Skip to main content
Advertisement
  • Loading metrics

Trends in dengue research in the Philippines: A systematic review

  • Kristal An Agrupis,

    Roles Data curation, Writing – review & editing

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

  • Michelle Ylade,

    Roles Writing – review & editing

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

  • Josephine Aldaba,

    Roles Writing – review & editing

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

  • Anna Lena Lopez,

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

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

  • Jacqueline Deen

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

    deen.jacqueline@gmail.com

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

Abstract

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.

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.

Methods

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.

Results

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 [851], 21 (16%) entomologic or vector control studies [5272], 16 (12%) studies on dengue virology and serologic response [7388], 13 (10%) socio-behavioral and economics studies [89101], 11 (8%) clinical trials [102112], 10 (7%) on burden of disease [113122], 10 (7%) investigations on markers of disease severity [123132], 7 (5%) on dengue diagnostics [133139], and 3 (2%) modeling studies [140142]. The majority (102/135, 76%) of the dengue research locations were in Metro Manila.

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).

thumbnail
Fig 2. Comparison of annual number of Philippine and worldwide dengue publications.

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 [851]. 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 [5272], six investigated dengue mosquito vector key breeding sites and potential interventions [52, 5658, 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 [7488]. 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 [8993, 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 [102105] and seven were on vaccine trials [106112]. 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 [106108, 110112], 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 [113122]. 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, 119121]. 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.

thumbnail
Table 1. Estimated incidence of laboratory-confirmed symptomatic dengue infections from studies in the Philippines.

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 [123127, 130132], 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 [133135, 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 [140142]. 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.

