they experience two sequential DENV infections with two different DENV types separated in time by more than 18 months 9 , 10 . Additional risk factors under exploration include genetic background, pre-existing medical conditions (obesity, renal and cardiovascular disease, diabetes), and female sex 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . The contributions of human–vector–virus interactions and the potential evolution, and co-evolution, of human immunity, vector competence, and changes in virus genotype/lineage are also being studied 19 , 20 , 21 , 22 , 23 , 24 .

The exact immunopathogenic mechanisms of sequential heterotypic DENV infections are incompletely understood, but considerable evidence points to humoral and cellular adaptive immune responses occurring in response to the first infection facilitating increased DENV replication during the second infection which, in turn, drives pro-inflammatory cytokine secretion 25 , 26 , 27 , 28 , 29 , 30 , 31 . The exact number of annual dengue fatalities is not known but the estimates range between 5000 and 40,000 with many deaths occurring in children 32 , 33 .

Supportive treatment (antipyretics, judicious intravascular volume repletion) delivered by clinicians with experience treating dengue is very effective with low case fatality rates. Unfortunately, variance in clinical care exists and dengue has high morbidity and mortality in many endemic countries 34 . Currently, no anti-DENV antivirals or immune-based (monoclonal antibodies) prophylactics or therapeutics are approved for use, but promising efforts are underway 35 , 36 .

Reducing human arboviral infections through mosquito control strategies has had intermittent success. The widely held opinion that mosquito control is a necessary component of a comprehensive dengue control strategy requires the expanded study of available and novel approaches 37 , 38 . The recent development and deployment of mosquito control methods using genetic- or microbial-based alterations to mosquito populations offers the potential for improved outcomes 39 , 40 .

Vaccination has long been recognized as the required foundation of a multi-pronged approach to reducing the global dengue burden but developing a safe and effective dengue vaccine has been very difficult. For more than 75 years, scientists and product developers have attempted to design and advance safe and efficacious dengue vaccine candidates, but the challenges have been substantial and formidable (Box 1 ) 41 , 42 . Although numerous different approaches are being explored, only live attenuated virus vaccines have achieved licensure or reached advanced clinical development 43 .

Box 1. Dengue vaccine development challenges

Existence of four DENV types (1–4), each capable of causing infection, disease, and death

No validated immune correlate of protection

Animal models do not comprehensively recapitulate the human dengue infection/disease experience

Immunologic assays are unable to precisely define DENV type-specific (homotypic) immune responses

Requirement for very large efficacy trials to demonstrate benefit across diverse populations and clinical endpoints

Sanofi Pasteur licensed the first dengue vaccine (Dengvaxia®) in Mexico in 2015, and more than 20 countries thereafter, based on the safety and efficacy demonstrated in two phase III trials and a single season of disease surveillance. Unfortunately, the optimisim that a dengue vaccine was finally available quickly became disappointment when a safety signal was observed in vaccine recipients who were dengue non-immune at the time of vaccine administration 44 , 45 . In the third year of the phase III clinical trial, the youngest, non-immune vaccine recipients experienced increased rates of hospitalized and severe dengue compared to their unvaccinated peers 46 .

Many hypotheses were offered to explain this occurrence including the idea that imbalanced homotypic and heterotypic immunity across the four DENV types primed dengue naive (serostatus negative) vaccine recipients for antibody-dependant enhancement (ADE) when they encountered their first natural infection 47 . Others postulated that the absence of DENV non-structural proteins in the vaccine construct prevented the formation of protective cellular immunity and/or anti-NS1 antibodies 48 . Younger age was also proposed as an independent risk factor for clinically apparent and more severe dengue. Unfortunately, the phase III trials’ study design and limited blood sampling at baseline did not allow for a stratified analysis of vaccine safety and efficacy by baseline dengue serostatus. Instead, Sanofi tested volunteers one month after their last vaccine dose using an anti-NS1 antibody assay. The idea was that dengue serostatus negative vaccine recipients would be without NS1 antibodies because the vaccine does not contain NS1 proteins, in contrast to serostatus positive recipients who would have been naturally infected and exposed to NS1 49 , 50 .

The safety signal in year three became less pronounced over time but the damage was done. Sanofi had already decided to seek an indication only for older children (9 years and above) and regulators forced the company to modify the vaccine’s label stating that only individuals previously infected by a DENV should be vaccinated. There was an outcry in the Philippines as hundreds of thousands of children had been vaccinated between the time of licensure and acknowledgement of the safety signal. The country subsequently revoked the vaccine’s license.

The World Health Organization Strategic Advisory Group of Experts on Immunization (SAGE) modified its original endorsement of Dengvaxia® recommending it only be used in dengue immune individuals 51 . Although Dengvaxia was proven safe and efficacious in dengue immune recipients, especially against more severe forms of disease, and remains licensed in many countries, including the U.S., vaccination implementation and uptake has been low 52 , 53 , 54 . There has been little information on the outcomes, good or bad, of over 800,000 children who were vaccinated with Dengvaxia®, including hundreds of thousands who received only a single dose when the vaccination program was shut down 55 .

