{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:05:34Z","timestamp":1791558334337,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pntd.0011537","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000}}],"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T00:00:00Z","timestamp":1691539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>Severe dengue occurrence has been attributed to increasing age and different dengue virus (DENV) serotypes that cause secondary infections and immune-enhancing phenomena. Therefore, we examined if the effect of age on dengue severity was mediated by infectivity status while controlling for sex and region. Further, we assessed the spatial clustering of dengue severity for individuals with primary and secondary infection across Mexican municipalities. Health data from 2012 to 2017 was retrieved from Mexico\u2019s Ministry of Health. A mediation analysis was performed using multiple logistic regression models based on a directed acyclic graph. The models were explored for the direct effect of age on dengue severity and its indirect impact through secondary infection. In addition, severe dengue clusters were determined in some Northeastern and Southeastern municipalities through spatial analysis. We observed a nonlinear trend between age and severe dengue. There was a downward trend of severe dengue for individuals between 0 and 10 years and an upward trend above 10 years. The effect of age on dengue severity was no longer significant for individuals between 10 and 60 years after introducing infectivity status into the model. The mediating role of infectivity status in the causal model was 17%. Clustering of severe dengue among individuals with primary infection in the Northeastern region may point to the high prevalence of DENV-3 in the region. Public health efforts may prevent secondary infection among infants and the aged. In addition, there should be a further investigation into the effect of DENV-3 in individuals with primary disease.<\/jats:p>","DOI":"10.1371\/journal.pntd.0011537","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T17:39:02Z","timestamp":1691602742000},"page":"e0011537","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":35,"title":["Direct and indirect effects of age on dengue severity: The mediating role of secondary infection"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9816-0958","authenticated-orcid":true,"given":"Esther","family":"Annan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Trevi\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso J.","family":"Rodriguez-Morales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ubydul","family":"Haque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,9]]},"reference":[{"issue":"6","key":"pntd.0011537.ref001","doi-asserted-by":"crossref","first-page":"e1180","DOI":"10.1371\/journal.pntd.0001180","article-title":"Age-specificity of clinical dengue during primary and secondary infections","volume":"5","author":"KT Thai","year":"2011","journal-title":"PLoS Negl Trop Dis"},{"issue":"7353","key":"pntd.0011537.ref002","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1136\/bmj.324.7353.1563","article-title":"Dengue: an escalating problem","volume":"324","author":"RV Gibbons","year":"2002","journal-title":"Bmj"},{"issue":"7","key":"pntd.0011537.ref003","doi-asserted-by":"crossref","first-page":"e747","DOI":"10.1371\/journal.pntd.0000747","article-title":"Dengue dynamics in Binh Thuan province, southern Vietnam: periodicity, synchronicity and climate variability","volume":"4","author":"KT Thai","year":"2010","journal-title":"PLoS neglected tropical diseases"},{"issue":"11","key":"pntd.0011537.ref004","doi-asserted-by":"crossref","first-page":"e355","DOI":"10.1016\/S1473-3099(18)30269-X","article-title":"Unexpected outbreaks of arbovirus infections: lessons learned from the Pacific and tropical America","volume":"18","author":"D Musso","year":"2018","journal-title":"Lancet Infect Dis"},{"issue":"1","key":"pntd.0011537.ref005","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1093\/infdis\/jiaa132","article-title":"Dengue Endemicity, Force of Infection, and Variation in Transmission Intensity in 13 Endemic Countries","volume":"225","author":"J Nealon","year":"2020","journal-title":"The Journal of Infectious Diseases"},{"key":"pntd.0011537.ref006","doi-asserted-by":"crossref","first-page":"e111","DOI":"10.26633\/RPSP.2018.111","article-title":"Economic impact of dengue fever in Latin America and the Caribbean: a systematic review","volume":"42","author":"A Laserna","year":"2018","journal-title":"Rev Panam Salud Publica"},{"issue":"2","key":"pntd.0011537.ref007","first-page":"280","article-title":"Potential influence of climate variability on dengue incidence registered in a western pediatric Hospital of Venezuela","volume":"27","author":"AD Herrera-Martinez","year":"2010","journal-title":"Trop Biomed"},{"issue":"1","key":"pntd.0011537.ref008","doi-asserted-by":"crossref","first-page":"19017","DOI":"10.1038\/s41598-020-75891-z","article-title":"Risk