Estimating the annual dengue force of infection from the age of reporting primary infections across urban centres in endemic countries

Abstract Background Stratifying dengue risk within endemic countries is crucial for allocating limited control interventions. Current methods of monitoring dengue transmission intensity rely on potentially inaccurate incidence estimates. We investigated whether incidence or alternate metrics obtained from standard, or laboratory, surveillance operations represent accurate surrogate indicators of the burden of dengue and can be used to monitor the force of infection (FOI) across urban centres. Methods Among those who reported and resided in 13 cities across the Philippines, we collected epidemiological data from all dengue case reports between 2014 and 2017 (N 80,043) and additional laboratory data from a cross-section of sampled case reports (N 11,906) between 2014 and 2018. At the city level, we estimated the aggregated annual FOI from age-accumulated IgG among the non-dengue reporting population using catalytic modelling. We compared city-aggregated FOI estimates to aggregated incidence and the mean age of clinically and laboratory diagnosed dengue cases using Pearson’s Correlation coefficient and generated predicted FOI estimates using regression modelling. Results We observed spatial heterogeneity in the dengue average annual FOI across sampled cities, ranging from 0.054 [0.036–0.081] to 0.249 [0.223–0.279]. Compared to FOI estimates, the mean age of primary dengue infections had the strongest association (ρ −0.848, p value<0.001) followed by the mean age of those reporting with warning signs (ρ −0.642, p value 0.018). Using regression modelling, we estimated the predicted annual dengue FOI across urban centres from the age of those reporting with primary infections and revealed prominent spatio-temporal heterogeneity in transmission intensity. Conclusions We show the mean age of those reporting with their first dengue infection or those reporting with warning signs of dengue represent superior indicators of the dengue FOI compared to crude incidence across urban centres. Our work provides a framework for national dengue surveillance to routinely monitor transmission and target control interventions to populations most in need.

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A serological framework to investigate acute primary and post-primary dengue cases reporting across the Philippines

BMC Medicine ◽

10.1186/s12916-020-01833-1 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Joseph R. Biggs ◽

Ava Kristy Sy ◽

Oliver J. Brady ◽

Adam J. Kucharski ◽

Sebastian Funk ◽

...

Keyword(s):

At Risk ◽

Immune Status ◽

Case Reports ◽

Severe Disease ◽

Dengue Infection ◽

Significant Proportion ◽

The Philippines ◽

Dengue Case ◽

Cross Sectional ◽

Populations At Risk

Abstract Background In dengue-endemic countries, targeting limited control interventions to populations at risk of severe disease could enable increased efficiency. Individuals who have had their first (primary) dengue infection are at risk of developing more severe secondary disease, thus could be targeted for disease prevention. Currently, there is no reliable algorithm for determining primary and post-primary (infection with more than one flavivirus) status from a single serum sample. In this study, we developed and validated an immune status algorithm using single acute serum samples from reporting patients and investigated dengue immuno-epidemiological patterns across the Philippines. Methods During 2015/2016, a cross-sectional sample of 10,137 dengue case reports provided serum for molecular (anti-DENV PCR) and serological (anti-DENV IgM/G capture ELISA) assay. Using mixture modelling, we re-assessed IgM/G seroprevalence and estimated functional, disease day-specific, IgG:IgM ratios that categorised the reporting population as negative, historical, primary and post-primary for dengue. We validated our algorithm against WHO gold standard criteria and investigated cross-reactivity with Zika by assaying a random subset for anti-ZIKV IgM and IgG. Lastly, using our algorithm, we explored immuno-epidemiological patterns of dengue across the Philippines. Results Our modelled IgM and IgG seroprevalence thresholds were lower than kit-provided thresholds. Individuals anti-DENV PCR+ or IgM+ were classified as active dengue infections (83.1%, 6998/8425). IgG− and IgG+ active dengue infections on disease days 1 and 2 were categorised as primary and post-primary, respectively, while those on disease days 3 to 5 with IgG:IgM ratios below and above 0.45 were classified as primary and post-primary, respectively. A significant proportion of post-primary dengue infections had elevated anti-ZIKV IgG inferring previous Zika exposure. Our algorithm achieved 90.5% serological agreement with WHO standard practice. Post-primary dengue infections were more likely to be older and present with severe symptoms. Finally, we identified a spatio-temporal cluster of primary dengue case reporting in northern Luzon during 2016. Conclusions Our dengue immune status algorithm can equip surveillance operations with the means to target dengue control efforts. The algorithm accurately identified primary dengue infections who are at risk of future severe disease.