The next generation of dengue vaccines

As expected, every dengue vaccine candidate following Dengvaxia® is being stringently reviewed for safety and efficacy in dengue immunes and non-immunes, across a broad age range of recipients, and for their ability to protect against the full spectrum of disease outcomes caused by infection with any DENV type. There is also a requirement for demonstrating safety and efficacy across more than one dengue season 56 , 57 , 58 .

Two new live attenuated dengue vaccines have now completed phase III efficacy trials and there is room for cautious optimism once again. Takeda recently received approval from Indonesia, European Commission, and Brazilian regulators for use of their two-dose vaccine (TAK-003) in people 4 years of age and older, regardless of baseline dengue immune status. Approval was based on safety, immunogenicity, and efficacy data from 19 phase I, II, and III trials with more than 28,000 participants spanning a broad age range. Dengue surveillance in the phase III trial extended for 4.5 years.

The primary study endpoint for the phase III trial was efficacy against any dengue, of any severity, caused by any DENV type in either dengue immune or non-immune recipients. Within 12 months of the second dose vaccine efficacy was 80.2% 59 . At the 18-month timepoint, vaccine efficacy against all dengue in dengue immune recipients was 76.1% and 66.2% in dengue non-immune recipients. Efficacy against hospitalized dengue was 90.4% and 85.9% against dengue hemorrhagic fever (DHF) (WHO, 1997 criteria). DENV type-specific efficacy was 69.8% for DENV-1, 95.1% for DENV-2, and 48.9% for DENV-3 with variable confidence intervals 60 . At 54 months, overall vaccine efficacy had waned to 61.2% with efficacy of 64.2% in dengue immune recipients and 53.5% in dengue non-immunes. Efficacy against hospitalized dengue was 84.1%. DENV type specific efficacy in dengue non-immunes was 78.4% for DENV-1, 100% for DENV-2, there was no efficacy for DENV-3, and not enough DENV-4 cases to calculate a value. DENV-3 efficacy in dengue immunes was 74%. Efficacy against DHF caused by any DENV type was 70.0% and against severe dengue (determined by an adjudication committee) was 70.2%. These data have not been presented in the peer-reviewed scientific literature but are accessible from the sponsor’s Summary of Product Characteristics ( https://www.takeda.com/siteassets/system/newsroom/2022/qdenga/ema-combined-h-5155-en.pdf ) (accessed 21 January 2023).

The dengue working group of the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recently (February 23, 2023) reviewed TAK-003 performance indicating; (1) the vaccine protected seropositive recipients against all dengue and hospitalized dengue caused by infection with any serotype; (2) the vaccine protected seronegative recipients against all and hospitalized dengue due to DENV-1 and -2 infection; (3) the vaccine did not protect seronegative recipients against all dengue and hospitalized dengue due to DENV-3; and (4) the vaccine’s performance against DENV-4 infection outcomes in seronegative children could not be conclusively determined due to low event numbers. The lack of a defined immune correlate of protection made the significance of the presented immunogenicity data unclear.

More recently, the Instituto Butantan, U.S. NIH, and Merck (MSD) reported the first results from a phase III trial in Brazil with over 16,000 participants and at least two years of disease surveillance. The vaccine (Butantan-DV) was made using materials licensed from the U.S. NIH and is analogous to the NIH’s TV003 formulation tested previously 61 , 62 . MSD joined the collaboration when they entered into a co-development and licensing agreement in 2018. The phase III trial was initiated in 2016 and included participants ranging in age from 2 to 59 years who received a single dose of vaccine and were followed for any dengue, of any severity, caused by any DENV type. Dengue immune and non-immune participants were included in the trial.

Overall efficacy was 79.6% with dengue immunes having higher efficacy (89.2%) compared to dengue non-immunes (75.3%). Efficacy data is only available for DENV-1 (89.5%) and DENV-2 (69.6%) due to the low circulation of types DENV-3 and -4 during the trial. DENV type specific data by dengue immune status reveals higher efficacy against DENV-1 in dengue immunes (96.8%) compared to non-immunes (85.5%) and similar findings for DENV-2 (immune 83.6%, non-immune 57.9%). There were no severe cases or cases with clinical warning signs reported. The trial will continue until 2024 leaving open the possibility there will be sufficient cases caused by DENV-3 and -4 to gain a clearer view of vaccine performance against these types. These data have not been published in the peer reviewed scientific literature but are accessible from the Butantan website ( https://butantan.gov.br/noticias/butantan%27s-dengue-vaccine-has-79.6-efficacy-partial-results-from-2-year-follow-up-show ) (accessed 21 January 2023).

In summary, the three live attenuated dengue vaccines which have generated clinical endpoint efficacy data have all demonstrated; (1) higher efficacy in dengue immune recipients; (2) higher efficacy against more severe clinical phenotypes; (3) variance in DENV type specific efficacy, and (4) the challenge of capturing data for all desired clinical endpoints (any dengue, severe dengue, hospitalized dengue), across all DENV-1–4 types, in both dengue immune and non-immune recipients.

Assessing dengue vaccine performance

With new dengue vaccine efficacy data becoming available, regulators, public health officials, and scientists are grappling with how to assess the risk and benefit of imperfect dengue vaccines.

