Annelies Wilder-Smith

Geographic Expansion of Dengue: The Impact of International Travel

Dengue has emerged as an international public health problem. Reasons for the resurgence of dengue in the tropics and subtropics are complex and include unprecedented urbanization with substandard living conditions, lack of vector control, virus evolution, and international travel. Of all these factors, urbanization has probably had the most impact on the amplification of dengue within a given country, and travel has had the most impact for the spread of dengue from country to country and continent to continent. Epidemics of dengue, their seasonality, and oscillations over time are reflected by the epidemiology of dengue in travelers. Sentinel surveillance of travelers could augment existing national public health surveillance systems.

GeoSentinel surveillance of illness in returned travelers, 2007-2011.

BACKGROUND International travel continues to increase, particularly to Asia and Africa. Clinicians are increasingly likely to be consulted for advice before travel or by ill returned travelers. OBJECTIVE To describe typical diseases in returned travelers according to region, travel reason, and patient demographic characteristics; describe the pattern of low-frequency travel-associated diseases; and refine key messages for care before and after travel. DESIGN Descriptive, using GeoSentinel records. SETTING 53 tropical or travel disease units in 24 countries. PATIENTS 42 173 ill returned travelers seen between 2007 and 2011. MEASUREMENTS Frequencies of demographic characteristics, regions visited, and illnesses reported. RESULTS Asia (32.6%) and sub-Saharan Africa (26.7%) were the most common regions where illnesses were acquired. Three quarters of travel-related illness was due to gastrointestinal (34.0%), febrile (23.3%), and dermatologic (19.5%) diseases. Only 40.5% of all ill travelers reported pretravel medical visits. The relative frequency of many diseases varied with both travel destination and reason for travel, with travelers visiting friends and relatives in their country of origin having both a disproportionately high burden of serious febrile illness and very low rates of advice before travel (18.3%). Life-threatening diseases, such as Plasmodium falciparum malaria, melioidosis, and African trypanosomiasis, were reported. LIMITATIONS Sentinel surveillance data collected by specialist clinics do not reflect healthy returning travelers or those with mild or self-limited illness. Data cannot be used to infer quantitative risk for illness. CONCLUSION Many illnesses may have been preventable with appropriate advice, chemoprophylaxis, or vaccination. Clinicians can use these 5-year GeoSentinel data to help tailor more efficient pretravel preparation strategies and evaluate possible differential diagnoses of ill returned travelers according to destination and reason for travel. PRIMARY FUNDING SOURCE Centers for Disease Control and Prevention.

Update on Dengue: Epidemiology, Virus Evolution, Antiviral Drugs, and Vaccine Development

Dengue virus is the most widespread geographically of the arboviruses and a major public health threat in the tropics and subtropics. Scientific advances in recent years have provided new insights about the pathogenesis of more severe disease and novel approaches into the development of antiviral compounds and dengue vaccines. Phylogenetic studies show an association between specific subtypes (within serotypes) and severity of dengue. The lack of association between maternal antibodies and development of severe dengue in infants in a recent study has called for the rethinking or refinement of the current antibody-dependent enhancement theory of dengue hemorrhagic syndrome in infancy. Such studies should stimulate new directions of research into mechanisms responsible for the development of severe dengue. The life cycle of dengue virus readily shows that virus entry and replication can be targeted by small molecules. Advances in a mouse model (AG 129 mice) have made it easier to test such antiviral compounds. The efforts to find specific dengue inhibitors are intensifying and the tools to evaluate the efficacy of new drugs are now in place for rapid translation into trials in humans. Furthermore, several dengue vaccine candidates are in development, of which the chimeric dengue/yellow fever vaccine has now entered phase 3 trials. Until the availability of a licensed vaccine, disease surveillance and vector population control remain the mainstay of dengue prevention.

Seasonality, Annual Trends, and Characteristics of Dengue among Ill Returned Travelers, 1997–2006

Atypical patterns may indicate onset of epidemic activity.

Disability in people affected by leprosy: the role of impairment, activity, social participation, stigma and discrimination

Background : Leprosy-related disability is a challenge to public health, and social and rehabilitation services in endemic countries. Disability is more than a mere physical dysfunction, and includes activity limitations, stigma, discrimination, and social participation restrictions. We assessed the extent of disability and its determinants among persons with leprosy-related disabilities after release from multi drug treatment. Methods : We conducted a survey on disability among persons affected by leprosy in Indonesia, using a Rapid Disability Appraisal toolkit based on the International Classification of Functioning, Disability and Health. The toolkit included the Screening of Activity Limitation and Safety Awareness (SALSA) scale, Participation Scale, Jacoby Stigma Scale (anticipated stigma), Explanatory Model Interview Catalogue (EMIC) stigma scale and Discrimination assessment. Community members were interviewed using a community version of the stigma scale. Multivariate linear regression was done to identify factors associated with social participation. Results : Overall 1,358 persons with leprosy-related disability (PLD) and 931 community members were included. Seventy-seven percent of PLD had physical impairments. Impairment status deteriorated significantly after release from treatment (from 59% to 77%). Around 60% of people reported activity limitations and participation restrictions and 36% anticipated stigma. As for participation restrictions and stigma, shame, problems related to marriage and difficulties in employment were the most frequently reported problems. Major determinants of participation were severity of impairment and level of education, activity and stigma. Reported severity of community stigma correlated with severity of participation restrictions in the same districts. Discussion : The majority of respondents reported problems in all components of disability. The reported physical impairment after release from treatment justifies ongoing monitoring to facilitate early prevention. Stigma was a major determinant of social participation, and therefore disability. Stigma reduction activities and socio-economic rehabilitation are urgently needed in addition to strategies to reduce the development of further physical impairment after release from treatment.