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Serological inference of past primary and secondary dengue infection: implications for vaccination

Journal of The Royal Society Interface ◽

10.1098/rsif.2019.0207 ◽

2019 ◽

Vol 16 (156) ◽

pp. 20190207 ◽

Cited By ~ 1

Author(s):

Ha Minh Lam ◽

Huynh Thi Phuong ◽

Nguyen Ha Thao Vy ◽

Nguyen Thi Le Thanh ◽

Pham Ngoc Dung ◽

...

Keyword(s):

Dengue Infection ◽

Screening Method ◽

Transmission Intensity ◽

World Health ◽

Severe Illness ◽

Age Group ◽

Force Of Infection ◽

Screening Performance ◽

Health Organization ◽

Igg Level

Owing to the finding that Dengvaxia ® (the only licensed dengue vaccine to date) increases the risk of severe illness among seronegative recipients, the World Health Organization has recommended screening individuals for their serostatus prior to vaccination. To decide whether and how to carry out screening, it is necessary to estimate the transmission intensity of dengue and to understand the performance of the screening method. In this study, we inferred the annual force of infection (FOI; a measurement of transmission intensity) of dengue virus in three locations in Vietnam: An Giang (FOI = 0.04 for the below 10 years age group and FOI = 0.20 for the above 10 years age group), Ho Chi Minh City (FOI = 0.12) and Quang Ngai (FOI = 0.05). In addition, we show that using a quantitative approach to immunoglobulin G (IgG) levels (measured by indirect enzyme-linked immunosorbent assays) can help to distinguish individuals with primary exposures (primary seropositive) from those with secondary exposures (secondary seropositive). We found that primary-seropositive individuals—the main targets of the vaccine—tend to have a lower IgG level, and, thus, they have a higher chance of being misclassified as seronegative than secondary-seropositive cases. However, screening performance can be improved by incorporating patient age and transmission intensity into the interpretation of IgG levels.

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Mapping global variation in dengue transmission intensity

Science Translational Medicine ◽

10.1126/scitranslmed.aax4144 ◽

2020 ◽

Vol 12 (528) ◽

pp. eaax4144 ◽

Cited By ~ 18

Author(s):

Lorenzo Cattarino ◽

Isabel Rodriguez-Barraquer ◽

Natsuko Imai ◽

Derek A. T. Cummings ◽

Neil M. Ferguson

Keyword(s):

