dengue research papers

A Multi-Perspective Review on Dengue Research

Affiliation.

• 1 Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Mohali, India.
• PMID: 31339068
• 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..

Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Publication types

• Antiviral Agents / pharmacology
• Antiviral Agents / therapeutic use*
• Carica / chemistry
• Clinical Trials as Topic
• Computer-Aided Design
• Dengue / immunology
• Dengue / therapy*
• Dengue / virology
• Dengue Vaccines / immunology
• Dengue Vaccines / therapeutic use*
• Dengue Virus / drug effects
• Dengue Virus / immunology*
• Drug Development / trends*
• Endemic Diseases / prevention & control
• Molecular Targeted Therapy / methods
• Plant Extracts / therapeutic use
• Plant Leaves / chemistry
• Viral Proteins / antagonists & inhibitors
• Viral Proteins / metabolism
• Yellow fever virus / immunology
• Antiviral Agents
• Dengue Vaccines
• Plant Extracts
• Viral Proteins

• 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.

Peer Review reports

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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Additional file 1: appendix s1..

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Additional file 3: Appendix S3.

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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 infection in India: A systematic review and meta-analysis

Parasuraman ganeshkumar.

1 Department of Epidemiology, National Institute of Epidemiology, Chennai, Tamil Nadu, India

Manoj V. Murhekar

Veeraraghavadoss poornima.

2 School of Public Health, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Velusamy Saravanakumar

Krishnendu sukumaran, anandan anandaselvasankar.

3 Campbell Collaboration, New Delhi, India

Sanjay M. Mehendale

4 Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India

Associated Data

All relevant data are within the paper and its Supporting Information files.

Introduction

Dengue is the most extensively spread mosquito-borne disease; endemic in more than 100 countries. Information about dengue disease burden, its prevalence, incidence and geographic distribution is critical in planning appropriate control measures against dengue fever. We conducted a systematic review and meta-analysis of dengue fever in India

We searched for studies published until 2017 reporting the incidence, the prevalence or case fatality of dengue in India. Our primary outcomes were (a) prevalence of laboratory confirmed dengue infection among clinically suspected patients, (b) seroprevalence in the general population and (c) case fatality ratio among laboratory confirmed dengue patients. We used binomial–normal mixed effects regression model to estimate the pooled proportion of dengue infections. Forest plots were used to display pooled estimates. The metafor package of R software was used to conduct meta-analysis.

Of the 2285 identified articles on dengue, we included 233 in the analysis wherein 180 reported prevalence of laboratory confirmed dengue infection, seven reported seroprevalence as evidenced by IgG or neutralizing antibodies against dengue and 77 reported case fatality. The overall estimate of the prevalence of laboratory confirmed dengue infection among clinically suspected patients was 38.3% (95% CI: 34.8%–41.8%). The pooled estimate of dengue seroprevalence in the general population and CFR among laboratory confirmed patients was 56.9% (95% CI: 37.5–74.4) and 2.6% (95% CI: 2–3.4) respectively. There was significant heterogeneity in reported outcomes (p-values<0.001).

Conclusions

Identified gaps in the understanding of dengue epidemiology in India emphasize the need to initiate community-based cohort studies representing different geographic regions to generate reliable estimates of age-specific incidence of dengue and studies to generate dengue seroprevalence data in the country.

Author summary

Dengue fever, an extensively spread mosquito-borne disease, is endemic in more than 100 countries. Information about dengue disease burden, its prevalence and incidence and geographic distribution is necessary to guide in planning appropriate control measures including the dengue vaccine that has recently been licensed in a few countries. We performed a systematic review and meta-analysis of published studies in India on dengue. The overall estimate of the prevalence of laboratory confirmed dengue infection based on testing of more than 200,000 clinically suspected patients from 180 Indian studies was 38.3%. The pooled estimate of dengue seroprevalence in the general population and CFR among laboratory confirmed dengue patients was 56.9% and 2.6% respectively. There were no community-based studies reporting incidence of dengue. Our review also identified certain knowledge gaps about dengue epidemiology in the country. Identified gaps in the understanding of dengue epidemiology in India emphasize the need to initiate community-based cohort studies representing different geographic regions to generate reliable estimates of age-specific incidence of dengue and studies to generate dengue seroprevalence data in the country.

Dengue is the most extensively spread mosquito-borne disease, transmitted by infected mosquitoes of Aedes species. Dengue infection in humans results from four dengue virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) of Flavivirus genus. As per the WHO 1997 classification, symptomatic dengue virus infection has been classified into dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). The revised WHO classification of 2009 categorizes dengue patients according to different levels of severity as dengue without warning signs, dengue with warning signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing haematocrit with decreasing platelets) and severe dengue [ 1 , 2 , 3 ]. Dengue fever is endemic in more than 100 countries with most cases reported from the Americas, South-East Asia and Western Pacific regions of WHO [ 1 ]. In India, dengue is endemic in almost all states and is the leading cause of hospitalization. Dengue fever had a predominant urban distribution a few decades earlier, but is now also reported from peri-urban as well as rural areas [ 4 , 5 ]. Surveillance for dengue fever in India is conducted through a network of more than 600 sentinel hospitals under the National Vector Borne Disease Control Program (NVBDCP) [ 6 ], Integrated Disease Surveillance Program (IDSP) [ 7 ] and a network of 52 Virus Research and Diagnostic Laboratories (VRDL) established by Department of Health Research [ 8 ]. In 2010, an estimated 33 million cases had occurred in the country [ 9 ]. During 2016, the NVBDCP reported more than 100,000 laboratory confirmed cases of dengue [ 6 ]. It is therefore possible that dengue disease burden is grossly under-estimated in India.

High dengue disease burden and frequent outbreaks result in a serious drain on country’s economy and stress on the health systems. In India, case detection, case management, and vector control are the main strategies for prevention and control of dengue virus transmission [ 6 ]. A new dengue vaccine is now available and several vaccines are in the process of development [ 10 , 11 , 12 ]. Information about dengue disease burden, its prevalence, incidence and geographic distribution is necessary in decisions on appropriate utilization of existing and emerging prevention and control strategies. With this background, we conducted a systematic review and meta-analysis to estimate the disease burden of dengue fever in India. We also reviewed serotype distribution of dengue viruses in circulation, and estimated case fatality ratios as well as proportion of secondary infections.

Search strategy and selection criteria

This systematic review is registered in PROSPERO (Reg. No. CRD 42017065625). We searched Medline (PubMed), Cochrane Central, WHOLIS, Scopus, Science Direct, Ovid, Google Scholar, POPLINE, Cost-Effectiveness Analysis (CEA) Registry and Paediatric Economic Database Evaluation (PEDE) databases for articles published up to 2017. The main search terms included incidence, prevalence, number of reported cases, mortality, disease burden, cost of illness, or economic burden of dengue in India. The complete search strategy is described in S1 Appendix . Back referencing of included studies in bibliography was also done to identify additional studies.

