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. Dengue is a mosquito-borne, acute febrile illness that is an important public health problem in tropical countries. 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, islands and is located in the western Pacific Ocean in Southeastern Asia. The population of the Philippines in was ,, [ 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.
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.
Dengue and dengue-like fevers in children. Antiviral Res. Scientific research related to calcium channel blockers poisoning: bibliometric analysis in Scopus, — Facing the local and imported borderless Aedes-linked vector-borne viral diseases threat and epidemics burden, the Health Committee of the Gulf Cooperation Council GCC , including the Saudi Arabian government, announced that all Gulf Introduction Dengue is a mosquito-borne, acute febrile illness that is an important public health problem in tropical countries. Emerg Infect Dis.
There is no protocol for this systematic review. 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. 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 the earliest year data was available and in [ 7 ].
We identified published articles on dengue research in the Philippines during the past six decades Fig 1. 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 In comparison, there was a dramatic rise in the annual number of worldwide dengue publications from around articles in to over 20, in Fig 2. 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 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 ]. One article described the dengue prevention and response strategies applied after a natural disaster, Typhoon Haiyan that occurred in [ 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. 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.
As newer strategies become available e. In , 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 ].
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. 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 , ]. Six assessed dengue-related knowledge and preventive practices in different communities [ 89 , 90 , 92 , 93 , 96 , 98 ].
One documented anecdotal use of a local herb in the treatment of dengue [ ].
There were four economics studies [ 94 , 97 , 99 , ]. One published in , 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 ]. The potential cost-effectiveness of a dengue vaccination program was discussed in another paper [ ].
It will be useful to estimate the economic benefits of new dengue control methods in the country, as they become available. Of the 11 publications on dengue-related clinical trials, four were on therapeutic interventions [ — ] and seven were on vaccine trials [ — ]. The therapeutic interventions assessed included a hemostatic agent [ ], fluids [ ] and immunoglobulin [ , ]. 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 [ — , — ], as well as concomitant dengue and MMR vaccination [ ].
As newer dengue vaccines and therapeutics become available, it will be important to investigate these interventions in the country. Ten studies assessed the burden of dengue infections [ — ]. A study from reported an attack rate of 0.
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. Another paper quantified epidemiologic trends in dengue disease burden in 5 Asian countries, including the Philippines, over a year period using data from DengueNet and the WHO [ ].
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 [ , , — ].
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. The incidence of symptomatic clinically apparent infant dengue infections was 16 per 1, person-years Table 1 , of which hospitalized episodes occurred at 8 per 1, person-years.
The incidence of confirmed symptomatic dengue infections was 34 per 1, person-years Table 1. In the third study, participants 6 months to over 50 years of age underwent active fever surveillance and annual serological assessment [ ]. 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, participants 2 to 16 years of age at two Philippine study sites [ , ].
The children were followed for acute febrile illness and dengue infection was confirmed by means of both NS 1 antigen and RT-PCR assays. 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. We derived data on dengue seroprevalence in Filipinos from two studies that conducted baseline serologic assessments prior to fever surveillance [ , ].
First, among participants over 6 months of age in Cebu City, dengue seroprevalence assessed by hemagglutination inhibition assay increased sharply with age [ ]. Ten studies looked for associations between biomarkers and clinical presentation of dengue disease. Eight studies assessed levels of various immune-related or enzymatic biomarkers [ — , — ], while two evaluated the potential role of adiposity [ , ]. More research is needed to better understand the host characteristics that contribute to dengue disease severity.