dengue research studies

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

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

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

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

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

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

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

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

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

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

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

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

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

Study design

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

Study setting

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

Sample size

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

Participants

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

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

Data collection

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

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

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

mortality and severity of dengue burden—5 questions

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

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

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

Statistical methods

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Limitations and recommendations for future research

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

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

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

Availability of data and materials

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

Abbreviations

Dengue virus

Knowledge attitudes and practices

Ordinary level at school

Advanced level at school

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Acknowledgements

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

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

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

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Supplementary Information

Additional file 1: appendix s1..

Questionnaire in English.

Additional file 2: Appendix S2.

Questionnaire in Sinhala.

Additional file 3: Appendix S3.

Questionnaire in Tamil.

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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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Trends in dengue research in the Philippines: A systematic review

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• PMID: 31022175
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• DOI: 10.1371/journal.pntd.0007280

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.

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Scientists demystify why subsequent bouts of dengue are worse than a first-time infection

by Delthia Ricks , Medical Xpress

A massive upsurge in dengue cases marked by multiple outbreaks is occurring worldwide and raising new questions about who is at elevated risk of severe forms of the mosquito-transmitted disease.

Incidence of the infection has increased by orders of magnitude throughout the so-called dengue belt, which encompasses Central and South America, Sub-Saharan Africa, Southeast Asia and swaths of the South Pacific, home to densely populated islands. Dengue, without question, is the most widespread and rapidly increasing vector-borne disease in the world, according to the World Health Organization.

In the Americas alone, more than 5.2 million cases have been documented and more than 1,000 deaths were reported within the first three months of 2024, the Pan American Health Organization reported in April, noting a marked surge over the same period in 2023.

The story is similar in other dengue-affected areas of the world where lapses in vector control have conspired with global climate change to create an explosion of bloodthirsty mosquitoes, swarms of them moving into regions once considered dengue-free. Only female mosquitoes feed on blood, they're in constant need of the nutrients in it to nurture their eggs.

Now, more than two decades of dengue surveillance in Thailand is answering a slew of questions at a time when the world needs guidance most.

Findings from the research have revealed how various subgroups—what virologists call subtypes—of the dengue virus influence future risk of severe infection. It has been known for years that those who become infected in subsequent outbreaks, after a usually mild bout with a first-time infection, are at significant risk of severe disease in later dengue exposures. New research finally has analyzed more than 15,000 cases to discern why that is so.

Writing in Science Translational Medicine , a global team of scientists has explained how the four dengue viral subtypes—DENV-1, 2, 3, and 4—influence the risk of repeated severe infections. The findings provide a new framework for disease monitoring and lay the foundation for vaccination strategies as the new dengue immunizations emerge.

The team also underscored how dengue, a pernicious tropical malady, can be understood within the context of other common viral diseases that circle the globe.

"The ability of viruses, such as SARS-CoV- 2 and influenza, to continuously change their genetic structure in response to the selective pressure of population immunity complicates control efforts," said Dr. Lin Wang, lead author of the dengue study.

"In the case of dengue virus, an arbovirus that infects more than 100 million people each year, the situation is even more complex," Wang continued. "Individuals with high dengue virus antibody titers are protected from infection and developing severe disease.

"However, individuals with sub-neutralizing antibody titers have been shown to have the highest risk of severe disease, through multiple hypothesized mechanisms including antibody-dependent enhancement," emphasized Wang, a researcher in the genetics department at the University of Cambridge in England.

A dengue infection can be tricky. Some patients who have weathered an infection but get infected in a subsequent outbreak can have more severe symptoms the second time around. Yet, most research on repeat dengue infections has regarded each of the serotypes as no different from the other, Wang and colleagues contend, noting that an assessment of each serotype's genetic differences was needed to provide a clearer picture of potential risks.

To develop that clearer picture, researchers studied each serotype in more than 15,000 patients' infections as a way to peel away much of the mystery surrounding why first-time dengue illnesses are traditionally milder than subsequent ones. Working with Wang were collaborators from two centers in Bangkok, Thailand; multiple research institutes in the United States and one in France.

To determine how each of the viral serotypes affects the risk of severe disease, Wang and colleagues analyzed viral genetic data. The team also studied cases of patients hospitalized for dengue to determine which viral subtype caused their infections. Researchers gathered data from 21 years of dengue surveillance, ranging from 1994 to 2014, in a children's hospital in Bangkok, encompassing 15,281 individual cases. This allowed them to find repeat cases and each viral subtype in all infections.

Based on the pediatric patients' hospital records, researchers discovered a link between hospitalization and the order in which patients became infected with different dengue-virus serotypes. They were also able to determine which combinations of viral subtypes pointed to mild or severe forms of dengue. For instance, people who became infected with serotypes that were very similar, such as DENV-3 and DENV-4, or very different serotypes as in the case of DENV-1 and DENV-4, tended to have a lower risk of severe disease during the second infection.

That said, patients who were infected with serotypes that were only moderately different had a higher risk of severe symptoms in subsequent infections. The highest risk group in this category involved patients who had an initial infection with DENV-2 followed by a subsequent infection triggered by DENV-1.

The new research adds clarity to a disease risk that may seem paradoxical to the lay public. For example, most people infected with dengue virus for the first time develop extremely mild signs of the disease or none at all. But for those who do get sick, soaring fever, headache, body aches, nausea and rash are the primary symptoms, and they intensify in severe manifestations of the infection.

For more than a century a severe bout with dengue has been known as breakbone fever because of the intensity of the pain and accompanying muscle spasms.

The virus is carried in the tropics and subtropics by Aedes aegypti and Aedes albopictus mosquitoes, which are endemic in the dengue belt. But while the belt, which runs through latitudes 35-degrees North and 35-degrees South, has traditionally been home to dengue-carrying mosquitoes, the arthropods have been extending their range northward as global climate change intensifies, scientists say.

Wang, meanwhile, reports that the collaborative research has set the stage to better understand immune system function in subsequent, severe dengue infections.

"These findings suggest that immune imprinting helps determine dengue disease risk and provides a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines," Wang concluded. "This will become increasingly important as dengue vaccines begin to get used."

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Different domains of dengue research in the Philippines: A systematic review and meta-analysis of questionnaire-based studies

Rhanye mac guad.

1 Faculty of Pharmacy, Department of Pharmaceutical Life Sciences, Universiti Malaya, Kuala Lumpur, Malaysia

2 Faculty of Medicine and Health Science, Department of Biomedical Science and Therapeutics, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia

Rogie Royce Carandang

3 Department of Community and Global Health, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Judilynn N. Solidum

4 College of Pharmacy, University of the Philippines, Manila, Philippines

Andrew W. Taylor-Robinson

5 School of Health, Medical & Applied Sciences, Central Queensland University, Brisbane, QLD, Australia

6 College of Health & Human Sciences, Charles Darwin University, Casuarina, NT, Australia

7 College of Health Sciences, Vin University, Gia Lam District, Hanoi, Vietnam

Yuan Seng Wu

8 Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor, Malaysia

9 Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor, Malaysia

Yin Nwe Aung

10 Faculty of Medicine & Health Sciences, UCSI University, Port Dickson, Negeri Sembilan, Malaysia

Wah Yun Low

11 Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

12 Asia-Europe Institute, Universiti Malaya, Kuala Lumpur, Malaysia

Maw Shin Sim

Shamala devi sekaran, nornazirah azizan.

13 Department of Pathology and Microbiology, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia

Associated Data

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

Dengue is the most rapidly spreading mosquito-borne viral disease of humans worldwide, including southeast Asia region. This review provides a comprehensive overview of questionnaire-related dengue studies conducted in the Philippines and evaluates their reliability and validity in these surveys.

A review protocol constructed by a panel of experienced academic reviewers was used to formulate the methodology, research design, search strategy and selection criteria. An extensive literature search was conducted between March–June 2020 in various major electronic biomedical databases including PubMed, EMBASE, MEDLINE and ScienceDirect. A systematic review and meta-analysis (PRISMA) were selected as the preferred item reporting method.

Out of a total of 34 peer-reviewed dengue-related KAP studies that were identified, 15 published from 2000 to April 2020 met the inclusion criteria. Based on the meta-analysis, a poor mean score was obtained for each of knowledge (68.89), attitude (49.86) and preventive practice (64.69). Most respondents were equipped with a good knowledge of the major clinical signs of dengue. Worryingly, 95% of respondents showed several negative attitudes towards dengue prevention, claiming that this was not possible and that enacting preventive practices was not their responsibility. Interestingly, television or radio was claimed as the main source of gaining dengue information (range 50–95%). Lastly, only five articles (33.3%) piloted or pretested their questionnaire before surveying, of which three reported Cronbach’s alpha coefficient (range 0.70 to 0.90).

This review indicates that to combat the growing public health threat of dengue to the Philippines, we need the active participation of resident communities, full engagement of healthcare personnel, promotion of awareness campaigns, and access to safe complementary and alternative medicines. Importantly, the psychometric properties of each questionnaire should be assessed rigorously.

Introduction

Mosquito-borne pathogens, such as the causative agents of malaria, chikungunya, Zika and dengue, are major contributors to the global burden of human infectious disease [ 1 ]. In particular, the geographical distribution of dengue virus has increased alarmingly in recent decades to become a worldwide public health concern [ 2 ]. Currently, this flavivirus is reported in around 130 countries, with up to 400 million new cases of clinical infection recorded annually [ 3 ]. It is hyperendemic in southeast Asian countries, including Cambodia [ 4 ], Malaysia [ 5 ], Thailand [ 6 ], Bhutan [ 7 ], Brunei [ 8 ], Indonesia [ 9 ], Myanmar [ 10 ], Vietnam [ 11 ] and the Philippines [ 2 , 12 ]. The World Health Organization (WHO) projects that in excess of 2.5 billion people live in dengue-endemic areas, a significant contributing factor to an estimated annual death toll of 25,000 [ 13 ]. Nonetheless, the possibility of unapparent and under-reported infections should be recognized, not only due to accelerating geographical spread but also passive case detection; for instance, failure to detect persons with dengue who do not seek health care or to report all symptomatic dengue patients [ 14 , 15 ].

In common with many other tropical countries the risk level of dengue in the Philippines is considered as frequent or continuous due to regular outbreaks or ongoing transmission [ 16 ]. This is affected by several factors such as seasonal meteorological patterns (mean temperature, average relative humidity, and total rainfall) [ 17 ], increased urbanisation and volume of international air travel [ 18 ] that has led to an increase in the viability/reproduction/range of Aedes vector mosquitoes. Despite the fact that the first published report of a dengue epidemic in southeast Asia is from 1954, dengue outbreaks in the Philippines were documented in hospital records as early as 1926 [ 19 ]. During the years 2000–2011 all 17 administrative regions of the Philippines reported increased incidence of dengue, especially in the most populated urban areas, with all four virus serotypes co-circulating and exhibiting temporal and spatial variation. It is estimated that 80% of dengue-related deaths occurred in individuals ≤ 20 years old, with the highest number of cases in children between 5–14 years of age [ 18 ]. Most recently, in 2019 the Philippines Department of Health (DOH) issued a dengue alert in several regions due to a drastically elevated (85%) clinical case load over a six-month period [ 20 , 21 ]. Although the overall incidence of dengue in the Philippines has risen more than eight-fold between 2000 to 2019, this could be partly due to the altered reporting and recording system of dengue cases employed by the WHO and the Philippines DOH.

