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A Growing Problem in the United States

Environmental factors contributing to dengue as a public health threat, pathogenesis, clinical considerations, presentation and evaluation, diagnostic testing for symptomatic denv infection, traditional prevention measures, novel vector control efforts, current dengue vaccines, principles of live-attenuated dengue vaccines, history of dengvaxia, safety and efficacy, prevaccination laboratory testing, conclusion and future directions, acknowledgment, dengue: a growing problem with new interventions.

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Joshua M. Wong , Laura E. Adams , Anna P. Durbin , Jorge L. Muñoz-Jordán , Katherine A. Poehling , Liliana M. Sánchez-González , Hannah R. Volkman , Gabriela Paz-Bailey; Dengue: A Growing Problem With New Interventions. Pediatrics June 2022; 149 (6): e2021055522. 10.1542/peds.2021-055522

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Dengue is the disease caused by 1 of 4 distinct, but closely related dengue viruses (DENV-1–4) that are transmitted by Aedes spp. mosquito vectors. It is the most common arboviral disease worldwide, with the greatest burden in tropical and sub-tropical regions. In the absence of effective prevention and control measures, dengue is projected to increase in both disease burden and geographic range. Given its increasing importance as an etiology of fever in the returning traveler or the possibility of local transmission in regions in the United States with competent vectors, as well as the risk for large outbreaks in endemic US territories and associated states, clinicians should understand its clinical presentation and be familiar with appropriate testing, triage, and management of patients with dengue. Control and prevention efforts reached a milestone in June 2021 when the Advisory Committee on Immunization Practices (ACIP) recommended Dengvaxia for routine use in children aged 9 to 16 years living in endemic areas with laboratory confirmation of previous dengue virus infection. Dengvaxia is the first vaccine against dengue to be recommended for use in the United States and one of the first to require laboratory testing of potential recipients to be eligible for vaccination. In this review, we outline dengue pathogenesis, epidemiology, and key clinical features for front-line clinicians evaluating patients presenting with dengue. We also provide a summary of Dengvaxia efficacy, safety, and considerations for use as well as an overview of other potential new tools to control and prevent the growing threat of dengue.

Dengue is the disease caused by 4 closely related but distinct viruses, dengue virus 1–4 (DENV-1–4), referred to as virus types or serotypes. DENVs are most commonly transmitted by the bite of an infected female Aedes spp. mosquito. It is the most common arboviral disease globally, with an estimated 390 million dengue virus infections and 96 million symptomatic cases annually. 1   Global incidence has almost doubled in the last 3 decades and is expected to continue growing in Asia, sub-Saharan Africa, and Latin America. About half of the global population now lives in areas that are suitable for dengue transmission ( Fig 1 ). 2 , 3   Historically, the highest burden of dengue has been in children, adolescents, and young adults. 4   In 2019, countries across the Americas reported more than 3 million dengue cases, the highest number ever recorded, 5   with a greater proportion of severe dengue cases and increased mortality in the pediatric population of children aged 5 to 9 years. 6   Dengue is increasingly common as an etiology of fever in international travelers 7   and has been reported as the leading febrile disease etiology for travelers from some endemic regions during epidemic years. 8   In addition to circulation of all four DENVs worldwide, surveillance of returning travelers with dengue has demonstrated high genetic diversity among circulating DENV genotypes within serotypes, with potential implications for immune or vaccine escape. 9 , 10  

Map showing the risk of dengue by country as of 2020. “Frequent or Continuous” risk indicates that there are either frequent outbreaks or ongoing transmission. “Sporadic or Uncertain” indicates that risk is either variable and unpredictable or that data from that country are not available. For updated information, visit https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html .

Increasing numbers of dengue cases in the United States are a growing concern. In parts of the United States and freely associated states with endemic dengue transmission, including American Samoa, Puerto Rico, US Virgin Islands, Federated States of Micronesia, Republic of Marshall Islands, and the Republic of Palau, dengue outbreaks can be explosive, overwhelming the health care system capacity. In Puerto Rico, the largest US territory where dengue is endemic, the highest incidence of dengue cases and hospitalizations from 2010 to 2020 occurred among children aged 10 to 19 years. 11   For the same period, confirmed dengue cases ranged from a minimum of 3 cases in 2018 to a maximum of 10 911 cases in 2010, 11   although suspected case counts during outbreak years were considerably higher. 12  

Although local dengue transmission does not occur frequently in most states, increasing numbers of US travelers 13   with dengue have been reported in recent years, with a record 1475 cases in 2019, more than 50% higher than the previous peak in 2016 ( Fig 2 ). 14   Viremia among travel-associated dengue cases can also result in focal outbreaks in nonendemic areas, with competent mosquito vectors for dengue present in approximately half of all US counties. 15   Local dengue cases have been reported in multiple states in recent years, including 70 cases in Florida in 2020, 14   200 cases in Hawaii in 2015, 14   and 53 cases in Texas in 2013. 16  

Annual number of travel-associated cases of dengue reported into ArboNET, the national arboviral surveillance system managed by the CDC, from all US jurisdictions from 2010 to 2019 ( n = 6967).