Discussion

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

References

  1. 1. Quintos FN, Lim L, Julians L, Reyes A, Lacson P. Hemorrhagic fever observed among children in the Philippines. Philippine Journal of Pediatrics. 1954;3(1).
  2. 2. Lim LE, Stransky E. On infectious acute thrombocytopenic purpura (hemorrhagic fever) observed in children in the Philippines. Annales paediatrici International review of pediatrics. 1956;187(4):309–20. Epub 1956/10/01. pmid:13363112.
  3. 3. Bravo L, Roque VG, Brett J, Dizon R, L'Azou M. Epidemiology of dengue disease in the Philippines (2000–2011): a systematic literature review. PLoS neglected tropical diseases. 2014;8(11):e3027. pmid:25375119; PubMed Central PMCID: PMCPMC4222740.
  4. 4. Philippines National Statistics Office. 2015 Census of Population. https://psa.gov.ph/content/highlights-philippine-population-2015-census-population Accessed 10 June 2018.
  5. 5. World Health Organization. The Philippines health system review. 2011 http://www.wpro.who.int/philippines/areas/health_systems/financing/philippines_health_system_review.pdf Accessed 10 June 2018.
  6. 6. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS medicine. 2009;6(7):e1000097. pmid:19621072; PubMed Central PMCID: PMCPMC2707599.
  7. 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.
  8. 8. Del Mundo F, Barrion LE. Dengue and dengue-like fevers in children. Journal of the Philippine Medical Association. 1963;39:42–53. Epub 1963/01/01. pmid:14026564.
  9. 9. Mundo FD, Barrion LE. Further observations on dengue infections among Filipino children (1964). Journal of the Philippine Medical Association. 1965;41(6):390–5. Epub 1965/06/01. pmid:5828783.
  10. 10. Basaca-Sevilla V. The hemorrhagic-fever problem in the Philippines and some laboratory findings. Journal of the Philippine Medical Association. 1966;42(11):687–700. Epub 1966/11/01. pmid:5979374.
  11. 11. Basaca-Sevilla V, Halstead S. Laboratory detection of arthropod-borne virus infection in the Philippines. Journal of the Philippine Medical Association. 1966;1966.
  12. 12. Reyes VM. The pathology of hemorrhagic fever in the Philippines. Bulletin of the World Health Organization. 1966;35:49–50. pmid:20604243
  13. 13. San Juan RB, Dizon JJ. Epidemiological research on Philippine hemorrhagic fever. Journal of the Philippine Medical Association. 1966;42(11):795–820. Epub 1966/11/01. pmid:5978414.
  14. 14. Basaca-Sevilla V. Recent incidence of hemorrhagic fever in the Philippines. Japanese journal of medical science & biology. 1967;20 Suppl:75–9. Epub 1967/12/01. pmid:5301569.
  15. 15. Caviles AP, Tan JS. Hemorrhagic fever in adults. Acta medica Philippina. 1967;3:209–11. pmid:6038221
  16. 16. Del Mundo F, Soriano L. Clinical manifestations of serologically proven dengue viral infections during the 1966, epidemic, Philippines. Journal of the Philippine Islands Medical Association. 1967;43(9):760–76.
  17. 17. Dizon JJ. Philippine hemorrhagic fever—epidemiologic aspects. Journal of the Philippine Medical Association. 1967;43(5):346–65. Epub 1967/05/01. pmid:6060989.
  18. 18. Fresh JW, Reyes V, Clarke EJ, Uylangco CV. Philippine hemorrhagic fever: a clinical, laboratory, and necropsy study. The Journal of laboratory and clinical medicine. 1969;73(3):451–8. Epub 1969/03/01. pmid:5766189.
  19. 19. Dukellis E, Fabie AE, Marchette NJ, Rudnick A, Venzon EL. The Greater Manila dengue hemorrhagic fever epidemic of 1966. Journal of the Philippine Medical Assocation. 1972;48:297–313.
  20. 20. Belmonte C. Dengue hemorrhagic fever in the Philippines in review. J Philipp Med Women's Assoc. 1976;14(4):141–5.
  21. 21. Oliveros LAV, de Monteverde RD, Olliveros CM. A five year study pf Philippines Dengue Hemorrhagic Fever at St. Luke's Medical center. Phil J Microbiol Infect Dis 1984;13(2):102.
  22. 22. Chan VF. Virological and epidemiological studies of Dengue haemorrhagic fever in the Philippines. The Southeast Asian journal of tropical medicine and public health. 1987;18(3):275–7. pmid:3433158.
  23. 23. Songco RS, Hayes CG, Leus CD, Manaloto CO. Dengue fever/dengue haemorrhagic fever in Filipino children: clinical experience during the 1983–1984 epidemic. The Southeast Asian journal of tropical medicine and public health. 1987;18(3):284–90. Epub 1987/09/01. pmid:3433159.
  24. 24. Chua MN, Molanida R, de Guzman M, Laberiza F. Prothrombin time and partial thromboplastin time as a predictor of bleeding in patients with dengue hemorrhagic fever. The Southeast Asian journal of tropical medicine and public health. 1993;24 Suppl 1:141–3. Epub 1993/01/01. pmid:7886557.
  25. 25. Radda A, Escalona T, Dippe H. Occurrence of dengue and Japanese Encephalitis viruses in Oriental Mindoro, Philippines. Parasitologie. 1993;15:179–82.