Disease Incidence ◽

The Philippines ◽

Transmission Intensity ◽

Global Public Health ◽

African Countries ◽

Cross Sectional ◽

Force Of Infection ◽

High Transmission ◽

Dengue Transmission ◽

The Impact

Intervention planning for dengue requires reliable estimates of dengue transmission intensity. However, current maps of dengue risk provide estimates of disease burden or the boundaries of endemicity rather than transmission intensity. We therefore developed a global high-resolution map of dengue transmission intensity by fitting environmentally driven geospatial models to geolocated force of infection estimates derived from cross-sectional serological surveys and routine case surveillance data. We assessed the impact of interventions on dengue transmission and disease using Wolbachia-infected mosquitoes and the Sanofi-Pasteur vaccine as specific examples. We predicted high transmission intensity in all continents straddling the tropics, with hot spots in South America (Colombia, Venezuela, and Brazil), Africa (western and central African countries), and Southeast Asia (Thailand, Indonesia, and the Philippines). We estimated that 105 [95% confidence interval (CI), 95 to 114] million dengue infections occur each year with 51 (95% CI, 32 to 66) million febrile disease cases. Our analysis suggests that transmission-blocking interventions such as Wolbachia, even at intermediate efficacy (50% transmission reduction), might reduce global annual disease incidence by up to 90%. The Sanofi-Pasteur vaccine, targeting only seropositive recipients, might reduce global annual disease incidence by 20 to 30%, with the greatest impact in high-transmission settings. The transmission intensity map presented here, and made available for download, may help further assessment of the impact of dengue control interventions and prioritization of global public health efforts.

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A Cluster of Dengue Cases in Travelers: A Clinical Series From Thailand

10.20944/preprints202107.0618.v1 ◽

2021 ◽

Author(s):

Hisham A Imad ◽

Juthamas Phadungsombat ◽

Emi E Nakayama ◽

Lapakorn Chatapat ◽

Phimphan Pitusan ◽

...

Keyword(s):

Mosquito Species ◽

Dengue Infection ◽

Clinical Manifestations ◽

Warning Signs ◽

Rt Pcr ◽

Clinical Series ◽

Serotype 1 ◽

Ns1 Antigen ◽

The Mean ◽

Global Travel

Dengue is an overlooked tropical disease for which billions of people are at risk. The disease, caused by a Flavivirus with four distinct serotypes, is transmitted primarily by urbanized Aedes mosquito species. The infection leads to a spectrum of clinical manifestations, with the majority being asymptomatic. Primary dengue and, to a greater extent, subsequent infection, mainly secondary dengue infection, are associated with increased severity. Increased global travel and recreational tourism expose naïve individuals to dengue, the most common arboviral infections in travelers. We describe a cluster of possible primary acute dengue infections in a group of 12 individuals who presented to Bangkok Hospital for Tropical Diseases in 2017. Infection was confirmed by dengue NS1 antigen and multiplex real-time RT-PCR. Nine individuals required hospitalization, and four developed dengue warning signs. The mean arterial pressure was significantly lower in the group with dengue warning signs. The period from the day of arrival in Thailand and the first day of symptoms was significantly shorter in adolescents with warning signs. Leukocytes, neutrophils, and platelets declined significantly at defervescence and were negatively correlated with day of illness. Six clinical isolates were identified as dengue serotype-1, with identical sequences suggesting that these patients were infected with the same virus.

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Liver function tests to predict the severity of dengue fever in serologically positive children below 18 years of age

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20190069 ◽

2019 ◽

Vol 6 (2) ◽

pp. 358

Author(s):

Yashwanth Raju H. N. ◽

Rajendra Kumar ◽

Sudha Rudrappa

Keyword(s):

Serum Albumin ◽

Dengue Fever ◽

Hepatic Dysfunction ◽

Dengue Infection ◽

Liver Function Tests ◽

Relevant Information ◽

Warning Signs ◽

Severe Dengue ◽

Cross Sectional ◽

The Mean

Background: Dengue fever presents with a diverse clinical spectrum. Although liver is not a major target organ, hepatic dysfunction is a well-recognized feature. In this study authors attempted to study the pattern of hepatic involvement in children with dengue and its association with disease severity.Methods: This was a cross sectional study conducted at Cheluvamba hospital during the period of 1 year. Children <18 years of age with dengue Ns1 Ag and IgM positive were included in this study. After obtaining informed consent, a pre-structured proforma was used to record the relevant information from each subject. After detailed clinical examination and haematological investigation children were categorized into three groups as dengue fever with no warning signs (DNWS), dengue fever with warning signs (DWWS) and severe dengue fever (SDF) according to WHO classification. Statistical analysis was done to know the strength of association between different clinical and biochemical variables and outcome of the disease.Results: The mean age of the study population was 8.65 years with male preponderance. The mean total bilirubin, serum albumin, SGOT, SGPT, ALP, PT and INR were 0.76 mg/dl, 3.8g/dl, 233.18U/L, 118.15U/L, 200.65 U/L, 12.9s and 1.09 respectively. The mean SGOT was significantly higher than SGPT. The degree of deranged LFTs was significantly more in SDF group than DNWS and DWWS groups. Serum albumin was significantly decreased in children with SDF group correlating with disease severity, prognosis and outcome.Conclusions: Hepatic dysfunction was present in all forms of dengue infection, with SGOT rising significantly more than SGPT. All biochemical liver parameters were significantly deranged in patients with severe dengue fever indicating prolonged illness and poor prognosis.