In dengue-endemic areas, environmental factors such as standing water where mosquitoes lay eggs, poor housing quality, lack of air conditioning, and climatic factors (ie, temperature, precipitation, and humidity) increase the abundance, distribution, and risk of exposure to Aedes aegypti , the main vector responsible for dengue transmission, or other Aedes spp. mosquitoes that can also transmit dengue. 2 , 17 – 21   Climate change is predicted to further increase the population at risk for dengue primarily through increased transmission in currently endemic areas and secondarily through expansion of the geographic range of Aedes spp. mosquitoes ( Fig 3 ). 2 , 22   Urbanization, increasing population density, human migration, and growing social and environmental factors associated with poverty and forced displacement are also expected to drive the increase in dengue incidence and force of infection globally. 21 , 23 – 26   Travel is an important driver of dengue expansion by introducing dengue into nonendemic areas with competent vectors 13 , 23   or by introducing new serotypes into endemic areas naïve to the new serotype, thereby increasing the risk for antibody-dependent enhancement (ADE) and severe disease. 27 , 28   Combined environmental effects of poverty and the increased scale and rapidity of human movement can also increase the risk for dengue. 24 , 29   The combined environmental effects of climate change, urbanization, poverty, and human migration together expand the threat of dengue for both individuals and public health systems in the future.

A-C, Projections of average trends in environmental suitability for dengue transmission from 2015 to 2020, 2020 to 2050, and 2050 to 2080. D–F, Areas with expansion or contraction of the Aedes vector range over the same time periods. (Reprinted with permission from Messina JP, Brady OJ, Golding N, Kraemer MUG, Wint GRW, Ray SE, et al. The current and future global distribution and population at risk of dengue. Nature Microbiology. 2019;4(9):1510.)

DENVs belong to the genus Flavivirus in the family Flaviviridae . Because there are 4 dengue serotypes, individuals living in endemic areas can be infected up to 4 times in their life. Although most dengue virus infections are asymptomatic or only cause mild disease, severe disease can occur and is characterized by plasma leakage, a pathophysiologic process by which the protein rich fluid component of blood leaks into the surrounding tissue, leading to extravascular fluid accumulation resulting in shock, coagulopathy, or end organ impairment. 30 , 31  

Infection with 1 dengue serotype induces life-long protection against symptomatic infection with that specific serotype (homotypic immunity) 32 , 33   and induces only short-term cross-reactive protection from disease to the other serotypes (heterotypic immunity) for several months to years. 34 , 35   Older children and adults experiencing their second dengue infection are at the highest risk for severe disease because of ADE. ADE has also been observed among infants, in that infants born to mothers with previous dengue virus infection had the lowest risk for dengue shortly after birth and a period of higher risk for severe disease approximately 4 to 12 months after birth, followed by a decrease in risk for severe disease from approximately 12 months after birth. 36   The initial period of lowest risk was correlated with high levels of passively acquired maternal dengue antibodies immediately after birth, and the period of enhanced risk with a decline in these antibodies to subneutralizing levels. After further degradation of these maternal antibodies, there was neither protection from dengue afforded by high levels of antibodies postnatally nor enhanced risk of dengue and severe disease from the intermediate levels of antibodies. 37   Later work showed that lower heterotypic antibody titers are ineffective at neutralizing the virions but still bind them, facilitating binding to Fcγ receptors on circulating monocyte cells, and result in higher viremia than in primary infections ( Fig 4 ). 38   The feared sequela of plasma leakage is believed to be mediated by high levels of DENV nonstructural protein 1 (NS1), a key protein for viral replication and pathogenesis, 39 , 40   that damages endothelial glycocalyces and disrupts endothelial cell junctions. 41 , 42   Cell-mediated immunity through dengue-specific CD8 T cells is thought to protect against ADE and severe disease. 43 , 44  

The proposed mechanism of antibody-dependent enhancement with heterotypic antibodies binding to the dengue viruses and entering monocytes through Fcγ receptors. Viral replication occurs in the infected monocyte and releases high levels of virus and dengue virus NS1 protein, which, in turn, lead to increased vascular permeability contributing to severe disease. (Reprinted with permission from Whitehead SS, Blaney JE, Durbin AP, Murphy BR. Prospects for a dengue virus vaccine. Nature Reviews Microbiology. 2007;5(7):524.)

Although ADE occurs in infants due to the interaction between maternal antibodies and primary infection, it is also explanatory for severe disease in older children and adults where the heterotypic antibodies produced after a primary dengue infection will wane over time to subneutralizing levels, resulting in the highest risk for severe disease with secondary infection. Following secondary infection, potent cross-neutralizing/multitypic antibodies are induced that then protect against severe disease in tertiary and quaternary infections. 45 , 46   Although the risk of severe dengue is highest with secondary infection, it can also occur in primary, tertiary, and quaternary infections, and possibly following Zika virus infection. 47 , 48   Identifying cases of severe dengue and understanding the pathogenesis of disease severity is an active area of research with important implications for future vaccines and interventions. 49  

DENV infections have a wide range of presentations from asymptomatic infection (approximately 75% of all infections 50   ) to mild to moderate febrile illness to severe disease with associated coagulopathy, shock, or end organ impairment ( Table 1 ). 30 , 31   Symptomatic infections most commonly present with fever accompanied by nonspecific symptoms such as nausea, vomiting, rash, myalgias, arthralgias, retroorbital pain, headache and/or leukopenia. 51   Severe disease develops in as many as 5% of all patients with dengue, although certain populations such as infants aged ≤1 year, pregnant individuals, and adults aged ≥65 years, or individuals with specific underlying conditions such as diabetes, class III obesity, hypertension, asthma, coagulopathy, gastritis or peptic ulcer disease, hemolytic disease, chronic liver disease, anticoagulant therapy, or kidney disease, are at increased risk of severe disease. 52 , 53   In all patients with dengue, warning signs are specific clinical findings that can predict progression to severe disease and are used by the World Health Organization (WHO) to help clinicians in triage and management decisions. Dengue warning signs include abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy or restlessness, liver enlargement of >2 cm, and increasing hematocrit concurrent with rapid decrease in platelet count ( Table 1 ). 52  