  26. 26. Capeding MR, Paladin FJ. Hospital-based retrospective assessment of dengue infection among Filipinos. Dengue Bulletin. 1997;21.
  27. 27. Capeding MR, Paladin FJ, Miranda EG, Navarro XR. Dengue surveillance in Metro Manila. The Southeast Asian journal of tropical medicine and public health. 1997;28(3):530–4. Epub 1998/04/30. pmid:9561603.
  28. 28. Montalban CS. Dengue—is it milder in adults. The Philippine Journal of Microbiology and Infectious Diseases. 1998;27(2):S7.
  29. 29. Deen JL. Late presentation and increased mortality in children with dengue haemorrhagic fever. Tropical doctor. 2000;30(4):227–8. Epub 2000/11/15. pmid:11075659.
  30. 30. Magpusao NS, Monteclar A, Deen JL. Slow improvement of clinically-diagnosed dengue haemorrhagic fever case fatality rates. Tropical doctor. 2003;33(3):156–9. pmid:12870602.
  31. 31. Carlos CC, Oishi K, Cinco MT, Mapua CA, Inoue S, Cruz DJ, et al. Comparison of clinical features and hematologic abnormalities between dengue fever and dengue hemorrhagic fever among children in the Philippines. The American journal of tropical medicine and hygiene. 2005;73(2):435–40. pmid:16103617.
  32. 32. Oishi K, Mapua CA, Carlos C, Cinco-Abanes MT, Saito M, Inoue S, et al. Dengue and other febrile illness among children in the Philippines. Dengue Bulletin. 2006;30:26–34.
  33. 33. Nishiura H, Halstead SB. Natural history of dengue virus (DENV)-1 and DENV-4 infections: reanalysis of classic studies. The Journal of infectious diseases. 2007;195(7):1007–13. pmid:17330791.
  34. 34. Su GL. Correlation of climatic factors and dengue incidence in Metro Manila, Philippines. Ambio. 2008;37(4):292–4. pmid:18686509.
  35. 35. Panogadia-Reyes CM. Rainfall, temperature, relative humidity and dengue cases in Metro Manila, Philippines. Emilio Aguinaldo College Research Bulletin. 2009;8(1):24–35.
  36. 36. Cinco MT, Carlos C, Oishi K, Inoue S, Matias R, Cruz DJ, et al. The clinical, serological, and virological aspects of dengue fever/dengue hemorrhagic fever in a private tertiary care hospital in Manila, Philippines. St Luke's Journal of Medicine. 2010;6(1):19–22.
  37. 37. Anker M, Arima Y. Male-female differences in the number of reported incident dengue fever cases in six Asian countries. Western Pacific surveillance and response journal: WPSAR. 2011;2(2):17–23. Epub 2011/04/01. pmid:23908884; PubMed Central PMCID: PMCPMC3730962.
  38. 38. Garcia FB, de las Llagas LA. An examination of the spatial factors of dengue cases in Quezon City, Philippines: a geographic information system (GIS)-based approach, 2005–2008. Acta medica Philippina. 2011;45(1):53–62.
  39. 39. Edillo FE, Madarieta S. Trends of dengue infections (1997–2008) in Cebu Province, Philippines. Dengue Bulletin. 2012;36.
  40. 40. Picardal J, Elnar A. Rainfall, temperature and the incidence of dengue in Central Visayas, Philippines are not correlated. Cebu Normal University Journal of Higher Education. 2012;6.
  41. 41. Dulay AVS, Bautista JR, Teves FG. Climate change and incidence of dengue fever (DF) and dengue hemorrhagic fever (DHF) in Iligan City, Lanao del Norte, Philippines. International Research Journal of Biological Sciences. 2013;2(7):37–41.
  42. 42. Pasay J, Awa A, Ocapan J. Incidence of dengue in Ozamiz City, Philippines. J Multidisciplinary Studies. 2013;2.
  43. 43. Velasco JM, Alera MT, Ypil-Cardenas CA, Dimaano EM, Jarman RG, Chinnawirotpisan P, et al. Demographic, clinical and laboratory findings among adult and pediatric patients hospitalized with dengue in the Philippines. The Southeast Asian journal of tropical medicine and public health. 2014;45(2):337–45. pmid:24968673.
  44. 44. Aumentado C, Cerro BR, Olobia L, Suy LL, Reyes A, Kusumawathie PH, et al. The prevention and control of dengue after Typhoon Haiyan. Western Pacific surveillance and response journal: WPSAR. 2015;6 Suppl 1:60–5. Epub 2016/01/15. pmid:26767138; PubMed Central PMCID: PMCPMC4710066.
  45. 45. Capeding MR, L'Azou M, Manalaysay M, Vince-Woo CR, Rivera RG, Kristy Sy A, et al. Laboratory-confirmed Dengue in Children in Three Regional Hospitals in the Philippines in 2009–2010. The Pediatric infectious disease journal. 2015;34(11):1145–51. Epub 2015/07/17. pmid:26181893; PubMed Central PMCID: PMCPMC4605279.
  46. 46. Abello JE, Gil Cuesta J, Cerro BR, Guha-Sapir D. Factors Associated with the Time of Admission among Notified Dengue Fever Cases in Region VIII Philippines from 2008 to 2014. PLoS neglected tropical diseases. 2016;10(10):e0005050. pmid:27780199; PubMed Central PMCID: PMCPMC5079576.
  47. 47. Chang MP, Simkin DJ, de Lara ML, Kirsch TD. Characterizing Hospital Admissions to a Tertiary Care Hospital After Typhoon Haiyan. Disaster medicine and public health preparedness. 2016;10(2):240–7. Epub 2016/02/03. pmid:26832860.