Several measures to prevent or control mosquito behaviour and breeding have been recommended in order to combat the spread of dengue virus. These actions include: personal protection from mosquito bites; provision of public engagement activities to educate local communities to improve household participation rates against the mosquito vector; emergency use of insecticides in outbreaks to achieve reactive vector control; and rolling out a range of local government-led proactive mosquito control and surveillance initiatives [ 22 , 23 ]. Similarly, the Philippines DOH has developed national programmes for dengue prevention and control, comprising surveillance, case management and diagnosis, integrated vector management, outbreak response, health promotion and advocacy, and research. Moreover, the DOH has implemented a so-called 4S strategy (Search and destroy, Seek early consultation, Self-protection measures, Say yes to fogging only during outbreaks) to strengthen the policy’s effectiveness [ 24 ]. Both the Philippines Integrated Disease Surveillance and Response and the Department of Virology of the Research Institute for Tropical Medicine took part in this programme, particularly in regard to surveillance.

For questionnaire-based research, different behaviours and perceptions are used to measure social aspects of dengue in the Philippines, such as knowledge, attitude and preventive practices (KAP), dengue vaccine acceptance, the health belief model (HBM) association with dengue, and complementary and alternative medicines (CAM) to treat dengue. Far-reaching conclusions have been drawn from questionnaire surveys conducted in other endemic countries, providing a useful guide to decision makers in setting health policy priorities [ 25 ], assessing dissemination, application and cost-effectiveness of current guidelines, and closing important gaps in our knowledge of patterns of dengue transmission [ 26 ]. Studies have suggested that a combination of multidisciplinary and bottom-up approaches is more likely to be successful and sustainable way to combat dengue [ 27 ]. Prevention and control should be promoted in school and university curricula, as should the crucial role of healthcare volunteers in implementing effective social networks to raise dengue awareness of householders that may influence their attitudes and behaviour towards dengue [ 28 ]. Despite this, there has been a limited number of questionnaire-based studies in the Philippines compared to neighbouring countries, such as Malaysia, Thailand, and Indonesia.

Furthermore, the collective scopes have not been discussed previously in the context of researching a pattern for guidance. In addition, the accuracy of findings from questionnaire-based studies is a matter of concern, as the accuracy of results depends largely on the reliability of the questionnaires used in the survey [ 29 ]. A comprehensive review of questionnaire-based dengue-related studies is required to highlight the findings from all relevant previously published work on the behavioural and practice aspects related to dengue prevention, to assess the validity and reliability of questionnaires used in such research, as well as to draw broad conclusions. Thus, this systematic review and meta-analysis aims to summarize existing questionnaire-based studies conducted in the Philippines, which may help to improve survey design relating to different domains on the behavioural and practice aspects related to dengue infection. In addition, it highlights future research needs and serves as a valuable reference for policymaking or health interventions focusing on the Filipino population.

Methodology

Study design.

The research protocol is in line with recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 13 ] ( S1 Appendix ).

Search strategy

The methodology, research design, search strategy and selection criteria were based on the review protocol ( S2 Appendix ) developed by the team of researchers who comprise experts in public health, infectious diseases and clinical medicine. An extensive literature search was conducted during March–June 2020 using various major electronic biomedical databases, such as PubMed, Goggle Scholar, EMBASE, MEDLINE and ScienceDirect. A checklist of preferred reporting items for systematic reviews and meta-analysis (PRISMA) [ 30 ] was used to present the flow of research strategy, consisting of selection, including and excluding the relevant articles, as shown in Fig 1 .

Screening and eligibility

All articles in English that were collected, compiled and eventually included in this review, reported a peer-reviewed dengue questionnaire-related research study conducted in the Philippines and published between January 2000 –April 2020. Moreover, any article considered as part of the review was cross-checked through references and in-text citations to ensure the inclusion of all relevant articles. In this review, we offered no restrictions on the type of participants included in the study; community residents, university students, in-patients, parents, and caregivers were included. For the intervention/exposure, all questionnaire-related dengue studies conducted in the Philippines were included. We did not have any comparison group in this review. Regarding the outcomes, we summarized the main findings that reported dengue-related knowledge, attitude, and practices.

A non-questionnaire-based study (13 studies), simple reports with no evidence of peer review (three studies) and conference proceedings or theses (three studies) were excluded due to lack of information for data extraction and/or evidence of peer review. The relevance of each article was determined using individual keywords or a string combining ‘dengue’, ‘questionnaire’ and ‘Philippines’. Additionally, the Boolean operators “AND”, “OR” and “NOT” were used to link categories of keywords, thereby aiming to increase sensitivity and specificity of the query. No limits by sex, age and ethnicity of study participants as well as language of the articles were imposed. Similar keyword(s) were applied to all electronic databases to search for articles.

Data extraction and management

The decision whether or not to include each article was made after reaching a consensus among the research team following group discussion between members via email. A total of 34 articles were retrieved electronically, with further papers that were not open access being acquired by emailing the paper’s corresponding author. After removing duplicate publications 14 articles were identified as either irrelevant or to not fulfil the abovementioned criteria, and hence each was excluded.

Risk of bias assessment

The remaining 20 articles were assessed further during the first round of review, undertaken by six expert reviewers (public health authorities and infectious diseases specialists) based on titles and abstracts, from which five articles were eventually excluded for not being a questionnaire-related study (e.g. a workshop protocol on dengue prevention and control or fieldwork on breeding sites of Aedes species mosquito). The second round of review was performed by three expert reviewers to ensure that based on the selection criteria only relevant articles were included in the final selection; no further papers were excluded. All papers fulfilling the inclusion criteria were critically appraised based on the eight critical appraisal tools of the critical appraisal skills programme (CASP) Checklist [ 31 ] (S3 & S4 Appendices). Therefore, this review contained a total of 15 articles, as indicated in Table 1 . In this systematic review, 15 papers related with knowledge, attitude and practice on dengue study in the Philippine were included. However, as the number of studies fewer than 10 in the meta-analysis, not all these papers recorded the same effect size. Therefore, an assessment of publication bias using graphical methods (e.g. funnel plot asymmetry) or statistical methods (e.g. Egger’s test) was not possible.

Statistical analysis

We conducted quantitative synthesis to derive meta-estimates of knowledge, perception and attitude of the study population and qualitative synthesis to describe the study population, study design, sampling methodology and outcomes presented in the paper. For each study, primary outcome (knowledge, attitude and practice score) and secondary outcome (percentage of population with good knowledge, acceptable attitude, and practice) were extracted. Knowledge, attitude and practice score were standardized to cent percent and pooled estimates are presented as mean and 95% confidence interval. Prevalence of population with good knowledge, acceptable attitude and practice were also identified, meta-analysed and presented also as mean and 95% confidence interval. Forest plots were used to display pooled estimates. Heterogeneity was tested using likelihood ratio test. Analyses were performed using STATA 16 statistical software. For meta-analysis interpretation, based on previous studies [ 27 , 40 ] the cut-off values used for standardized knowledge scores were as follows: < 64, poor; 64–80, good; > 80, very good.

Awareness and knowledge of dengue infection

Based on percentage scale, the mean knowledge score was 68.89 ( Fig 2 ). The current systematic review shows that most respondents (95%) held several erroneous beliefs: that (1) dengue transmission cannot be prevented; (2) elimination of larval breeding sites is the responsibility solely of public health staff and healthcare volunteers; (3) eliminating such sites is very complicated, poor use of public funds and a waste of time; (4) insecticide fogging is sufficient to prevent mosquitoes; (5) individuals who have experienced dengue infection once cannot be infected subsequently; and (6) a fit and healthy person will not get dengue infection [ 32 , 35 ].

In 2004, Kwon & Crizaldo [ 32 ] reported that more than half of participants (56.3%) had moderate knowledge of dengue, whereas in 2013 Yboa & Labrague [ 40 ] reported higher knowledge of dengue (91.6%) among rural residents in Samar Province, Philippines. This is despite the fact that the two studies employed different sampling techniques: the former used purposive random sampling [ 32 ], whereas the latter used convenience sampling [ 40 ] ( Fig 3 ). In terms of recognition of symptoms of dengue infection, most respondents answered correctly that fever is the major clinical feature of uncomplicated dengue [ 24 , 32 – 34 ] affecting infants, young children and adults [ 33 ]. Other symptoms claimed by respondents include chills, headache, pain upon eye movement, lower back ache, stomach ache, skin rashes, vomiting, bleeding of the nose and gums, muscle pain and diarrhoea [ 32 , 33 , 35 , 36 ].

Interestingly, most respondents answered correctly questions assessing their knowledge of dengue transmission. For instance, they identified that the dengue virus is transmitted to humans through the bite of an infectious female Aedes aegypti : 89.6%, [ 32 ]; 56.07%, [ 34 ]. Furthermore, the majority of respondents recognized that Aedes mosquitoes bite during daytime: 66.7%, [ 32 ]; 28.85–46%, [ 36 ]; 17–37.67%, [ 33 ]. However, an incorrect perception of biting time at night has also been reported; 64%, [ 34 ]. Up to 95.8% of survey participants correctly identified stagnant water collected in discarded tyres, trash cans and flowerpots as providing good breeding sites for mosquitoes [ 32 , 36 ]. More than 50% of respondents acknowledged that not all mosquitoes carry dengue, flies and ticks do not transmit the virus and that disease may be contracted through transfusion of infected blood [ 34 ], and also that heavy rainfall provides conditions favourable to rising numbers of mosquitoes responsible for dengue [ 33 ], due to formation of larval breeding sites [ 32 ]. Additionally, around 50% of respondents claimed that combating dengue vector mosquitoes is the only way to control infection [ 32 ], or that sleeping under a mosquito net prevents infection [ 37 ]. Only 25% of respondents realised either the possibility of contracting dengue if a family member had been infected with the virus or that the rainy season (June–February) is, historically at least, the only epidemic period for dengue infection in the Philippines [ 32 ].

The knowledge of survey participants regarding an individual’s risk of dengue infection was unsatisfactory as 23% thought that a fit and healthy person could not be infected more than once in a lifetime. Moreover, only 12.5% of respondents strongly agreed that it is possible to recover completely from infection [ 32 ]. A study by Herbuela et al. (2019) [ 38 ] demonstrated that knowledge of dengue is not always directly proportional to educational attainment; for instance, paediatric patients in senior high school knew more about dengue compared to those who were in college who had experienced dengue for the first time.

Attitude towards dengue infection

After standardising to percentage scale, the overall attitude score was 49.86, reflecting a poor attitude among Philippines populations towards dengue ( Fig 4 ).

It is of interest to note that those patients who were high school seniors or who experienced a longer stay in hospital tended to have a better attitude towards dengue. However, this association decreased as the patients aged [ 38 ]. Other positive attitudes of Filipino communities when infected with dengue were reported [ 36 ]. These included consulting a physician, taking plenty of rest, drinking copious water when affected by the disease, and seeking herbal medicine (mangagaw, tawa-tawa or gatas-gatas). Drinking apple tonic, installing residential door and window screens, sleeping under mosquito nets, and burning mosquito coils and dried leaves were each also mentioned as a method used to prevent dengue.

Furthermore, two studies have demonstrated a good attitude towards dengue among mothers of young children in Malaybalay, the capital city of the province of Bukidnon. They believed that dengue is a serious disease (60%); it cannot be treated at home (92.5%); it is preventable (70.7%); it can be prevented by controlling breeding sites of mosquitoes (69.6%); government is not solely responsible for control (71.7%); and control requires active community participation (95%) [ 32 , 34 ]. Lennon (2004) reported that students from Dumaguete, a city on Negros Island in the southern Philippines, showed a positive attitude towards dengue control and prevention as they practised the following: (1) cleaning inside their house and its immediate surroundings; (2) eliminating collection of stagnant water by keeping opened cans and other vessels upturned or in a suitable place; and (3) applying insecticide spray, all of which are measures of mosquito larvae control [ 39 ]. However, Lennon (2004) also mentioned that lack of knowledge and correct behaviour (characterized as ignorance, apathy, laziness, perceived lack of time and/or lack of cooperation) among students could manifest in poor attitudes towards combatting dengue.

