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

Fitzpatrickʼs Dermatology in General Medicine

Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic urticaria (CU), is more common than previously thought. At any time, 0.5-1% of the population suffers from the disease (point prevalence). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1-5 years but is likely to be longer in more severe cases, cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity). Chronic spontaneous urticaria has major detrimental effects on quality of life, with sleep deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in terms of direct and indirect health care costs as well as reduced performance at work and in private life. In the majority of patients, an underlying cause cannot be identified making a causal and/or curative treatment difficult. Nonsedating H₁-antihistamines are the mainstay of symptomatic therapy, but treatment with licensed doses relieves symptoms effectively in < 50% of patients. Although guideline-recommended updosing up to fourfold increases symptom control in many patients, a substantial number of patients have only little benefit from H₁ -antihistamines. Consequently, there is a great need for new therapeutic strategies.

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Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report.

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.

The purpose of our study was to assess the prevalence and clinical course of patients with chronic idiopathic urticaria (CIU), as well as possible causes or associated findings, laboratory findings and the duration of the disease in patients with chronic urticaria (CU). We retrospectively reviewed the 450 case record forms of patients with CU and/or angioedema who attended the Department of Dermatology, Siriraj Hospital, during the period 2000-2004. Of 450 patients with CU, 337 patients (75%) were diagnosed as CIU. Forty-three patients (9.5%) had physical urticaria, while 17 patients (3.8%) had infectious causes. Other possible causes were food, thyroid diseases, atopy, drugs, dyspepsia and collagen vascular diseases. In eighty-nine percent of patients, no abnormalities were detected at the time of physical examination. The most common abnormal laboratory finding was minimal elevation of the erythrocyte sedimentary rate (42%). In 61 patients, autologous serum skin tests had been done. Fifteen patients (24.5%) had positive results i.e. autoimmune urticaria. Anti-thyroglobulin and anti-microsomal antibodies were positive in 16 % and 12% of CIU patients respectively. After 1 year from the onset of the symptoms, 34.5% of CIU patients were free of symptoms and after 1.2 years from the onset of the symptoms, 56.5% of autoimmune urticaria patients were free of symptoms. The median disease duration of CIU and autoimmune urticaria were 390 days and 450 days respectively. Our study provided an overview of CU and CIU in a large series of Thai patients, based on etiological aspects and clinical courses.

Chronic idiopathic urticaria: prevalence and clinical course.

Objectives: To examine the impact of high-dose multiple micronutrient supplementation on survival and disease progression among HIV-infected individuals in Thailand. Design: Randomized placebo-controlled trial. Methods: Four-hundred and eighty-one HIV-infected men and women living in and around Bangkok with CD4 cell counts in the range 50 X 10(6) – 550 X 10(6)/l were randomized to receive micronutrients or placebo for a period of 48 weeks. Trial participants were examined clinically 12-weekly and tested for CD4 cell count 24- weekly. A subset were tested for HIV plasma viral load at 48 weeks. Results: Seventy-nine (16%) trial participants were lost to follow-up and 23 (5%) died. The death rate was lower in the micronutrients arm with the mortality hazard ratios [95% confidence interval (CI)] of 0.53 (0.22–1.25; P = 0.1) overall and 0.37 (0.13– 1.06; P = 0.052) and 0.26 (0.07–0.97; P = 0.03) among those with CD4 cell counts < 200 X 10(6)/l and < 100 X 10(6)/l respectively. There was no impact on CD4 cell count or plasma viral load. Conclusions: Multiple micronutrient supplementation may enhance the survival of HIV-infected individuals with CD4 cell counts < 200 X 10(6)/l. This could have important public health implications in the developing world where access to antiretrovirals remains poor. The clinical findings need to be reproduced in other settings and the mechanism which appears to be independent of change in CD4 cell count merits further investigation. (authors)

A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok.

Background: Pityriasis rosea is a common self-limiting disease. UV light has been mentioned as helpful, but only a few studies substantiate this possibility. Objective: Our purpose was to evaluate the clinical efficacy of UVB phototherapy in pityriasis rosea and the course of the disease after treatment. Methods: Seventeen patients with extensive pityriasis rosea were treated with unilateral UVB phototherapy in a bilateral comparison study. One joule of UVA was used as a "placebo" on the untreated side. The treatments were given five times per week for 2 weeks. The rate of clearing was monitored by estimation of the severity score. Results: Ten daily erythemogenic exposures of UVB resulted in substantially decreased severity of disease, greater than that on the untreated side in 15 of 17 patients. The overall reduction of severity score showed a significant difference after the third treatment; the UVB irradiation was superior. However, during the follow-up period the two sides were indistinguishable in regard to severity score ( p = 0.6784). No significant difference in pruritus was noted between the two sides ( p > 0.1638). The duration of disease did not relate to the success of UVB phototherapy. Conclusion: During the treatment period UVB phototherapy resulted in decreased severity of disease. However, the itching and the course of the disease were unchanged.

UVB phototherapy for pityriasis rosea: A bilateral comparison study

Background Direct immunofluorescence (DIF) studies in patients with lichen planus (LP) show the deposition of multiple immunoglobulins (Igs) at the cytoid bodies (CBs) and fibrin at the dermoepidermal junction (DEJ). The deposition of Ig at the DEJ, as in patients with lupus erythematosus (LE), is occasionally found. For cases with no specific clinical and histologic characteristics, or with ambiguous features, DIF studies may be helpful in disease differentiation.

Methods  From 1996 to 2004, data from 72 patients with LP, diagnosed on the basis of clinical and histologic criteria at the Department of Dermatology, Siriraj Hospital, Bangkok, Thailand, were collected. The results of DIF studies were analyzed.

Results Deposits at the DEJ and CBs were detected in 53% and 60% of cases, respectively. A combination of DEJ (mostly fibrin) and CB (mostly IgM) deposits was found in 38% of cases. A combination of IgM and other immunoreactant deposits, including fibrin at the CBs, was found in 56% of cases.

Conclusions  This study showed that the positive yield of DIF in LP was 75%. Shaggy fibrin deposition at the DEJ, which is the single best indicator in the diagnosis of LP, was found in 56% of cases. The presence of CBs only, which is a poorer indicator than the shaggy deposition of fibrin along the DEJ, was found in 22% of cases. There were no statistically significant differences in positive DIF yield between specimens derived from glabrous skin and oral lesions (P = 0.67). Forty-four per cent of cases had immunoreactants other than fibrin deposited along the DEJ, which resembled those of LE.

Sukhum Jiamton

Papers

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

Chronic idiopathic urticaria: prevalence and clinical course.

A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok.

UVB phototherapy for pityriasis rosea: A bilateral comparison study

Direct immunofluorescence study in patients with lichen planus.