  48. 48. Kusama Y, Ito K, Tajima S, Kutsuna S. A pediatric case of imported dengue hemorrhagic fever in Japan. J Gen Fam Med. 2017;18(6):414–7. pmid:29264075; PubMed Central PMCID: PMCPMC5729368.
  49. 49. Mateo JEP, de Guzman FS. Predictive diagnostic value of the tourniquet test and correlation of laboratory profile for the diagnosis of dengue infection among patients. The Filipino Family Physician. 2017;55(3):110–8.
  50. 50. Pangilinan MAP, Gonzales DPG, Leong RNF, Co FF. Spatial analysis of the distribution of reported dengue incidence in the National Capital Region, Philippines. Acta medica Philippina. 2017;51(2):126–32.
  51. 51. Sumi A, Telan EF, Chagan-Yasutan H, Piolo MB, Hattori T, Kobayashi N. Effect of temperature, relative humidity and rainfall on dengue fever and leptospirosis infections in Manila, the Philippines. Epidemiology and infection. 2017;145(1):78–86. pmid:27608858.
  52. 52. Schultz GW. Cemetery vase breeding of dengue vectors in Manila, Republic of the Philippines. J Am Mosq Control Assoc. 1989;5(4):508–13. pmid:2614399.
  53. 53. Schultz GW. Seasonal abundance of dengue vectors in Manila, Republic of the Philippines. The Southeast Asian journal of tropical medicine and public health. 1993;24(2):369–75. pmid:8266245.
  54. 54. Madarieta SK, Salarda A, Benabaye MRS, Bacus MB, Tagle JR. Use of Permethrin-Treated Curtains for Control of Aedes aegypti in the Philippines. Dengue Bulletin 1999;23:51–4.
  55. 55. Dayrit JF, Gabriel MT, Sta. Ana ML. A Preliminary Study on the Mosquito Repellent Effect of Tea Tree (Melaleuca alternifolia) Oil. Journal of the Philippine Dermatological Society. 2005;14(1):33–7.
  56. 56. Cruz E, Salazar F, Porras E, Mercado RD, Orais V, Bunyi J. Entomological survey of dengue vectors as basis for developing vector control measures in Barangay Poblacion, Muntinlupa City, Philippines, 2008. Dengue Bulletin. 2008;32:167–70.
  57. 57. Tun-Lin W, Lenhart A, Nam VS, Rebollar-Tellez E, Morrison AC, Barbazan P, et al. Reducing costs and operational constraints of dengue vector control by targeting productive breeding places: a multi-country non-inferiority cluster randomized trial. Tropical medicine & international health: TM & IH. 2009;14(9):1143–53. Epub 2009/07/25. pmid:19624476.
  58. 58. Edillo FE, Roble ND, Otero ND 2nd. The key breeding sites by pupal survey for dengue mosquito vectors, Aedes aegypti (Linnaeus) and Aedes albopictus (Skuse), in Guba, Cebu City, Philippines. The Southeast Asian journal of tropical medicine and public health. 2012;43(6):1365–74. pmid:23413699.
  59. 59. Espino F, Marco J, Salazar NP, Salazar F, Mendoza Y, Velazco A. Community-based dengue vector control: experiences in behavior change in Metropolitan Manila, Philippines. Pathogens and global health. 2012;106(8):455–61. pmid:23318237; PubMed Central PMCID: PMCPMC3541901.
  60. 60. Sommerfeld J, Kroeger A. Eco-bio-social research on dengue in Asia: a multicountry study on ecosystem and community-based approaches for the control of dengue vectors in urban and peri-urban Asia. Pathogens and global health. 2012;106(8):428–35. Epub 2013/01/16. pmid:23318234; PubMed Central PMCID: PMCPMC3541880.
  61. 61. van den Berg H, Velayudhan R, Ebol A, Catbagan BH, Jr., Turingan R, Tuso M, et al. Operational efficiency and sustainability of vector control of malaria and dengue: descriptive case studies from the Philippines. Malar J. 2012;11:269. pmid:22873707; PubMed Central PMCID: PMCPMC3425236.
  62. 62. Bantoto V, Dy D. The larvicidal activity of brown algae Padina minor (Yamada 1925) and Dicyota linearis (Greville 1830) against the dengue vector, Aedes aegypti (Linn 1762) (Diptera: Culicidae). Journal of vector borne diseases. 2013;50(1):68–70. Epub 2013/05/25. pmid:23703444.
  63. 63. Duncombe J, Espino F, Marollano K, Velazco A, Ritchie SA, Hu WB, et al. Characterising the spatial dynamics of sympatric Aedes aegypti and Aedes albopictus populations in the Philippines. Geospatial health. 2013;8(1):255–65. Epub 2013/11/22. pmid:24258900.
  64. 64. Salamat MSS, Cochon KL, Crisostomo GCC, Gonzaga PBS, Quijano NA, Torio JF, et al. Entomological survey of artificial container breeding sites of dengue vectors in Batasan Hills, Quezon City. Acta medica Philippina. 2013;47:63–8.
  65. 65. Torres RC, Garbo AG, Walde RZ. Larvicidal activity of Persea americana Mill. against Aedes aegypti. Asian Pacific journal of tropical medicine. 2014;7s1:S167–70. Epub 2014/10/15. pmid:25312114.
  66. 66. Edillo FE, Sarcos JR, Sayson SL. Natural vertical transmission of dengue viruses in Aedes aegypti in selected sites in Cebu City, Philippines. J Vector Ecol. 2015;40(2):282–91. pmid:26611963.
  67. 67. Fonzi E, Higa Y, Bertuso AG, Futami K, Minakawa N. Human-Mediated Marine Dispersal Influences the Population Structure of Aedes aegypti in the Philippine Archipelago. PLoS neglected tropical diseases. 2015;9(6):e0003829. Epub 2015/06/04. pmid:26039311; PubMed Central PMCID: PMCPMC4454683.