Preventive practice towards dengue infection

After standardising to percentage scale, the overall practice score was 64.69%, indicating that preventive practice towards dengue among Filipino populations is acceptable regardless of a poor attitude score ( Fig 5 ). Based on previous studies, the most preferred options for preventive practice were “search and destroy mosquito breeding sites” including covering water storage containers after use (> 90%), examining toilet cisterns for mosquito larvae (88%), regular disposal of refuse into garbage bins (> 80%) [ 33 , 35 ]. Progressively less popular options included using mosquito nets/mosquito coils in the house (77%), checking and cleaning roof gutters during the rainy season (69%), and insecticide fogging (67%) [ 32 , 35 , 40 , 41 ].

Further results showed that the best self-protection method was covering water storage containers immediately after use (92%) [ 32 , 33 , 40 ], screening of windows (88%), use of mosquito bed nets (92%) or using an electric fan [ 33 , 35 , 40 , 41 ]. Some survey respondents (63%) reported that they had used professional pest control in an attempt to prevent dengue infection [ 40 , 41 ]. Other preventive measures that have been practised by respondents are: (1) traditional fogging to disperse mosquitoes, especially during the afternoon; (2) wearing long-sleeved shirts and trousers, especially by small children. A recent study by Rufo & Amparado (2017) indicated the practices of scrubbing water storage vessels and cleaning roof guttering at least once a week or a preference for fogging to be important means of dengue management practice [ 24 ]. Additionally, Herbuela et al. (2019) revealed that mosquito larvae-eating fish, screen windows and dengue vaccination were each identified as a protective factor against dengue infection, of which the biological control method of using larvivorous fish was the strongest factor in the model with an adjusted odds ratio (AOR) of 8.69 (95% CI: 3.67–20.57, p ≤ 0.001) [ 38 ].

In contrast, a study in Lugait, a municipality in the province of Misamis Oriental, identified several negative practices performed by resident communities [ 33 ]. These included: (1) leaving water storage containers uncovered for more than a week inside the house (57.67%); (2) overwatering of flower vases and potted plants (21.67%); (3) the presence in the neighbourhood of plants such as bananas in which mosquitoes are known to shelter (65.33%); (4) discarding tyres, cans, bottles and other containers in which water may collect (43.33%); (5) rivers, ponds and puddles of water that form after raining (26.00%); (6) coconut shells (23.67%); (7) no proper drainage (13.67%); and (8) dirty surroundings (9.67%).

Treatment-seeking behaviour

In terms of treatment-seeking behaviour, most respondents associated fever as being the principal manifestation of dengue infection (86.5%) [ 24 ]. Interestingly, parents would preferentially choose to bring a child with fever to a district hospital (54.75%) rather than to a rural health unit (44.75%), private clinic (40.25%), tertiary hospital (27.50%) or quack doctor (7.5%).

Sociodemographic variables and KAP regarding dengue infection

Based on this meta-analysis, a significant positive correlation between knowledge and attitude domains was observed among paediatric patients with confirmed dengue infection, although this is not statistically strong (Spearman’s rank correlation coefficient, Rs = 0.2). However, Herbuela et al. (2019) reported that neither the knowledge nor the attitude of dengue patients correlated with their practices [ 38 ]. Other studies have also reported an insignificant association between sociodemographic variables, knowledge, attitude or practice regarding dengue among communities in the Philippines [ 24 , 32 , 36 , 40 ]. Sociodemographic and economic data collected include, for example, age, sex, education, migration background and ethnicity, religious affiliation, marital status, household, employment, and income.

Sources of information on dengue infection

It is noteworthy that most of the articles analysed reported the main source of information on dengue infection being provided by television (ranging from 49.7% to 93.8%) [ 32 , 33 , 37 , 40 ] and radio (73.37%) [ 33 , 37 , 40 ]. Yet, respondents gained information from a variety of other sources: for instance, via health workers (80.33%) [ 32 ], (5.11%) [ 40 ]; schools (34.00%) [ 33 ]; internet (9.67%) [ 33 ]; posters (3.33%) [ 33 ]; and by speaking with neighbours and/or friends (4.20%) [ 32 , 33 , 37 ].

Dengue vaccination

In a hospital-based cross-sectional study, the acceptance rate of dengue vaccination was 81.3% (113 out of 139) among parents and caregivers. Completion of secondary or tertiary education (AOR = 0.22, 95% CI: 0.01–4.1, p < 0.0001) and lower income group (AOR = 2.8, 95% CI: 0.06–5.1, p < 0.0001) were the independent factors associated with dengue vaccine acceptance [ 40 ]. On the other hand, a community-based survey revealed that 95.5% (193 out of 202) of primary caregivers accepted dengue vaccination, a very high rate [ 42 ].

Based on this meta-analysis, good attitude towards vaccination (AOR = 10.62, 90% CI: 1.73–26.28) and large household size (AOR = 9.63, 90% CI: 2.04–45.38) were each positively associated with vaccine acceptance within a community. In contrast, good knowledge of dengue (AOR = 0.10, 90% CI: 0.03–0.74) and age of 44 years or more (AOR = 0.14, 90% CI: 0.03–0.61) were two factors that negatively influenced acceptance rate [ 43 ].

For the aspect of willingness to pay (WTP) for a single dengue vaccine and the household demand function for dengue vaccines, Palanca-Tan (2008) reported that the mean WTP for a vaccine ranged from USD 27–32, and the household demand averaged two persons per household [ 44 ]. For lower income groups with less capacity to pay, a mass vaccination campaign programme was suggested instead, through which at least part of the financial costs is covered.

Complementary and alternative dengue prevention

Indigenous communities in the province of Pangasinan, located on the island of Luzon, use Euphorbia hirta , locally known as tawa-tawa, as a Filipino tradition for dengue [ 45 ]. The most widely used treatments are decoctions of the leaves and bark. The plant extract was reported to be effective as a symptomatic CAM for dengue in the initial, febrile and recovery stages, as well as for supportive therapy [ 45 ].

Reliability and validity of questionnaire

Out of 15 articles reviewed, 5 had piloted or pretested the questionnaire [ 24 , 37 , 38 , 42 , 44 ] before surveying. Three articles that were adapted [ 34 , 38 , 40 ] and 8 articles containing a new questionnaire [ 32 , 33 , 35 , 36 , 39 , 42 , 43 , 45 ] were considered as having a high risk of bias on the questionnaire due to lack of evidence on reliability and validity.

This systematic review provides the first description and insight into questionnaire-based studies conducted in different dengue-endemic communities in the Philippines, where an upward trend of dengue cases has been reported for more than a decade [ 12 ]. Filipinos prefer a healthcare facility that provides a higher level of medical attention than those offering basic services despite the availability of the latter in the locality of respondents. Television and radio play an important role in delivering dengue information to resident communities. Although a high vaccination acceptance rate was reported among community residents, this needs to be re-assessed due to the ‘Dengvaxia’ dengue vaccine controversy. It was found that the majority of respondents have an inadequate KAP level regarding dengue, which is associated with several factors.

The Philippines, like many other countries in the tropics, is plagued by dengue [ 16 , 46 ]. For decades vector surveillance and control measures have remained the mainstay of dengue control and prevention programmes. There is a pressing need for these to be effective as dengue has no cure and patients are subjected only to symptomatic management after becoming infected [ 2 ]. Moreover, the only vaccine currently available, Dengvaxia®, has variable safety and efficacy by age and serostatus such that its licensure has proved controversial [ 47 ]. In fact, human living practices play a crucial role in maintaining dengue virus transmission via Ae . aegypti carriage by providing a suitable breeding environment and ready source of blood meal for this peridomestic dengue vector. Therefore, here we have focused on questionnaire-based studies in relation to different domains of human behaviour towards dengue, such as KAP, sources of information, preventive treatments, HBM and CAM. In addition, this review also analysed the reliability and validity of survey questionnaires used in the included articles. The findings reported herein stress that the development of a proactive dengue control programme should be prioritized in order to protect the health of all layers of Filipino society, especially those located communities in highly endemic areas.

In this systematic review of the population of the Philippines, cut-off values were based on a 100-point scale (i.e. for instance, an 80.00% score is considered as good). Overall, the respondents achieved 68.89%, 49.85% and 64.69% scores for knowledge, attitude and preventive practices towards dengue, respectively. This KAP score revealed that more than half of the entire cohort had adequate knowledge regarding dengue, specifically of dengue infection per se and of its signs and symptoms. The level of knowledge among Filipinos revealed here is lower compared to studies conducted in Malaysia (more than 90%) [ 48 ] and Laos (70.9%) [ 49 ]. In comparison, 50% of the rural population in Kancheepuram district of Tamil Nadu, India [ 50 ] and the population of the earthquake- and tsunami-affected area of Aceh Indonesia [ 51 ] were knowledgeable about dengue symptoms. These findings shows that communities living in regions where the fatality rate from dengue is high have less knowledge, perhaps placing them at greater risk. Hence, increased mortality from dengue appears to be correlated with ignorance of its virus aetiology, vector transmission and disease symptoms, thereby reiterating the paramount importance of public health education programmes. Interestingly, a study conducted in Nepal reported corroborative findings that compared to participants resident in the lowlands a significantly lower proportion of those living in highland areas, which experience low dengue fatality rates, were able to correctly identify typical symptoms of dengue [ 28 ]. Similar to the observations made in the Philippines such differences may be attributed to intensified education and awareness campaigns in highly endemic areas leading to an increased level of knowledge. Due to the incrementally expanding distribution of Aedes mosquitoes as a direct result of climate change, future dengue awareness campaigns should target communities in both endemic and potentially endemic areas, not only in the Philippines but elsewhere in tropical and subtropical zones [ 52 ]. Among Filipino communities in areas of high endemicity for dengue, public health engagement should focus on those identified factors associated with attainment of knowledge. Plausibly, the meta-analysis also found an inverse association between level of education and knowledge of dengue, suggesting that a better understanding and comprehension of information on dengue does not necessarily depend on the level of education which a person has reached. It is recommended that in order to raise knowledge of dengue, public health campaign materials should be piloted and evaluated routinely with community members of all educational backgrounds, as well as training of personnel to deliver educational information effectively to address knowledge gaps regarding dengue in the community.

The current meta-analysis reveals a poor attitude (49.85%) and preventive practice (64.69%) towards dengue among communities in the Philippines. Approaching half of an urban community (43.80%) [ 32 ] held an erroneous belief that chemical fogging by the local government authority is adequate to reduce dengue transmission compared to only around a third reported for a similar Malaysian urban population (31.8%) [ 53 ]. In fact, existing policies should revisit the implementation of insecticide use, such as fogging periodically instead of sporadically and its deployment as an adjunct vector control method. A reduction in mosquito and larval density after fogging as measured by a drop in mean ovitrap index value from 71.67% to 69.42% has been reported [ 54 ]. However, sole dependency on preventive fogging may lead to the emergence of insecticide resistance [ 55 ]. Furthermore, of the included articles, two studies showed that some respondents believed that eliminating breeding sites is the exclusive responsibility of public health staff and healthcare volunteers (52.10% and 28.30%, respectively) [ 32 , 34 ]. These values are comparable with those reported by a previous study in an Indian population (49.00%) [ 56 ]. This attitude needs to change because achieving a reduction of the vector population and prevention of virus transmission requires the active participation of affected communities. In order to combat mosquito breeding, all residents should take personal responsibility to regularly clean their housing and immediate surroundings. Nonetheless, local government authorities should spearhead this effort as studies have reported that search and destroy practices require trained personnel to have good knowledge and skills to be able to remove Aedes breeding sites more effectively [ 2 ].