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Serological Evidence of Widespread Zika Transmission across the Philippines

Viruses ◽

10.3390/v13081441 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1441

Author(s):

Joseph R. Biggs ◽

Ava Kristy Sy ◽

Oliver J. Brady ◽

Adam J. Kucharski ◽

Sebastian Funk ◽

...

Keyword(s):

Case Reports ◽

Sporadic Case ◽

The Philippines ◽

Cross Reactivity ◽

Short Term ◽

Serum Samples ◽

Force Of Infection ◽

Laboratory Surveillance ◽

Infection Risk Factors

Zika virus (ZIKV) exposure across flavivirus-endemic countries, including the Philippines, remains largely unknown despite sporadic case reporting and environmental suitability for transmission. Using laboratory surveillance data from 2016, 997 serum samples were randomly selected from suspected dengue (DENV) case reports across the Philippines and assayed for serological markers of short-term (IgM) and long-term (IgG) ZIKV exposure. Using mixture models, we re-evaluated ZIKV IgM/G seroprevalence thresholds and used catalytic models to quantify the force of infection (attack rate, AR) from age-accumulated ZIKV exposure. While we observed extensive ZIKV/DENV IgG cross-reactivity, not all individuals with active DENV presented with elevated ZIKV IgG, and a proportion of dengue-negative cases (DENV IgG-) were ZIKV IgG-positive (14.3%, 9/63). We identified evidence of long-term, yet not short-term, ZIKV exposure across Philippine regions (ZIKV IgG+: 31.5%, 314/997) which was geographically uncorrelated with DENV exposure. In contrast to the DENV AR (12.7% (95%CI: 9.1–17.4%)), the ZIKV AR was lower (5.7% (95%CI: 3–11%)) across the country. Our results provide evidence of widespread ZIKV exposure across the Philippines and suggest the need for studies to identify ZIKV infection risk factors over time to better prepare for potential future outbreaks.

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Dengue Endemicity, Force of Infection, and Variation in Transmission Intensity in 13 Endemic Countries

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa132 ◽

2020 ◽

Author(s):

Joshua Nealon ◽

Alain Bouckenooghe ◽

Margarita Cortes ◽

Laurent Coudeville ◽

Carina Frago ◽

...

Keyword(s):

Secondary Infection ◽

The Philippines ◽

Study Data ◽

Transmission Intensity ◽

Significant Heterogeneity ◽

Serological Study ◽

Force Of Infection ◽

Increasing Risk ◽

Vaccination Campaigns ◽

Level Analysis

Abstract Dengue endemicity varies but comparative, multicountry data are extremely limited. An improved understanding is needed to prioritize prevention, including vaccination, which is currently recommended only under specific epidemiological conditions. We used serological study data from 46 geographical sites in 13 countries to estimate dengue force of infection (FOI, the proportion of children seroconverting per year) under assumptions of either age-constant or age-varying FOI, and the age at which 50% and 80% of children had been infected. After exclusions, 13 661 subjects were included. Estimated constant FOI varied widely, from 1.7% (Singapore) to 24.1% (the Philippines). In the site-level analysis 44 sites (96%) reached 50% seroconversion and 35 sites (75%) reached 80% seroconversion by age 18 years, with significant heterogeneity. These findings confirm that children living in dengue-endemic countries receive intense early dengue exposure, increasing risk of secondary infection, and imply serosurveys at fine spatial resolutions are needed to inform vaccination campaigns.