  68. 68. Santiago VS, Alvero RG, Villasenor IM. Aedes aegypti larvicide from the ethanolic extract of Piper nigrum black peppercorns. Natural product research. 2015;29(5):441–3. Epub 2014/08/15. pmid:25118563.
  69. 69. Sayson SL, Gloria-Soria A, Powell JR, Edillo FE. Seasonal Genetic Changes of Aedes aegypti (Diptera: Culicidae) Populations in Selected Sites of Cebu City, Philippines. Journal of medical entomology. 2015;52(4):638–46. Epub 2015/09/04. pmid:26335470; PubMed Central PMCID: PMCPMC4592349.
  70. 70. Torres RC, Garbo AG, Walde RZ. Characterization and bioassay for larvicidal activity of Anacardium occidentale (cashew) shell waste fractions against dengue vector Aedes aegypti. Parasitology research. 2015;114(10):3699–702. Epub 2015/06/24. pmid:26099240.
  71. 71. Almanzor BL, Ho HT, Carvajal TM. Ecdysis period and rate deviations of dengue mosquito vector, Aedes aegypti reared in different artificial water-holding containers. Journal of vector borne diseases. 2016;53(1):37–45. Epub 2016/03/24. pmid:27004577.
  72. 72. Carvajal TM, Hernandez LF, Ho HT, Cuenca MG, Orantia BM, Estrada CR, et al. Spatial analysis of wing geometry in dengue vector mosquito, Aedes aegypti (L.) (Diptera: Culicidae), populations in Metropolitan Manila, Philippines. J Vector Borne Dis. 2016;53(2):127–35. pmid:27353582.
  73. 73. Hammon WM, Rudnick A, Sather GE. Viruses associated with epidemic hemorrhagic fevers of the Philippines and Thailand. Science (New York, NY). 1960;131(3407):1102–3. Epub 1960/04/15. pmid:14399343.
  74. 74. Basaca-Sevilla V, Halstead SB. Recent virological studies on haemorrhagic fever and other arthropod-borne virus infections in the Philippines. The Journal of tropical medicine and hygiene. 1966;69(9):203–8. Epub 1966/09/01. pmid:5918698.
  75. 75. Halstead SB. Etiologies of the experimental dengues of Siler and Simmons. The American journal of tropical medicine and hygiene. 1974;23(5):974–82. Epub 1974/09/01. pmid:4615598.
  76. 76. Tupasi TE, Montalban CS, Zeta MRM, Moriles RC, Paladin FE. Virological and clinical studies in dengue infection in the Philippines. Phil J Microbiol Infect Dis. 1987;16(1):1–4.
  77. 77. Manaloto CR, Hayes CG. Isolation of dengue viruses from hospitalized patients in the Philippines, 1983–1986. The Southeast Asian journal of tropical medicine and public health. 1989;20(4):541–7. pmid:2700845.
  78. 78. Matias RR, Hasebe F, Igarashi A. Comparative nucleotide and amino acid sequences of the nonstructural (NS1) gene of dengue virus serotype 3 isolated during a 1995 outbreak in Metro Manila, Philippines. Transactions of the National Academy of Science & Technology. 1998;20:598.
  79. 79. ter Meulen J, Grau M, Lenz O, Emmerich P, Schmitz H, Oh F, et al. Isolation and partial characterization of dengue virus type 2 and 4 strains from dengue fever and dengue haemorrhagic fever patients from Mindanao, Republic of the Philippines. Tropical medicine & international health: TM & IH. 2000;5(5):325–9. pmid:10886794.
  80. 80. Inoue S, Morita K, Matias RR, Tuplano JV, Resuello RR, Candelario JR, et al. Distribution of three arbovirus antibodies among monkeys (Macaca fascicularis) in the Philippines. Journal of medical primatology. 2003;32(2):89–94. Epub 2003/06/26. pmid:12823631.
  81. 81. Aguila FS, Alfon JAR, Buerano CC, Carlos CC, Cinco-Abanes MTD, Daroy MLG, et al. Serotypes of dengue viruses isolated from paediatric patients admitted at St. Luke's Medical Center for year 2001. 2004;2:25–30.
  82. 82. Salda LT, Parquet MD, Matias RR, Natividad FF, Kobayashi N, Morita K. Molecular epidemiology of dengue 2 viruses in the Philippines: genotype shift and local evolution. The American journal of tropical medicine and hygiene. 2005;73(4):796–802. pmid:16222028.
  83. 83. Baclig MO, Gervacio LT, Suarez LA, Buerano CC, Matias RR, Kumatori A, et al. Flow cytometric analysis of dengue virus-infected cells in peripheral blood. The Southeast Asian journal of tropical medicine and public health. 2010;41(6):1352–8. Epub 2011/02/19. pmid:21329310.
  84. 84. Matias RR, Espiritu MGV, Buerano CC, Natividad FF, Igarashi A. Molecular detection and serotyping of dengue virus in Metro Manila, Philippines. St Luke's Journal of Medicine. 2010;6(1):83–5.
  85. 85. Yamanaka A, Tabuchi Y, Mulyatno KC, Susilowati H, Hendrianto E, Soegijanto S, et al. Dengue virus infection-enhancing and neutralizing antibody balance in children of the Philippines and Indonesia. Microbes Infect. 2012;14(13):1152–9. pmid:22841680.
  86. 86. Kato F, Ishida Y, Kawagishi T, Kobayashi T, Hishiki T, Miura T, et al. Natural infection of cynomolgus monkeys with dengue virus occurs in epidemic cycles in the Philippines. The Journal of general virology. 2013;94(Pt 10):2202–7. pmid:23851439.