Review approach

The search results were initially imported to Zotero software (Version 4.0.29.5) and duplicate records were removed. During title screening, we examined relevant studies from various databases. Our inclusion criterion was studies reporting dengue infection in India, not restricted to setting, design, purpose and population. Titles thus selected were subjected to abstract screening. Studies were considered eligible for further examination in full text if their abstracts reported incidence, prevalence, number of reported cases, mortality or the burden of dengue fever anywhere in India. Studies reporting complications of dengue, serotype details of dengue virus as well as seroprevalence of dengue were also included. Using a pre-designed data extraction form, two reviewers extracted details from selected studies independently. The data, which differed between the reviewers, were resolved by consensus. Information about the year of publication, study setting (hospital/laboratory based, or community-based), study location, study period, laboratory investigations, number of suspected patients tested and positives, age distribution of cases, and details of dengue serotypes were abstracted ( S1 Dataset ).

The primary outcome measures of interest were (a) prevalence (proportion) of laboratory confirmed dengue infection among clinically suspected patients in hospital/laboratory based or community-based studies, (b) seroprevalence of dengue in the general population and (c) case fatality ratio among laboratory confirmed dengue patients. The diagnosis of acute dengue infection among the clinically suspected patients was based on any of the following laboratory criteria: (a) detection of non-structural protein-1 (NS1) antigen, (b) Immunoglobulin M (IgM) antibodies against dengue virus (c) haemagglutination inhibition (HI) antibodies against dengue virus, (d) Real-time polymerase chain reaction (RT-PCR) positivity or (e) virus isolation. Seroprevalence of dengue was based on detection of IgG or neutralizing antibodies against dengue virus. Studies providing prevalence (proportion) of laboratory confirmed dengue infection among clinically suspected patients were classified into (a) hospital/laboratory-based surveillance studies and (b) outbreak investigations or hospital/laboratory-based surveillance studies when the outbreak was ongoing in the area, as mentioned in the original research paper. Studies regarding outbreak investigations considered an increase in number of reported cases of febrile illness in a geographical area, as the criteria for defining an outbreak. The outbreak investigations included one or more of the following activities: active search for case-patients in the community, calculation of attack rates for suspected case-patients, confirmation of aetiology and entomological investigations. For the case fatality ratio, the numerator included reported number of deaths due to dengue and denominator as laboratory confirmed dengue patients.

Our secondary outcomes of interest were the following: (a) proportion of primary and secondary infections among the laboratory confirmed dengue patients. This classification was made based on the information about dengue serology provided in the paper. Primary dengue infection was defined as acute infection, as indicated by qualitative detection of NS1 antigen, and/or IgM or HI antibodies or RT-PCR positivity and absence of IgG antibodies against dengue virus. A case of acute infection as defined above, in presence of IgG antibodies, was considered as secondary dengue infection [ 2 , 13 , 14 ]. Some of the studies used the ratio of IgG to IgM antibodies as the criteria for differentiating primary and secondary infections [ 14 ]; (b) distribution of predominant and co-circulating dengue virus serotypes; (c) proportion of severe dengue infections based on WHO 1997 or WHO 2009 criteria [ 1 , 2 ]. The category of severe dengue infection included patients with DHF and DSS as per the WHO 1997 classification as well as severe dengue infections classified as per the WHO 2009 classification and (d) cost of illness, which included reported direct and indirect costs associated with dengue hospitalization.

Risk of bias

The risk of bias was assessed using a modified Joanna Briggs Institute (JBI) appraisal checklist for studies reporting prevalence data [ 15 ] and essential items listed in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [ 16 ]. The criteria for assessing bias primarily included methods for selecting participants, methods for laboratory testing, and outcome variables (Supplementary file S2 Appendix ).

Statistical analysis

We conducted quantitative synthesis to derive meta-estimates of primary and secondary outcomes (severity of disease and primary/ secondary infections) and qualitative synthesis to describe the serotype distribution and economic burden due to dengue. We followed Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [ 17 ]. For each study, primary outcomes (prevalence of acute infection, seroprevalence and CFR) were summarized as proportion and their 95% confidence intervals were computed. We used logit and inverse logit transformations for variance stabilization of proportions [ 18 ]. Binomial–Normal mixed effects regression model was used to estimate the pooled proportion of dengue infections. Forest plots were used to display pooled estimates. Heterogeneity was tested using likelihood ratio test. Funnel plots with logit prevalence on x-axis and standard errors on y-axis and Egger’s test were used to evaluate publication bias. Independent variables potentially associated with the prevalence of laboratory confirmed dengue were included as fixed-effects in univariate and multivariate binomial meta-regression models. P <0.05 was considered statistically significant. Sensitivity analysis was carried out by leaving out one study at a time in the order of publication to check for consistency of pooled estimates. Analyses were performed in the R statistical programming language using the ‘metafor’ package [ 19 , 20 ].

Characteristics of included studies

The search strategy initially identified 2,285 articles from different databases. After removal of duplicates, 1,259 articles were considered for title and abstract screening. Seven hundred and forty-six articles were excluded for reasons provided in Fig 1 . Thus, 513 articles were found to be eligible for full-text review. After the review of full-text articles, 233 studies were included for the analysis [ 21 – 253 ]. The details of the studies included in the review are provided in the PRISMA flowchart ( Fig 1 ). None of the studies reported incidence of dengue fever.

Primary outcomes

Prevalence (proportion) of laboratory confirmed dengue fever.

Of the 233 studies included in the analysis, 180 provided information about proportion of laboratory confirmed dengue cases among clinically suspected patients [ 21 – 200 ]. This included 154 studies conducted in hospital or laboratory setting [ 21 – 174 ] and 26 studies reporting outbreak investigations [ 175 – 200 ]. Of the 154 studies conducted in hospital/ laboratory setting, 40 were conducted when an outbreak was ongoing in the area [ 135 – 74 ]. The diagnosis of acute dengue infection was based on a single assay in 86 studies (IgM antibodies = 68, RT-PCR = 11, HI antibodies = 4, virus isolation = 2, detection of NS1 antigen = 1) and more than one assay in 95 studies.

Case definitions used : Of the 154 studies conducted in hospital settings, WHO or NVBDCP case definitions were used by 39 and 2 studies respectively. The remaining studies used case definitions such as acute febrile illness/acute undifferentiated illness (n = 20), and clinically suspected dengue fever (n = 93). Similarly, of the 26 reported outbreaks, investigators used WHO or NVBDCP case definitions in 7 and 2 settings respectively, whereas acute febrile illness and clinically suspected dengue fever case definitions were used in 5 and 12 settings respectively.

