bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Spatial and epidemiologic features of dengue in Sabah, 2 Malaysia 3 4 Amanda Murphy1,2*, Giri Shan Rajahram3,4, Jenarun Jilip5, Marilyn Maluda5, Timothy 5 William4,6, Wenbiao Hu7, Simon Reid8, Gregor J. Devine1^, Francesca D. Frentiu2^. 6 7 8 9 1 Mosquito Control Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, 10 Australia 11 2 School of Biomedical Sciences, and Institute for Health and Biomedical Innovation, 12 Queensland University of Technology, Brisbane, Australia 13 3 Queen Elizabeth Hospital, Ministry of Health Malaysia, Kota Kinabalu, Malaysia 14 4 Infectious Disease Society of Kota Kinabalu-Menzies School of Health Research Clinical 15 Research Unit, Kota Kinabalu, Malaysia 16 5 Sabah Department of Health, Ministry of Health Malaysia, Kota Kinabalu, Malaysia 17 6 Gleneagles Kota Kinabalu Hospital Sabah, Kota Kinabalu, Malaysia 18 7 School of Public Health and Social Work, Queensland University of Technology, Brisbane, 19 Australia 20 8 School of Public Health, University of Queensland, Brisbane, Australia 21 22 23 * Corresponding author 24 E-mail: [email protected] 25 26 27 ^ These authors contributed equally to this work 28 29 30 Keywords: dengue, rural, Sabah, Aedes albopictus, Borneo, South East Asia 31 32 1 bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 33 Abstract 34 35 In South East Asia, dengue epidemics have increased in size and geographical distribution in 36 recent years. Most studies investigating dengue transmission and control have had an urban 37 focus, while less consideration is currently given to rural settings, or where urban and rural 38 areas overlap. We examined the spatiotemporal distribution and epidemiological 39 characteristics of reported dengue cases in the predominantly rural state of Sabah, in 40 Malaysian Borneo – an area where sylvatic and urban circulation of pathogens are known to 41 intersect. We found that annual dengue incidence rates were spatially variable over the 7- 42 year study period from 2010-2016 (state-wide mean annual incidence of 21 cases/100,000 43 people; range 5-42/100,000), but were highest in rural localities in the western districts of 44 the state (Kuala Penyu, Nabawan, Tenom and Kota Marudu). The eastern districts exhibited 45 lower overall dengue rates; however, we noted a concentration of severe (haemorrhagic) 46 dengue cases (44%) in Sandakan and Tawau districts. Dengue incidence was slightly higher 47 for males than females, and was significantly higher for both genders aged between 10 and 48 29 years (24/100,000; p=0.029). The largest ever recorded outbreaks occurred during 2015- 49 2016, with the vector Aedes albopictus found to be most prevalent in both urban and rural 50 households (House Index of 64%), compared with Ae. Aegypti (15%). These findings suggest 51 that dengue outbreaks in Sabah are driven by the sporadic expansion of dengue virus in both 52 urban and rural settings. This may require tailoring of preventative strategies to suit 53 different transmission ecologies across Sabah. Further studies to better understand the 54 drivers of dengue in Sabah may aid dengue control efforts in Malaysia, and more broadly in 55 South East Asia. 2 bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 56 Author summary 57 58 In order to combat the rising regional incidence of dengue in South East Asia, the drivers of 59 transmission must be better characterised across different environmental settings. We 60 conducted the first retrospective analysis of dengue epidemiology in the predominantly rural 61 state of Sabah, Malaysia, where both urban and sylvatic transmission cycles exist. Human 62 notification data over a 7-year period were reviewed and spatiotemporal and demographic 63 risk factors identified. We found: 64 1. Urban habitats and population density are not the only determinants mediating the 65 spread of epidemic dengue in Sabah. Case from both urban and rural localities 66 contributed equally to dengue outbreaks. 67 2. Human demographic risk factors included being aged between 10 and 29 years, and 68 being male. 69 3. High incidence areas for dengue do not predict the occurrence of severe dengue. Severe 70 dengue was largely localised to lower incidence districts in the east of the state. 