The negative behaviour among university students towards dengue prevention [ 38 , 39 ] could be explained by using the health belief model, conceivably due to weak confidence in the effectiveness of the proposed measures to control mosquitoes and thereby to prevent dengue transmission. A perception of reduced benefits coupled with elevated barriers may result in a lesser possibility of change, as reported in a Malaysian population [ 57 ]. Self-efficacy is another HBM construct that, in addition to the perceived threat of dengue and other parameters, encourages an individual to implement preventive practices. Not surprisingly, university students might have a low self-efficacy or confidence in doing something with which they are unfamiliar, which could have led to their low interest to carry out mosquito control tasks. In this context, although they have a higher level of education, and therefore may have the ability to understand various information on dengue [ 58 ], they may not have the self-confidence to perform regular, comprehensive environmental clean-up tasks, as claimed by studies conducted in Malaysia [ 59 ] and Pakistan [ 60 ]. Hence, it is important to identify the trigger for a person’s motivation to contribute to vector control initiatives. This is unlikely to be the same for different people or groups within a community where there will be several cultural and social factors at play. We suggest that a public health campaign should incorporate guidance on how to conduct steps of an environmental action plan for dengue control. Furthermore, this should be based on an HBM construct specific for the Filipino population in order to increase their self-efficacy and behaviours regarding mosquito control.

Pre- and post-educational intervention in Malaysia achieved via public health campaigns and further disseminated by discussion among students revealed that educational intervention was effective in generating awareness of dengue (mean scores for pre- and post-intervention were 10 ± 2.46 vs 12.61 ± 0.17, 8.82 ± 1.35 vs 9.01 ± 1.09 and 6.92 ± 2.5 vs 7.11 ± 2.49 for knowledge, attitude and practice, respectively) [ 61 , 62 ]. Educational intervention should include promotion of skills development that may help to reduce the perception among students of time as a limitation to performing mosquito control activities. Other studies have highlighted additional barriers to the effectiveness of public health campaigns, including not being conducted on a routine basis [ 63 ] and initiatives being driven from the top down, thus creating resistance from community residents to participate in interventions [ 64 ].

Most respondents claimed that fever is associated with dengue, prompting them to attend the nearest healthcare facility to seek treatment. This finding is in accordance with HBM, whereby self-regulation emphasizes that people have or can develop autonomy, self-control, self-direction and self-discipline due to the assumption that all behaviours are motivated by the desire to achieve goals that are personally important [ 65 ]. Following this principle, individuals make progress towards their goals by selecting and monitoring their behaviour over time [ 66 ]. In contrast, HBM also hypothesizes that fever is not sufficient a cue to action to make respondents proceed as for dengue. The uncertainty of the model’s conditions regarding the presence of fever increases the perception of susceptibility to dengue [ 67 ]. In a Venezuelan population, this explains a person’s intention to seek medical assistance as their first action if they suspect dengue infection, whereas treating at home would be their first choice in case of fever only [ 68 ]. Furthermore, most respondents prefer a healthcare facility that provides a higher level of medical attention than those offering basic services such as the barangay health stations, rural health units or private clinics which are readily available in the locality of respondents, reflecting the need to improve healthcare facilities in order to provide immediate and effective treatment to dengue patients. An interesting study in Cambodia reported a range of thought processes involved in the selection of healthcare facilities [ 69 ]. A lack of confidence over the quality of healthcare at the village level, suspicion as to the quality and provenance of locally available drugs, and real or perceived financial barriers to seeking care were predominant reasons for the sequence of treatment-seeking behaviours that was observed.

The systematic review also indicated no significant association between knowledge, attitude, and preventive practice regarding dengue was observed in Filipino populations. Although studies from Nepal [ 28 ], Indonesia [ 51 ], Vietnam [ 70 ] and Coimbatore, southern India [ 71 ] have each reported a positive association between KAP domains, other populations such as in Malaysia [ 72 , 73 ] and the Indian cities of Delhi and Kolkarta [ 74 , 75 ] have reported no correlation. An effective and sustainable strategy for combatting dengue is critically required when translating a community’s knowledge into good practices, such as the need to change their behaviour towards prevention of virus transmission. On account of this, carefully tailored practical approaches should be integrated into public health-related educational programmes, such as house-to-house inspections undertaken by healthcare personnel to conduct Aedes surveillance and to convey information and educate residents in a more personalised manner and familiar setting. Also, religious organisations, notably the predominant Roman Catholic Church in the Philippines, should be encouraged to influence and motivate habit change and to spur social mobilization, as is practised in other countries [ 76 , 77 ].

Sources of information on dengue fever infection

This systematic review demonstrates that the principal sources by which information on dengue is disseminated to communities in the Philippines are television and radio. These outlets are key to delivering important knowledge regarding dengue, suggesting a need to maximize mass media in educating the population. A similar finding has been reported elsewhere [ 51 , 78 , 79 ]. The reason that television and radio are significant predictors of adequate knowledge of dengue could be that globally, and especially in developing countries, these traditional forms of audio-visual broadcast media remain the most popular means of communication that appeal to all age groups and to every socioeconomic class, encompassing both literate and illiterate members of the community. Thus, this finding indicates that television and radio should be fully utilized as an effective and accessible way to promote dengue awareness among Filipino communities. Surprisingly, it was also found that healthcare workers in the Philippines held a subsidiary role as dengue informants, in contrast to the data reported by studies conducted in Indonesia [ 51 ], Chitradurga in southwest India [ 80 ] and Malaysia [ 62 ]. The disparate findings may be due to patients’ perceived trustworthiness and acceptance of healthcare services. This could lead to behavioural impacts among the community such as the notable recent Dengvaxia® vaccine controversy experienced in the Philippines [ 81 ]. Given this possibility, dengue intervention programmes may need to be reviewed stringently to enable healthcare workers to maximize their educational impact on patients and their family members during clinic consultations, house visits or community outreach events.

The acceptance rates of dengue vaccination in this systematic review, ranging from 81.3 to 95.5% [ 40 , 42 ], are comparable to those reported by two studies conducted in Aceh Indonesia (70% and 77.3%, respectively) [ 82 ], one in Bandung, Indonesia (94.2%) [ 83 ] and another in Penang, Malaysia (88.4%) [ 84 ]. Although a higher level of education is associated with a better attitude towards dengue vaccine acceptance [ 85 ], a negative association has also been found [ 83 ]. Nonetheless, education is considered as an intermediate factor that could be affected by other considerations, which may explain the conflicting result as a predictor of dengue vaccine acceptance. Thus far, the association of income class and vaccine acceptance is not fully explained. In fact, it was proposed that wealthier people are more likely to comply with dengue vaccination primarily because they would consider the cost more affordable compared to people in a lower income class [ 83 ]. However, this systematic review showed opposite findings. Given that the majority of respondents included in the analysed studies were of lower income status and that more people were accepting of dengue vaccination, this might have tipped the scales appreciably towards significance.

Nonetheless, a previous study in Metro Manila, the Philippines, indicated a sufficiently high WTP for dengue vaccination, with mean WTP ranging between USD 27–32 [ 44 ]. This is greater than mean figures reported from comparative studies conducted in other countries; in Indonesia (USD 13.60) [ 83 ] and (USD 4.04) [ 85 ], in Nha Trang, Vietnam (USD 26.10) [ 86 ]; and in Medellin, Colombia (USD 22.60) [ 87 ]. On the contrary, the WTP for dengue vaccination of consumers was marginally higher in Brazil (USD 33.61) [ 88 ] and markedly so in Thailand (USD 69.80) [ 87 ]. Interestingly, a Vietnamese study of dengue patients with a history of hospital admission (for any ailment, not necessarily dengue) showed their elevated WTP for a vaccine (USD 67.40) [ 86 ]. This is probably due to an inflated awareness of the escalation of dengue cases due to time spent on hospital wards combined with the occurrence of a large-scale dengue outbreak in southeast Asia at the time reiterating the potential health benefits of vaccination.

Complementary and alternative approaches to dengue control and prevention

In the Philippines the use of E . hirta to treat dengue exemplifies the importance of traditional medicine, particularly of herbal origin, to rural and remote communities lacking adequate vector control and with limited access to modern healthcare facilities, as reported previously [ 89 , 90 ]. Interestingly, the utilisation of herbal plants among community residents of Lugait in the Philippines has been reportedly endorsed by its local healthcare centres [ 32 ]. Similarly, in a study in the US, 53.10% of healthcare providers recommended at least one CAM to their patients [ 91 ]. This is in contrast to the perspectives of healthcare providers of using CAM as an adjunct to allopathic medicine in American Samoa [ 92 ] and Sierra Leone [ 93 ].

A recent systematic review of available scientific evidence reported the potential of E . hirta against dengue as it holds significant antiviral and platelet-increasing activities [ 94 ]. These conclusions may have been drawn due to this plant’s high concentration of reducing polyphenols as an active ingredient [ 95 ]. However, the mechanism of antimicrobial action remains to be determined, and the antiviral properties and its ability to stimulate blood platelet production are both currently under investigation [ 96 ]. Therefore, well-controlled clinical trials as well as contemporary pharmacological approaches, including activity-guided fractionation and elucidation of the mode of action in increasing platelet activity, are warranted to establish the potential use of E . hirta in a clinical setting.

Lack of evidence on questionnaire reliability and validity

This systematic review demonstrates a clear need to determine the psychometric properties of the questionnaires used in dengue surveys conducted in the Philippines in order that KAP assessments are reliable, and the results are valid. A KAP study is a focused evaluation that measure changes in human knowledge, attitudes and practices in response to a specific intervention. As such, it is a quantitative research method that has the power to reveal a wealth of useful information on a significant aspect of research investigation. Therefore, if the questionnaire is well-constructed and the survey conducted by trained operators, a KAP study should assist in obtaining relevant data in a highly reliable and valid manner [ 97 ]. Reliability and validity are extremely important qualities required in order to measure the accuracy and consistency of this and other survey tools [ 98 ].

The survey questions should provide reproducible results (reliability test) and be assessed in three major forms of reliability: test-retest; alternate form; and internal consistency [ 99 ]. An Rs of value 0.70 or greater is generally accepted and indicates good reliability [ 100 ]. Despite the need to determine reliability during pretesting only a small minority of studies have reported Cronbach’s alpha coefficients during the pilot study and thereby confirmed the adequacy of internal consistencies of these scales [ 29 ].

In regard to validity there are several subtypes, namely face, content, criterion and construct validity [ 101 ]. The underlying construct of the items should be analysed by factor analysis to predict the discriminant and convergent validity [ 29 , 102 ]. In this systematic review, the majority of articles reported neither the results of a pilot study nor those of a pretest questionnaire–if these were indeed actually undertaken. Reliability, content and construct validity of a KAP structured questionnaire should be carefully examined. It is crucial to harmonize and validate the content of all the surveys with the aim of reducing the variability of findings based on questionnaires used for data collection.

Strength and limitation

Several limitations of this review including inaccessibility of the original questionnaires which may have resulted in the heterogeneity of the findings in this review. Additionally, this could have resulted from the differences in statistical analysis or sociodemographic characteristics of the populations under study.

Conclusions

This systematic review demonstrates a good level of knowledge, attitude and preventive practice regarding dengue among the resident population of the Philippines, particularly in highly endemic areas. Moreover, there is no association between KAP domains. Therefore, there is a great need to prioritize public health campaigns to target identified factors based on HBM. This is in order to raise the level of knowledge of dengue, to influence attitudes towards vector control and prevention and thereby to increase the uptake of preventive practices. These goals can be achieved through the active participation of communities and engagement with healthcare personnel, in combination with promotion of dengue awareness and safe complementary medicines through the use of television and radio. Equally important, there is an urgent need to determine the psychometric properties of KAP questionnaires before use in future dengue surveys in the Philippines in order for such assessments to be valid and conducted reliably.

