China CDC Weekly

Preplanned Studies

Dengue Fever Outbreaks Caused by Varied Serotype Dengue — Province, China, 2019

De Wu1,#; Xin Zhang1; Aiping Deng2; Huan Zhang1; Yintao Zhang2; Qiqi Tan1; Zhiqiang Peng2; Jiandong Li3; Tie Song2

(Figure 1). As of November 30, a total of 5,968 cases, Summary including 3 deaths, were reported to the Guangdong What is already known about this topic? Provincial CDC. Among them, 1,207 cases were cases (DF) outbreaks affect hundreds of imported from abroad, and 4,761 cases were acquired millions of people worldwide and have increased through presumed local mosquito-borne transmission. significantly in Guangdong Province in 2019. The cities with the most reported cases were What is added by this report? Guangzhou (1,376), Shantou (914), Foshan (375), This paper described briefly DF outbreaks were Zhanjiang (336), Chaozhou (288), Jiangmen (256), attributed to several types of dengue virus Jieyang (246), Zhongshan (239), Shenzhen (208), (DENV) including DENV-1, DENV-2, and DENV-3 Dongguan (116), and Qingyuan (110); all other cities in 2019 in Guangdong, tracked the sources of in Guangdong Province had less than 100 reported through phylogenetic analysis and epidemiological cases. investigation, and primarily revealed the In this study, 21 city-level CDCs were involved in epidemiological links among the outbreaks. collection of serum specimens of suspected DF cases What are the implications for public health from respective local hospitals, and these samples were practice? sent to Guangdong Provincial CDC for laboratory The introduction of DENV from DF endemic areas detection and further analysis. As of November 20, a increased pressure on the prevention and control of DF total of 2,293 serum specimens were collected, in Guangdong. Early detection of suspected cases and detected, and serotyped using real-time RT-PCR. A typing and genotyping of circulating viruses should be total of 2,175 samples were positive for dengue virus, prioritized and enhanced to promptly assess the and the serotyping results showed that 1,919 samples likelihood of local transmission, of introduction, and of were type I, 159 were type II, 93 were type III, and 4 subsequent sustained local transmission of the virus to were type IV DENV infection. Virus isolation was implement optimal prevention and control strategies performed using RT-PCR to detect positive samples and measures. using cell culture technology, and 427 strains were successfully isolated including 359 strains of type I, 47 Dengue fever (DF) is a major threat to human life strains of type II, 18 strains of type III, and 3 strains of and affects a large number of populations in the type IV. tropical and subtropical zones with serious To trace the origins of DENV circulating in consequences. Over 300 million people are infected Guangdong, the entire E gene of DENV samples were worldwide with dengue virus (DENV), which causes sequenced from imported cases, sporadic cases DF, every year per the World Health Organization acquired through presumed local transmission, and (WHO) (1). Since 1978, DF outbreaks occurred representative virus strains obtained in outbreaks from endemically and reached epidemic levels every 4 to 7 different period in 2019. A total of 326 sequences were years in China, and increased significantly in recent successfully obtained, and the US National Library of decades in Guangdong Province (2). According to Medicine Basic Local Alignment Search Tool (BLAST) China Information System for Disese Control and from the US National Center for Biotechnology Prevention, DF outbreaks occurred from May to Information (NCBI) analysis showed that 287 November in Guangdong in 2019, and the reported sequences belong to type I DENV (75 from imported number of cases started to increase rapidly in August, cases and 212 from local acquired cases), 27 type II (16 peaking in October, and decreasing by November imported and 11 local), 10 type III (7 imported and 3