Place and time distribution of studies : Of the 154 studies conducted in hospital setting, 75, 41, 27 and 7 were from north, south, east and western Indian states respectively, whereas 3 studies were from north-eastern states. One study reported data from VRDL network, covering multiple regions in India [ 65 ]. Of the 26 outbreaks, most (10, 38.5%) were reported from Southern states, followed by 9 (34.6%) in the north, 4 (15.4%) in the east, and 3 (11.5%) in the north-eastern Indian states. Most (65, 42.2%) studies conducted in hospital settings were between 2011–2017, while 48 (31.2%) were conducted between 2006–2010 and 41 (26.6%) were conducted before 2006. Eighteen (69.2%) of the 26 outbreaks were reported after 2000.

Of the 180 studies which reported proportion of dengue cases, 74 studies (30%) provided the details of laboratory confirmed cases by month with most (n = 60, 81%) reporting higher dengue positivity between August and November months.

Age distribution of dengue cases : The age distribution of laboratory confirmed dengue patients was available from 52 out of 180 studies. The pooled median age of laboratory confirmed dengue cases in these studies was 22 years ( Fig 2 ). Fifteen (28.8%) studies reported the median age of dengue cases below 15 years.

Estimates of prevalence (proportion) : The overall estimate of the prevalence of laboratory confirmed dengue infection in the random effects model based on testing of 213,285 clinically suspected patients from 180 studies was 38.3% (95% CI: 34.8%–41.8%) ( Fig 3 ). There was a significant heterogeneity in the prevalence reported by the 180 studies (LRT p<0.001). The prevalence of laboratory confirmed dengue infection was higher in studies reporting outbreaks or hospital-based surveillance studies during outbreaks (47.3%, 95% CI: 40.9–53.8) as compared to hospital-based surveillance studies (33.6%, 95% CI: 29.9–37.5) ( S1A and S1B Fig ). The attack rates of suspected dengue case patients were available in 8 out of the 26 outbreak investigations reports. The attack rates ranged between 1.9% and 19.5%.

Error bars indicate 95% confidence intervals. Diamonds show the pooled estimates with 95% confidence intervals based on random effects (RE) model.

In the univariate mixed effect meta-regression model, odds of laboratory confirmation were higher in case of outbreaks or hospital-based studies conducted during outbreaks (OR = 1.8, 95% CI: 1.3–2.4). Studies which used WHO/ NVBDCP case definitions for enrolment of patients also had higher odds of detecting laboratory confirmed dengue compared to studies which used acute febrile illness/ clinically suspected dengue cases as case definitions. Compared to studies conducted before 2006–10, studies conducted between 2011 and 2017 had higher odds of identifying laboratory confirmed patients (OR = 1.33, 95% CI: 0.93–1.9). The odds of laboratory confirmation did not differ by region ( Table 1 ). In the multivariate meta-regression model constructed by including all covariates, case definition (WHO/NVBDCP), type of study (hospital-based surveillance studies conducted during outbreaks or outbreaks) and period of study (prior to 2005 and 2011–2017) were associated with higher odds of dengue cases being laboratory confirmed.

Ref—Reference category; CI—Confidence interval; P*–P value.

Seroprevalence of dengue among healthy individuals

We included 7 studies reporting seroprevalence of dengue based on detection of IgG (n = 5), neutralizing antibodies (n = 1) or HI antibodies (n = 1) against dengue in the analysis [ 201 – 207 ]. These studies, conducted in 12 Indian states [Andaman and Nicobar islands (n = 1), Andhra Pradesh (n = 2), Tamil Nadu (n = 3), Delhi (n = 4), West Bengal (n = 1), and Maharashtra (n = 1)], surveyed 6,551 individuals. The study population surveyed in these studies included healthy children (n = 2), general population (n = 3), blood donors (n = 1) and neighbourhood contacts of dengue confirmed cases (n = 1). The overall seroprevalence of dengue fever based on these studies was 56.9% (95% CI: 37.5–74.4) ( Fig 4 ). The age-specific prevalence of IgG antibodies was available in three studies [ 201 , 204 , 206 ]. There was a significant heterogeneity in the seroprevalence reported by the seven studies (LRT p<0.001). In the 3 studies which provided age specific seroprevalence, by the age of 9 years, 47.6% -73.4% children were reported to have developed IgG or neutralizing antibodies against dengue ( Table 2 ).

Figure in square bracket indicate reference

Case fatality ratios (CFR)

Seventy-seven studies provided information about case fatality ratios; most of them (n = 72, 93.5%) were conducted after 2000. The reported CFRs in these studies ranged from 0% to 25%. There was a significant heterogeneity in the CFRs reported by the 74 studies (LRT p<0.001). Twenty (25.9%) studies reported CFR of 2% or more. Three studies [ 30 , 239 , 195 ] which affected overall meta-estimates due to small denominator and hence were excluded from analysis. The pooled estimate of CFR was 2.6% (95% CI: 2.0–3.4) ( Fig 5 ).

Secondary outcomes

Primary and secondary dengue infection.

A total of 49 studies provided data which enabled classification of laboratory confirmed dengue into primary and secondary dengue infections. The number of patients with acute dengue infections in these studies ranged between 13 and 1752. Only two studies estimated the proportion of secondary infection based on IgG to IgM ratio [ 174 , 237 ]. The prevalence of secondary dengue infection was <10% in 6 studies, 10–25% in 9 studies, 26–50% in 12 studies, 51–75% in 17 studies and >75% in 5 studies. The overall proportion of secondary dengue infection among laboratory confirmed patients was 42.9% (95%CI: 33.7–52.6) ( Fig 6 ).

Proportion of severe cases

Information about severity of dengue was available in 49 studies. Most studies (n = 46, 93.9%) used the WHO 1997 classification while 3 studies used the WHO 2009 classification for dengue severity. The reported proportion of severe dengue cases among laboratory confirmed patients ranged between 1.4% and 97.4%. The overall proportion of severe dengue among laboratory confirmed studies in the random effects model was 28.9% (95% CI: 22.2–36.6) ( Fig 7 ).

Serotypes of dengue virus

Information about dengue serotypes was available in 51 studies. These studies were conducted in 19 Indian states; with a regional distribution of north (n = 28), south (n = 13), east (n = 4), northeast (n = 4), and west (n = 2). Thirty-eight (75%) of the 51 studies reported circulation of more than one serotype. The predominant serotypes reported in these studies were DEN-2 and DEN-1 in the northern region, DEN-2 and DEN-3 in the southern region, and DEN-1 and DEN-2 in the eastern and the western regions. In the four studies reported from the north-eastern region, the predominant serotypes was DEN-3 followed by DEN-1 and DEN-2 serotypes ( Table 3 ).

Key for coloured cell: Blue—One circulating serotype, Yellow—two co-circulating serotypes, Green—three co- circulating serotypes, Orange—four co- circulating serotypes. Numbers mentioned in the cell indicate predominant serotypes, in descending order.