Supporting information

S1 appendix, s2 appendix, s3 appendix, s4 appendix, funding statement.

Rhanye Mac Guad and Nornazirah Binti Azizan obtained funding from Universiti Malaysia Sabah; Skim Penyelidikan Pensyarah Lantikan Baru (SLB0181-2018) and Skim Penyelidikan Bidang Keutamaan (SBK0414-2018), respectively. The funding body was not involved in the study's design, analysis, or data interpretation.

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• Introduction
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Lin H , Chou H , Chiang Y , Chang R , Chen Y , Juan Y. Neurological or Psychiatric Disorders After Dengue Fever. JAMA Netw Open. 2024;7(5):e2410075. doi:10.1001/jamanetworkopen.2024.10075

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Neurological or Psychiatric Disorders After Dengue Fever

• 1 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
• 2 Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
• 3 Department of Orthopedics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
• 4 School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
• 5 Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
• 6 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
• 7 Department of Administration, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
• 8 Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan

Dengue fever, which has an estimated annual infection rate of up to 390 million, mainly affects Central and South America and Southeast Asia. 1 , 2 Apart from possible direct invasion of dengue fever virus to the neurological system, the disease has been reported to be associated with neurological complications probably attributable to autoimmune reactions and metabolic alterations. 3 Several studies 4 , 5 have found an association between dengue fever and neurologic and psychiatric disorders, including anxiety and depression symptoms. This retrospective nationwide cohort study attempted to further scrutinize the association between dengue fever and risk of subsequent neurological or psychiatric complications.

This cohort study, conducted in 2022, adhered to the STROBE reporting guidelines. Institutional review board approval was secured from the E-Da Hospital of Taiwan, which waived informed consent requisites owing to the anonymization of personal information.

Using data from the National Health Insurance Research Database, which covers 99% of the Taiwanese population, the research enrolled patients diagnosed with dengue fever from 2000 to 2015 who were propensity score matched at a 1:4 ratio with a comparator group without dengue fever based on various demographic and health factors. End points were the appearance of any outcome of interest, end of the study (ie, end of 2017), and death. The primary objective was to investigate whether dengue fever was associated with increased risk of neurological or psychiatric disorders. We excluded patients with preexisting conditions or who were younger than 18 years. The study used International Classification of Diseases, Ninth Revision ( ICD-9 ) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision ( ICD-10 ) codes to identify relevant diagnoses and Cox proportional hazards regression models for analysis.

A total of 48 884 adults with dengue fever (26 415 male [54.04%]; mean [SD] age, 43.08 [16.54] years) and 195 536 individuals without the diagnosis (105 660 male [54.04%]; mean [SD] age, 43.08 [16.54] years) were identified ( Table 1 ). Adjusted hazard ratios (aHRs) showed an increased risk for neurological and psychiatric disorders in the group with vs without dengue fever, including Guillain-Barré syndrome (1.10; 95% Cl, 1.03-1.18), myoneural junction disease (1.15; 95% CI, 1.08-1.23); Parkinson disease (1.44; 95% CI, 1.12-1.86); dementia (1.23; 95% CI, 1.07-1.41), and psychotic, mood, and anxiety disorders (1.13; 95% CI, 1.08-1.19). No significant difference was observed in the risk of intracranial hemorrhage or ischemic stroke ( Table 2 ). Subgroup analysis based on age reinforced main findings, with aHRs showing an increased risk of composite psychiatric disorders after dengue infection for all age groups (18 to 30 years: 1.14; 95% CI, 1.05-1.24; >30 to 60 years: 1.07; 95% CI, 1.02-1.12; >60 years: 1.22; 95% CI, 1.13-1.31), while a significantly increased risk of neurological disorders was observed in individuals older than 60 years (aHR, 1.17; 95% CI, 1.07-1.28). Sex subgroup analysis revealed a universally higher risk of neurological and psychiatric disorders in the dengue fever group ( Table 2 ).

This cohort study’s findings support those of previous research suggesting a potential association between dengue fever and neurological and psychiatric complications, especially in individuals older than 60 years. Although prior case reports and smaller studies 4 , 5 noted the neurotropic nature of the dengue fever virus, this study stands out due to its extensive scale and use of long-term, comprehensive national health data, which may avoid selection bias inherent in smaller datasets. 6 The study has several limitations. Diagnoses were based on ICD codes, which may be prone to misclassification. The lack of detailed patient information (eg, lifestyle factors and severity of dengue fever) may have influenced results. Furthermore, our findings may not be generalized beyond the Taiwanese population.

This population-based retrospective study provides updated epidemiological evidence for the association of dengue fever with increased risk of neurological and psychiatric disorders. Findings may highlight the need for awareness and monitoring of neuropsychiatric complications in this patient population. However, further research is necessary to understand mechanisms behind these associations.

Accepted for Publication: February 26, 2024.

Published: May 7, 2024. doi:10.1001/jamanetworkopen.2024.10075

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Lin HC et al. JAMA Network Open .

Corresponding Authors: Yao-Shen Chen, MD, Department of Administration, Kaohsiung Veterans General Hospital, Kaohsiung, No.386, Dazhong 1st Rd., Zuoying District, Kaohsiung City 813414, Taiwan ( [email protected] ); Yu-Chung Juan, MD, Department of Neurosurgery, China Medical University Hospital, Taichung, No. 2, Yude Rd., North District, Taichung City 404327, Taiwan ( [email protected] ).

Author Contributions: Dr Chang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lin and Chou contributed equally as first authors in this article.

Concept and design: Chou, Chiang, Chang, Chen.

Acquisition, analysis, or interpretation of data: Lin, Chou, Juan.

Drafting of the manuscript: Lin, Chou, Chiang, Chang.

Critical review of the manuscript for important intellectual content: Lin, Chou, Chen, Juan.

Statistical analysis: Chou, Chang, Chen.

Obtained funding: Lin, Chou.

Administrative, technical, or material support: Lin, Chou.

Supervision: Lin, Chen, Juan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by grants KSVGH-113-117 from Kaohsiung Veterans Hospital and EDAHS110009 from E-Da Hospital.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See the Supplement .

Additional Contributions: We acknowledge Chang-Bi Wang, PhD (E-Da Hospital), for his assistance in data collection, analysis, and table formatting. We acknowledge I-Ming Jou, PhD (E-Da Hospital.), for his assistance in interpretation of data in draft. These individuals were not compensated for this work.

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Open Access

Peer-reviewed

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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https://doi.org/10.1371/journal.pntd.0007280.g001

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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• 7. World Bank. World development Indicators: Philippines GDP per capita https://www.google.com/publicdata/explore?ds=d5bncppjof8f9_&met_y=ny_gdp_pcap_cd&hl=en&dl=en-!ctype=l&strail=false&bcs=d&nselm=h&met_y=ny_gdp_pcap_cd&scale_y=lin&ind_y=false&rdim=country&idim=country:PHL&ifdim=country&hl=en_US&dl=en&ind=false Accessed 10 June 2018.

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• Published: 14 October 2023

Early biomarkers for prediction of severe manifestations of dengue fever: a systematic review and a meta-analysis

• Samaneh Moallemi 1 , 2 ,
• Andrew R. Lloyd 2 &
• Chaturaka Rodrigo 1 , 2  

Scientific Reports volume  13 , Article number:  17485 ( 2023 ) Cite this article

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• Predictive markers

Early identification of dengue patients at risk of adverse outcomes is important to prevent hospital overcrowding in low- to middle- income countries during epidemics. We performed a systematic review to identify which biomarkers measured in first 96 h of fever could predict dengue haemorrhagic fever (DHF, World Health Organization 1997 clinical classification) or severe dengue (SD, WHO 2009, clinical classification). PubMed, Scopus, CINAHL, Web of Science, and EMBASE databases were searched for prospective cohort and nested case–control studies published from 1997 to Feb 27, 2022. The protocol for the study was registered in PROSPERO (ID: CRD42021230053). After screening 6747 publications, and analysing 37 eligible studies reporting on 5925 patients, elevated C-reactive protein, aspartate aminotransferase, interleukin-8 and decreased albumin levels were strongly associated with dengue haemorrhagic fever (by meta-analyses of multiple studies, p < 0.05), while elevated vascular cell adhesion protein 1, syndecan-1, aspartate aminotransferase and C-reactive protein levels were strongly associated with severe dengue (by meta-analyses of multiple studies, p < 0.05). Further 44 and 28 biomarkers were associated with the risk of DHF and SD respectively, but only in a single study. The meta-analyses suggest the importance of early acute inflammation with hepatic involvement in determining the subsequent course of illness in dengue.

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Introduction.

Dengue infection, despite having a case fatality rate of less than 1% 1 , imposes a significant burden on healthcare resources due to the very large number of infections reported annually (an estimated 50–200 million cases annually worldwide) 2 . Active disease transmission occurs in 128 countries, and most of the disease burden is in tropical, low- and middle-income countries 2 . The incidence of dengue in these countries is typically seasonal, with a large proportion of cases being reported within the space of a few months during and after the wet season, overwhelming limited healthcare resources and putting both dengue and non-dengue patients at risk of preventable adverse outcomes. In dengue, adverse outcomes mostly occur in a subgroup of patients experiencing plasma leakage (increased capillary permeability with fluid extravasation), and this typically occurs after the first 96 h, around days 5–7 of fever. Thus, a system to predict those at risk of severe disease early in the infection (within first 96 h of fever) could prevent unnecessary hospital admissions and enable early discharges, ensuring equitable distribution of resources to patients who will most likely benefit from hospital admission. Individual studies have identified demographic, clinical, genetic, virological and immunological risk predictors for severe disease, 3 but with often conflicting findings across studies.

Systematic reviews of these studies to identify commonly observed trends in risk predictors for severe dengue while adjusting for confounders across studies may be informative. Unfortunately, the quality of systematic reviews on dengue are affected by the heterogeneity of study designs and varied outcome definitions. The ideal study design for predicting risk factors for adverse outcomes in dengue is a prospective cohort study (or a nested case–control study within a prospective cohort) collecting data and samples for analysis within the first 96 h of the illness when the likelihood of serious adverse outcomes is low. Patients should then be followed prospectively to systematically record the occurrence of adverse outcomes according to criteria agreed a priori. Retrospective studies are unlikely to achieve the precision and reliability of prospective study designs because when outcomes (e.g., severe dengue, plasma leakage) are extracted from hospital records, the inter-observer bias (of those originally recording the observation) is not controlled. Furthermore, outcomes such as plasma leakage can be determined in several ways (haematocrit, ultrasonography or both) and uniformity of outcome definition cannot be guaranteed retrospectively as can be done by a study protocol for a prospective study. Even with prospective studies, the variation in outcome definitions reported in individual studies according to either the 1997 or 2009 World Health Organization clinical disease classifications 4 , 5 , as well as other classification systems (i.e., presence or absence of plasma leakage) 6 pose a problem for systematic reviews as these outcomes are not directly comparable to allow inclusion in a meta-analysis even if reporting on the same risk factor.

The aim of this systematic review was to identify host biomarkers, measured within the first 96 h of onset of disease, associated with severe disease manifestations recorded later in the course of illness. Only prospective cohort studies and nested case control studies were considered to preserve the quality of evidence. There are few previous systematic reviews which have examined a similar research question on dengue. However, these focussed only on children 7 , a single type of biomarker (e.g., lipoproteins) 8 , included retrospective or cross-sectional case control studies affecting the quality of evidence, or included measurements beyond the first 96 h of fever, thus diminishing the clinical relevance of evidence 9 . Some other comprehensive recent systematic reviews on risk associations for severe dengue do not address the topic of biomarkers in-depth 3 . The last review on biomarkers in dengue with comparable scientific rigor had a search date in 2019 10 , and several new eligible studies were published in the interval.