The local and systemic reactogenicity profile of a dengue vaccine must be acceptable and on par with other licensed vaccines. In addition, the rates of dengue and severe dengue cannot be greater in vaccine recipients compared to unvaccinated peers. Lack of benefit against a specific clinical outcome may be acceptable when taken in the larger context of all benefits, but associations between vaccination and developing the disease the vaccine is intended to prevent is not.

How to assess for the potential of vaccine-associated dengue is not straight forward. After two years of surveillance in the Butantan study there were no severe dengue cases nor cases with clinical warning signs. The Takeda experience, however, is more complex, and even though clinical and regulatory review committees for the European Commission and Brazil’s National Health Surveillance Agency (ANVISA) did not believe there was a safety signal in dengue non-immune recipients, this a point of contention 63 , 64 , 65 . Two issues may prevent achieving a consensus on the Takeda data: (1) low numbers of severe and DENV type-specific cases reducing the statistical power to make generalizable conclusions and (2) using hospitalization as a surrogate for severe disease.

One would think hospitalizing an individual is an accurate reflection of disease severity but differences in hospitalization practice across countries calls this into question. As a routine practice, trial sponsors defer to the local standards of medical care. This makes sense but presents opportunities for site-to-site variance and introduces potential confounders into data analysis. For example, some sites may admit all patients based on diagnosis alone while others only admit patients based on clinical necessity.

Markers of severe disease such as clinical signs or symptoms, or laboratory evidence of plasma leakage and/or hemorrhage would also appear to be a clear method to classify disease severity, but this approach has the potential to confound due to variance in diagnostic resources across trial sites. For example, some sites may have access to, and routinely use, ultrasound to detect fluid collections such as ascites or pleural effusions indicating the occurrence of plasma leakage. Other sites may lack these resources and must rely on less sensitive methods such as abdominal palpation or lung auscultation. Adding to the complexity of this issue is that documentation methods supporting clinical trials may not be nuanced enough to distinguish between the mere occurrence of a finding from the clinical relevance of a finding.

Even when the decision is made to utilize published classification systems of severe disease there is potential for variance. For example, vaccine developers may choose to utilize severity criteria contained within the WHO 1997 guidelines or choose the revised 2009 document 66 , 67 . Concern that these guidelines were designed to support clinical care and were not a good fit for use in research settings prompted the U.S. NIH to lead an effort to develop guidelines for use in interventional trials 68 , 69 . Sponsors may also commission external experts to develop additional criteria and guidelines like Takeda did with their dengue case adjudication committee 65 .

Expectations based on extrapolation

Differences in vaccine construct may translate into significant qualitative differences in immune responses following vaccination. These differences should be kept in mind when predicting vaccination outcomes with newer vaccine candidates using Dengvaxia® as the reference.

Most humoral immunity epitopes are located within the domains of the DENV envelop (E) protein while cellular immunity epitopes are located on the non-structural (NS) proteins 27 , 70 . As noted in Fig. 1 , Dengvaxia is based on a Yellow Fever (YF) 17D backbone with DENV-1-4/YF chimeras made through the introduction of DENV prM and E genes and removal of the YF prM and E genes. The vaccine contains no DENV NS proteins. The Takeda vaccine uses a DENV-2 backbone to create DENV-1/-2, -3/-2, and -4/-2 chimeras and therefore has only DENV-2 NS proteins. The NIH/Butantan/MSD vaccine has full genome DENV-1, -3, and -4 components with a DENV-2/-4 chimera based on a DENV-4 backbone. This vaccine possesses NS proteins from DENV-1, -3, and -4. These important differences in vaccine construct should motivate a pause before trying to directly and broadly extrapolate the Dengvaxia® experience to all vaccines 43 .

DENV genome components of Sanofi, Takeda, and NIH/Bhutantan/MSD dengue vaccine candidates with the location of known attenutating mutations.

However, when it comes to multi-component replicating dengue vaccines, construct alone may not be sufficient to explain variance in immunogenicity and efficacy. Both the Sanofi and Takeda vaccines appear to have a dominant single vaccine virus which replicates after administration (Sanofi—DENV-4, Takeda—DENV-2) despite having all four DENV types included in the vaccine 71 , 72 , 73 . In contrast, MSD’s formulation of the NIH vaccine induced replication of three or more vaccine viruses in 64% of flavivirus non-immune recipients 74 . How this will translate into efficacy across the five years of follow up and DENV type-specific efficacy remains to be seen.

Immunogenicity does not guarantee efficacy

It is unclear whether homotypic immunity to each DENV type is necessary to be protected against disease caused by infection with any DENV type. Sequential infections with two different DENV types appears to impart a mix of broadly protective homo- and heterotypic immunity, as evidenced by the very rare occurrence of clinically relevant third and fourth DENV infections 75 . Vaccine developers must pursue the development of tetravalent vaccine formulations containing antigens to each DENV type, but it has been difficult, especially with replicating vaccines, to avoid some element of immunodominance and an imbalance of homotypic immunity to the dominant DENV type and cross-reactive immunity to the others 76 , 77 , 78 , 79 , 80 , 81 , 82 . As a result, a major lesson learned when assessing dengue vaccine performance is that immunogenicity does not necessarily translate into clinical efficacy.