Classification of Dengue Severity and Case Management 51 ,134, 135

Although warning signs are useful for evaluating patients with a high suspicion of dengue (for example, during an outbreak), they are not intended to differentiate dengue from other infectious and noninfectious diseases such as influenza, coronavirus disease 2019, malaria, Zika, measles, leptospirosis, rickettsial disease, typhoid, Kawasaki, or idiopathic thrombocytopenic purpura. Because prompt recognition and early treatment of dengue can greatly reduce morbidity and mortality, 54 , 55   clinicians practicing in the United States and other nonendemic areas should keep dengue in the differential diagnosis for febrile illness in travelers and in areas with competent mosquito vectors.

For symptomatic dengue patients, nucleic acid amplification tests (NAATs) on serum, plasma, or whole blood detect DENV RNA during the first 7 days of illness with high sensitivity and specificity. 56 , 57   Likewise, NS1 antigen can also be detected within the first 7 days and provides confirmatory evidence of DENV infection. 58   For patients with a negative NAAT or patients presenting more than 7 days after symptom onset, a positive anti-DENV immunoblobulin M (IgM) can suggest recent infection, although with less certainty than NAAT or NS1 testing, owing to cross-reactivity with other flaviviruses. Notably, Zika virus is a flavivirus that has been transmitted in most countries where DENV transmission is present. 59   In patients from areas with ongoing transmission of another flavivirus (eg, Zika virus) and whose only evidence of dengue is a positive anti-DENV IgM test, plaque reduction neutralization tests (PRNT) quantifying virus-specific neutralizing antibody titers can distinguish DENV from other flaviviruses, in some but not all cases. PRNTs, however, are rarely available in clinical laboratories and typically do not provide results within a timeframe that is meaningful for clinicians managing acute disease. PRNT’s may be valuable in circumstances where confirming the diagnosis may have important clinical implications, such as distinguishing dengue from a Zika virus infection in a pregnant individual, or epidemiologic implications for a region, such as distinguishing yellow fever from dengue. 60 , 61  

The US Food and Drug Administration (FDA) has approved a NAAT for use on serum and whole blood, an NS1 antigen enzyme-linked immunosorbent assay test in serum, and an IgM enzyme-linked immunosorbent assay in serum. 56 , 59 , 62 – 64   Other non–FDA-approved tests for DENV infection are used in clinical practice and are commercially available at accredited laboratories.

Although several medications have been explored as potential therapeutics for dengue, none have demonstrated a reduction in viremia, clinical manifestations, or complications. 30 , 65   As such, dengue treatment focuses on supportive care. Clinicians should evaluate all patients at presentation and in follow-up for warning signs or other signs and symptoms of severe dengue ( Table 1 ). Most patients without warning signs may be treated as outpatients, whereas patients at high risk of progression to severe disease based on age or underlying conditions, patients with warning signs, or patients with challenging social circumstances should be evaluated for observation or inpatient management. 66  

For outpatients, fever can be controlled with acetaminophen and physical cooling measures; because of the risk of bleeding and thrombocytopenia, aspirin and nonsteroidal anti-inflammatory drugs are not recommended. Early, abundant oral hydration has been associated with lower hospitalization rates in children with dengue and is a key component of outpatient dengue care. 67 – 69  

Early recognition of warning signs or severe dengue is essential for the prompt initiation of systematic intravenous fluid management to restore intravascular volume and avoid related complications and disease progression. 30 , 70   Large-volume resuscitation with isotonic solutions is recommended for patients in shock. 54 , 71 – 73   Fluid management in dengue requires continuous clinical and laboratory monitoring and rate adjustments to maintain adequate volume but also to prevent fluid overload. Mortality for untreated severe dengue can be 13% or higher 74 , 75   but can be reduced to <1% with early diagnosis and appropriate management. 55   Detailed information on systematic fluid management is provided in the current WHO, Pan American Health Organization, and Centers for Disease Control and Prevention (CDC) guidelines. 72 , 73 , 76  

Corticosteroids, 77   immunoglobulins, 78   and prophylactic platelet transfusions 79 , 80   have not demonstrated benefits in patients with dengue and are not recommended.

Prevention of dengue involves protection against mosquito bites. Travelers to and residents of endemic areas can prevent mosquito bites by using US Environmental Protection Agency–approved insect repellents ( https://www.epa.gov/insect-repellents ) and wearing clothing that covers arms and legs. The use of screened windows and doors, air conditioning, and bed nets has been associated with protection from dengue infections. 24 , 81 – 87   Sites where mosquitoes lay eggs should be eliminated by emptying and scrubbing, covering, or eliminating standing water receptacles around the house. Mosquito bite prevention measures are important for all persons at risk for dengue, including vaccinated children.