  87. 87. Petronio JAG, Vinarao RB, Flores KMG, Destura RV. Continued circulation of a single genotype of dengue virus serotype 2 in the Philippines. Asian Pacific journal of tropical medicine. 2014;7(1):30–3. pmid:24418079
  88. 88. Sharma BK, Klinzing DC, Ramos JD. Modulatory activities of Zingiber officinale Roscoe methanol extract on the expression and activity of MMPs and TIMPs on dengue virus infected cells. Asian Pacific Journal of Tropical Disease. 2015;5, Supplement 1:S19–S26. https://doi.org/10.1016/S2222-1808(15)60849-0.
  89. 89. Lennon JL. Knowledge of dengue haemorrhagic fever by Filipino university students. Dengue Bulletin. 1996;20.
  90. 90. Tomayao A. People's knowledge and practice and aedes aegypti infestation in Cebu City, Philippines and implications for community-based dengue control. The Philippine Scientist. 2000;37:79–83.
  91. 91. DeRoeck D, Deen J, Clemens JD. Policymakers' views on dengue fever/dengue haemorrhagic fever and the need for dengue vaccines in four southeast Asian countries. Vaccine. 2003;22(1):121–9. pmid:14604579.
  92. 92. Mahilum MM, Ludwig M, Madon MB, Becker N. Evaluation of the present dengue situation and control strategies against Aedes aegypti in Cebu City, Philippines. J Vector Ecol. 2005;30(2):277–83. pmid:16599163.
  93. 93. Almazar C, Raquepo R. Factors that contribute in the occurrence of dengue fever in Sitio Tabon, Barangay La Huerta Paranaque City. Olivarez College Journal. 2007;2007.
  94. 94. Palanca-Tan R. The demand for a dengue vaccine: a contingent valuation survey in Metro Manila. Vaccine. 2008;26(7):914–23. Epub 2008/01/22. pmid:18206277.
  95. 95. Santamaria R, Martinez E, Kratochwill S, Soria C, Tan LH, Nuñez A, et al. Comparison and critical appraisal of dengue clinical guidelines and their use in Asia and Latin America. International Health. 2009;1(2):133–40. pmid:24036557
  96. 96. Gascon MG. Traditional ecological knowledge system of the Matigsalug Tribe in mitigating the effects of dengue and malaria outbreak. Asian Journal of Health. 2011;1(1).
  97. 97. Shepard DS, Undurraga EA, Halasa YA. Economic and disease burden of dengue in Southeast Asia. PLoS neglected tropical diseases. 2013;7(2):e2055. Epub 2013/02/26. pmid:23437406; PubMed Central PMCID: PMCPMC3578748.
  98. 98. Yboa BC, Labrague L. Dengue knowledge and preventive practices among rural residents in Samar Province, Philippines. American Journal of Public Health Research. 2013;1(2):47–52.
  99. 99. Edillo FE, Halasa YA, Largo FM, Erasmo JN, Amoin NB, Alera MT, et al. Economic cost and burden of dengue in the Philippines. The American journal of tropical medicine and hygiene. 2015;92(2):360–6. pmid:25510723; PubMed Central PMCID: PMCPMC4347342.
  100. 100. de Guzman GQ, Dacanay AT, Andaya BA, Alejandro GJ. Ethnopharmacological studies on the uses of Euphorbia hirta in the treatment of dengue in selected indigenous communities in Pangasinan (Philippines). J Intercult Ethnopharmacol. 2016;5(3):239–43. pmid:27366349; PubMed Central PMCID: PMCPMC4927128.
  101. 101. Shim E. Dengue Dynamics and Vaccine Cost-Effectiveness Analysis in the Philippines. The American journal of tropical medicine and hygiene. 2016;95(5):1137–47. pmid:27601519; PubMed Central PMCID: PMCPMC5094230.
  102. 102. Palaruan CS, Canonizado RM, Cantre TC, Causon BI, Blasco EE. Supression of plasma leakage by carbazochrome sodium sulfonate (AC-17) in dengue hemorrhagic fever. Philipp J Pediatr. 1994;43 (2):261–74.
  103. 103. Cifra HL, Velasco JNJ. A comparative study of the efficacy of 6% Haes-Steril and Ringer's Lactate in the management of dengue shock syndrome 5552003. 95–100 p.
  104. 104. de Castro RA, de Castro JA, Barez MY, Frias MV, Dixit J, Genereux M. Thrombocytopenia associated with dengue hemorrhagic fever responds to intravenous administration of anti-D (Rh(0)-D) immune globulin. The American journal of tropical medicine and hygiene. 2007;76(4):737–42. Epub 2007/04/12. pmid:17426181.
  105. 105. Dimaano EM, Saito M, Honda S, Miranda EA, Alonzo MT, Valerio MD, et al. Lack of efficacy of high-dose intravenous immunoglobulin treatment of severe thrombocytopenia in patients with secondary dengue virus infection. The American journal of tropical medicine and hygiene. 2007;77(6):1135–8. Epub 2008/01/01. pmid:18165536.
  106. 106. Capeding RZ, Luna IA, Bomasang E, Lupisan S, Lang J, Forrat R, et al. Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines. Vaccine. 2011;29(22):3863–72. pmid:21477675.
  107. 107. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014;384(9951):1358–65. pmid:25018116.
  108. 108. Capeding MR, Laot TM, Boaz M, Wartel TA, Crevat D. Immunogenicity and safety of a tetravalent dengue vaccine during a five-year follow-up period. Trials in Vaccinology. 2015;4(Supplement C):19–23. https://doi.org/10.1016/j.trivac.2015.03.002.