Economic burden

Direct and Indirect cost analysis : An estimate of direct and indirect costs was reported in three studies. The average direct cost per case of dengue ranged between USD 23.5 and USD 161 and the indirect cost was around USD 25 whereas the average cost of hospitalization ranged between USD 186 and USD 432.2 [range 249 -252]. The cost of dengue treatment in the private health sector was two to four times higher than that in the public sector hospitals [ 249 , 253 ].

Economic impact of dengue on National Economy : Three macro-level studies addressed the economic impact of dengue faced by India [ 250 , 251 , 253 ]. It was estimated that the average total economic burden due to dengue in India was USD 27.4 million [ 251 ]. Another study estimated that the total direct medical cost of dengue in 2012 was USD 548 million [ 253 ]. The overall economic burden of dengue would be even higher if the cost borne by individual patients is combined with the society level cost of dengue prevention, vector control, disease control and its management, dengue surveillance as well as the cost of research and development [ 250 , 251 , 253 ].

Publication bias and sensitivity analysis

Funnel plots and Egger’s test revealed no publication bias in the estimates of dengue prevalence in hospital-based surveillance studies, hospital-based surveillance studies during outbreaks and outbreak investigations. CFR estimates, however, showed a significant publication bias, and studies with high prevalence were more likely to be published. In the sensitivity analysis, the estimated pooled proportions were found to be consistent for all study outcomes. ( S3 Appendix )

The present study has estimated the burden of dengue fever based on published literature from India spanning over five decades. Most of the published literature included in the analysis were hospital/ laboratory-based surveillance studies or reports of dengue outbreak investigations. Additionally the published data from VRDL network has been included in the analysis [ 65 , 96 ]. The data from the other two nationally representative surveillance platforms could not be used for the analysis because surveillance data from NVBDCP only reports the number of laboratory confirmed dengue cases, while the IDSP data is not available in the public domain.

There was no community-based epidemiological study reporting the incidence of dengue fever. Our analysis revealed that among the clinically suspected dengue fever patients, the estimated prevalence of laboratory-confirmed dengue infection was 38%. The burden of dengue was also variable in studies conducted in different settings. Our findings indicated that most of the laboratory confirmed dengue cases in India occurred in young adults. Dengue positivity was higher between the months of August and November, corresponding to monsoon and post-monsoon season in most states in India.

In the meta-regression, studies that had used WHO/NVBDCP case definitions and the hospital based studies conducted during outbreaks or studies reporting outbreaks were more likely to have laboratory confirmation of dengue. The odds of laboratory confirmation were also higher among studies conducted during the period of 2011 to 2017, as compared to studies conducted prior to the year 2000.

Information about seroprevalence of dengue in the general population is a useful indicator for measuring endemicity of dengue fever. The dengue vaccine (CYD-TDV) manufactured by Sanofi Pasteur has been introduced in two sub-national programs in Philippines and Brazil [ 254 ] and it has been suggested that vaccine acts by boosting the naturally acquired immunity [ 255 ]. WHO SAGE conditionally recommends the use of this vaccine for areas in which dengue is highly endemic as defined by seroprevalence in the population targeted for vaccination [ 12 , 256 ]. The results of the two vaccine trials and mathematical modelling suggest that optimal benefits of vaccination if seroprevalence in the age group targeted for vaccination was in the range of ≥70% [ 255 , 256 ]. In 2018, WHO revised the recommendation from population sero-prevalence criteria to pre-vaccination screening strategy [ 257 ]. The pooled estimate based on the seven studies conducted in India indicated a dengue seroprevalence of 57%. However, this estimated seroprevalence is not representative of the country, as these studies were conducted only in 12 Indian states, and some had used a convenience sampling method [ 201 ].

The computed pooled estimate of case fatality due to dengue in India was 2.6% with a high variability in the reported CFRs. The CFR estimated in our study was higher than the estimate of 1.14% (95% CI: 0.82–1.58) reported in the meta-analysis of 77 studies conducted globally; in the 69 studies which adopted WHO 1997 dengue case classification, the pooled CFR was 1.1% (0.8–1.6) while the pooled CFR for 8 studies which used the WHO 2009 case definition, the pooled CFR was 1.6% (95% CI: 0.64–4.0) [ 258 ]. Higher CFR observed in our analysis could be due to smaller sample sizes as 14 of the 35 studies that reported CFR of 2.6 or higher had a sample size of 100 or less, while in the remaining 21 studies the denominator ranging between 101 and 400. Also, we only considered laboratory confirmed dengue cases in the denominator for the calculation of CFR. As per the NVBDCP surveillance data, a total of 683,545 dengue cases and 2,576 deaths were reported in India during 2009–2017 giving a CFR of 0.38% [ 6 ]. The lower CFR estimates from NVBDCP data could probably be on account of under-reporting of deaths due to dengue, or inclusion of higher number of mild cases in the denominator [ 259 ]. As per the NVBDCP surveillance data, an average of 28,227 dengue cases and 154 deaths were reported annually during 2009–2012. The number of dengue cases reported increased thereafter, with an average of 100,690 cases per year during 2013–2017. However, the reported number of deaths did not increase proportionately. The information about severity of dengue cases is not available from NVBDCP surveillance data.

The published studies from India indicated circulation of all the four-dengue serotypes, with DEN-2 and DEN-3 being the more commonly reported serotypes. Two third of the studies reported circulation of more than one serotype. Co-circulation of multiple serotypes was particularly evident from the published studies in Delhi. More than two third (16/19) studies from Delhi reported circulation of more than one serotype; and most of the studies conducted in the last 10 years identified co-circulation of more than one serotype [ Table 3 ]. Our review also revealed that more than two-fifth of the laboratory confirmed infections were secondary dengue infections and nearly one-fourth of the cases were severe in nature. Circulation of numerous dengue serotypes is known to increase the probability of secondary infection, leading to a higher risk of severe dengue disease [ 260 ].

Our systematic review has certain limitations. First, our study included only peer-reviewed literature from selected databases and we excluded grey literature which may have provided additional data. Second, most of the studies on disease burden were hospital-based, with no community-based studies estimating incidence. Hospital-based studies do not provide any information about the community level transmission as hospitalization is a function of health-seeking behaviour of the population. In absence of the information about health seeking behaviour provided in these studies, we estimated the prevalence of dengue using number of patients tested in the hospitals as the denominator. Third, the hospital-based studies used varying case definitions and laboratory tests to confirm dengue infection. Fourth, information about the type of health facility (public or private), or residential status of patients (urban or rural), and age was not uniformly reported and hence we did not estimate the dengue prevalence by these variables.