Traditional vector control interventions can be time consuming and inefficient. 88   Furthermore, chemical control is limited by widespread insecticide resistance in endemic areas. 89   In response to these challenges, novel vector control methods have been developed including several strategies employing genetically modified mosquito technology and 2 strategies using Wolbachia pipientis , an intracellular bacterium found in about 60% of all insects but not commonly found in wild Aedes mosquitos. 90 – 92  

The first strategy utilizing Wolbachia is Wolbachia -mediated suppression, in which a reduction in wild populations of Aedes mosquitoes is achieved by continuously releasing infected males into the environment. 93   When the infected males mate with wild females, the resultant eggs are inviable, leading to a decline in wild mosquito populations. 94   Some reports have documented reduction of the wild populations that can transmit dengue by more than 80%. 95 , 96  

The second strategy is the Wolbachia replacement method, where both Wolbachia -infected male and female mosquitoes are released. Because Wolbachia is transmitted maternally, the mosquitoes that hatch from the eggs of infected females will be infected with Wolbachia from birth. 97 , 98   Wolbachia infection in female mosquitoes taking a bloodmeal reduces transmission of arboviruses, including dengue, chikungunya, and Zika. This method has demonstrated significant reductions of nearly 80% for the outcomes of dengue infection and related hospitalizations in areas where it has been implemented 99   and is currently being deployed in several countries.

Extensive studies have found no evidence of Wolbachia in the plants, soil, or other insects in contact with the Wolbachia -infected mosquitoes or any evidence of Wolbachia transmission to humans from the bites of infected mosquitoes, indicating that safety risks from Wolbachia -based interventions for humans and the environment are low. 100  

ACIP made the first recommendation of a dengue vaccine (Dengvaxia) for use in the United States on June 24, 2021, marking an historic moment for dengue control following decades of global efforts to develop a safe and effective vaccine. Two other vaccines, TAK-003 developed by Takeda and TV003 developed by the National Institutes of Health, are in late-stage trials with efficacy results published or expected in 2022.

All 3 are live vaccines and contain 4 different attenuated vaccine viruses (tetravalent) targeting each of the dengue virus serotypes ( Fig 5 ) with the goal of achieving balanced protective immunity against all 4 serotypes, in both those who are DENV naïve and those who have been previously infected with DENV. Vaccine virus replication (infectivity) of each vaccine serotype after immunization will lead to antigenic stimulation, which then results in homotypic immunity. Infectivity by vaccine virus serotype differed among the 3 vaccines ( Table 2 ).

Key features of the 3 live attenuated dengue vaccines. Each DENV serotype is represented by a color (DENV-1 = green, DENV-2 = gray, DENV-3 = crimson, and DENV-4 = blue). Dengvaxia is comprised of 4 chimeric viruses in which the prM and E of each DENV serotype replaces those of yellow fever 17D (yellow). 132   TAK-003 is comprised of 1 full-length DENV-2 and 3 chimeric viruses (prM and E of DENV-1, DENV-3, and DENV-4 on a DENV-2 background). 133   TV003 is comprised of 3 full-length DENV and 1 chimeric virus. 123   The total number of dengue proteins in each vaccine is also shown.

Percentage of Vaccine Recipients with Detectable Vaccine Virus Serotype by RT-PCR after a Single Dose of the Indicated Vaccine in Persons without Previous Dengue Virus Infections

Data are presented as percentage.

These differences in vaccine serotype specific infectivity mirrored the induction of neutralizing homotypic antibody titers. Dengvaxia induced approximately 70% homotypic antibody for DENV-4 but <50% for DENV-1, DENV-2, and DENV-3. 101   Antibodies induced by TAK-003 were 83% homotypic for DENV-2 and 5%, 12%, and 27% homotypic for DENV-1, DENV-3, and DENV-4, respectively. 102   TV003 induced a balanced homotypic antibody response to DENV-1 (62%), DENV-2 (76%), DENV-3 (86%), and DENV-4 (100%). 103   Although homotypic antibody titers are associated with serotype specific vaccine efficacy, immune correlates that reliably predict vaccine efficacy have not yet been identified and remain an area of active research. 46  

Dengvaxia uses a 3-dose schedule with each dose given 6 months apart (at months 0, 6, and 12). It was developed by Washington and St Louis Universities and Acambis and licensed to Sanofi Pasteur in the 2000s, entered phase 3 trials in the 2010s, and was first recommended by WHO in 2016 for persons aged 9 years and older living in highly endemic areas. Long-term follow-up data (over 5 years) from the phase 3 trials and further analyses of the efficacy results 104 – 107   demonstrated that children with evidence of previous DENV infection were protected from virologically confirmed dengue illness, including severe dengue if they were vaccinated with Dengvaxia. However, risk of hospitalization for dengue and severe dengue was increased among children without previous dengue infection who were vaccinated with Dengvaxia and had a subsequent dengue infection in the years after vaccination. In children without a previous dengue infection, the vaccine acts as a silent primary dengue infection resulting in a “secondary-like” infection upon their first infection with wild-type DENV and an increased risk of severe disease due to ADE ( Fig 6 ). 108 , 109   After these findings, WHO revised their recommendations for the vaccine to only be given to children with laboratory-confirmed evidence of a past infection. Following WHO’s recommendation, the FDA licensed Dengvaxia in 2019, and in 2021, ACIP recommended routine use of Dengvaxia for children aged 9–16 years with laboratory confirmation of previous DENV infection and living in areas where dengue is endemic. Dengvaxia is the first dengue vaccine recommended for use in the United States.

Proposed mechanism of Dengvaxia efficacy based on prior dengue antigen exposure. Risk of severe disease is represented by color (low = green, medium = yellow, and high = red). Exposure to dengue antigens is represented by mosquito figure for wild-type exposure and by a syringe for Dengvaxia exposure. The first row shows an unvaccinated individual exposed to 4 different dengue serotypes in their life with highest risk for severe disease with second infection and low risk of severe disease in the third and fourth infection. The second row shows an individual without previous dengue exposure who receives Dengvaxia, which acts as a silent primary infection, and then has higher risk for severe disease upon their first exposure to wildtype dengue, the equivalent of the second exposure to dengue antigen. The third row shows an individual with previous wild-type infection who receives Dengvaxia which acts as a silent second dengue exposure with lower risk for severe disease in subsequent exposures to wild-type dengue.