Inclusion criteria

Prospective cohort studies and nested case control studies, which recruited laboratory confirmed dengue patients (adults and children) within the first 96 h from the onset of illness and compared concentrations of biomarkers assessed within this time window, as predictors of prospectively defined disease severity categories were eligible. The definition of biomarkers in this review included peptides or proteins, metabolites, electrolytes, and lipoproteins measured in plasma/serum, urine or other body fluids (e.g., saliva). The adverse outcomes were classified according to three systems commonly used in dengue clinical research: dengue fever vs. dengue haemorrhagic fever grades I-IV 5 , dengue fever with or without warning signs vs. severe dengue 4 , and absence vs. presence of plasma leakage.

Retrospective and cross-sectional case control studies, studies reporting secondary data (systematic reviews), those not reporting biomarker measurements within the first 96 h of fever, those only reporting on demographic, genetic, transcriptomic, viral, haematological (cell counts), and clinical (signs and symptoms) risk predictors, and those only involving animal or in vitro studies were excluded. The full list of exclusion criteria is provided in Supplementary Table S1 .

Search strategy

We searched PubMed, Scopus, CINAHL, Web of Science and EMBASE using the keywords "dengue" and ("plasma leakage" OR "critical phase" OR "hemorrhag*" OR "DHF" OR shock), and ("risk" OR "biomarkers" OR "predict" OR "prognos*") in abstract, title and keywords, without language restrictions (Table 1 ). Bibliographies of eligible articles and that of previous similar systematic reviews were searched manually as a secondary search. Only articles published after 1997 were considered to maintain recency of evidence and to avoid conflicts in outcome definitions due to older clinical classifications. The last date of the search was 27th February 2022. Authors of eligible studies were contacted for missing information and both published and unpublished data were included.

Data collection and analysis

Study selection.

Two authors (SM and CR) independently screened abstracts and identified articles for full-text review. Any disagreements were resolved by consensus and after consulting with the third author (AL). In addition to exclusion criteria given in Supplementary Table S1 , some studies initially considered eligible were later removed after full-text review and these are listed in the characteristics of excluded tables (Supplementary Table S2 ).

Data extraction

From the included studies (Table 2 and Supplementary File S1 ), the following data were extracted: study population and time window of recruitment, country of origin, clinical classification system of severity, method of dengue diagnosis, method of biomarker measurement, sample size in each disease severity category, name and concentrations of biomarkers assessed. Initial data extraction was done by SM using Microsoft Excel 365 and all entries were independently re-checked by CR. When studies reported biomarker levels for the entire duration of the illness, only data reported for the first 96 h of fever (or a time window within that period) were extracted. If the biomarker concentrations and their variance were only reported in a figure (not in text or within supplementary material), an enhanced version of the figure was printed out and measures of central tendency (e.g., mean, median) and the measure of dispersion (e.g., standard deviation or interquartile range) was estimated from the y axis of the graph. Data reported as relative concentrations or fold changes (instead of absolute values) were only considered for narrative descriptions. For meta-analyses, median and interquartile ranges were converted to mean and standard deviation using an approximation method described by Wan et al. 11 . Standard error of mean and confidence intervals of mean were converted to standard deviation using methods described in the Cochrane handbook 12 .

Quality assessment

Multiple quality assessment tools were considered for this study and the closest which met the requirements for this meta-analysis was the tool developed by Wirsching et al. 50 to assess the quality of biomarker based cross-sectional studies (BIOCROSS). A version with minor modifications was developed to fit prospective cohort studies (Supplementary Table 3 ). The quality of studies was independently evaluated by CR and SM. The modified BIOCROSS tool includes ten items covering five domains: ‘Study rationale’ ‘Design/Methods’ ‘Data analysis’, ‘Data interpretation’, and ‘Biomarker measurement’ with a maximum score of 20. An arbitrary cut-off score of 14 (70% of total score) was used to define “Tier 1” studies of high quality. All other studies were assigned to “Tier 2”. Any disagreements were resolved by consensus of all authors. Study quality assessment was also recorded on a Microsoft Excel 365 worksheet.

Data analysis

Studies were combined in a meta-analysis only if they were comparable both for the biomarker assessed and the outcomes reported (e.g., WHO 1997 or 2009 clinical guidelines). If one study reported daily variation of biomarkers and another the mean value over many days within the 96-h time window, daily mean and standard deviation values were combined according to the Cochrane-recommended formula for meta-analysis to have the overall mean and standard deviation representative of the 96 h period 51 . Some studies combined all 4 grades of dengue haemorrhagic fever (DHF I-IV) together, while others reported biomarker levels separately. To avoid heterogeneity, such studies were not combined. Meta-analyses were done with Review Manager version 5.4.1. (Cochrane Collaboration, 2020) using a fixed effect model. A p-value < 0.05 was considered statistically significant.

Assessment of heterogeneity

The strict selection criteria mentioned above was expected to reduce study heterogeneity in a meta-analysis, but we also assessed heterogeneity post-meta-analyses using the I 2 statistic (> 70% for high heterogeneity) 51 . In the case of high heterogeneity, the results were re-analysed with a random effects model.

Assessment of reporting bias

This was performed only if more than 10 studies were eligible to be combined in a single meta-analysis.

Subgroup and sensitivity analysis

A subgroup analysis was not done. However, a sensitivity analysis undertaken by combining following categories as “severe disease”: severe dengue according to 2009 WHO classification, all categories of DHF according to 1997 WHO classification, and plasma leakage when this outcome alone was reported. All other patients were categorised as “non-severe disease”. This approach has been used previously in a meta-analysis by Sangkaew et al. 3 .

Study protocol

The protocol for this systematic review was registered in PROSPERO ( https://www.crd.york.ac.uk/prospero/ , ID: CRD42021230053).

Thirty-seven studies that included 5925 patients met the inclusion criteria. Of these, 17 studies reported outcomes according to the WHO 1997 clinical classification (DF vs. DHF) 14 , 15 , 16 , 17 , 19 , 20 , 21 , 22 , 24 , 28 , 32 , 33 , 36 , 38 , 39 , 40 , 45 , and 17 reported outcomes according to the WHO 2009 clinical classification 18 , 25 , 26 , 27 , 29 , 30 , 31 , 34 , 35 , 37 , 41 , 42 , 44 , 46 , 47 , 48 , 49 , One study reported outcomes according to both WHO clinical classifications 13 , and two reported the severity outcome as the presence or absence of plasma leakage 23 . Since the latter group had only a limited number of studies, presence of plasma leakage in this group was considered as similar to DHF in the 1997 clinical classification for the purpose of the meta-analyses. Thirteen studies initially considered as eligible were later excluded (see excluded studies table, Supplementary Table S2 ). The eligible studies recruited patients between 1995 and 2019, mostly from South and Southeast Asian countries and Latin American countries. 19 studies were combined in a meta-analysis as two or more reported on the same biomarkers and outcomes (Fig.  1 ). Seven studies, despite measuring a biomarker that had been assessed in one or more other studies, did not report variation of measurements or the units of measurements 14 , 20 , 21 , 24 , 31 , 37 , 49 . Three studies reported only percentage or -fold differences between patient groups 17 , 30 , 39 . The results of these studies and those that reported on a biomarker not assessed in another study are discussed narratively. Authors of eight studies were contacted for further information 14 , 15 , 20 , 21 , 24 , 31 , 34 , 39 , but only those from two studies responded 15 , 34 .

PRISMA flow diagram of study selection.

Risk of bias and study quality assessment

Of the included studies, twenty-three were classified as Tier 1 studies according to BIOCROSS grading and the rest were Tier 2 studies. The range of total scores varied from 10 to 17. Most of the variation was accounted for by poor scoring in BIOCROSS items 3, 4, 8, 9, 10 which indicates problems in representativeness of study populations, poor reporting of study population characteristics, inadequate details of specimen characteristics and assay methods, laboratory measurements (i.e., quality control measures, testing samples in duplicate), and insufficient information on biomarker data modelling (i.e., normal or non-normal distribution of data, handling of outliers). The scores for each BIOCROSS item for all studies are given in Supplementary Table S4 .

Biomarkers predicting the risk of dengue haemorrhagic fever (WHO 1997 classification)

Twenty-four biomarkers assessed by eleven studies were eligible to be combined in a meta-analysis 13 , 15 , 16 , 22 , 23 , 28 , 34 , 36 , 38 , 40 , 45 (Fig.  2 a and b). Of these only four biomarkers showed statistically significant results associated with DHF. These were increased aspartate aminotransferase levels (AST, RR: 48.72, 95% CI 19.20, 78.23, 2 studies, 534 participants, p = 0.001) 34 , 40 , increased C-reactive protein levels (CRP, RR: 0.51, 95% CI 0.46, 0.56, 3 studies, 480 participants, p < 0.00001) 15 , 22 , 34 , increased interleukin-8 (IL-8 or CXCL8, RR: 17.87, 95% CI 7.73, 28, 2 studies, 114 participants, p < 0.0005) 16 , 22 , and decreased serum albumin levels (RR: − 1.64, 95% CI − 3.21, − 0.07, 2 studies, 534 participants, p = 0.04) 34 , 40 . The biomarkers which were not significantly associated with the risk of DHF (p > 0.05) were angiopoietin-2 (Ang-2, 2 studies, 148 participants) 15 , 28 , granulocyte colony stimulating factor (G-CSF, 2 studies, 114 participants) 16 , 22 , interferon gamma (IFN-γ, 3 studies, 359 participants) 16 , 22 , 38 , interleukin-4 (IL-4, 2 studies, 114 participants) 16 , 22 , interleukin-6 (IL-6, 2 studies, 407 participants) 22 , 38 , interleukin-10 (IL-10, 4 studies, 570 participants) 15 , 16 , 22 , 38 , interleukin 1 beta (IL-1β, 2 studies, 114 participants) 16 , 22 , macrophage inflammatory protein-1 beta (MIP-1β or CCL3, 2 studies, 114 participants) 16 , 22 , tumour necrosis factor alpha (TNF-α, 2 studies, 397participants) 16 , 38 , vascular endothelial growth factor (VEGF, 2 studies, 234 participants) 15 , 22 , Regulated upon activation normal T Cell expressed and presumably secreted chemokine (RANTES or CCL5, 2 studies, 114 participants) 16 , 22 , low-density lipoprotein (LDL, 2 studies, 988 participants) 13 , 40 , high-density lipoprotein (HDL, 2 studies, 988 participants) 13 , 40 , total cholesterol (TC, 2 studies, 988 participants) 13 , 40 , fibroblast growth factor-basic (FGF, 2 studies, 114 participants) 16 , 22 , Angiopoietin-1 (Ang-1, 2 studies, 148 participants) 15 , 28 , complement Factor D (2 studies, 223 participants) 15 , 45 , alanine aminotransferase (ALT, 2 studies, 534 participants) 34 , 40 , creatinine phosphokinase (CPK, 2 studies, 534 participants) 34 , 40 , Syndecan-1 (SDC1, 2 studies, 137 participants) 23 , 36 . Of these G-CSF, MIP-1β and TNF-α had statistically significant differences when assessed with a fixed effect model but were noted to have high heterogeneity. When re-analysed with random effects model, the results were not statistically significant.

Meta-analysis of biomarkers between patients with dengue haemorrhagic fever (DHF) and those with non-DHF dengue fever (DF)—( A ) Fixed effect model, ( B ) random effect model.