The Global Meningococcal Initiative: recommendations for reducing the global burden of meningococcal disease

The Global Meningococcal Initiative (GMI) is composed of an international group of scientists, clinicians and public health officials with expertise in meningococcal immunology, epidemiology and prevention. The primary goal of the GMI is the promotion of the global prevention of invasive meningococcal disease through education and research. The GMI members reviewed global meningococcal disease epidemiology, immunization strategies, and research needs. Over the past decade, substantial advances in meningococcal vaccine development have occurred and much has been learned about prevention from countries that have incorporated meningococcal vaccines into their immunization programs. The burden of meningococcal disease is unknown for many parts of the world because of inadequate surveillance, which severely hampers evidence-based immunization policy. As the field of meningococcal vaccine development advances, global surveillance for meningococcal disease needs to be strengthened in many regions of the world. For countries with meningococcal vaccination policies, research on vaccine effectiveness and impact, including indirect effects, is crucial for informing policy decisions. Each country needs to tailor meningococcal vaccination policy according to individual country needs and knowledge of disease burden. Innovative approaches are needed to introduce and sustain meningococcal vaccination programs in resource-poor settings with a high incidence of meningococcal disease.

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 years Phase II randomized controlled trial in Singapore

This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2–11 years) or influenza vaccine for adolescents (12–17 years) and adults (18–45 years). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2-11 y) or influenza vaccine for adolescents (12-17 y) and adults (18-45 y). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.

A global study of pathogens and host risk factors associated with infectious gastrointestinal disease in returned international travellers

OBJECTIVES Infectious gastrointestinal disease (IGD) is a significant cause of morbidity in returned international travellers. This study aims to elucidate host and travel characteristics associated with IGD presentation, and describe the broad spectrum of aetiological pathogens responsible by geographic region of acquisition and reason for travel. METHODS We analyzed demographic, clinical and microbiological data recorded for ill, returned international travellers presenting to GeoSentinel Surveillance Network sites globally during the period September 1996-December 2005. RESULTS A total of 25,867 returned travellers were analyzed, of whom 7442 (29%) patients had a total of 8273 IGD diagnoses. Multivariate analysis demonstrated that IGD presentation was associated significantly with female sex (OR: 1.11; p=0.001); younger age group; attending a pre-travel medical appointment (OR: 1.28; p<0.0001); and travelling for the reason of tourism. Travelling for longer periods (>28 days) was associated with lower risk (OR: 0.93; p=0.04). Of the 2902 clinically significant pathogens isolated, 65% were parasitic, 31% bacterial and 3% viral. Presentation of IGD by specific pathogen varied markedly dependent on geographic region of recent travel, and reason for travel. CONCLUSIONS Host characteristics, region of travel and category of traveller, significantly impact on the relative likelihood of presenting with a broad range of pathogen-specific IGD.

Travel-associated illness trends and clusters, 2000-2010.

Longitudinal data examining travel-associated illness patterns are lacking. To address this need and determine trends and clusters in travel-related illness, we examined data for 2000–2010, prospectively collected for 42,223 ill travelers by 18 GeoSentinel sites. The most common destinations from which ill travelers returned were sub-Saharan Africa (26%), Southeast Asia (17%), south-central Asia (15%), and South America (10%). The proportion who traveled for tourism decreased significantly, and the proportion who traveled to visit friends and relatives increased. Among travelers returning from malaria-endemic regions, the proportionate morbidity (PM) for malaria decreased; in contrast, the PM trends for enteric fever and dengue (excluding a 2002 peak) increased. Case clustering was detected for malaria (Africa 2000, 2007), dengue (Thailand 2002, India 2003), and enteric fever (Nepal 2009). This multisite longitudinal analysis highlights the utility of sentinel surveillance of travelers for contributing information on disease activity trends and an evidence base for travel medicine recommendations.

Combination strategies for pandemic influenza response - a systematic review of mathematical modeling studies

BackgroundIndividual strategies in pandemic preparedness plans may not reduce the impact of an influenza pandemic.MethodsWe searched modeling publications through PubMed and associated references from 1990 to 30 September 2009. Inclusion criteria were modeling papers quantifying the effectiveness of combination strategies, both pharmaceutical and non-pharmaceutical.ResultsNineteen modeling papers on combination strategies were selected. Four studies examined combination strategies on a global scale, 14 on single countries, and one on a small community. Stochastic individual-based modeling was used in nine studies, stochastic meta-population modeling in five, and deterministic compartmental modeling in another five. As part of combination strategies, vaccination was explored in eight studies, antiviral prophylaxis and/or treatment in 16, area or household quarantine in eight, case isolation in six, social distancing measures in 10 and air travel restriction in six studies. Two studies suggested a high probability of successful influenza epicenter containment with combination strategies under favorable conditions. During a pandemic, combination strategies delayed spread, reduced overall number of cases, and delayed and reduced peak attack rate more than individual strategies. Combination strategies remained effective at high reproductive numbers compared with single strategy. Global cooperative strategies, including redistribution of antiviral drugs, were effective in reducing the global impact and attack rates of pandemic influenza.ConclusionCombination strategies increase the effectiveness of individual strategies. They include pharmaceutical (antiviral agents, antibiotics and vaccines) and non-pharmaceutical interventions (case isolation, quarantine, personal hygiene measures, social distancing and travel restriction). Local epidemiological and modeling studies are needed to validate efficacy and feasibility.