For children aged 9 to 16 years with evidence of previous dengue infection, Dengvaxia has an efficacy of about 80% against the outcomes of symptomatic virologically confirmed dengue (VCD) followed over 25 months as well as hospitalization for dengue and severe dengue as defined by criteria set by the trial’s independent data monitoring committee and followed over 60 months ( Table 3 ). 105 , 106   The efficacy by serotype mirrored its induction of a homotypic immune response 101   with highest protection against DENV-4 (89%), followed by DENV-3 (80%), and lowest against DENV-1 (67%) and DENV-2 (67%) ( Table 3 ). 106   Protection against mortality could not be reported because there were no dengue-related deaths in the phase 3 trials.

Dengvaxia Efficacy by Outcome and by Serotype in Persons 9–16 Years Old with Evidence of Previous Dengue Virus Infection

Pooled vaccine efficacy data are from CYD14 and CYD15 (clinical trial registration: NCT01373281, NCT01374516). CI, confidence interval; VE, vaccine efficacy. Data are presented as perentages.

Follow-up over 25 mo.

Follow-up over 60 mo.

The most frequently reported side effects (regardless of the dengue serostatus before vaccination) were headache (40%), injection site pain (32%), malaise (25%), asthenia (25%), and myalgia (29%) ( n = 1333). 108   Serious adverse events (ie, life-threatening events, hospitalization, disability or permanent damage, and death) within 28 days were rare in both vaccinated participants (0.6%) and control participants (0.8%) and were not significantly different. At 6 months, fewer severe adverse events were reported in the vaccine (2.8%) than in the control arm (3.2%). 108  

Children who were seronegative for dengue at the time of vaccination had increased risk of severe illness on subsequent dengue infections. Risk of dengue-related hospitalization was approximately 1.5 times higher, and risk of severe dengue was approximately 2.5 times higher among seronegative children aged 9 to 16 years who were vaccinated than control participants over a 5-year period. 106  

The requirement for a laboratory test before administration creates a unique challenge for Dengvaxia implementation. In areas with ongoing transmission of flaviviruses other than dengue, qualifying laboratory tests include a positive NAAT or NS1 test performed during an episode of acute dengue or a positive result on prevaccination screening tests for serologic evidence of previous infection that meet specific performance characteristics. In areas without other ongoing flavivirus transmission, a positive dengue IgM assay during an episode of acute dengue is also considered a qualifying laboratory test. 11  

Prevaccination screening is critical because many DENV infections are asymptomatic or do not result in medical visits and testing. Thus, a significant proportion of previously infected individuals who could benefit from the vaccine will not be aware of or have laboratory documentation of their previous dengue infection. 110 – 113   One of the most challenging aspects in selecting a prevaccination test is defining benchmarks for test performance, as explored by several international working groups. 114 , 115   To reduce the risk of vaccinating someone without previous DENV infection, test specificity is a priority. Although test specificity and sensitivity are independent of seroprevalence, positive predictive value (PPV) and negative predictive value are dependent on seroprevalence and describe the likelihood of a true positive if a patient tests positive or the likelihood of a true negative if a patient tests negative ( Table 4 ). In areas with moderate or low seroprevalence (eg, 30%–50%), high test specificity (>98%) is required to achieve a PPV of 90% and therefore reduce the risk of misclassifying seronegative individuals. In these settings, near-perfect specificity at the expense of sensitivity is preferred to minimize the risk of vaccinating a misclassified negative individual and subsequently increasing their risk of severe dengue. However, high-prevalence areas (eg, >60%) would benefit from a higher test sensitivity and more moderate specificity (eg, 95%), which would increase identification of children who would benefit from the vaccine. 116  

Test Performance for a Dengue Prevaccination Screening Test in Different Seroprevalence Scenarios 11  

NPV, negative predictive value; PPV,  positive predictive value.

CDC recommends that prevaccination screening tests that determine previous dengue infection have a minimum sensitivity of 75% and a minimum specificity of 98%. The recommendations also specify that the tests should be used in populations where they will achieve a positive predictive value (PPV) of ≥90% and a negative predictive value (NPV) of ≥75%. These rows demonstrate that tests with the same CDC recommended minimum sensitivity and specificity will have different PPV and NPV depending on the seroprevalence of the population in which they are used.

Because dengue seroprevalence at age 9 to 16 years is estimated to be approximately 50% in Puerto Rico 117 , 118   (where most of the eligible population for Dengvaxia in the United States and its territories and freely associated states reside), the CDC recommends that tests have a minimum sensitivity of 75% and a minimum specificity of 98%. The recommendations also specify that the test performance in the population should achieve a PPV of ≥90% and a negative predictive value of ≥75%. 11   These test characteristics were used to model the risks and benefits of implementing Dengvaxia. Using Puerto Rico’s population and an estimated seroprevalence of 50%, the model found that Dengvaxia vaccination would avert approximately 4148 symptomatic disease cases and 2956 hospitalizations over a 10-year period. This implementation would also result in an additional 51 hospitalizations caused by vaccination of people without previous dengue infection who were misclassified by the screening test. 119   The most common cause of hospitalization among vaccinated children will be breakthrough disease because the vaccine is not 100% efficacious.