Sanofi learned this lesson following unblinding of its phase 2b efficacy trial results from Thailand 83 . The expectation was that generation of measurable neutralizing antibodies to a specific DENV type would portend a reasonable likelihood of having protection against disease if infected with the same type. But, despite having balanced geometric mean neutralizing antibody titers greater than 100 for all DENV types and high rates (>95%) of seropositivity after three vaccine doses, the trial failed to meet its primary efficacy endpoint. The immunogenicity and efficacy mismatch by DENV type would occur again during subsequent phase III testing of Dengvaxia® and Takeda’s vaccine 46 , 59 , 60 , 65 , 84 , 85 , 86 , 87 , 88 . Based on early efficacy data from the Butantan trial, the disconnect will likely persist based on review of the vaccine’s historic immunogenicity data and the recent disclosure of lower DENV-2 efficacy 61 , 89 .

A safe and good dengue vaccine is better than no vaccine

A perfect dengue vaccine would safely deliver benefit across a myriad of scenarios. The perfect vaccine would: (1) protect across a diverse age range, (2) prevent infection (ideally) and disease caused by any DENV type and possibly numerous genotypes within each type, (3) prevent all clinically relevant phenotypes of dengue, not only severe disease, (4) protect recipients regardless of their flavivirus immunity status at the time of vaccination, (5) disrupt transmission of virus between people and mosquitoes, and (6) have durable protection until the recipient transitioned out of the risk window by acquiring a profile of homo- and heterotypic immunity like what is observed after two natural DENV infections. Shared gaps in the performance of current vaccines include a reduced ability to protect the non-immune recipient from clinically relevant, but more mild disease, caused by any DENV type.

A dengue vaccine available only to dengue immune recipients may have clinical value but lack the necessary practical attributes to support meaningful uptake. A ‘test and vaccinate’ strategy, although feasible, could be very difficult to operationalize across the multitude of dengue endemic areas 90 , 91 , 92 , 93 , 94 . A good vaccine not used for vaccination delivers no benefit.

Less severe forms of dengue contribute substantially to the overall public health burden 33 , 95 , 96 , 97 . Prevention of milder forms of dengue would not only reduce morbidity but also the economic and other opportunity costs of missed school or work. However, a vaccine which reliably only prevents hospitalization or more severe forms of dengue still has the potential to make a major public health impact, especially during high-transmission outbreaks (epidemics). This is particularly true in low- and middle-income countries where resources for the critically ill are scarce or in locations where experience with treating severely ill dengue patients is lacking. In addition, when hospital beds are not occupied by dengue patients, these resources can be allocated towards other public health burdens such as respiratory or gastrointestinal diseases.

A dengue vaccine that is efficacious against some, but not all DENV types can still deliver value. In many dengue endemic areas, numerous DENV types co-circulate and infect populations 98 , 99 . A vaccine which does not increase the recipient’s risk of dengue and can reduce the risk of disease caused by even some of the DENV types would still deliver an overall public health net benefit. This is especially true for DENV types more commonly associated with disease (DENV-1, -2) and more severe clinical outcomes (DENV-2) 11 , 100 .

It is clear the perfect dengue vaccine is not on the immediate horizon, but the Sanofi, Takeda, and Butantan/NIH/Merck experiences do inform us that it is possible to effectively immunize some people against disease scenarios that constitute dengue’s burden. I would contend when it comes to dengue countermeasure development, safety is non-negotiable, but all other expectations must be managed and considered in the aggregate. Our challenges with effectively communicating coronavirus disease 2019 vaccine performance characteristics should be a cautionary tale in this regard. Pursuit of the perfect dengue vaccine is a laudable goal, but not at the cost of overlooking imperfect options that could safely deliver tangible, albeit smaller scale, public health benefit.

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Thomas, S.J. Is new dengue vaccine efficacy data a relief or cause for concern?. npj Vaccines 8 , 55 (2023). https://doi.org/10.1038/s41541-023-00658-2

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Volume 30, Number 7—July 2024

Research Letter

Emergence of indigenous dengue fever, niger, october 2023.

Suggested citation for this article

Dengue fever is a growing worldwide public health concern. In mid-October 2023, multiple cases of uncommon febrile illness were reported among patients in Niamey, Niger. Fifteen samples were tested by using molecular methods, from which 7 (46.66%) were confirmed positive for mosquitoborne dengue virus belonging to serotypes 1 and 3.

Dengue fever is a mosquitoborne arbovirus infection, mainly reported in tropical and subtropical regions. Dengue fever is caused by the 4 types of dengue virus (DENV), 1–4 ( 1 ). Patients with DENV infection have onset of high and abrupt fevers which are often accompanied by redness of the face, cutaneous erythema, myalgia, arthralgia, and headaches ( 2 , 3 ). In severe cases, healthcare workers will find evidence of hemorrhagic manifestations and signs of shock. The most common laboratory findings from a complete blood count are leukopenia, thrombocytopenia, and increased hematocrit (hemoconcentration) ( 4 ).