71 4. The sole presence of Aedes albopictus in and around the majority of urban and rural 72 case households suggests that this vector may play a major role in facilitating outbreaks. 73 A complex interplay of risk factors likely mediates dengue transmission in Sabah, influenced 74 by both regional climate trends and localised human and ecological influences. This study 75 emphasises that the increasing spread of dengue in urban South East Asia is also mirrored in 76 more rural areas, and suggests a need for control strategies that address both urban and 77 rural dengue risk. 78 3 bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 79 Introduction 80 81 Dengue is the most rapidly spreading vector-borne disease in the world, and the most 82 prevalent arboviral disease of humans (1). Now endemic in more than 100 countries, the 83 disease causes an enormous burden on communities and health care systems in tropical and 84 sub-tropical regions (2). The causative agent of dengue is dengue virus (DENV), transmitted 85 between humans by Aedes mosquitoes across a range of domestic and sylvatic 86 environments. Urban expansion, human migration, travel and trade have facilitated an 87 increasing number of infections, primarily in Asia, Africa and the Americas (3, 4). These areas 88 experience up to 70% of the estimated 390 million annual dengue infections worldwide (1, 89 4). Explosive outbreaks have become common in recent decades, and both classical and 90 severe (haemorrhagic) forms of dengue now occur in previously unaffected countries (1, 3, 91 5). South East Asia has one of the highest burdens of dengue, following marked increases in 92 the number, severity and geographical distribution of dengue epidemics since the 1950s. 93 During this dramatic expansion, the four virus serotypes (DENV 1-4) have become well- 94 established and commonly co-circulate within the region (6). 95 In Malaysia, dengue has been considered a major public health problem since 1973 (7), with 96 regular epidemics resulting in significant morbidity and economic burden (8, 9). The majority 97 of reported cases are concentrated in the large, urban cities of Kuala Lumpur and Penang, 98 which are located on the Malaysian peninsula. The circulation of all DENV serotypes has 99 been documented across the country, as well as the presence of unique sylvatic strains (10- 100 12). As with many South East Asian countries, the characterisation and control of 101 transmission in Malaysia is primarily focused on highly populated urban areas (13). The 102 majority of spatial and eco-epidemiological studies to date have therefore focused on 4 bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 103 peninsular Malaysia, and relatively few studies have explored the factors driving 104 transmission in rural parts of the country. 105 The Malaysian states of Sabah and Sarawak, located on the island of Borneo, report lower 106 incidence rates than mainland Malaysia (14) and patterns of transmission in these states are 107 not well characterised. The island possesses rapidly developing urban areas in close 108 proximity to disturbed forest environments, with potential risk of spill-over of sylvatic 109 pathogens to human populations (15). Sabah state, positioned on the northern tip of 110 Borneo, reports the highest incidence of the sylvatic malaria parasite Plasmodium knowlesi, 111 with transmission risk linked to deforestation (16, 17). The emergence of other zoonotic 112 pathogens has also been documented in Sabah (18, 19), including Zika virus in 2015 (20). 113 Given the marked environmental change occurring in Sabah, and the increase in dengue 114 cases noted in recent years (12, 14), it is essential from a public health perspective to 115 understand current transmission patterns and their drivers. This study examined the 116 epidemiology of dengue in the state of Sabah, in Malaysian Borneo, between 2010 and 2016. 117 We aimed to document recent spatial and temporal trends of dengue disease, and to 118 identify some potential risk factors driving DENV transmission and spread in this 119 understudied region of the country. 120 121 Methods 122 123 Ethics statement 124 This study was approved by the Medical Research and Ethics Committee (MREC), Ministry of 125 Health Malaysia; and the Human Research Ethics Committee (HREC) of the QIMR Berghofer 5 bioRxiv preprint doi: https://doi.org/10.1101/657031; this version posted May 31, 2019.