TAK-003, developed by Takeda, consists of 2 doses given 3 months apart. The clinical trial population was primarily composed of children aged 4 to 16 years. At 18 months after vaccination, vaccine efficacy was found to be 80.2% against VCD, which waned to 62.0% by 3 years after vaccination. 120 , 121   Efficacy against hospitalization for dengue remained higher, at 83.6% at 3 years after vaccination. Differences in efficacy were observed by history of previous dengue infection, with higher efficacy among persons with previous infection compared with those without previous infection (65.0%–54.3%), and by age, with higher efficacy in older children. In contrast to findings from Dengvaxia at 25 months, children who were seronegative at the time of TAK-003 vaccination did not show an overall increased risk for hospitalization and severe disease compared with the placebo group at 3 years, although efficacy varied by DENV serotype and an age effect could not be ruled out ( Table 5 ). 106 , 120   Efficacy against both VCD and hospitalization varied by serotype and corresponded to the homotypic antibody titers, 102   with highest efficacy against DENV-2 and lowest against DENV-3 and DENV-4. Among children without previous DENV infection, there was no observed efficacy for VCD against DENV-3 or DENV-4. In the safety analysis, the number of serious adverse events was similar between vaccine (2.9%) and placebo (3.5%) groups.

TAK-003 Efficacy by Serostatus, Outcome, Serotype, and Age Group in Persons Aged 4–16 Years Over 36 Months of Follow-Up 120  

Vaccine efficacy data are from clinical trial NCT02747927. CI, confidence interval; VE, vaccine efficacy. Data presented as percentage.

In March 2021, Takeda submitted TAK-003 to the European Medicines Agency for prevention of dengue from any DENV serotype among people aged 4 to 60 years. 122   The company will also be submitting filings to regulatory agencies in Argentina, Brazil, Colombia, Indonesia, Malaysia, Mexico, Singapore, Sri Lanka, and Thailand during 2021 and has future plans to submit to the FDA.

TV003 was developed by the National Institutes of Health and was formulated by selecting serotype-specific components that were determined to provide the most balanced safety and immunogenicity profile based on an evaluation of multiple monovalent and tetravalent candidates. 123 , 124   Because antibody titers failed to predict the efficacy of Dengvaxia, a human infection model was developed to assess the protective immunity induced by TV003 against DENV-2 challenge. Forty-eight volunteers were enrolled and randomized to receive TV003 (24) or placebo (24). Six months later, volunteers were administered a naturally attenuated DENV-2 challenge virus. 125   The primary efficacy endpoint was protection against detectable viremia after challenge. After challenge, DENV-2 was recovered by culture or reverse transcription-polymerase chain reaction (RT-PCR) from 100% of placebo recipients ( n = 20) and 0% of TV003 recipient ( n = 21) ( P < .0001). Postchallenge, rash was observed in 80% of placebo recipients compared with 0% of TV003 recipients ( P < .0001).

TV003 has been licensed to several manufacturers globally, including Merck & Co in the United States and the Instituto Butantan in Brazil. Phase 3 trials in Brazil are underway with efficacy and safety results expected in late 2022 (Clinical trial registration: NCT02406729).

Dengue is the most common arboviral disease worldwide and is projected to increase in range and global burden of disease. Although advancements in the field have progressed incrementally for decades, the recent approval of Dengvaxia for routine use marks a major step forward for control and prevention efforts in the United States and paves the way for future dengue vaccines.

Dengvaxia has several complexities that necessitate future research, including the possibility of fewer doses in the initial schedule followed by booster doses in later years. 30   Because it is the first vaccine to require laboratory testing before administration, public–private partnerships to develop more specific, sensitive, and accessible tests or testing algorithms will be key to minimize vaccination of persons without previous DENV infection and maximize benefit to those with previous infection. Jurisdictions that wish to use Dengvaxia will need to gather seroprevalence data and ensure that prevaccination screening tests meet the requirements for positive and negative predictive values. Furthermore, behavioral science assessments to elicit community-level perceptions and concerns combined with health systems research on optimal “test-and-vaccinate” strategies will result in dengue vaccination programs that are well accepted, efficient, and tailored to individual communities.

TAK-003 and TV003 are in late-stage trials and could soon be approaching licensure. An indication for use in travelers would offer clinicians in nonendemic areas of the United States a prophylactic therapeutic option for their patients. While awaiting the approval of a vaccine with balanced serotype immunity, a mix-and-match strategy guided by differences in serotype-dominant immune responses in each vaccine (TAK-003 followed by Dengvaxia, for example) could potentially lead to higher levels of protection against dengue, but it has yet to be evaluated for safety and efficacy in clinical trials. 126   For all 3 vaccines, studies evaluating efficacy against emerging DENV serotype variants will be important to assess long-term protection induced by the vaccine strains. 10 , 127  

Future vaccines against dengue could also benefit from the lessons learned from the COVID-19 pandemic, namely that new vaccine platform technologies plus political will can result in rapid development of safe and effective vaccines and that clear communication with the public is crucial to successful vaccine implementation. 128 – 130   Dengue vaccines based on an mRNA platform are already under investigation. 131  

Vaccines are a powerful new tool in our arsenal against dengue, but they are only 1 of many interventions, including novel vector control strategies, to control a virus with a complex epidemiology, immunopathogenesis, and clinical picture influenced by climate change, urbanization, poverty, and human migration. Clinicians should remain vigilant in recognizing and diagnosing patients with dengue, because early treatment remains the cornerstone for reducing morbidity and mortality. However, with the recent approval of Dengvaxia, we are 1 step closer on the path to dengue elimination and can expect exciting new developments in dengue interventions in the near future.

We thank Ms Alexia E. Rodriguez, MPH, for her review of the manuscript.