In recent years, DENV infection has progressed worldwide and become a major public health concern ( 5 ). Annually, > 390 million infections are reported across the globe, of which 96 million have clinical manifestations and > 25,152 result in death ( 6 , 7 ). DENV is now endemic in > 34 countries in Africa ( 7 ). In 2023, a total of 171,991 suspected cases of dengue fever, including 70,223 confirmed cases and 753 deaths, were reported from 15 countries in West Africa. Burkina Faso is the most affected by dengue fever, accounting for 85% of reported cases and 91% of recorded fatalities ( 8 ). In Niger, there was a lack of data related to DENV infection until the recent confirmation of an imported case in November 2022 ( 9 ). In this report, we describe findings from 7 indigenous confirmed DENV cases in Niger. The Niger National Ethical Committee at the Ministry of Health approved the surveillance protocol as minimal risk research, and written consent forms were not required. Oral consent was obtained from the patients. All methods, including the use of human samples, were conducted in accordance with the Declaration of Helsinki.

• Figure . Distribution and results of dengue fever testing of suspected cases according to hospital or clinical origin in Niamey, Niger, October 2023. CERMES, Centre de Recherche Medicale et Sanitaire.

From October 25–27, 2023, several public and private hospitals in Niamey reported cases of febrile syndrome including fever (>38°C), persistence of headaches despite administration of analgesics, muscle pain, and vomiting ( Figure ). None of the patient complaints included a body rash or hemorrhage, and the initial provider assessment was otherwise unremarkable. We conducted microscopic blood smear examinations of 15 patient samples; all were negative for malarial parasites. Our clinical management of the patients (hospitalized and ambulatory) consisted of symptom treatment. We observed thrombocytopenia and leukopenia an average of 72 hours after the initial examination. Of note, we tested all 15 patients for DENV infection within 7 days of symptom onset.

Because of the suggestive symptomatology of our cases and the ongoing DENV epidemic in neighboring countries, particularly Burkina Faso, we collected blood samples and sent them to the National Reference Laboratory for arboviruses at the Centre de Recherche Medicale et Sanitaire for virological confirmation. Testing was conducted by using qRT-PCR with specific primers and probes for the detection of the 3 main arboviruses, DENV, Chikungunya, and Zika virus ( 10 ). Differentiation of DENV serotypes 1, 2, 3, and 4 was conducted by using the Dengue Real-TMGenotype kit (Sacace Biotechnology, https://sacace.com ).

A total of 15 samples were tested for all 3 viruses, of which 7 (46.66%) were positive for DENV. No detection of chikungunya or Zika virus was confirmed. Among the patients tested, 8 (53%) were male and 7 (47%) female; mean age was 34 (range 13–76) years. In the confirmed cases of DENV, the average age was 36 (range 13–51) years, 4 (57%) were male, and 3 (43%) were female ( Table ). The 7 confirmed DENV cases were linked to residents from Niamey, the capital city of Niger, and had no reported travel history outside the county. The detection of DENV serotypes was successful in 4 of the positive samples; 2 were DENV-1 and 2 DENV-3. Serotyping was not possible for the other 3 samples because of low viral levels ( Table ). The 7 cases, both hospitalized and ambulatory, recovered from the DENV infection without any severe complications.

After the official notification to the National Health Authorities, public health actions were implemented to contain the spread of the virus. An investigation team was dispatched by the Ministry of Health to investigate all confirmed cases of dengue fever. Prevention and control measures were put into place, namely awareness raising at the community level and awareness raising and training of healthcare personnel on the diagnosis and management of dengue fever. An entomologic survey was also conducted around patients’ residences and hospitalization facilities, but 2 Aedes spp. mosquitoes captured and tested yielded no positive results for dengue, chikungunya, or Zika viruses.

In conclusion, we describe 7 indigenous cases of dengue fever in Niger. Dengue fever cases are underreported in Africa, where it is often misdiagnosed as malaria ( 1 ). Misdiagnosis and underreporting highlights the need to train healthcare staff on the recognition and diagnosis of dengue fever. Strong vector control measures are also beneficial for containing the spread of dengue fever ( 4 ).

Dr. Idé Amadou works as a researcher with the Centre de Recherche Medicale et Sanitaire. Her interests include field epidemiology, pediatrics, and health emergencies.

Acknowledgments

We thank the medical staff who were engaged in patient care and the patients for participation in this study.

Author contributions: conceptualization (H.I.A., S.M., I.M.L., and A.L.); experiments and testing (I.I.A., S.A., B.A., and A.L.); field investigations (H.I.A. and S.M.); formal analysis (H.I.A., A.O., I.M.L., and A.L.); writing (H.I.A., S.M., and A.L.); review and editing (H.I.A., S.M., I.I.A., A.O., I.M.L., and A.L.). All authors read and approved the final version of the manuscript.

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• Table . Clinical and paraclinical characteristics of indigenous dengue confirmed patients in Niamey, Niger, October 2023

Suggested citation for this article : Idé Amadou H, Moussa S, Arzika II, Ousmane H, Amadou S, Aoula B, et al. Emergence of indigenous dengue fever, Niger, October 2023. Emerg Infect Dis. 2024 Jul [ date cited ]. https://doi.org/10.3201/eid3007.240301

DOI: 10.3201/eid3007.240301

Original Publication Date: May 23, 2024

Table of Contents – Volume 30, Number 7—July 2024

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Dengue fever.

