Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

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The global distribution and burden of dengue

The publication of the Global Burden of Disease Study 2010 (GBD 2010) and the accompanying collection of Lancet articles in December 2012 provided the most comprehensive attempt to quantify the burden of almost 300 diseases, injuries, and risk factors, including neglected tropical diseases (NTDs) [1]–[3]. The disability-adjusted life year (DALY), the metric used in the GBD 2010, is a tool which may be used to assess and compare the relative impact of a number of diseases locally and globally [4]–[6]. Table 1 lists the major NTDs as defined by the World Health Organization (WHO) [7] and their estimated DALYs [1]. With a few exceptions, most of the NTDs currently listed by the WHO [7] or those on the expanded list from PLOS Neglected Tropical Diseases [8] are disablers rather than killers, so the DALY estimates represent one of the few metrics available that could fully embrace the chronic effects of these infections.

Table 1
Estimated DALYs (in millions) of the NTDs from the Global Burden of Disease Study 2010.

Disease	DALYs from GBD 2010 (numbers in parentheses indicate 95% confidence intervals) [1]	
NTDs	26.06 (20.30–35.12)	
Intestinal nematode infections	5.19 (2.98–8.81)	
Hookworm disease	3.23 (1.70–5.73)	
Ascariasis	1.32 (0.71–2.35)	
Trichuriasis	0.64 (0.35–1.06)	
Leishmaniasis	3.32 (2.18–4.90)	
Schistosomiasis	3.31 (1.70–6.26)	
Lymphatic filariasis	2.78 (1.8–4.00)	
Food-borne trematodiases	1.88 (0.70–4.84)	
Rabies	1.46 ((0.85–2.66)	
Dengue	0.83 (0.34–1.41)	
African trypanosomiasis	0.56 (0.08–1.77)	
Chagas disease	0.55 (0.27–1.05)	
Cysticercosis	0.50 (0.38–0.66)	
Onchocerciasis	0.49 (0.36–0.66)	
Trachoma	0.33 (0.24–0.44)	
Echinococcosis	0.14 (0.07–0.29)	
Yellow fever	<0.001	
Other NTDs *	4.72 (3.53–6.35)	


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* Relapsing fevers, typhus fever, spotted fever, Q fever, other rickettsioses, other mosquito-borne viral fevers, unspecified arthropod-borne viral fever, arenaviral haemorrhagic fever, toxoplasmosis, unspecified protozoal disease, taeniasis, diphyllobothriasis and sparganosis, other cestode infections, dracunculiasis, trichinellosis, strongyloidiasis, enterobiasis, and other helminthiases.



Even DALYs, however, do not tell the complete story of the harmful effects from NTDs. Some of the specific and potential shortcomings of GBD 2010 have been highlighted elsewhere [9]. Furthermore, DALYs measure only direct health loss and, for example, do not consider the economic impact of the NTDs that results from detrimental effects on school attendance and child development, agriculture (especially from zoonotic NTDs), and overall economic productivity [10], [11]. Nor do DALYs account for direct costs of treatment, surveillance, and prevention measures. Yet, economic impact has emerged as an essential feature of the NTDs, which may trap people in a cycle of poverty and disease [10]–[12]. Additional aspects not considered by the DALY metrics are the important elements of social stigma for many of the NTDs and the spillover effects to family and community members [13], [14], loss of tourism [15], and health system overload (e.g., during dengue outbreaks). Ultimately NTD control and elimination efforts could produce social and economic benefits not necessarily reflected in the DALY metrics, especially among the most affected poor communities [11].

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The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases.

Background In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development. Methods In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection. Results A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval [CI], 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events. Conclusions The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.)

Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America

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The role of CD8(+) T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8(+) responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8(+) T cells is associated with protection from dengue virus disease.

https://www.pnas.org/content/pnas/110/22/E2046.full.pdf

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

Despite the growing worldwide burden of dengue fever, the global economic impact of dengue illness is poorly documented. Using a common protocol, we present the first multicountry estimates of the direct and indirect costs of dengue cases in eight American and Asian countries. We conducted prospective studies of the cost of dengue in five countries in the Americas (Brazil, El Salvador, Guatemala, Panama, and Venezuela) and three countries in Asia (Cambodia, Malaysia, and Thailand). All studies followed the same core protocol with interviews and medical record reviews. The study populations were patients treated in ambulatory and hospital settings with a clinical diagnosis of dengue. Most studies were performed in 2005. Costs are in 2005 international dollars (I$). We studied 1,695 patients (48% pediatric and 52% adult); none died. The average illness lasted 11.9 days for ambulatory patients and 11.0 days for hospitalized patients. Among hospitalized patients, students lost 5.6 days of school, whereas those working lost 9.9 work days per average dengue episode. Overall mean costs were I$514 and I$1,394 for an ambulatory and hospitalized case, respectively. With an annual average of 574,000 cases reported, the aggregate annual economic cost of dengue for the eight study countries is at least I$587 million. Preliminary adjustment for under-reporting could raise this total to $1.8 billion, and incorporating costs of dengue surveillance and vector control would raise the amount further. Dengue imposes substantial costs on both the health sector and the overall economy.

http://www1.saude.rs.gov.br/dados/1298556190825Cost%20of%20dengue%20-%20ARTIGO.pdf

Cost of dengue cases in eight countries in the Americas and Asia: a prospective study.

In 2005, Panama experienced the largest dengue epidemic since 1993. We conducted both a prospective clinical and a national economic study. The full cost analysis measured costs of dengue cases and of dengue control efforts in the entire country. Costs are in 2005 US$. Ambulatory patients were 130 of the 136 participants, with 82% adults (18+) and 62% women. Duration of fever and illness averaged 6.1 (standard deviation [SD], 5.3) and 21.2 (SD 13.5) days, respectively. Loss in quality of life averaged 67% (SD 21) during the worst days of illness. An average ambulatory and hospitalized case cost $332 and $1,065, respectively. Although 5,489 cases were officially reported, the Ministry of Health (MOH) estimated 32,900 actual cases, implying a total cost of $11.8 million. Additionally, estimated government spending on dengue control efforts was $5 million. This dengue epidemic had a major disease impact and an economic cost of $16.9 million ($5.22 per capita).

Clinical characteristics and national economic cost of the 2005 dengue epidemic in Panama.

Although the disease burden of dengue is increasing, the impact on the quality of life (QoL) has not been investigated. A study to determine the QoL of confirmed dengue patients using the EuroQol visual thermometer scale was carried out at the University Malaya Medical Center. Of the 207 participants, 40% were ambulatory and 60% were hospitalized. Of eight health domains, 6.2 and 5.0 domains were affected in the hospitalized and ambulatory cohorts, respectively (P < 0.001), with cognition and interpersonal activities affected most. All patients experienced a drastic decrease in their QoL from the onset of symptoms. The QoL deteriorated to the lowest point (40% of healthy status) between the third and seventh days of illness. The duration of impaired QoL (9 days for ambulatory or 13 days for hospitalized patients) was longer than the duration of fever (5 and 7 days, respectively). Symptomatic dengue has major effects on patients' health.

Quality of Life of Dengue Patients

Dengue infection is endemic among children in Cambodia. Few studies have described the clinical characteristics, diagnoses and the socioeconomic impact of hospitalized dengue cases. As part of a multicountry prospective dengue study, we analysed interviews and record reviews of 123 consecutive cases of children hospitalized with confirmed dengue in a major public provincial hospital. About 80% of cases evidenced plasma leak. On average, a hospitalized dengue case lasted 6.3 days, with 3.3 days of inpatient care, and cost US$116 (Singapore dollar 48). The majority (88%) of these cases’ households reported a substantial adverse economic impact, perhaps explained by their inability to afford medical care (39%), or on account of loss of five or more days of income (91%), need to borrow money beyond family or friends (39%), being compelled to sell or sale of property (53%) to pay for treatment. Hospitalized dengue has major clinical and socioeconomic consequences in Cambodia.

Binod K. Sah

Papers

Cost of dengue cases in eight countries in the Americas and Asia: a prospective study.

Clinical characteristics and national economic cost of the 2005 dengue epidemic in Panama.

Quality of Life of Dengue Patients

Clinical characterization, diagnosis and socioeconomic impact of hospitalized dengue in Cambodia.