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Coronavirus disease 2019 and dengue: two case reports

Journal of Medical Case Reports ◽

10.1186/s13256-021-02707-7 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Abdullah Isneen Hilmy ◽

Rajib Kumar Dey ◽

Hisham Ahmed Imad ◽

Abdul Azeez Yoosuf ◽

Ali Nazeem ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Severe Acute Respiratory Syndrome ◽

Reverse Transcription ◽

Case Reports ◽

Dengue Infection ◽

Warning Signs ◽

Tropical Diseases ◽

Chain Reaction ◽

Polymerase Chain ◽

Asian Male

Abstract Background The pandemic of this century has overwhelmed the healthcare systems of affected countries, and all resources have been diverted to coronavirus disease 2019. At the onset, coronavirus disease 2019 can present as any other acute febrile undifferentiated illness. In tropical regions, clinicians are increasingly challenged to differentiate these febrile illnesses without the use of diagnostics. With this pandemic, many of these tropical diseases are neglected and go underreported. Dengue is holoendemic in the Maldives, and dengue viruses circulate throughout the year. Reports about coinfections with dengue virus and severe acute respiratory syndrome coronavirus 2 are scarce, and the outcome and the dynamics of the disease may be altered in the presence of coinfection. We have described the clinical manifestation and serial laboratory profile, and highlighted the atypical findings uncommon in dengue infection. Case presentation Case 1 was a 39-year old Asian male, presented on day 6 of dengue infection with warning signs. Reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 that was done as per hospital protocol was found to be positive. Case 2 was a 38-year old Asian male, was admitted on day 5 of illness with symptoms of acute respiratory infection with positive reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2. Evaluation of progressive leukopenia and thrombocytopenia showed positive dengue serology. Conclusion Clinicians must be conscientious when working on the differential diagnosis of possible tropical diseases in cases of coronavirus disease 2019, specifically, when patients develop hemoconcentration, thrombocytopenia, and transaminitis with elevated expression of aspartate higher than alanine transaminase, which is frequently observed in dengue infection. Caution must be taken during the administration of intravenous fluids when treating patients with coronavirus disease 2019 and dengue coinfection, as coronavirus disease 2019 patients are more prone to develop pulmonary edema. Timely diagnosis and appropriate management are essential to avoid the devastating complications of severe forms of dengue infection. It is important to repeat and reconfirm the dengue serology in coronavirus disease 2019 patients to avoid false positivity. Diligence and care must be taken not to neglect other endemic tropical diseases in the region during the present pandemic.

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Analysis of Clinical, Imaging, and Pathologic Features of 36 Patients with Primary Intraspinal Primitive Neuroectodermal Tumors: A Case Series and Literature Review

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0041-1723810 ◽

2021 ◽

Author(s):

Xuefeng Wei ◽

Xu Zhang ◽

Zimu Song ◽

Feng Wang

Keyword(s):