In conclusion, the findings of our systematic review indicate that dengue continues to be an important public health problem in India, as evidenced by the high proportion of dengue positivity, severity and case fatality as well as co-circulation of multiple dengue virus serotypes. Our review also identified certain research gaps in the understanding on dengue epidemiology in the country. There is a need to initiate well planned community-based cohort studies representing different geographic regions of the country in order to generate reliable estimates of age-specific incidence of dengue fever in India. As such studies are cost intensive, a national level survey to estimate age-stratified dengue seroprevalence rates could be an alternative. Such estimates could be used to derive the relative proportions of primary and secondary infections using mathematical models [ 261 ]. Well planned studies in different geographic settings are also needed to generate reliable data about economic burden from India. Although the existing dengue surveillance platforms of NVBDCP, IDSP and VRDL are generating data about dengue disease burden, these systems could be strengthened to also generate data about dengue serotypes, severity, and primary and secondary infection from India.

Supporting information

S1 appendix, s2 appendix, s3 appendix, s1 checklist, funding statement.

The study was funded by the Department of Bio-technology, Govt of India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Research Article

Trends in dengue research in the Philippines: A systematic review

Roles Data curation, Writing – review & editing

Affiliation Institute of Child Health and Human Development, National Institutes of Health, University of the Philippines, Manila, Philippines

Roles Writing – review & editing

Roles Conceptualization, Data curation, Supervision, Writing – review & editing

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

* E-mail: [email protected]

• Kristal An Agrupis, 
• Michelle Ylade, 
• Josephine Aldaba, 
• Anna Lena Lopez, 
• Jacqueline Deen

• Published: April 25, 2019
• https://doi.org/10.1371/journal.pntd.0007280
• Reader Comments

Dengue is an important public health problem in the Philippines. We sought to describe the trends in dengue research in the country. We searched four databases and identified published studies on dengue research in the Philippines during the past 60 years. We reviewed 135 eligible studies, of which 33% were descriptive epidemiologic studies or case series, 16% were entomologic or vector control studies, 12% were studies on dengue virology and serologic response, 10% were socio-behavioral and economics studies, 8% were clinical trials, 7% were on burden of disease, 7% were investigations on markers of disease severity, 5% were on dengue diagnostics, and 2% were modeling studies. During the last decade, dengue research in the Philippines has increased and evolved from simple descriptive studies to those with more complex and diverse designs. We identified several key topics where more research would be useful.

Author summary

Dengue is a disease caused by four separate but related viruses transmitted by mosquitos. In this systematic review, we aimed to describe dengue research in the Philippines, where the disease is of great concern, to better understand the types of dengue research and the main findings and important gaps. We identified 135 studies that described dengue research in the Philippines during the past 60 years. Our review showed that in the early years, dengue studies were mainly simple descriptive studies and case reports. Recently the types of investigations have become more complex and diverse, reflecting advancement in local research capacity and infrastructure but more research activity would be beneficial in several areas.

Citation: Agrupis KA, Ylade M, Aldaba J, Lopez AL, Deen J (2019) Trends in dengue research in the Philippines: A systematic review. PLoS Negl Trop Dis 13(4): e0007280. https://doi.org/10.1371/journal.pntd.0007280

Editor: Benjamin Althouse, Institute for Disease Modeling, UNITED STATES

Received: November 6, 2018; Accepted: March 4, 2019; Published: April 25, 2019

Copyright: © 2019 Agrupis 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.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

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

Competing interests: No authors have competing interests.

Introduction

Dengue is a mosquito-borne, acute febrile illness that is an important public health problem in tropical countries. In the early 1950’s, the disease was described in the Philippines as hemorrhagic fever or infectious acute thrombocytopenic purpura [ 1 , 2 ]. Dengue continues to cause considerable concern in the country because of its widespread endemicity, the minimal success of vector control strategies, the possibility of severe disease caused by sequential infection by a different serotype, the potential for fatal outcomes and the consequent social and economic burden. The four dengue virus serotypes circulate in the country where the disease is predominantly reported among children [ 3 ].

Findings from dengue studies could provide policy-makers with information needed for rational decision-making regarding dengue preventive and control efforts. The focus of dengue research may vary widely. This could include basic laboratory research, the estimation of dengue seroprevalence and incidence; the assessment of risk factors for severe disease; the quantification of its economic burden; the elucidation of local transmission and epidemiology; the development of improved diagnostic tests or the evaluation of interventions.

We reviewed published studies on dengue research in the Philippines during the past 60 years. The objective of the review is to better understand the trends in dengue research and the findings from these studies. The results of the review could provide an impression of local capacity and infrastructure for dengue research and help determine important knowledge gaps. These gaps need to be identified since research interest and support for funding can only be achieved if scientists, decision makers and other stakeholders are able to understand developments related to the disease and recognize areas where more information is needed.

The Philippines is an archipelago of 7,107 islands and is located in the western Pacific Ocean in Southeastern Asia. The population of the Philippines in 2015 was 100,981,437 [ 4 ]. Philippine health status indicators show that the country lags behind most of Southeast and North Asia in terms of health outcomes [ 5 ]. Communicable diseases continue to be major causes of morbidity and mortality in the country. Health care in the Philippines is provided through a mixed public-private system.

This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [ 6 ]. In June 2018, we searched articles on PubMed, the Cochrane Library, ScienceDirect and the Health Research and Development Information Network (HERDIN) from 1 January 1958 to 31 December 2017 combining MeSH and free-text terms for the following: dengue, “dengue fever”, “hemorrhagic fever”, “dengue hemorrhagic fever”, “dengue shock syndrome”, DF, DHF, DSS and Philippines without any language or age restrictions. The search on HERDIN, an electronic database of health research in the Philippines, was done to ensure that articles from local journals not indexed on international databases are included. The completed PRISMA checklist ( S1 Table ) is shown in the Supporting information. There is no protocol for this systematic review.

The articles were compiled in Endnote (Thomson Reuters, San Francisco, CA, USA). Titles and abstracts were screened for eligibility. Published articles on dengue research in the Philippines and on Filipinos that reported objectives, methods and results or descriptive epidemiologic and case reports were included.

We excluded unpublished articles, studies that were not focused on dengue or not focused on the Philippines, those reporting aggregated results from various countries or analysis of a global or regional collection of viral isolates and specimens from which findings specific to the Philippines could not be retrieved, those reporting the same data from another publication (duplicates), reviews and updates (not original research), meeting or news reports, program descriptions, commentaries, guidelines on dengue (prevention, treatment or diagnosis) and studies on expatriates and non-Filipinos. Towards the goal of assessing the broad picture of dengue research in the Philippines, we included studies that met the basic standard requirements and did not exclude studies based on methodology or risk of bias or selective reporting.

The relevant full papers were downloaded and reviewed in detail. Information from each eligible paper was extracted and entered into an Excel spread sheet (Microsoft Office 2007, Seattle, WA, USA). These included the study title, the year of publication, the journal, the study site primary location, type of study, brief methods and study findings. The summary measures were descriptive.

