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

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

Dengue virus (DENV) is a mosquito-borne member of the Flavivirus genus and includes four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4), each of which is capable of causing dengue fever and dengue hemorrhagic fever/dengue shock syndrome. Serious disease can be seen during primary infection but is more frequent following second infection with a serotype different from that of a previous infection. Infection with wild-type DENV induces high-titered neutralizing antibody that can provide long-term immunity to the homotypic virus and can provide short-term immunity (only several months duration) to a heterotypic DENV. The high level of virus replication seen during both secondary infection with a heterotypic virus and during primary DENV infection in late infancy is a direct consequence of antibody-dependent enhancement of replication. This enhanced virus replication is mediated primarily by preexisting, nonneutralizing, or subneutralizing antibodies to the virion surface antigens that enhance access of the virion-antibody complex to FcγR-bearing cells. Vaccines will need to provide long-term protection against each of the four DENV serotypes by inducing neutralizing antibodies, and live, attenuated and various nonliving virus vaccines are in development.

Immune Response to Dengue Virus and Prospects for a Vaccine

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.

Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: comparing estimates for 7-valent, 10-valent, and 13-valent vaccines.

Objective To determine how Community Health Centers (CHCs) perform relative to other primary care providers. Research design A retrospective cohort study of Medicaid claims comparing provider groups on the basis of avoidable hospitalizations and costs. Results Avoidable hospitalization rates did not differ significantly across care settings. Hospital outpatient departments and CHCs had comparable total costs, whereas physicians had slightly but significantly lower total costs. Conclusions Understanding determinants of care cost differences could inform future performance improvement initiatives. Care quality variance within provider groups may be more significant than care quality performance across care settings.

Comparative performance of community health centers and other usual sources of primary care.

Efforts to measure quality of care have focused on ambulatory care providers. We examined the performance of community health centers serving children on Medicaid in 3 states. Descriptive analysis showed considerable patient population heterogeneity, and regression analysis demonstrated that variation explained by the assigned provider was small (mean R2 = 4.3%) compared with the variation explained by patient demographic variables (mean R2 = 29.9%). The results reinforce the need for caution when one is attributing quality differences to provider performance.

Methodological Challenges of Measuring Primary Care Delivery to Pediatric Medicaid Beneficiaries Who Use Community Health Centers

Efforts to measure quality of care have focused on ambulatory care providers. We examined the performance of community health centers serving children on Medicaid in 3 states. Descriptive analysis showed considerable patient population heterogeneity, and regression analysis demonstrated that variation explained by the assigned provider was small (mean R 2 = 4.3%) compared with the variation explained by patient demographic variables (mean R 2 = 29.9%). The results reinforce the need for caution when one is attributing quality differences to provider performance. (Am J Public Health. 2013;103:273‐275. doi: 10.2105/AJPH.2012.300884)

Karen R. Tyo

Papers

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

Cost-effectiveness of conjugate pneumococcal vaccination in Singapore: comparing estimates for 7-valent, 10-valent, and 13-valent vaccines.

Comparative performance of community health centers and other usual sources of primary care.

Methodological Challenges of Measuring Primary Care Delivery to Pediatric Medicaid Beneficiaries Who Use Community Health Centers

Methodologicaluring PrimaryCareDeliveryto PediatricMedicaid BeneficiariesWhoUse CommunityHealth