  109. 109. Crevat D, Brion JD, Gailhardou S, Laot TM, Capeding MR. First Experience of Concomitant Vaccination Against Dengue and MMR in Toddlers. The Pediatric infectious disease journal. 2015;34(8):884–92. Epub 2015/05/15. pmid:25966916.
  110. 110. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. The New England journal of medicine. 2015;373(13):1195–206. pmid:26214039.
  111. 111. Saez-Llorens X, Tricou V, Yu D, Rivera L, Jimeno J, Villarreal AC, et al. Immunogenicity and safety of one versus two doses of tetravalent dengue vaccine in healthy children aged 2–17 years in Asia and Latin America: 18-month interim data from a phase 2, randomised, placebo-controlled study. The Lancet Infectious diseases. 2017. Epub 2017/11/11. pmid:29122463.
  112. 112. Sáez-Llorens X, Tricou V, Yu D, Rivera L, Tuboi S, Garbes P, et al. Safety and immunogenicity of one versus two doses of Takeda's tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study. The Lancet Infectious Diseases. 2017;17(6):615–25. pmid:28365225
  113. 113. Imlan J, Marbella M, Arciaga M, Cristobal FL. Dengue hemorrhagic fever in Zamboanga City: a recent scourge. Philippine Journal of Public Health. 1992;26(19–22).
  114. 114. Capeding RZ, Brion JD, Caponpon MM, Gibbons RV, Jarman RG, Yoon IK, et al. The incidence, characteristics, and presentation of dengue virus infections during infancy. The American journal of tropical medicine and hygiene. 2010;82(2):330–6. Epub 2010/02/06. pmid:20134013; PubMed Central PMCID: PMCPMC2813177.
  115. 115. Arima Y, Matsui T. Epidemiologic update of dengue in the Western Pacific Region, 2010. Western Pacific surveillance and response journal: WPSAR. 2011;2(2):4–8. pmid:23908882; PubMed Central PMCID: PMC3730957.
  116. 116. Arima Y, Edelstein ZR, Han HK, Matsui T. Epidemiologic update on the dengue situation in the Western Pacific Region, 2011. Western Pacific surveillance and response journal: WPSAR. 2013;4(2):47–54. pmid:24015372; PubMed Central PMCID: PMC3762964.
  117. 117. Capeding MR, Chua MN, Hadinegoro SR, Hussain II, Nallusamy R, Pitisuttithum P, et al. Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLoS neglected tropical diseases. 2013;7(7):e2331. Epub 2013/08/13. pmid:23936565; PubMed Central PMCID: PMCPMC3723539.
  118. 118. Arima Y, Chiew M, Matsui T, Emerging Disease S, Response Team DoHS, Emergencies WHOROftWP. Epidemiological update on the dengue situation in the Western Pacific Region, 2012. Western Pacific surveillance and response journal: WPSAR. 2015;6(2):82–9. pmid:26306221; PubMed Central PMCID: PMCPMC4542491.
  119. 119. Alera MT, Srikiatkhachorn A, Velasco JM, Tac-An IA, Lago CB, Clapham HE, et al. Incidence of Dengue Virus Infection in Adults and Children in a Prospective Longitudinal Cohort in the Philippines. PLoS neglected tropical diseases. 2016;10(2):e0004337. pmid:26845762; PubMed Central PMCID: PMCPMC4742283.
  120. 120. L'Azou M, Moureau A, Sarti E, Nealon J, Zambrano B, Wartel TA, et al. Symptomatic Dengue in Children in 10 Asian and Latin American Countries. The New England journal of medicine. 2016;374(12):1155–66. Epub 2016/03/24. pmid:27007959.
  121. 121. Nealon J, Taurel AF, Capeding MR, Tran NH, Hadinegoro SR, Chotpitayasunondh T, et al. Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial. PLoS neglected tropical diseases. 2016;10(8):e0004918. Epub 2016/08/18. pmid:27532617; PubMed Central PMCID: PMCPMC4988713.
  122. 122. Wartel TA, Prayitno A, Hadinegoro SR, Capeding MR, Thisyakorn U, Tran NH, et al. Three Decades of Dengue Surveillance in Five Highly Endemic South East Asian Countries. Asia-Pacific journal of public health. 2017;29(1):7–16. Epub 2017/02/16. pmid:28198645.
  123. 123. Baylon HG, Ecarma RM. SGPT and PTT as early predictors of dengue hemorrhagic fever: A preliminary study. Philippine Journal of Internal Medicine. 1999;37(4):169–72.
  124. 124. Yasutan H, Ndhlovu LC, Lacuesta TL, Leano PS, Telan EF, Niki T, et al. Elevated levels of circulating galectin-9, a novel immune-modulator, in acute dengue virus Infection reflects disease severity. The Journal of Immunology. 2012;188:18.
  125. 125. Chagan-Yasutan H, Ndhlovu LC, Lacuesta TL, Kubo T, Leano PS, Niki T, et al. Galectin-9 plasma levels reflect adverse hematological and immunological features in acute dengue virus infection. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2013;58(4):635–40. Epub 2013/11/19. pmid:24239423; PubMed Central PMCID: PMCPMC3880569.
  126. 126. Chagan-Yasutan H, Lacuesta TL, Ndhlovu LC, Oguma S, Leano PSA, Telan EFO, et al. Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities. Thrombosis research. 2014;134(2):449–54. pmid:24861695