We compared the annual number of Philippine-related dengue publications with other markers. As a measure of economic growth in the country, we assessed the Philippine Gross Domestic Product (GDP) per capita (in current US dollars) in 1960 (the earliest year data was available) and in 2017 [ 7 ]. For comparison, we also obtained the annual number of publications worldwide on PubMed combining the terms: dengue, “dengue fever”, “hemorrhagic fever”, “dengue hemorrhagic fever”, “dengue shock syndrome”, DF, DHF, DSS, from 1958 to 2017, without location, language or age restrictions.

We identified 836 published articles on dengue research in the Philippines during the past six decades ( Fig 1 ). We removed 77 duplicates and screened the titles and abstracts of 759 articles, of which 624 (82%) were excluded and 135 (18%) full text articles were downloaded and reviewed. The 135 articles were classified as follows: 44 (33%) descriptive epidemiologic studies or case series [ 8 – 51 ], 21 (16%) entomologic or vector control studies [ 52 – 72 ], 16 (12%) studies on dengue virology and serologic response [ 73 – 88 ], 13 (10%) socio-behavioral and economics studies [ 89 – 101 ], 11 (8%) clinical trials [ 102 – 112 ], 10 (7%) on burden of disease [ 113 – 122 ], 10 (7%) investigations on markers of disease severity [ 123 – 132 ], 7 (5%) on dengue diagnostics [ 133 – 139 ], and 3 (2%) modeling studies [ 140 – 142 ]. The majority (102/135, 76%) of the dengue research locations were in Metro Manila.

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We assessed the annual number of Philippine dengue studies, by study type and year of publication, and compared this with the annual number of dengue publications worldwide ( Fig 2 ). There were very few articles on dengue research in the Philippines published during the early decades but an increasing annual number in recent years, peaking at 19 articles in 2016. This was associated with an increase in the Philippine GDP per capita from $254 in 1960 to $2,989 in 2017. In comparison, there was a dramatic rise in the annual number of worldwide dengue publications from around 900 articles in 1958 to over 20,000 in 2017 ( Fig 2 ).

https://doi.org/10.1371/journal.pntd.0007280.g002

Descriptive epidemiologic studies and case series

The most common studies during the 1960’s were descriptive and these types of studies continue to be published in recent years. The 44 publications included in this category described demographic, clinical and laboratory findings in Filipino patients with suspected or confirmed dengue in hospital or community settings [ 8 – 51 ]. One study of 100 patients who died of clinically-diagnosed dengue hemorrhagic fever reported necropsy findings of intravascular thrombosis and hemorrhages; dengue virus (DENV) was isolated in 32 per cent of the patients [ 18 ]. A re-analysis of dengue experimental infection studies in the 1920’s allowed the calculation of an average incubation period for dengue infection of about 6 days [ 33 ]. One article described the dengue prevention and response strategies applied after a natural disaster, Typhoon Haiyan that occurred in 2013 [ 44 ] while another paper characterized hospital admissions to a tertiary care hospital, including dengue cases, after the typhoon [ 47 ]. Five studies assessed the correlation between dengue fever and climate or weather patterns [ 34 , 35 , 40 , 41 , 51 ]. Longer-term comparative reporting and analysis of dengue fever from around the country would be useful to assess geographic and temporal epidemiologic patterns, risk factors for severe disease, variations in clinical management and changes in case-fatality rates.

Entomologic and vector control studies

These studies help improve our understanding of the dengue vectors, which could be useful in developing effective control strategies. Of the 21 articles in this category [ 52 – 72 ], six investigated dengue mosquito vector key breeding sites and potential interventions [ 52 , 56 – 58 , 60 , 64 ], three described the response to or efficiency of vector control measures introduced in communities [ 54 , 59 , 61 ], five assessed the larvicidal activity of various agents against Aedes aegypti [ 55 , 62 , 65 , 68 , 70 ], three explored the characteristics and behavior of Ae . aegypti or Ae . albopictus [ 63 , 67 , 72 ], one quantified vertical transmission of dengue viruses in Ae . aegypti [ 66 ], two described the population and genetic changes of Ae . aegypti populations during the dry and wet seasons [ 53 , 69 ] and one investigated the role of different water-holding containers on the development of Ae . aegypti [ 71 ]. As newer strategies become available (e.g. mosquito sterilization and Wolbachia -based approaches), it will be important to investigate these vector control methods in the country.

Studies on dengue virology and serologic response

In 1960, an article described how viruses isolated from specimens collected in Manila (12 from human sera and 2 from wild-caught mosquitoes) were adapted to suckling mice and shown to be dengue viruses [ 73 ]. This was followed by the publication of 15 studies on virologic and serologic aspects of dengue in the Philippines [ 74 – 88 ]. These included one from 1974 reporting how antibody assessments of sera collected from nine participants of dengue experimental infection studies in the 1920’s showed that DENV 1 and 4 were transmitted in these experiments [ 75 ]. Several studies described the isolation of various dengue serotypes circulating in the community [ 76 , 77 , 79 , 81 , 84 ]. A paper compared the nucleotide and amino acid sequences of the nonstructural-1 gene of dengue virus serotype 3 isolated in Metro Manila [ 78 ] and another described the molecular epidemiology of DENV 2 [ 82 ]. Two studies assessed the presence of dengue antibodies among monkeys in the Philippines suggesting possible sylvatic transmission cycles [ 80 , 86 ]. In another study, flow cytometric analysis of peripheral blood samples from clinically suspected dengue cases found that B cells are a major replication site for dengue viruses [ 83 ]. More recent studies described the continued circulation of a single genotype of DENV 2 in the Philippines [ 87 ] and the modulatory effects of compounds on dengue virus infected cells [ 88 ]. Continued monitoring of the circulating dengue viruses in the Philippines would help in understanding better the epidemiology of the disease.

Socio-behavioral and economics studies

Together with epidemiologic studies that quantify the incidence and seroprevalence of disease, socio-behavioral and economic research provides information on how dengue impacts affected communities. There were nine dengue socio-behavioral studies [ 89 – 93 , 95 , 96 , 98 , 100 ]. Six assessed dengue-related knowledge and preventive practices in different communities [ 89 , 90 , 92 , 93 , 96 , 98 ]. Two were multi-country studies that included the Philippines and used questionnaires and focus group discussions to assess policymakers’ views on dengue and the need for a dengue vaccine [ 91 ] and health care providers’ use of dengue clinical guidelines [ 95 ]. One documented anecdotal use of a local herb in the treatment of dengue [ 100 ]. In light of the recent dengue vaccination controversy in the country, a study on policymakers’ understanding of dengue's complicated pathophysiology and immunologic responses would be useful in addressing unresolved issues and also for considering what would be needed when implementing future dengue control strategies.