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• Continuing Education Activity

Dengue is a mosquito-transmitted virus, and dengue fever is the leading cause of arthropod-borne viral disease worldwide, posing a significant global health concern. This disease is also known by various monikers, such as breakbone or 7-day fever, and is characterized by intense muscle spasms, joint pain, and high fever, reflecting both the severity and the duration of symptoms. Most dengue virus cases are asymptomatic, yet severe illness and mortality can occur, especially in regions where female  Aedes mosquitoes— Aedes aegypti and Aedes albopictus —primarily transmit the virus. Dengue fever, with over 100 million cases annually and 20 to 25,000 deaths, presents a substantial public health challenge, marked by epidemics across different regions globally. Diagnosis usually entails identifying virus antigens using diverse laboratory techniques. 

This activity explores the epidemiology of dengue fever, highlighting the increasing incidence observed in tropical and subtropical regions over recent decades, with some areas becoming endemic. This activity also analyzes the complexities of dengue hemorrhagic fever—a severe complication occurring in individuals previously infected with a dengue virus subspecies and subsequently infected with another. In addition, this activity aids clinicians in understanding the etiology, clinical presentation, diagnostic approaches, and management strategies for both dengue fever and dengue hemorrhagic fever, essential for effectively evaluating and addressing this global health threat and providing care to affected individuals.

• Identify the clinical manifestations and symptoms of dengue fever.
• Screen patients for dengue fever based on presenting symptoms, travel history, and exposure risk.
• Apply evidence-based treatment protocols for managing dengue fever, including fluid repletion and symptom management.
• Collaborate with interprofessional healthcare providers, including infectious disease specialists and public health authorities, to manage dengue virus outbreaks and improve patient outcomes.
• Introduction

Dengue is a mosquito-transmitted virus and is the leading cause of arthropod-borne viral disease worldwide, posing a significant global health concern. This disease is also known by various monikers, such as breakbone or 7-day fever, and is characterized by intense muscle spasms, joint pain, and high fever, reflecting both the severity and the duration of symptoms. Although most dengue fever cases are asymptomatic, severe illness and mortality can occur.  Aedes mosquitoes, primarily including the female vectors Aedes aegypti and A albopictus , transmit the virus and are common in tropical and subtropical parts of the world.

The incidence of dengue fever has increased dramatically over the past few decades, and the infection is now endemic in some parts of the world, possibly due to increased global travel. Dengue fever poses a significant public health challenge, with over 100 million cases annually and 20 to 25,000 deaths, marked by epidemics across different regions globally. After infection with a subspecies known as dengue hemorrhagic fever (DHF), some individuals previously infected with one subspecies of the dengue virus (DENV) develop severe capillary permeability and bleeding. [1] [2] [3]  Although the symptoms and signs overlap with several viral prodromes, the identifying features are discussed in the next sections.

Dengue fever is caused by any of the 4 distinct serotypes (DENV-1 to DENV-4) of single-stranded RNA viruses belonging to the genus Flavivirus . Infection by one serotype confers lifelong immunity to that serotype but not to others. [4] [5] [6]

• Epidemiology

Dengue fever is the fastest-spreading mosquito-borne viral disease worldwide, affecting over 100 million people annually. This disease also leads to 20 to 25,000 deaths, primarily among children, and is prevalent in more than 100 countries. Epidemics occur yearly in the Americas, Asia, Africa, and Australia.

The dengue virus is maintained by the following 2 transmission cycles:

• Mosquitoes carry the virus from a nonhuman primate to another nonhuman primate
• Mosquitoes transmit the virus from human to human

The human-mosquito cycle primarily occurs in urban environments. Whether the virus transmits from affected humans to mosquitoes depends on the viral load of the mosquitoes' blood meal. The primary vectors of the disease are female mosquitoes of the species Aedes aegypti and Aedes albopictus . Although A aegypti is associated with most infections, the geographic range of A albopictus is expanding. A albopictus , being more cold-tolerant, exhibits aggressive feeding behavior but does so less frequently, which may contribute to its increasing numbers. These mosquito species typically inhabit indoor environments and are active during the day. Modes of transmission include perinatal transmission, blood transfusions, breast milk, and organ transplantation. 

Between 1990 and 2010, the mean age of patients was 27.2, which has increased to 34 since 2010. The dengue viral serotype causing disease outbreaks has varied over time, along with the occurrence of severe dengue fever. [7] [8] Transmission of the dengue virus generally follows 2 patterns—epidemic dengue and hyperendemic dengue.

Epidemic dengue occurs when a single strain of dengue virus (DENV) is responsible for introduction and transmission, and such epidemics were more common before World War II. During epidemics, all age groups are affected, but the incidence of DHF is relatively low. Hyperendemicity, on the other hand, refers to the co-circulation of various serotypes of DENV in a community linked to periodic outbreaks. [9] In hyperendemic areas, children are affected more than adults, and the incidence of DHF is relatively higher.

• Pathophysiology

Belonging to the Flaviviridae family, the dengue virus is a 50-nm virion comprising 3 structural and 7 nonstructural proteins, a lipid envelope, and a 10.7-kb-capped positive-sense single strand of RNA. Infections are asymptomatic in up to 75% of affected individuals. The disease spectrum ranges from self-limiting dengue fever to severe hemorrhage and shock. A fraction of infections, between 0.5% and 5%, develop into severe dengue. Without proper treatment, fatality rates may exceed 20%, particularly among children. The typical incubation period for the disease is 4 to 7 days, with symptoms lasting from 3 to 10 days. Symptoms appearing more than 2 weeks after exposure are unlikely to be attributed to dengue fever. 