of dengue virus infection according to serostatus in individuals from dengue endemic areas of Mexico","volume":"10","author":"IY Amaya-Larios","year":"2020","journal-title":"Scientific Reports"},{"key":"pntd.0011537.ref009","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1146\/annurev.micro.62.081307.163005","article-title":"Global spread and persistence of dengue","volume":"62","author":"JL Kyle","year":"2008","journal-title":"Annu Rev Microbiol"},{"issue":"1","key":"pntd.0011537.ref010","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jmii.2017.12.005","article-title":"Diabetic patients suffering dengue are at risk for development of dengue shock syndrome\/severe dengue: Emphasizing the impacts of co-existing comorbidity(ies) and glycemic control on dengue severity","volume":"53","author":"I-K Lee","year":"2020","journal-title":"Journal of Microbiology, Immunology and Infection"},{"issue":"7","key":"pntd.0011537.ref011","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1002\/jmv.24464","article-title":"Dengue severity associated with age and a new lineage of dengue virus-type 2 during an outbreak in Rio De Janeiro, Brazil","volume":"88","author":"PC Nunes","year":"2016","journal-title":"J Med Virol"},{"key":"pntd.0011537.ref012","doi-asserted-by":"crossref","first-page":"845876","DOI":"10.1155\/2013\/845876","article-title":"Development of dengue infection severity score","volume":"2013","author":"S Pongpan","year":"2013","journal-title":"ISRN Pediatr"},{"issue":"1","key":"pntd.0011537.ref013","doi-asserted-by":"crossref","first-page":"127","DOI":"10.4269\/ajtmh.2011.10-0476","article-title":"Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam","volume":"84","author":"KL Anders","year":"2011","journal-title":"The American journal of tropical medicine and hygiene"},{"issue":"8","key":"pntd.0011537.ref014","doi-asserted-by":"crossref","first-page":"e0201441","DOI":"10.1371\/journal.pone.0201441","article-title":"Differences in clinical features and dengue severity between local and migrant Chinese with dengue infection in Singapore","volume":"13","author":"C Xu","year":"2018","journal-title":"PLoS One"},{"key":"pntd.0011537.ref015","unstructured":"Focks D, Barrera R. Dengue Transmission Dynamics: Assessment And Implications For Control. WHO Report of the Scientific Working Group meeting on Dengue, Geneva. 2006."},{"issue":"6","key":"pntd.0011537.ref016","doi-asserted-by":"crossref","first-page":"924","DOI":"10.3201\/eid1306.070008","article-title":"Age and clinical dengue illness","volume":"13","author":"JR Egger","year":"2007","journal-title":"Emerging infectious diseases"},{"key":"pntd.0011537.ref017","doi-asserted-by":"crossref","first-page":"6803098","DOI":"10.1155\/2016\/6803098","article-title":"Dengue Fever: Causes, Complications, and Vaccine Strategies","volume":"2016","author":"N Khetarpal","year":"2016","journal-title":"J Immunol Res"},{"issue":"2","key":"pntd.0011537.ref018","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1001\/jama.2007.31-a","article-title":"Dengue and Hemorrhagic FeverA Potential Threat to Public Health in the United States","volume":"299","author":"DM Morens","year":"2008","journal-title":"JAMA"},{"issue":"2","key":"pntd.0011537.ref019","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S1201-9712(02)90072-X","article-title":"Effect of age on outcome of secondary dengue 2 infections","volume":"6","author":"MG Guzm\u00e1n","year":"2002","journal-title":"International Journal of Infectious Diseases"},{"issue":"3","key":"pntd.0011537.ref020","doi-asserted-by":"crossref","first-page":"e617","DOI":"10.1371\/journal.pntd.0000617","article-title":"Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006","volume":"4","author":"JR Fried","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"issue":"5","key":"pntd.0011537.ref021","doi-asserted-by":"crossref","first-page":"e0154760","DOI":"10.1371\/journal.pone.0154760","article-title":"Meta-Analysis of Dengue Severity during Infection by Different Dengue Virus Serotypes in Primary and Secondary Infections","volume":"11","author":"KM Soo","year":"2016","journal-title":"PLoS One"},{"issue":"1","key":"pntd.0011537.ref022","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1186\/s12879-019-4379-3","article-title":"Spatial and temporal patterns of dengue incidence in northeastern Thailand 2006\u20132016","volume":"19","author":"T Phanitchat","year":"2019","journal-title":"BMC Infectious Diseases"},{"issue":"6","key":"pntd.0011537.ref023","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/cid\/cir451","article-title":"Dengue\u2014how best to classify it","volume":"53","author":"A Srikiatkhachorn","year":"2011","journal-title":"Clinical infectious diseases: an official publication of the Infectious Diseases Society of America"},{"key":"pntd.0011537.ref024","doi-asserted-by":"crossref","DOI":"10.1201\/9781315370279","volume-title":"Generalized Additive