  127. 127. Libraty DH, Zhang L, Obcena A, Brion JD, Capeding RZ. Circulating levels of soluble MICB in infants with symptomatic primary dengue virus infections. PloS one. 2014;9(5):e98509. Epub 2014/05/30. pmid:24869966; PubMed Central PMCID: PMCPMC4037195.
  128. 128. Libraty DH, Zhang L, Woda M, Giaya K, Kathivu CL, Acosta LP, et al. Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model. PloS one. 2014;9(2):e88944. Epub 2014/02/18. pmid:24533162; PubMed Central PMCID: PMCPMC3923068.
  129. 129. Libraty DH, Wang P, Guo Z, Bigcas V, Brion JD, Capeding RZ. The Pattern of Adipose Tissue Accumulation during Early Infancy Provides an Environment for the Development of Dengue Hemorrhagic Fever. PLoS neglected tropical diseases. 2015;9(12):e0004267. Epub 2015/12/05. PubMed Central PMCID: PMCPMC4670217. pmid:26636570
  130. 130. Libraty DH, Zhang L, Obcena A, Brion JD, Capeding RZ. Anti-dengue virus envelope protein domain III IgG ELISA among infants with primary dengue virus infections. Acta tropica. 2015;142:103–7. Epub 2014/12/03. pmid:25460346; PubMed Central PMCID: PMCPMC4277722.
  131. 131. Mercado ES, Espino FE, Perez ML, Bilar JM, Bajaro JD, Huy NT, et al. HLA-A*33:01 as protective allele for severe dengue in a population of Filipino children. PloS one. 2015;10(2):e0115619. Epub 2015/02/07. pmid:25659158; PubMed Central PMCID: PMCPMC4319754.
  132. 132. Vasquez Velasquez C, Roman AD, Lan NTP, Huy NT, Mercado ES, Espino FE, et al. Alpha tryptase allele of Tryptase 1 (TPSAB1) gene associated with Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) in Vietnam and Philippines. Human immunology. 2015;76(5):318–23. pmid:25797204
  133. 133. Natividad FF. Usefulness of sandwich ELISA in predicting the detection of dengue virus by RT-PCR from infected cultured fluids of C6/36 Aedes albopictus cells. Transactions of the National Academy of Science & Technology. 1998;20:597.
  134. 134. Buerano CC, Ibrahim IN, Contreras RC, Hasebe F, Matias RR, Natividad FF, et al. IgM-capture ELISA of serum samples collected from Filipino dengue patients. The Southeast Asian journal of tropical medicine and public health. 2000;31(3):524–9. Epub 2001/04/06. pmid:11289014.
  135. 135. Buerano CC, Natividad FF, Contreras RC, Ibrahim IN, Mangada MN, Hasebe F, et al. Antigen sandwich ELISA predicts RT-PCR detection of dengue virus genome in infected culture fluids of Aedes albopictus C6/36 cells. The Southeast Asian journal of tropical medicine and public health. 2008;39(5):817–21. Epub 2008/12/09. pmid:19058574.
  136. 136. Tan IL, Dimamay MP, Buerano CC, Alfon JA, Tanig CZ, Matias RR, et al. Development and evaluation of a fluorogenic real-time RT-PCR for the detection of dengue 3 virus. Journal of medical virology. 2010;82(12):2053–63. Epub 2010/10/29. pmid:20981793.
  137. 137. Ramos AKA, Mesa-Gaerlan FJC, Quilala PF, Mapua CA, Suarez LAC, Labayo HKM, et al. Prevalence of dengue infection and accuracy of the rapid dengue-NS1 antigen strip test as a screening tool for dengue infection among patients presenting with fever at the emergency room of St. Luke's Medical Center (A prospective study). St Luke's Journal of Medicine. 2012;8(1):31–8.
  138. 138. Tang YL, Chiu CY, Lin CY, Huang CH, Chen YH, Destura RV, et al. Establishment and Comparison of Two Different Diagnostic Platforms for Detection of DENV1 NS1 Protein. International journal of molecular sciences. 2015;16(11):27850–64. Epub 2015/11/28. pmid:26610481; PubMed Central PMCID: PMCPMC4661927.
  139. 139. Saito-Obata M, Saito M, Tan TC, Medado IA, Dapat C, Okamoto M, et al. Laboratory Diagnosis for Outbreak-Prone Infectious Diseases after Typhoon Yolanda (Haiyan), Philippines. PLoS currents. 2016;8. Epub 2016/12/06. pmid:27917305; PubMed Central PMCID: PMCPMC5104685.
  140. 140. Buczak AL, Baugher B, Babin SM, Ramac-Thomas LC, Guven E, Elbert Y, et al. Prediction of high incidence of dengue in the Philippines. PLoS neglected tropical diseases. 2014;8(4):e2771. pmid:24722434; PubMed Central PMCID: PMCPMC3983113.
  141. 141. van Panhuis WG, Choisy M, Xiong X, Chok NS, Akarasewi P, Iamsirithaworn S, et al. Region-wide synchrony and traveling waves of dengue across eight countries in Southeast Asia. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(42):13069–74. Epub 2015/10/07. pmid:26438851; PubMed Central PMCID: PMCPMC4620875.
  142. 142. Undurraga EA, Edillo FE, Erasmo JNV, Alera MTP, Yoon IK, Largo FM, et al. Disease Burden of Dengue in the Philippines: Adjusting for Underreporting by Comparing Active and Passive Dengue Surveillance in Punta Princesa, Cebu City. The American journal of tropical medicine and hygiene. 2017;96(4):887–98. pmid:28093542; PubMed Central PMCID: PMCPMC5392638.
  143. 143. Maula AW, Fuad A, Utarini A. Ten-years trend of dengue research in Indonesia and South-east Asian countries: a bibliometric analysis. Glob Health Action. 2018;11(1):1504398. pmid:30092158; PubMed Central PMCID: PMCPMC6095018.