The consequences of a mosquito bite injecting the dengue virus into the skin remain unclear. Skin macrophages and dendritic cells are believed to be the initial targets. These infected cells are thought to migrate to the lymph nodes and disseminate through the lymphatic system to other organs. Viremia, the presence of the virus in the bloodstream, may occur for 24 to 48 hours before the onset of symptoms.

The presentation of dengue fever, whether asymptomatic, typical, or severe, is influenced by a complex interplay of host and viral factors. Severe dengue fever, characterized by heightened microvascular permeability and shock syndrome, is often associated with infection by a second dengue virus serotype and the patient's immune response. However, severe cases of dengue fever can also arise from infection by a single serotype. Interestingly, microvascular permeability tends to escalate as viral titers decrease.

• History and Physical

The 3 phases of dengue fever include febrile, critical, and recovery stages (see Image. Primary Symptoms of Dengue Fever).

The febrile phase:  During the febrile phase, individuals typically experience a sudden onset of high-grade fever, reaching approximately 40 °C, which usually lasts for 2 to 7 days. Approximately 6% of cases may exhibit saddleback or biphasic fever, particularly in patients with DHF and severe dengue fever. The fever usually persists for at least 24 hours, followed by a subsequent spike lasting at least 1 more day. [10] Associated symptoms during this phase include facial flushing, skin erythema, myalgias, arthralgias, headache, sore throat, conjunctival injection, anorexia, nausea, and vomiting. Skin erythema manifests as a general blanchable macular rash within 1 to 2 days of fever onset and again on the last day. Alternatively, within 24 hours, a secondary maculopapular rash may develop.

The critical phase:  During the critical phase, defervescence marks a period when the temperature typically decreases to approximately 37.5 to 38 °C or lower, occurring between days 3 and 7. This phase is associated with heightened capillary permeability and typically lasts for 1 to 2 days. Before the critical phase, there is often a rapid decline in platelet count, accompanied by increased hematocrit levels. Leukopenia may also occur up to 24 hours before the platelet count drops and warning signs emerge. If left untreated, the critical phase can progress to shock, organ dysfunction, disseminated intravascular coagulation, or hemorrhage.

The recovery phase: The recovery phase involves the gradual reabsorption of extravascular fluid over 2 to 3 days. During this period, patients often exhibit bradycardia.

Expanded dengue virus syndrome refers to unusual or atypical manifestations seen in patients with involvement of various organs such as neurological, hepatic, and renal. This syndrome can be associated with profound shock. Neurological manifestations may include febrile seizures in young children, encephalitis, aseptic meningitis, and intracranial bleeding. Gastrointestinal involvement might present as hepatitis, liver failure, pancreatitis, or acalculous cholecystitis. In addition, this syndrome can manifest as myocarditis, pericarditis, acute respiratory distress syndrome, acute kidney injury, or hemolytic uremic syndrome.

Common laboratory findings include thrombocytopenia, leukopenia, and elevated levels of aspartate aminotransferase. The disease is classified as either dengue or severe dengue. [11] [12] [13]

• Probable dengue: The patient lives in or has traveled to a Dengue-endemic area. Symptoms include fever and 2 of the following: nausea, vomiting, rash, myalgias, arthralgias, rash, positive tourniquet test, or leukopenia.
• Warning signs of dengue:  Dengue symptoms include abdominal pain, persistent vomiting, clinical fluid accumulation such as ascites or pleural effusion, mucosal bleeding, lethargy, liver enlargement greater than 2 cm, increase in hematocrit, and thrombocytopenia.
• Severe dengue:  Severe dengue is characterized by dengue fever accompanied by severe plasma leakage, hemorrhage, impaired consciousness, myocardial dysfunction, pulmonary dysfunction, and organ dysfunction, including transaminitis greater than 1000 IU/L.
• Dengue shock syndrome clinical warnings: Symptoms include rapidly rising hematocrit, intense abdominal pain, persistent vomiting, and narrowed or absent blood pressure.

The virus antigen can be detected using enzyme-linked immunosorbent assay (ELISA) test, polymerase chain reaction (PCR), or by isolating the virus from body fluids. Serology typically shows a significant increase in immunoglobulins. A confirmed diagnosis is established through culture, antigen detection, PCR, or serologic testing. Notably, it is crucial to evaluate pregnant patients with dengue carefully, as the symptoms can resemble those of preeclampsia.

• Treatment / Management

The treatment approach for dengue fever varies depending on the patient's illness phase. Patients without warning signs can typically be treated as outpatients with acetaminophen and sufficient oral fluids. In addition, educating patients about the warning signs and advising them to seek immediate medical attention if any of these signs occur is important.

Patients presenting with warning signs of the disease, severe dengue fever, or having risk factors such as age, pregnancy status, diabetes mellitus, or those who are living alone should be evaluated for hospitalization. Individuals displaying warning signs can be started on intravenous (IV) crystalloids, with the fluid rate adjusted based on the patient's response. Patients in shock and not responding to initial crystalloid boluses may require colloids.