There were four economics studies [ 94 , 97 , 99 , 101 ]. One published in 2008, prior to the licensure of the first dengue vaccine, used a contingent valuation survey and found a high willingness to pay and household demand for a dengue vaccine [ 94 ]. In another study, investigators assessed the economic and disease burden of dengue in 12 Southeast Asian countries [ 97 ]. For the Philippines, they calculated the direct cost for each hospitalized and ambulatory dengue case (in 2010 US dollars) of $177 and $47, respectively, plus indirect costs of $36 and $17, respectively. In a later publication, an annual average of 842,867 clinically diagnosed dengue cases in the Philippines was estimated, with direct medical costs (in 2012 US dollars) of $345 million ($3.26 per capita) [ 99 ]. The potential cost-effectiveness of a dengue vaccination program was discussed in another paper [ 101 ]. It will be useful to estimate the economic benefits of new dengue control methods in the country, as they become available.

Clinical trials

Of the 11 publications on dengue-related clinical trials, four were on therapeutic interventions [ 102 – 105 ] and seven were on vaccine trials [ 106 – 112 ]. The therapeutic interventions assessed included a hemostatic agent [ 102 ], fluids [ 103 ] and immunoglobulin [ 104 , 105 ]. Multi-country randomized controlled trials of candidate dengue vaccines included study sites in the Philippines and the seven papers we identified reported on vaccine safety, immunogenicity and efficacy [ 106 – 108 , 110 – 112 ], as well as concomitant dengue and MMR vaccination [ 109 ]. As newer dengue vaccines and therapeutics become available, it will be important to investigate these interventions in the country.

Burden of disease

Ten studies assessed the burden of dengue infections [ 113 – 122 ]. A study from 1992 reported an attack rate of 0.2 dengue cases per 1,000 population for the period of July to December 1990 in Zamboanga city [ 113 ]. On a national scale, the annual dengue surveillance data from the Philippines (included among other countries in the World Health Organization Western Pacific Region) showed dengue fever notification rates of 1.5 per 1,000 population in 2010, 1.3 per 1,000 population in 2011 and 1.9 per 1,000 population in 2012 [ 115 , 116 , 118 ]. Another paper quantified epidemiologic trends in dengue disease burden in 5 Asian countries, including the Philippines, over a 30-year period using data from DengueNet and the WHO [ 122 ]. The estimated dengue incidence and mortality in the Philippines increased by 24% and 29%, respectively, but the authors acknowledged that implementation of more sensitive surveillance methods over the study period may have contributed to a reporting bias. These data provide an overall picture but are based on routine passive notification, often of clinically diagnosed cases, and may be weakened by incomplete reporting and delays.

Among the burden of disease articles, incidence of laboratory-confirmed symptomatic dengue infections were estimated in several prospective surveillance studies that actively followed a cohort for acute febrile illness [ 114 , 117 , 119 – 121 ]. Incidence was calculated using the number of new cases arising from the defined cohort as the numerator and the years of observation time contributed by each person in the cohort as the denominator. Table 1 shows the estimated incidence of laboratory-confirmed symptomatic dengue infections from the articles. In the first study, Capeding and co-workers followed 4,441 healthy infants; and dengue infection was confirmed by serotype specific reverse transcriptase-polymerase chain reaction (RT-PCR) in acute-phase sera and dengue IgM/IgG enzyme linked immunosorbent assay (ELISA) in paired acute and convalescent phase sera [ 114 ]. The incidence of symptomatic (clinically apparent) infant dengue infections was 16 per 1,000 person-years ( Table 1 ), of which hospitalized episodes occurred at 8 per 1,000 person-years. Serologic testing of serial blood samples from a subset of 250 infants without reported febrile illnesses in 2007 showed an incidence of clinically-inapparent dengue infections (defined as a > 4-fold rise in dengue virus 50% plaque-reduction neutralization titers between two time points with a monotypic pattern), that was 6-fold higher than that of symptomatic infections at 103 per 1,000 person-years (95% CI 64–155). Second, in a multi-center study, 300 healthy children 2 to 14 years at two sites in the Philippines were actively followed for febrile illness and dengue was confirmed using a nonstructural protein 1 (NS1) antigen ELISA in acute serum samples and IgM/IgG ELISA in both acute and convalescent samples [ 117 ]. The incidence of confirmed symptomatic dengue infections was 34 per 1,000 person-years ( Table 1 ). In the third study, 854 participants 6 months to over 50 years of age underwent active fever surveillance and annual serological assessment [ 119 ]. Acute sera were tested by dengue PCR and acute/convalescent samples by dengue IgM/IgG ELISA to identify symptomatic infections while enrolment and 12-month samples were tested by dengue hemagglutination inhibition assay to identify subclinical infections. The incidence of symptomatic dengue infection was 16 per 1,000 person-years ( Table 1 ) and clinically inapparent dengue infections occurred at 70 per 1,000 person-years (95% CI 54–90). Symptomatic dengue rarely occurred in those older than 15 years. Fourth, two articles reported the incidence of virologically-confirmed dengue in the control group of a multi-center phase 3 trial of a dengue vaccine, including 1,166 participants 2 to 16 years of age at two Philippine study sites [ 120 , 121 ]. The children were followed for acute febrile illness and dengue infection was confirmed by means of both NS 1 antigen and RT-PCR assays. The incidence of symptomatic dengue infection was 66 per 1,000 person-years ( Table 1 ), of which hospitalized episodes occurred at 7 per 1,000 person-years (95% CI 4–12). In comparison with the national data described above, these incidence data provide a more accurate estimate of the burden of dengue because of the active surveillance in a defined cohort and the laboratory-confirmation of cases. But they are limited by having been conducted at only three sites (Laguna, Metro Manila and Cebu) in the country. The wide differences in incidence of laboratory-confirmed symptomatic dengue infections in the studies ( Table 1 ) are due to the different age groups in the cohort and varying time periods (dengue has seasonal and cyclical epidemic patterns) but may also reflect variations in the dengue force of infection across the sites. Additionally, differences in fever detection methods and diagnostic confirmatory tests may have contributed to the variation in the incidence estimates.

https://doi.org/10.1371/journal.pntd.0007280.t001

We derived data on dengue seroprevalence in Filipinos from two studies that conducted baseline serologic assessments prior to fever surveillance [ 119 , 120 ]. First, among participants over 6 months of age in Cebu City, dengue seroprevalence assessed by hemagglutination inhibition assay increased sharply with age [ 119 ]. The proportion of participants with a multitypic dengue serologic profile was 40% in the 6 month to 5-year-old age group compared to 99% in the 31 to 50 year olds. Second, baseline dengue seropositivity prior to vaccination, assessed in 604 Filipino children by plaque-reduction seroneutralization assay, was 78% overall and 58%, 75%, 86% and 93% in the 2–4, 5–8, 9–12 and 13–16 year old age group, respectively [ 120 ].