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2,000

1,800

1,600

1,400

1,200

1,000

800 Number of cases 600

400

200

0 Jan Feb Mar Apr May June July Aug Sep Oct Nov Months

FIGURE 1. Number of dengue fever cases reported in 2019 in Guangdong Province, China. local), and 2 type IV sequences from imported cases. dominant genotype of the virus in subsequent local Phylogenetic analysis of the obtained E gene transmission was genotype I of type I DENV, which sequences were performed with 5 genotype circulated in more than 16 cities, and genotype V of representative sequences, which demonstrated that the type I DENV was mainly found in outbreaks occurred 287 type I E gene sequences were clustered into 2 in Zhongshan and Guangzhou (Figure 2). different genotypes, 280 sequences clustered to Type II and III viruses were found among cases genotype I and 7 clustered to genotype V. The 212 acquired both abroad and through local transmission, sequences of genotype I DENV E gene, obtained from while DENV of type IV was only detected in imported cases acquired through presumed local transmission, cases. A total of 27 sequences of type II DENV E gene were clustered into 6 distinct clades, and clade 6 were clustered into Asia I and cosmopolitan genotypes, contained 190 sequences followed by clade 4 10 sequences of cosmopolitan genotypes from cases containing 9 sequences, clade 3 containing 8 acquired through local transmission were clustered sequences, clade 5 containing 3 sequences, and clade 1 together with viruses circulating in and in and clade 2 containing 1 sequences. The sequences in clade 1 and clade 2, which revealed a from clade 6 and clade 3 were clustered together with possible source of the viruses causing local transmission viral sequence obtained from cases acquired in in Guangdong. The sequence of genotype Asia I of Cambodia and shared the highest homology at the local transmitted type II DENV clustered together nucleotide level, which suggested that sustained local with viruses introduced from . The 10 transmission might be caused by virus introduced from sequences of DENV type III viruses clustered into Cambodia. Clade 1 and clade 2 formed an genotype I and II respectively, among which two local independent branch, and they might be caused by strains belonged to genotype I, which clustered into virus introduced from and Myanmar. Clade the same clade with the virus imported from , 4 shared the highest homology at nucleotide level with and the sequence of local transmitted virus of genotype strains imported from Thailand (D19014), and clade 5 II showed high similarity with imported strains from shared the highest homology at nucleotide level with Cambodia. strains imported from Malaysia (D16167). In addition, the sequences of genotype V were clustered together DISCUSSION with strains imported from Indonesia (D19011). These results suggested that DF epidemics in In the history of Guangdong (including Hainan put great pressure on DF control and prevention in Province), more than 10,000 cases of DF have been Guangdong and that Cambodia, Thailand, East reported in six years, and the latest one was 2014, with Timor, Malaysia, and Indonesia were sources of more than 45,000 cases were reported (3–4). In recent DENV introduced into Guangdong in 2019. The years, the frequency of DF outbreaks increased in

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Guangdong and the affected area has expanded year after year. Before 2011, dengue fever was prevalent in Guangdong for only one to two months, and then