Fourteen studies that assessed DHF as an outcome reported on 139 biomarkers that were assessed in a single study only (no two studies assessed the same biomarker) 15 , 16 , 17 , 19 , 22 , 23 , 24 , 32 , 36 , 38 , 39 , 40 , 43 , 45 . Of these, six studies did not report variations of measurements, units of biomarker analysis or absolute abundance 14 , 17 , 20 , 21 , 24 , 39 . The number of participants in these 14 studies ranged from 34 to 344. Forty-four additional biomarkers were identified as being significantly (p < 0.05) associated with DHF but as mentioned before the evidence is restricted to a single study per biomarker. A full list of these biomarkers is shown in Table 3 .

Biomarkers predicting the risk of severe dengue (WHO 2009 classification)

Seven biomarkers assessed by seven studies were eligible to be combined in a meta-analysis 26 , 29 , 34 , 41 , 42 , 44 , 48 (Fig.  3 ). Of these four biomarkers were statistically significantly associated with the risk of severe dengue. There were: increased CRP (RR: 9.79, 95% CI 5.14–14.44, 3 studies, 2289 participants, p < 0.00001) 34 , 41 , 42 , increased vascular cell adhesion protein 1 (VCAM1, RR: 709.18, 95% CI 465.43–952.93, 2 studies, 861 participants, p < 0.00001) 41 , 44 , increased Syndecan-1 (RR: 0.71, 95% CI 0.52–0.90, 2 studies, 884 participants, p < 0.00001) 29 , 41 , and increased levels of AST (RR: 17.70, 95% CI 7.98–27.43, 4 studies, 1582 participants, p = 0.0004) 26 , 34 , 42 , 48 . The remaining biomarkers: ALT (4 studies, 1586 participants) 26 , 34 , 42 , 48 , alkaline phosphatase (ALP, 2 studies, 347 participants) 34 , 48 , and CPK (2 studies and 1347 participants) 34 , 42 were not associated with a higher risk of severe dengue (p > 0.05). Notably serum SDC1 levels were not associated with DHF, although they were significantly associated with severe dengue.

Meta-analysis of biomarkers between patients with severe dengue (SD) and others with dengue fever (DF)—fixed effect model.

Eleven studies that assessed SD as an outcome reported on 41 biomarkers that were assessed in one study only 18 , 27 , 29 , 30 , 31 , 34 , 35 , 41 , 46 , 48 , 49 . Three of these studies did not report variations of measurements or units of biomarker analysis 30 , 31 , 49 . The number of participants in these 11 studies ranged from 42 to 837. Twenty-eight additional biomarkers were identified as been significantly (p < 0.05) associated with SD where the evidence is restricted to one study per biomarker. A full list of these biomarkers is shown in Table 4 .

Sensitivity analysis

When the diagnoses of both DHF and SD were combined as “severe disease”, fourteen biomarkers assessed in seventeen studies were eligible to be combined in a meta-analysis 15 , 16 , 22 , 23 , 25 , 26 , 28 , 29 , 33 , 34 , 36 , 39 , 40 , 41 , 42 , 44 , 48 (Fig.  4 a and b). Of these, six biomarkers were statistically significantly associated with the progression to severe disease. There were increased Ang-2 (RR: 0.49, 95% CI 0.36–0.62, 3 studies, 985 participants, p < 0.00001) 15 , 28 , 41 , increased AST (RR: 19.96, 95% CI 10.56–29.37), 5 studies, 1781 participants, p < 0.0001) 26 , 34 , 40 , 42 , 48 , increased SDC-1 (RR: 0.71, 95% CI 0.52–0.90, 4 studies, 1021 participants, p < 0.00001) 23 , 29 , 36 , 41 , increased VCAM-1 (RR: 680.15, 95% CI 438.95–921.35, 3 studies, 863 participants, p < 0.00001) 25 , 33 , 41 , 44 , increased interferon-gamma-induced protein-10 ( IP-10 or CXCL10, RR: 1.33, 95% CI 0.35–2.30, 2 studies, 948 participants, p = 0.008) 15 , 41 , and increased hyaluronan (RR: 1.22, 95% CI 0.71–1.73, 2 studies, 211 participants, p < 0.00001) 26 , 36 . The remaining biomarkers that did not show significant differences (p > 0.05) between severe and non-severe disease were albumin (3 studies, 1639 participants) 34 , 40 , 42 , ALT (5 studies, 1785 participants) 26 , 34 , 40 , 42 , 48 , CPK (3 studies, 1546 participants) 34 , 40 , 42 , CRP (5 studies, 2434 participants) 15 , 22 , 34 , 41 , 42 , IL-10 (5 studies, 582 participants) 15 , 16 , 22 , 38 , 48 , IL-8 (3 studies, 951 participants) 16 , 22 , 41 , interleukin-17 (IL-17, 2 studies, 92 participants) 22 , 48 and interleukin-1 receptor antagonist (IL-1ra, 2 studies, 899 participants) 22 , 41 . Of these, CRP, IL-17, IL-1ra and IL-8 showed statistically significant results with high heterogeneity when using a fixed effects model, and the results were insignificant when re-analysed with a random effects model.

Meta-analysis of biomarkers between patients with severe disease (SD + DHF combined) and non-severe disease—( A ) Fixed effect model, ( B ) random effect model.

There were no data available to conduct a sensitivity meta-analysis by day of fever for any of the biomarkers. When Tier 2 studies were removed from the meta-analyses (to see if same associations remain when only studies with a lower risk of bias were considered) statistically significant results remained for all four biomarkers for DHF (albumin, CRP, AST, IL-8). However, for severe dengue (WHO 2009 criteria) only the association with AST remained (out of four previously significant biomarker associations). Similarly, for the “severe disease” category outlined in the previous paragraph, only two (CRP, AST) out of six significant associations remained after removal of Tier 2 studies. (Supplementary Fig. S1 a and b).

Ranking of biomarkers according to quality of evidence

A list of all biomarkers assessed in one or more of included studies in this review is listed accompanied with a ranking score in Supplementary File S2 according to the quality of evidence for each biomarker.

Summary of main results

In this meta-analysis elevated serum CRP and AST levels in early disease (up to 96 h of fever) were associated with an increased risk of progression to either DHF (WHO 1997 classification) or severe dengue (WHO 2009 classification). In addition, early increased levels of VCAM-1 and SDC-1 were also associated with increased risk of severe dengue, while increased IL-8 and lowered albumin were associated with an increased risk of DHF. Furthermore, 44 and 28 biomarkers were identified to be statistically significantly different in those developing DHF and SD respectively, in one-off studies that needs confirming in a second study. The association with severe disease and elevated AST was consistently observed across all disease severity classifications and sensitivity analyses performed within this systematic review.

Overall completeness and applicability of evidence

The methods of studies included in this review were highly heterogenous with different assays used to measure the same biomarker, patients from different countries and age groups included, measurements taken on different days within the 96-h period, and the final results being reported against two different dengue clinical classification systems. It is not possible to control for all these confounders without compromising the capacity to perform meta-analyses, but the quality of evidence was preserved by only including data from prospective cohort studies which conducted biomarker measurements within the first 96 h of fever, prior to the establishment of adverse disease manifestations. The results were reported separately for DHF (WHO 1997 classification) and severe dengue (WHO 2009 classification) to further reduce heterogeneity as these two clinical classifications are quite different. While there is a precedent for combining DHF and SD manifestations as “severe disease” 3 , the clinical utility of this approach is questionable as in our opinion as local guidelines in a country generally utilise one classification or the other. Overall, the findings of this review for each biomarker should only be applied within the participant (ethnicity, age group) and disease severity outcome groups for which evidence exists and should not be extrapolated to groups that were not assessed in primary research studies.

The top biomarkers identified in this review as associated with DHF have a common “hepato-centric” theme. AST elevation reflects hepatocellular injury resulting from direct viral infection or from the associated inflammation are the likely source for this observation 52 , 53 , 54 ). CRP is an acute phase reactant produced by the liver in response to acute inflammation 55 . Serum albumin, a multi-functional plasma protein produced by the liver is a negative acute phase reactant, meaning it is downregulated in inflammatory states 56 , or it may be catabolised, or lost from the circulation in the early stages of plasma leakage. All these patterns suggest that those who go on to have DHF have a more profound early liver involvement. Interestingly, although IL-8 or neutrophil chemotactic factor was the fourth biomarker associated with DHF, neutrophil accumulation in the liver is not a feature of dengue hepatitis. This chemokine which is produced by macrophages, epithelial cells and endothelial cells not only underpins acute neutrophilic inflammation but also promotes angiogenesis 57 . Nevertheless in early dengue fever, a neutrophilia is sometimes observed, prior to the relative lymphocytosis, and IL-8 may play a role in this manifestation 58 . Again, this effect may be more profound in those who go on to develop DHF.

In relation to severe dengue, in addition to CRP and AST, SDC-1 and VCAM-1 were also significant associations. Syndecans are transmembrane domain proteins (proteoglycans) that interact with several growth factors (VEGF, FGF, TGF-β) leading to their activation, and play an important role in cell-to-cell or cell-to-extracellular matrix adhesion. Syndecan-1 is predominantly expressed in epithelial and plasma cells 59 . VCAM-1 is another cell adhesion molecule of the immunoglobulin superfamily, which is expressed on endothelial cells in inflammation after stimulation by cytokines such as TNF-α, IL-1, IL-4) 60 . Elevation of both these biomarkers selectively in those developing severe dengue is interesting and potentially hints at a direct and early role of these molecules in the disease pathogenesis and plasma leakage. Both these biomarkers may still be relevant in DHF, except that there was insufficient evidence to assess in the meta-analysis. Given that patients with severe dengue generally have worse outcomes than DHF patients 4 , it is plausible that early biomarker profiles associated with these two outcomes may be different. By contrast, the meta-analyses reveal that CRP and AST are both early biomarkers of severe manifestations regardless of the outcome classification. It is interesting that elevation of ALT, the second transaminase which is also released with hepatocyte necrosis and hepatic inflammation was not associated with either SD or DHF. This raises the possibility that part of the AST elevation in serum may come from skeletal muscle, given that myalgia is a prominent symptom in early dengue infection.

Quality of the evidence

The biomarkers were arranged according to the quality of evidence in Supplementary File S2 in the following categories. Given the absence of a precedence to classify evidence in a similar review, these criteria were developed by the authors specifically for this review. The quality of evidence is highest for the categories of either extreme (categories I and VIII) and declines towards the middle.

Category I—confirmed as statistically significant in a meta-analysis.

Category II—confirmed as statistically significant in two or more studies that cannot be combined in a meta-analysis due to inadequate data reporting, differences in units of measurement or other reasons.

Category III—confirmed as statistically significant in one Tier 1 study.

Category IV—confirmed as statistically significant in one Tier 2 study.

Category V—confirmed as statistically insignificant in one Tier 2 study.

Category VI—confirmed as statistically insignificant in one Tier 1 study.

Category VII—confirmed as statistically insignificant in two or more studies that cannot be combined in a meta-analysis.

Category VIII—confirmed as statistically insignificant in a meta-analysis.

Potential biases of the review process

As mentioned, the evidence presented in this systematic review comes mostly from studies in South or South-eastern Asian and Latin American countries. There may be ethnic (including genetic and environmental factors), as well as viral serotype determined differences in immunity to dengue virus, which limits the extrapolation of results beyond the communities that were assessed in the primary research. Importantly this review does not differentiate between adults and children. As the criterion for inclusion children was different in each country (ranging from 12 to 18 years), it was not possible to have a uniform age consensus to extract data for a separate meta-analysis in children. It was also not possible to differentiate between primary and secondary dengue or infecting serotype as only a few eligible studies reported results stratified by these variables. It is well established that due to non-neutralising cross-reactive antibodies, secondary dengue infections from a different serotype are more likely to have severe manifestations. Finally, this analysis considers the first 96 h of infection as a “homogenous” period in the course of illness. This is not likely to be accurate as the disease evolves considerably even within this short time window. While an attempt was made to separate results by day of fever in the sensitivity analysis, it was not possible to do a meta-analysis for any of the biomarkers, due to inconsistent and inadequate reporting across eligible studies.