Models: An Introduction with R","author":"SN Wood","year":"2017","edition":"2"},{"key":"pntd.0011537.ref025","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev-publhealth-032315-021402","article-title":"Mediation Analysis: A Practitioner\u2019s Guide","volume":"37","author":"TJ VanderWeele","year":"2016","journal-title":"Annu Rev Public Health"},{"issue":"2","key":"pntd.0011537.ref026","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1177\/0193841X9301700202","article-title":"Estimating mediated effects in prevention studies","volume":"17","author":"DP MacKinnon","year":"1993","journal-title":"Evaluation review"},{"key":"pntd.0011537.ref027","article-title":"Statistical Mediation Analysis for Models with a Binary Mediator and a Binary Outcome: the Differences Between Causal and Traditional Mediation Analysis","author":"JJM Rijnhart","year":"2021","journal-title":"Prevention Science"},{"issue":"5","key":"pntd.0011537.ref028","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1177\/1740774507083434","article-title":"The intermediate endpoint effect in logistic and probit regression","volume":"4","author":"DP MacKinnon","year":"2007","journal-title":"Clinical Trials"},{"issue":"2","key":"pntd.0011537.ref029","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1097\/00001648-199203000-00013","article-title":"Identifiability and exchangeability for direct and indirect effects","volume":"3","author":"JM Robins","year":"1992","journal-title":"Epidemiology"},{"key":"pntd.0011537.ref030","unstructured":"Documentation SP. The CAUSALMED Procedure 2019 [5\/11\/2023]. Available from: http:\/\/documentation.sas.com\/doc\/en\/pgmsascdc\/9.4_3.4\/statug\/statug_causalmed_details01.htm."},{"key":"pntd.0011537.ref031","doi-asserted-by":"crossref","first-page":"7207","DOI":"10.3390\/ijerph10127207","article-title":"Spatial Autocorrelation of Cancer Incidence in Saudi Arabia","volume":"10","author":"K Alahmadi","year":"2013","journal-title":"International journal of environmental research and public health"},{"issue":"2","key":"pntd.0011537.ref032","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1538-4632.1995.tb00338.x","article-title":"Local indicators of spatial association\u2014LISA","volume":"27","author":"L. Anselin","year":"1995","journal-title":"Geographical analysis"},{"key":"pntd.0011537.ref033","unstructured":"Pro A. Optimized Outlier Analysis (Spatial Statistics) n.d [1\/27\/2022]. Available from: https:\/\/pro.arcgis.com\/en\/pro-app\/latest\/tool-reference\/spatial-statistics\/optimizedoutlieranalysis.htm."},{"issue":"7","key":"pntd.0011537.ref034","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1007\/s00705-013-1645-3","article-title":"Secondary infection as a risk factor for dengue hemorrhagic fever\/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection","volume":"158","author":"MG Guzman","year":"2013","journal-title":"Arch Virol"},{"issue":"1","key":"pntd.0011537.ref035","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00705-005-0595-9","article-title":"Dengue 2 genotypes in the state of Oaxaca, Mexico","volume":"151","author":"A Cisneros","year":"2006","journal-title":"Archives of Virology"},{"key":"pntd.0011537.ref036","doi-asserted-by":"crossref","first-page":"101986","DOI":"10.1016\/j.ecoinf.2023.101986","article-title":"The ecological determinants of severe dengue: A Bayesian inferential model","volume":"74","author":"E Annan","year":"2023","journal-title":"Ecological Informatics"},{"issue":"9","key":"pntd.0011537.ref037","doi-asserted-by":"crossref","first-page":"e0162649","DOI":"10.1371\/journal.pone.0162649","article-title":"Climate Change Influences Potential Distribution of Infected Aedes aegypti Co-Occurrence with Dengue Epidemics Risk Areas in Tanzania","volume":"11","author":"CN Mweya","year":"2016","journal-title":"PLoS One"},{"key":"pntd.0011537.ref038","unstructured":"Centers for Disease Control and Prevention. Dengue: Clinal Presentation 2021 [7\/26\/2022]. Available from: https:\/\/www.cdc.gov\/dengue\/healthcare-providers\/clinical-presentation.html."},{"issue":"4","key":"pntd.0011537.ref039","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1037\/a0020761","article-title":"A general approach to causal mediation analysis","volume":"15","author":"K Imai","year":"2010","journal-title":"Psychol Methods"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0011537","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:00:00Z","timestamp":1692576000000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011537","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T17:34:00Z","timestamp":1692639240000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0011537"}},"subtitle":[],"editor":[{"given":"Alberto Novaes","family":"Ramos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,9]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0011537","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0011537","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,9]]}}}