Drs Wong, Adams, and Paz-Bailey conceptualized and designed the structure of the review, drafted portions of the initial manuscript, and reviewed and revised the manuscript; Drs Durbin, Muñoz-Jordán, Sánchez-González, and Volkman drafted portions of the initial manuscript and reviewed and revised the manuscript; Dr Poehling reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: Dr Durbin is a scientific advisor to Merck & Co on dengue vaccine development. The other authors have no conflicts of interest to disclose.

Advisory Committee on Immunization Practices

antibody dependent enhancement

Centers for Disease Control and Prevention

dengue virus

Food and Drug Administration

immunoglobulin M

nucleic acid amplification test

nonstructural protein 1

positive predictive value

plaque reduction neutralization test

virologically confirmed dengue

World Health Organization

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• 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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Additional file 3: Appendix S3.

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

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• Dengue fever

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Dengue Fever: Causes, Complications, and Vaccine Strategies

Affiliations.

• 1 International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India; Department of Biochemistry, University of Delhi, Institute of Home Economics, Hauz Khas, New Delhi 110016, India.
• 2 International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
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• DOI: 10.1155/2016/6803098

Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals.

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Current Dengue Fever Research

Introduction, basic research on dengue.

What does basic dengue research involve? Basic research includes a wide range of studies focused on learning how the dengue virus is transmitted and how it infects cells and causes disease. This type of research investigates many aspects of dengue viral biology, including exploration of the interactions between the virus and humans and studies of how the dengue virus replicates itself.

One important field of basic research is dengue pathogenesis , the study of the process and mechanisms of dengue in humans. Scientists want to understand how the dengue virus causes damage to the human body and how the immune system responds to a dengue infection so that they can develop new treatments for the disease. For example, researchers want to understand why bleeding and vascular leakage occur in patients with severe dengue illnesses. Knowledge of the disease pathway may help doctors and clinicians diagnose dengue at earlier stages. Researchers want to find out whether there are genetic factors that result in an increased or decreased risk of infection for individuals. Some people may be genetically susceptible to develop more severe symptoms than other people.

Scientists are also studying the dengue viruses to understand which factors are responsible for transmitting the virus to humans. Researchers are investigating how the dengue virus replicates itself and the structure of the viral components, such as the capsid, membrane, and envelope proteins. Scientists also want to know — how do the dengue viruses manage to avoid detection by the immune system? Because viruses can evolve and gain mutations over time, researchers are examining dengue viral genetics and evolution to investigate changes in viral genomes over time. These variations may help the virus hide from the immune system. Scientists know that particular viral sequences are associated with more severe dengue symptoms. In addition, certain dengue sequence variations may produce more deadly viruses with a greater potential for causing epidemics. This kind of information can help scientists monitor the regional spread of particularly dangerous dengue strains to help communities prevent or prepare for dengue outbreaks.

Other dengue research focuses on vector biology. What is vector biology? This field of dengue research studies the disease vector, Aedes mosquitoes. Vector biology studies mosquito ecology, population biology, genetics, and behaviors to understand how mosquitoes transmit the dengue viruses. Researchers can also study dengue transmission patterns. As one example, researchers studied dengue infections in children living in Nicaragua and saw that patterns of dengue transmission depended on changes in climate and changes in the dengue serotypes in the area. Large-scale studies of patterns in dengue transmission can provide essential information to resist the disease, identify and diagnose dengue cases, and implement mosquito-control efforts.

Diagnostics

Patients with severe dengue illnesses can be treated successfully if they are diagnosed as early as possible. Scientists are working on improving dengue diagnostics so that patients infected with dengue can be treated quickly. What would the ideal diagnostic test for dengue do? The ideal diagnostic test would be able to distinguish dengue from other diseases with similar symptoms and distinguish one dengue serotype from another. An ideal diagnostic test would be highly sensitive during the acute stage of the infection, quick and easy to use, and affordable.

How is dengue diagnosed? A number of laboratory methods are used to diagnose dengue, including detection of the dengue virus, viral RNA, viral antigens, and antibodies against the virus in the patient's blood or tissues (Figure 1). The virus can be detected in the blood for only four to five days after the onset of symptoms. During this early stage of the disease, isolation of the virus, viral RNA, and viral protein can be used to diagnose dengue.

The detection of antibodies (IgM and IgG) in the blood of an infected individual is an indirect method to diagnose dengue. This method is commonly used to diagnose dengue in the later stage of the disease, after the viral levels have decreased. Antibodies against dengue can be detected in most patients five days after the onset of symptoms, and IgG can be detected for many months and even years after an infection (Figure 2). During a primary (first) dengue infection, IgM levels are very high, but during a secondary infection, IgM levels are lower. The levels of IgG actually increase during a secondary infection. Therefore, clinicians can measure the amounts of IgM and IgG to decide whether a patient has a primary or a secondary dengue infection. This test can be useful because patients with secondary infections are more likely to have severe dengue than those who have not had a previous infection. Because dengue can be mistaken for other diseases such as yellow fever, measles, and influenza, it is best to confirm a diagnosis of dengue by detecting the antibody response and testing for direct evidence of the virus.

Have researchers developed any new diagnostic tests to diagnose dengue? Recently, scientists developed a rapid, one-step test to detect and distinguish all four dengue serotypes. This test is based on reverse transcription polymerase chain reaction amplification of the viral RNA, and it is a sensitive, rapid, and cost-effective tool to diagnose patients with dengue. A second approach involves diagnosing dengue infections by detecting NS1, one of the seven nonstructural dengue proteins. NS1 is produced in large quantities during dengue viral replication, and it can be detected as early as the first day the patient experiences a fever.