99 gradually increased to seven to eight months. Clade 6 Outbreaks of DF have also started occurring yearly since 2011, ranging from thousands to tens of thousands of cases. The affected area had expanded from being concentrated in the Pearl River Delta to 75 D1/China/GDgz/D191239/2019 87 D1/China/GDyf/D19880/2019 88 D1/China/GDfs/D19373/2019 widely affecting most of Guangdong Province. This 98 D1/China/GDfs/D18023/2018(Malaysia) Clade 5 95 D1/China/GDzs/D16167/2016(Malaysia) may be related to the gradual rise of the earth’s 59 99 D1/China/GDfs/D18122/2018 D1/China/GDqy/D181375/2018 D1/China/GDfs/D19074/2019(East Timor) temperature and the rapid spread of DENV, but it 99 D1/China/GDfs/D19042/2019(Indonesia) 58 D1/China/GDfs/D19043/2019(Indonesia) 66 D1/China/GDfs/D18056/2018 could also be related to the rapid development of 73 JF960228/D1//2010(Genotype I) D1/China/GDsz/D18014/2018(Maldives ) 96 99 D1/China/GDgz/D18048/2018 91 China’s economy, the acceleration of urbanization, and D1/China/GDgz/D18049/2018 D1/China/GDqy/D18054/2018 99 50 D1/China/GDzj/D18655/2018 increasing foreign trade and tourism (5–6). D1/China/GDzj/D18708/2018 D1/China/GDzs/D18808/2018 99 D1/China/GDzj/D18778/2018 The annual circulation of DENV has expanded 44 D1/China/GDzj/D18720/2018 D1/China/GDzj/D18146/2018 D1/China/GDjy/D18114/2018 from a single type of DENV to multiple serotypes and D1/China/GDjm/D18790/2018 D1/China/GDzh/D18128/2018(Cambodia) D1/China/GDjm/D18787/2018 genotypes circulating simultaneously. DENV type I D1/China/GDzs/D18816/2018 D1/China/GDzs/D18802/2018 62 D1/China/GDzs/D18797/2018 has caused outbreaks every year since 2011; type II has 70 D1/China/GDjy/D18115/2018 D1/China/GDqy/D18110/2018 Genotype I D1/China/GDjm/D18107/2018 caused outbreaks every year since 2013, accounting for D1/China/GDjy/D18099/2018 56 D1/China/GDjy/D18098/2018 D1/China/GDgz/D18053/2018 the highest proportion in 2015 and reaching 63.82% D1/China/GDgz/D18036/2018 63 63 D1/China/GDfs/D18078/2018 of all cases; type III has caused local outbreaks in 2013, D1/China/GDfs/D18222/2018 D1/China/GDfs/D18008/2018(Thailand) 59 D1/China/GDcz/D18032/2018(Thailand) 2015, 2016, and 2019 (7–8); type IV virus was mainly D1/China/GDzh/D19854/2019(Thailand) D1/China/GDzh/D19106/2019(Thailand) D1/China/GDgz/D19681/2019 detected from imported cases with only a few local 25 D1/China/GDsg/D19685/2019 47 D1/China/GDgz/D19670/2019 D1/China/GDjy/D19848/2019 98 transmission caused by type IV virus were reported. In 15 D1/China/GDgz/ES19862/2019 Clade 4 D1/China/GDgz/D19672/2019 65 D1/China/GDgz/D19369/2019 2019, the dominant type of dengue virus in 68 D1/China/GDgz/D19358/2019 D1/China/GDgz/D19359/2019 15 D1/China/GDgz/D19014/2019(Thailand) Guangdong was type I, and type II and III were also D1/China/GDcz/D18073/2018(Thailand) 87 D1/China/GDqy/D181374/2018 D1/China/GDmm/D181459/2018 8733 detected in outbreaks through local transmission. D1/China/GDjy/D181497/2018(guangzhou) 3762 D1/China/GDjy/D181506/2018(guangzhou) 90 D1/China/GDgz/D18042/2018 DF outbreaks in Guangdong were still often local D1/China/GDmm/D181550/2018(Cambodia) 57 D1/China/GDzh/D19105/2019 D1/China/GDzh/D19112/2019(Cambodia) outbreaks caused by imported viruses. Cambodia was Clade 3 57 D1/China/GDzh/D19146/2019 D1/China/GDjy/D19589/2019 55 D1/China/GDazh/D19580/2019 the main source of DENV introduced to Guangdong D1/China/GDzh/D19110/2019(Cambodia) D1/China/GDjy/D19249/2019 D1/China/GDmm/D19295/2019 in 2019, followed by Indonesia, Thailand, and 62 D1/China/GDmm/D19296/2019 D1/China/GDmm/D19504/2019 72 19XN24386/MN923081/2019(Thailand) Malaysia. According to data from China Information 87 19XN24379/MN921415/2019(Thailand) 56 D1/China/GDhz/D19893/2019 System for Disese Control and Prevention, imported 91 17082803/MG523199/2017(Myanmar) Clade 2 86 08/MG696645/2017(Myanmar) 83 92 D1/China/GDst/D18040/2018(Thailand) dengue viruses from more than 43 countries and D1/China/GDst/D18041/2018(Thailand) 96 D1/China/GDzq/D18002/2018(Myanmar) YNPE1/MF405201/2015(China) 99 regions were found in Guangdong in 2019, and Mdy-181/KR051914/2013(Myanmar) 79 1611aTw/MG894961/2016(Myanmar) 68 Clade 1 Mandalay110/KX357925/2015(Myanmar) 74 Southeast Asia was the most important source, of 63 D1/China/GDzq/D19888/2019 19XN28258F/MN960676/2019(Myanmar) 99 DQ855297/D1/China/GD/GZ01/1995 (Genotype IV) Genotype IV which Cambodia contributed the largest number of D1/IDN/ 034/2010 (Genotype II) Genotype II AF425622/P72-1244 (Genotype III) Genotype III 56 KF419432/D1PY/AS12/11 (Genotype V) 99 imported cases, followed by Thailand and Malaysia. D1/China/GDsz/D19022/2019(SriLanka) 99 D1/China/GDzj/D18016/2018(Angola) 89 D1/China/GDhd/D19011/2019(Indonesia) The surveillance results are consistent with our 44 D1/China/GDgz/D19683/2019 Genotype V 99 D1/China/GDzs/TFK/2019 63 D1/China/GDzs/MJP/2019 molecular tracing results in this report, suggesting that D1/China/GDzs/HLJ/2019 D1/China/GDzs/LZH/2019 DF outbreaks in Guangdong were mainly caused by 0.01 imported virus. Therefore, early detection of suspected FIGURE 2. Phylogenetic tree of type-1 dengue virus cases and typing and genotyping of circulating viruses isolated from the 2019 outbreak in Guangdong Province, should be prioritized and enhanced to promptly assess China. A total of 287 E gene sequences from isolated the likelihood of local transmission, of introduction, strains were used for phylogenetic tree reconstructions, and of subsequent sustained local transmission of the and 5 genotypes were assigned according to previous studies. The outbreak isolates are indicated by red circles, virus to implement optimal prevention and control and the isolates from the imported cases are indicated by strategies and measures. blue circles. Acknowledgments: We acknowledge all of the staff

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