Literature Review ◽

Single Case ◽

Case Reports ◽

Case Series ◽

Subtotal Resection ◽

Study Cohort ◽

Primitive Neuroectodermal Tumors ◽

Pathologic Features ◽

Neuroectodermal Tumors ◽

The Mean

Abstract Background and Study Aims Primary intraspinal primitive neuroectodermal tumors (PNETs) account for ∼0.4% of all intraspinal tumors, but information about these tumors in the medical literature is limited to single case reports. We report four cases of primary intraspinal PNETs and present a systematic literature review of the reported cases. Materials and Methods We retrospectively reviewed and analyzed the clinical data of 4 patients with primary intraspinal PNETs who underwent neurosurgical treatment at our clinic between January 2013 and January 2020, and of 32 cases reported in the literature. Results The female-to-male ratio was 2.6:1. The mean patient age was 21.42 ± 15.76 years (range: 1–60 years), and patients <36 years of age accounted for 83.30% of the study cohort. Progressive limb weakness and numbness were the chief symptoms (accounting for ∼55.6%). The mean complaint duration was 0.89 ± 0.66 months for males and 2.72 ± 3.82 months for females (p = 0.028). Epidural (41.7%) was the most common site, and thoracic (47.3%) was the most frequent location. Most PNETs were peripheral, and magnetic resonance imaging (MRI) appearance was isointense or mildly hypointense on T1-weighted images and hyperintense on T2-weighted images. Homogeneous contrast enhancement was observed. The 1-year survival rate of patients who underwent chemoradiation after total or subtotal lesion resection was better compared with patients who did not undergo chemotherapy, radiotherapy, or total or subtotal resection. The modality of treatment was associated with survival time (p = 0.007). Conclusion Primary intraspinal PNETs mainly occur in young people with a female preponderance. In patients with a rapid loss of lower limb muscle strength and large intraspinal lesions on MRI, PNETs should be considered. Surgical resection and adjuvant radio chemotherapy are key prognostic factors.

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Country-level determinants of the severity of the first global wave of the COVID-19 pandemic: an ecological study

BMJ Open ◽

10.1136/bmjopen-2020-042034 ◽

2021 ◽

Vol 11 (2) ◽

pp. e042034

Author(s):

Tiberiu A Pana ◽

Sohinee Bhattacharya ◽

David T Gamble ◽

Zahra Pasdar ◽

Weronika A Szlachetka ◽

...

Keyword(s):

Mortality Rate ◽

Vaccination Coverage ◽

Urban Areas ◽

Ecological Study ◽

Environmental Parameters ◽

The Philippines ◽

International Travel ◽

Bcg Vaccination ◽

Country Level ◽

The Mean

ObjectiveWe aimed to identify the country-level determinants of the severity of the first wave of the COVID-19 pandemic.DesignEcological study of publicly available data. Countries reporting >25 COVID-19 related deaths until 8 June 2020 were included. The outcome was log mean mortality rate from COVID-19, an estimate of the country-level daily increase in reported deaths during the ascending phase of the epidemic curve. Potential determinants assessed were most recently published demographic parameters (population and population density, percentage population living in urban areas, population >65 years, average body mass index and smoking prevalence); economic parameters (gross domestic product per capita); environmental parameters (pollution levels and mean temperature (January–May); comorbidities (prevalence of diabetes, hypertension and cancer); health system parameters (WHO Health Index and hospital beds per 10 000 population); international arrivals; the stringency index, as a measure of country-level response to COVID-19; BCG vaccination coverage; UV radiation exposure; and testing capacity. Multivariable linear regression was used to analyse the data.Primary outcomeCountry-level mean mortality rate: the mean slope of the COVID-19 mortality curve during its ascending phase.ParticipantsThirty-seven countries were included: Algeria, Argentina, Austria, Belgium, Brazil, Canada, Chile, Colombia, the Dominican Republic, Ecuador, Egypt, Finland, France, Germany, Hungary, India, Indonesia, Ireland, Italy, Japan, Mexico, the Netherlands, Peru, the Philippines, Poland, Portugal, Romania, the Russian Federation, Saudi Arabia, South Africa, Spain, Sweden, Switzerland, Turkey, Ukraine, the UK and the USA.ResultsOf all country-level determinants included in the multivariable model, total number of international arrivals (beta 0.033 (95% CI 0.012 to 0.054)) and BCG vaccination coverage (−0.018 (95% CI −0.034 to –0.002)), were significantly associated with the natural logarithm of the mean death rate.ConclusionsInternational travel was directly associated with the mortality slope and thus potentially the spread of COVID-19. Very early restrictions on international travel should be considered to control COVID-19 outbreaks and prevent related deaths.

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