Is there a way to know which patients might develop severe dengue? Scientists want to find ways to quickly identify patients who are the most likely to develop severe dengue illnesses. To identify these patients, researchers must first discover predictive factors for severe dengue. One way researchers can discover these factors is to monitor the progression of the disease and look for factors that predict severe illness by taking frequent blood samples and ultrasound images from patients with dengue. Ultrasound can measure indicators of severe dengue, including the thickening of the gall bladder wall and excess fluids around the tissues and organs in the abdomen and chest cavity. Knowledge of additional predictive factors could help researchers design more effective diagnostic tests. Another strategy involves applying decision-making computer models to diagnose patients with dengue and predict their prognoses by using clinical data, such as the patient's platelet count and the presence of preexisting IgG antibodies against dengue in the blood.

Dengue Surveillance

What can other fields of research do to prevent and control dengue? In addition to performing basic research and improving diagnostics, improving dengue surveillance is an essential way to prevent and control dengue transmission. The World Health Organization — in partnership with ministries of health, research centers, and laboratories around the world — has developed a dengue surveillance system called DengueNet, a database that can be continuously updated to share current and historical data on dengue cases. The goals of DengueNet are to standardize reporting of dengue cases and to improve the preparedness of public health officials by providing early warnings prior to epidemics, which can help reduce fatality rates.

Monitoring mosquito populations is a first line of defense against dengue. Vector surveillance allows for a prompt response to control mosquito populations and limit dengue transmission. Studying vector competence, the ability of Aedes mosquitoes to acquire and transmit the dengue virus, can provide important information about variations in the transmission of the different dengue serotypes. Researchers have shown that delayed mosquito-control responses can lead to an exponential increase in both the number of infected people and health costs. Public health officials can prevent large dengue outbreaks by using surveillance information to plan mosquito-control efforts and interventions and to provide resources to affected areas. Vector surveillance is crucial for public health officials so that they can provide a prompt and preventative response to dengue.

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Trends in dengue research in the Philippines: A systematic review

Kristal an agrupis.

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

Michelle Ylade

Josephine aldaba, anna lena lopez, jacqueline deen, associated data.

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

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.

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.

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 ).

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.

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.

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Dengue virus (DENV) belongs to the Flavivirus genus and is transmitted by mosquitoes, including Aedes albopictus and Ae. aegypti. There are four serotypes of DENV (DEVN 1–4), which can cause a spectrum of outcomes ranging from subclinical to death. Four serotypes (DENV 1–4) are circulating in tropical and ...

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Widening Gender Gap in Life Expectancy in the US, 2010-2021

• 1 Department of Medicine, University of California, San Francisco School of Medicine, San Francisco
• 2 Harvard T.H. Chan School of Public Health, Boston, Massachusetts
• 3 Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland
• 4 Boston University School of Public Health, Boston, Massachusetts

As life expectancy at birth in the US decreased for the second consecutive year, from 78.8 years (2019) to 77.0 years (2020) and 76.1 years (2021), the gap between women and men widened to 5.8 years, its largest since 1996 and an increase from a low of 4.8 years in 2010. 1 , 2 For more than a century, US women have outlived US men, attributable to lower cardiovascular and lung cancer death rates related largely to differences in smoking behavior. 1 , 2 This study systematically examines the contributions of COVID-19 and other underlying causes of death to the widened gender life expectancy gap from 2010 to 2021.

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Yan BW , Arias E , Geller AC , Miller DR , Kochanek KD , Koh HK. Widening Gender Gap in Life Expectancy in the US, 2010-2021. JAMA Intern Med. Published online November 13, 2023. doi:10.1001/jamainternmed.2023.6041

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Computer Science > Computation and Language

Title: the impact of large language models on scientific discovery: a preliminary study using gpt-4.

Abstract: In recent years, groundbreaking advancements in natural language processing have culminated in the emergence of powerful large language models (LLMs), which have showcased remarkable capabilities across a vast array of domains, including the understanding, generation, and translation of natural language, and even tasks that extend beyond language processing. In this report, we delve into the performance of LLMs within the context of scientific discovery, focusing on GPT-4, the state-of-the-art language model. Our investigation spans a diverse range of scientific areas encompassing drug discovery, biology, computational chemistry (density functional theory (DFT) and molecular dynamics (MD)), materials design, and partial differential equations (PDE). Evaluating GPT-4 on scientific tasks is crucial for uncovering its potential across various research domains, validating its domain-specific expertise, accelerating scientific progress, optimizing resource allocation, guiding future model development, and fostering interdisciplinary research. Our exploration methodology primarily consists of expert-driven case assessments, which offer qualitative insights into the model's comprehension of intricate scientific concepts and relationships, and occasionally benchmark testing, which quantitatively evaluates the model's capacity to solve well-defined domain-specific problems. Our preliminary exploration indicates that GPT-4 exhibits promising potential for a variety of scientific applications, demonstrating its aptitude for handling complex problem-solving and knowledge integration tasks. Broadly speaking, we evaluate GPT-4's knowledge base, scientific understanding, scientific numerical calculation abilities, and various scientific prediction capabilities.

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Trends in dengue research in the Philippines: A systematic review

Roles Data curation, Writing – review & editing

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

Roles Writing – review & editing

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

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

* E-mail: [email protected]

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

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

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

Author summary

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

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

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

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

Copyright: © 2019 Agrupis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

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

Competing interests: No authors have competing interests.

Introduction

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

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

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

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

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

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

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

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

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

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

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

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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.

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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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