Agreements and disagreements with other similar reviews

The most recent similar systematic review by Thach et al. 10 on this topic had a search date of 20th September 2020, 1.5 years prior to the search date of this review. Six included studies in the current systematic review were published in 2021, and hence were not considered in the previous review. Thach et al. only considered data within the first 72 h of fever, while this review extended the period of interest to 96 h, provided an adverse outcome had not been recorded within this time window or at admission. The current review was restricted to studies with biomarkers, providing an in-depth exhaustive analysis of various biomarkers assessed for associations with severe disease paying attention to both significant and insignificant associations. The previous review also considered cell or platelet counts, viral determinants (e.g., viral load), as well as clinical symptoms and signs, and hence the focus and data generated on biomarkers was considerably less with results presented only for biomarkers that were combined in a meta-analysis. The risk of bias in the previous review was assessed using the National Heart, Lung, and Blood Institute (NHLBI) tool 61 , whereas the BIOCROSS tool 50 used in this review includes all relevant aspects covered by the NHBLI tool, but also has additional domains more tailored to quality assessment of biomarker studies. It is a challenge to find a tool to evaluate the quality of studies that have assessed biomarkers as most tools focus on clinical study designs and patient focussed outcomes (e.g., NHLBI tools). Problems such as reliability of assay measurements, test to test variation are not addressed in these tools. In our opinion, BIOCROSS is a more detailed, comprehensive tool which considers the errors in biomarker measurement and hence more suited for this type of review. The outcome classifications in the previous review are also different with DHF grades III and IV (WHO 1997 classification) and severe dengue (WHO 2009 classification) combined as “severe disease” and everything else as “non-severe”. The current review avoided combining different classification systems in the main analysis for ease of interpretation in patient management and better utilisation of data in research as most management guidelines and research studies use one classification or the other (rather than a combination). Despite these differences, both reviews agree that serum AST is a significant association for severe disease, and that serum ALT is not. Thach et al. did not observe a significant association with CRP and albumin levels with severe disease. although these results should be interpreted in the context of differences highlighted above. Data on IL-8, SDC-1 or VCAM-1 were not mentioned in the previous review.

Two other recent reviews by Sangkaew et al. 3 (last date of search: 31st January 2020) and Yuan et al. 9 (last date of search: December 2020) also assessed predictors for severe disease manifestations. However, both reviews considered a large number of demographic, clinical, immunological and virological parameters to process, and so considered biomarkers in limited detail. For example, Sangkaew et al. only reported variables that had been reported in four or more studies only, which reduced their reporting to only three biomarkers (elevated AST, ALT, and reduced albumin levels) presumably because these were the only statistically significant associations for severe disease. Sangkaew et al. combined clinical classifications from the WHO 1997 and 2009 guidelines to define a new “severe disease” category for the purpose of meta-analysis. For reasons mentioned above, the current review kept these classifications separate in the main analysis, but in sensitivity analysis the approach taken by Sangkaew et al. was followed. In that sensitivity analysis our results were similar for AST, but not for ALT or albumin, but these differences could not be further examined as individual studies backing these observations could not be identified from the previous review. It is noted however that when multiple observations were made of a biomarker during the febrile phase, Sangkaew et al. only considered the value reported on day 3 of fever while the current review used the average of all readings. The other review by Yuan et al. reported on several biomarkers, but the inclusion criteria were not restricted to the data from the first 72–96 h of fever or the “febrile” phase. Hence, the clinical utility of this review is limited in identifying early predictive biomarkers for severe disease and therefore, its findings cannot be compared with the present analysis.

Conclusions

Implications for practice.

This review identified several biomarkers that are differentially expressed in early disease in those who subsequently develop SD or DHF. Markers such as CRP, AST, and albumin are routinely measured even in resource limited settings as part of disease management. Clinicians and guideline development committees should consider analysing existing datasets to identify appropriate cut-off values for these parameters which can then be used in a clinical risk prediction system in combination with other non-biomarker severity predictors.

Implications for research

Biomarkers IL-8, VCAM-1 and Syndecan-1 identified in this review as predictors do not have low-cost tests to assess their concentration in human serum. Development of such tests will further enhance the predictive value of risk scoring systems within resource limited settings. In addition, there are many biomarkers already shown to be associated with severe disease manifestations in a single study where confirmation by a second study would increase the quality and certainty of evidence through a meta-analysis (biomarkers in categories II – IV in the quality of evidence ranking system). Prioritising immediate research on these biomarkers would be cost effective and potentially high yield in terms of generating clinically useful evidence for predicting severe manifestations of dengue fever.

Differences between review and protocol

The title of the protocol “early prognostic biomarkers for severe dengue and plasma leakage” was changed as the review encompasses all adverse manifestations namely severe dengue, DHF and plasma leakage. The search strategy was altered to capture relevant more articles than initially intended. The exclusion criteria were expanded as indicated above in the review compared to the protocol. DHF was included as a comparator group to the review (not mentioned in protocol) given the large number of studies using the 1997 WHO clinical classification for dengue.

Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information files).

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Acknowledgements

This research was supported by the National Health and Medical Research Council (NHMRC) under grant number APP1150078 and APP1173666. We would also like to express our appreciation to the University of New South Wales for providing resources and conducive research environment.

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Samaneh Moallemi & Chaturaka Rodrigo

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Moallemi, S., Lloyd, A.R. & Rodrigo, C. Early biomarkers for prediction of severe manifestations of dengue fever: a systematic review and a meta-analysis. Sci Rep 13 , 17485 (2023). https://doi.org/10.1038/s41598-023-44559-9

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DOI : https://doi.org/10.1038/s41598-023-44559-9

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As warming temperatures make many parts of the world increasingly hospitable to mosquitoes, the risk for dangerous tropical illnesses, such as dengue infection and chikungunya, is expected to spread .

Desiree LaBeaud and Dr. Bryson Ndenga search for mosquito larvae in a discarded tire in Kisumu, Kenya. (Image credit: HERI-Kenya)

In the face of this growing threat, a new study by Stanford researchers and their Kenyan colleagues sheds light on the factors that put communities at risk for these illnesses – including the presence of trash. With this knowledge, researchers say, communities can better protect themselves from infection.

The first-of-its-kind study followed a cohort of 3,521 children in western and coastal Kenya from 2014-2018, testing them for evidence of three potentially deadly, mosquito-borne illnesses: dengue, chikungunya, and malaria. Researchers followed children because it was easier to understand when and where infections occurred in this younger cohort. By mapping the infections and comparing them with demographic data they gathered, researchers found overlapping hot spots for all three diseases across multiple years. The hot spots were associated with the presence of litter near homes, crowded living arrangements, and relatively greater wealth.

The trash-disease connection

The study, published March 29 in BMC Infectious Diseases , adds to a growing body of research that finds strong links between plastic trash and mosquito-borne illness. With formal trash collection still a burgeoning trade in Kenya, many households instead manage their waste by storing it outside their homes and eventually burning it. Plastic containers and rubber tires can hold water that pools during heavy rains, making an ideal breeding ground for mosquitoes.

“These findings underscore our growing concerns over the risks that trash, particularly plastic waste, poses to human health,” said senior author Desiree LaBeaud , MD, a professor of pediatric infectious diseases and global health faculty fellow at the Stanford Center for Innovation in Global Health . “Empowering people to clean up trash from their communities is a clear win-win for human and environmental health.”

Exploring under-studied diseases

The study evolved from the researchers’ desire to better understand the prevalence of two mosquito-borne illnesses, dengue and chikungunya. Like malaria, these diseases are spread by mosquito bites and cause high fever and joint pain. While the symptoms are often mild to moderate, dengue and chikungunya infections can become severe, even deadly.

HERI-Kenya volunteers collected more than 1,000 pounds of trash during a recent trash cleanup in the town of Ukunda in November 2021. (Image credit: HERI-Kenya)

Despite this, there is little awareness or testing capacity to promptly diagnose dengue and chikungunya in Kenya. Researchers suspected that dengue and chikungunya were in fact responsible for many of the infections attributed to malaria, which is often assumed to be the cause of patients’ fevers.

“When a patient comes into the clinic with a fever, it’s important to be able to make an accurate diagnosis,” said Aslam Khan , DO, a clinical assistant professor of pediatric infectious diseases, global health faculty fellow, and lead author of the study. “Without the ability to make an accurate diagnosis, we risk over-prescribing ineffective antimalarials or antibiotics, building antibiotic resistance.”

Common hotspots offer win-win solutions

Overall, 9.8% of children in the study had antibodies in their bloodstream indicating a prior infection for chikungunya and 5.5% were for dengue. Of children who were tested, 39.1% were positive for malaria. The researchers were surprised to find hot spots where the risk for all three diseases was higher.

Desiree LaBeaud and Kenyan colleague Dr. Francis Mutuku plant saplings in discarded plastic containers recovered during a trash cleanup with local schoolchildren in March 2018. (Image credit: Desiree LaBeaud)

“These common hot spots suggest that both the built environment and social factors can significantly influence the risk of various mosquito-borne infections,” said Khan.

The study also indicated that malaria risk had the strongest association with litter.

Currently, most of Kenya’s prevention measures are targeted toward the Anopheles species of mosquito that causes malaria, which bites at night. For instance, bed netting is a common malaria intervention that does little to prevent dengue or chikungunya, which are spread by a mosquito active during the day. This study, Khan said, revealed measures that could be effective at targeting both mosquitoes, including using window screens, eliminating open water containers, and removing trash from around homes.

LaBeaud noted that the link between trash and malaria was particularly interesting given that a new malaria vector, Anopheles stephensi, was recently discovered for the first time in northern Kenya. Like the Aedes aegypti mosquito that spreads dengue and chikungunya, Anopheles stephensi has adapted to breeding in human-made water containers in urban areas. LaBeaud’s team is exploring future studies to see if this mosquito is involved in malaria transmission where they are working.

HERI Kenya, a nonprofit organization co-founded by LaBeaud in response to her findings about the connection between plastic trash and disease, is working to empower and educate Kenyan communities to clean up and recycle plastic trash.

Doing so offers many additional health and economic benefits to the community, including reduced pollution, fewer toxic fumes from burning waste, and new income opportunities for recyclers, LaBeaud said.

Khan hopes the study will also help support increased awareness and testing capacity for dengue and chikungunya. He said he has already seen a shift in awareness on the part of the health workers who helped with the study. “Our community team members are now very cognizant that dengue and chikungunya could be the culprits when they see a sick patient,” he said.

LaBeaud is also a senior fellow of the  Stanford Woods Institute for the Environment and a member of  Bio-X and the Maternal & Child Health Research Institute . Khan is also a global health faculty fellow at the Stanford Center for Innovation in Global Health and a member of the Maternal & Child Health Research Institute, which supported his salary for work on this project.

This research was funded by the National Institutes of Health.

To read all stories about Stanford science, subscribe to the biweekly  Stanford Science Digest .

Media Contacts

Aslam Khan, School of Medicine: (415) 562-7326; [email protected]

Jamie Hansen, Global Health Communications Manager: (707) 536-1436; [email protected]

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 7—July 2024

Research Letter

Emergence of indigenous dengue fever, niger, october 2023.

Suggested citation for this article

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

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

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

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

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

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

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

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

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

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

Acknowledgments

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

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

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

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

DOI: 10.3201/eid3007.240301

Original Publication Date: May 23, 2024

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

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