Blood transfusion is indicated in cases of severe or suspected bleeding when the patient remains unstable despite adequate fluid resuscitation and hematocrit falls. Platelet transfusion may be necessary if the platelet count drops below 20,000 cells per microliter and there is a high risk of bleeding. Notably, it is essential to avoid administering aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and other anticoagulants. No antiviral medications are recommended, and no laboratory tests can reliably predict the progression to severe disease.

• Differential Diagnosis

The clinical diagnosis of dengue fever can be challenging as many other illnesses can present similarly early in the disease course. Other differential diagnoses include measles, influenza, and mosquito-vector diseases such as Zika virus disease, West Nile infection, chikungunya, malaria, and yellow fever (see Image. Mosquito-Borne Diseases).

Obtaining a detailed history of immunizations, travel, and exposures is crucial for the diagnosis of dengue fever. Rapid laboratory identification of the dengue virus involves NS1 antigen detection and serological tests. Serological tests are only helpful after several days of infection and may yield false positives due to other Flavivirus infections, such as yellow fever or Zika virus.

Untreated severe dengue fever may have a mortality rate of 10% to 20%. However, with appropriate supportive care, the mortality rate can be reduced to approximately 1%.

• Complications

Complications of dengue fever may include liver injury, cardiomyopathy, pneumonia, orchitis, oophoritis, seizures, encephalopathy, and encephalitis.

• Postoperative and Rehabilitation Care

Patients should be encouraged to drink plenty of fluids. The return of appetite in a patient is a sign that the infection is subsiding.

• Consultations

Consulting an infectious disease specialist is recommended, as many clinicians have limited experience managing this infection. The Centers for Disease Control and Prevention (CDC) also provides a hotline offering treatment advice.

• Deterrence and Patient Education

The only way to avoid contracting dengue virus is to prevent mosquito bites and avoid endemic areas.

Preventative Measures

• Using bed nets from daytime onward.
• Utilizing insecticide-treated materials such as window curtains.
• Applying mosquito-repellant creams containing DEET, IR3535, or icaridin.
• Using mosquito-repellant coils.
• Developing the habit of wearing long-sleeved shirts and pants. [14]

Biological Control

• Fish: Introducing viviparous species of fish, such as Poecilia reticulata , into confined water bodies such as large water tanks or open freshwater wells, and utilizing native larvicidal fish.
• Predatory copepods: Implementing small freshwater crustaceans as effective predators, particularly in specific container habitats.
• Endosymbiotic control: Utilizing mosquitoes infected with Wolbachia, an intracellular parasite, as they demonstrate reduced susceptibility to DENV infection compared to wild-type mosquitoes  A aegypti . [15]

Chemical Control 

• Using larvicidal in big breeding containers.
• Applying insecticide sprays via space sprays, which can be administered as thermal fogs or cold aerosols.
• Using oil-based formulations, as they inhibit evaporation
• Using a few common insecticides such as organophosphorus compounds (fenitrothion and malathion) and pyrethroids (bioresmethrin and cypermethrin).

Environmental Measures

• Identifying and eliminating the breeding areas of mosquitoes and pests.
• Maintaining the rooftops and sunshades properly.
• Covering stored water in buckets, pots, and other vessels appropriately.

Health Education

Educating individuals about the dengue virus is crucial for effective public health interventions. Utilizing audiovisual and mass awareness campaigns can serve as initial steps in disseminating knowledge about the virus, which can be implemented at both individual and population levels. 

Vaccination

CYD-TDV, the first licensed live recombinant tetravalent dengue vaccine, is approved for use in endemic areas across 20 countries. [16]

• Enhancing Healthcare Team Outcomes

Diagnosing and managing dengue fever involve a multidisciplinary team of healthcare professionals comprising an infectious disease expert, a CDC consultant, an emergency department clinician, and an internist. Treatment primarily focuses on supportive care, including fluid repletion, acetaminophen for fever management, and blood transfusion if hemorrhage occurs. A confirmed diagnosis is established through various methods such as culture, antigen detection, polymerase chain reaction, or serologic testing.

Laboratory tests cannot reliably predict the progression to severe disease. Primary care clinicians and nurse practitioners play a crucial role in educating travelers on preventing mosquito bites and adopting preventive measures such as covering their exposed skin, using bed nets, mosquito repellents, and indoor insecticides, as well as eliminating mosquito breeding grounds such as standing water. While the prognosis for untreated dengue fever is poor, most patients can survive with supportive care, although some may experience residual multisystem organ damage. [17] [18]

• Review Questions
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• Comment on this article.

Primary Symptoms of Dengue Fever. The symptoms of dengue fever are multisystemic and encompass 3 distinct phases: febrile, critical, and recovery. Mikael Häggström, Public Domain, via Wikimedia Commons.

Mosquito-Borne Diseases. Mosquitoes are carriers of various diseases, including Zika, dengue fever, West Nile fever, chikungunya, yellow fever, and malaria. National Institute of Allergy and Infectious Diseases, National Institutes of Health

Disclosure: Timothy Schaefer declares no relevant financial relationships with ineligible companies.

Disclosure: Prasan Panda declares no relevant financial relationships with ineligible companies.

Disclosure: Robert Wolford declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Schaefer TJ, Panda PK, Wolford RW. Dengue Fever. [Updated 2024 Mar 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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