Investigations on markers of disease severity

Ten studies looked for associations between biomarkers and clinical presentation of dengue disease. Eight studies assessed levels of various immune-related or enzymatic biomarkers [ 123 – 127 , 130 – 132 ], while two evaluated the potential role of adiposity [ 128 , 129 ]. More research is needed to better understand the host characteristics that contribute to dengue disease severity.

Dengue diagnostics

There are several methods available for the diagnosis of dengue fever, including virus isolation, detection of viral components (RNA or antigen) and serological assays. In the Philippines, RT-PCR is the confirmatory test of choice but RT-PCR is expensive and time consuming, requires technical expertise and high-level laboratory equipment and does not provide immediate results that could be used for patient care. Dengue rapid diagnostic tests are used at the point-of-care but have insufficient sensitivity and specificity. We found seven published studies that assessed various dengue diagnostic tests, including ELISA [ 133 – 135 , 138 ], fluorogenic real-time RT-PCR [ 136 ] and rapid diagnostic tests [ 137 , 139 ]. The gold standard used for comparison in these studies was conventional RT-PCR. Definitive diagnosis of dengue is important for the clinical management of patients, disease surveillance and outbreak investigations. A dengue diagnostic assay with sufficient sensitivity and specificity, that is less cumbersome than RT-PCR and with results immediately available for clinical care would be very useful.

Modeling studies

There were three studies that used modeling techniques to estimate dengue burden and describe disease patterns [ 140 – 142 ]. Using historical epidemiological, environmental, socio-economic and climate data, one study developed prediction models for future dengue incidence in the Philippines [ 140 ]. From an analysis of 18 years of dengue surveillance reports in eight countries in Southeast Asia, including the Philippines, investigators found strong patterns of synchronous dengue transmission across the entire region coinciding with elevated temperatures associated with anomalies in Pacific Ocean surface temperatures (Oceanic Niño index) [ 141 ]. Another study estimated 794,255 annual dengue episodes and a disease burden of 535 DALYs per million population in the Philippines extrapolated from passive routinely-collected data compared with results from a prospective community-based cohort study at one site [ 142 ]. Modeling studies may be useful in the evaluation of dengue interventions or control studies that become available in the future, especially when field studies are not feasible.

We report on published, dengue research in the Philippines during the past 60 years. During the last decade, there have been an increasing number of dengue studies in the Philippines. From the 1960’s to the 1990’s, the studies were mainly descriptive epidemiologic assessments and case series, but during the recent years, the types of investigations have become more complex and diverse. We believe this reflects advancement in local research capacity and infrastructure. The improvement has coincided with an increase in annual GDP per capita. Globally, there has also been an upsurge in dengue-related publications over the recent decades, probably due to an increasing interest in dengue together with its geographic expansion, more research publications from dengue-endemic countries, the assessment of recently developed strategies against the disease, as well as the proliferation of medical journals.

Despite the increase in dengue research in the Philippines, we identified several dengue knowledge gaps. The vast majority were descriptive short-term hospital- or community-based studies. A longer-term comparative assessment of dengue epidemiologic patterns by site and year would be useful to understand the bigger picture of dengue in the country. As newer vector control methods and vaccine and therapeutic interventions become available, it will be important to investigate these strategies in the country. Sociobehavioral, economics and modeling studies related to these future interventions would be important to assess their impact. More studies on basic laboratory research, including continued monitoring of the circulating dengue viruses in the country and dengue serologic response would help to provide a better understanding of dengue epidemiology in the country. The incidence and seroprevalence data are available from a few sites and it is not known whether this is generalizable to other areas of the country.

Aside from these important research areas, it is essential that basic dengue information and updated findings be communicated to policymakers, health workers, academics and other stakeholders. Researchers may need to liaison with the media to avoid miscommunication to the general public. This is especially important to avoid issues arising from misunderstanding when new control measures are implemented. Perhaps the recent controversy that surrounded the dengue vaccination program could have been avoided by prior detailed communication and education for more informed decision-making.

There are several limitations of this review. First, although we searched four databases (including a local repository), it is possible that some publications were missed. Second, there was some overlap in topics covered by some papers and we selected the main theme covered in the classification and assessment of results. Third, although the majority of the articles (117/135 or 87%) included a Filipino author affiliated with a Philippine institution, foreign collaborators led many of the projects for which much of the laboratory work and data analysis were done outside the Philippines. Although dengue research capacity and infrastructure in the Philippines appears to have significantly increased during the recent decades, we are not able to exactly quantify the improvement. As local investigators gain more experience in developing proposals, obtaining grants and implementing research, we hope that more dengue projects will be lead by Filipino scientists. Fourth, this review on identifying dengue research gaps is just one step towards defining specific questions of interest on dengue in the Philippines. There needs to be a fuller engagement of scientists, policymakers and the public and the development of a continuing method to assess the evolving dengue research needs of the country.

The importance of dengue research is justified by the data showing a significant burden of the disease. These studies indicated a symptomatic laboratory-confirmed dengue incidence of 16 to 66 per 1,000 person-years (depending on the age group, the year when the study was done, the intensity of the surveillance method and the diagnostic method), while the incidence of hospitalized dengue was estimated at 7 to 8 per 1,000 person-years. Furthermore, clinically inapparent or asymptomatic dengue infections occur quite frequently, many folds higher than symptomatic dengue, due to the intense transmission of the virus. The available incidence and seroprevalence data confirm the high endemicity of dengue infections in the country, which results in a heavy socio-economic burden.

The epidemiology of dengue varies in different geographical areas around the world. Describing what is happening in the Philippines can provide a template for other dengue-endemic areas. A standardized protocol could be developed from this and other reviews [ 143 ] for those who wish to conduct a similar activity in other dengue-endemic countries. Publishing data on the research needed to improve health care delivery is part of the communication that is central and key to successful implementation of public health programs. This is particularly true in the Philippines where dengue vaccination has recently been in the limelight when it was introduced in 2016 and stopped the year after. Initial introduction and subsequent events that resulted in highly controversial issues were partly due to misunderstanding of dengue's complicated pathophysiology and immunologic responses.

In conclusion, this review showed that dengue studies in the country have increased in number and evolved from simple to more complicated types of investigations. We identified several important areas for increased research efforts. Studies such as this can help raise awareness on the significance of the disease and the need for better treatment and preventive strategies.

Supporting information

S1 table. prisma checklist..

https://doi.org/10.1371/journal.pntd.0007280.s001

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• 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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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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S.J.T. is an academic physician and scientist with federal grants and industry support for a wide variety of dengue research initiatives. He has/is supporting dengue countermeasure development efforts as a consultant, advisory board member, or blinded case adjudication committee member for GlaxoSmithKline, Sanofi, Takeda, and/or Merck and was/is compensated for his time. S.J.T. has a patent related to dengue vaccines and all rights were assigned to the U.S. government.

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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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DOI : https://doi.org/10.1038/s41541-023-00658-2

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