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Journal of Clinical Medicine Article Estimation of the Actual Incidence of Coronavirus Disease (COVID-19) in Emergent Hotspots: The Example of Hokkaido, Japan during February–March 2020 Andrei R. Akhmetzhanov 1,2 , Kenji Mizumoto 3,4 , Sung-Mok Jung 1,5 , Natalie M. Linton 1,5 , Ryosuke Omori 6 and Hiroshi Nishiura 1,5,7,* 1 Graduate School of Medicine, Hokkaido University, Kita 15 Jo Nishi 7 Chome, Kita-ku, Sapporo-shi, Hokkaido 060-8638, Japan; [email protected] (A.R.A.); [email protected] (S.-M.J.); [email protected] (N.M.L.) 2 Global Health Program, Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 10055, Taiwan 3 Graduate School of Advanced Integrated Studies in Human Survivability, Kyoto University, Yoshida-Nakaadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; [email protected] 4 Hakubi Center for Advanced Research, Kyoto University, Yoshidahonmachi, Sakyo-ku, Kyoto 606-8306, Japan 5 School of Public Health, Kyoto University, Yoshidakonoe cho, Sakyo ku, Kyoto 606-8501, Japan 6 Research Center for Zoonosis Control, Hokkaido University, Kita 19 Jo Nishi 10 Chome, Kita-ku, Sapporo-shi, Hokkaido 001-0019, Japan; [email protected] 7 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan * Correspondence: [email protected]; Tel.: +81-75-753-4490 Citation: Akhmetzhanov, A.R.; Mizumoto, K.; Jung, S.-M.; Linton, Abstract: Following the first report of the coronavirus disease 2019 (COVID-19) in Sapporo city, N.M.; Omori, R.; Nishiura, H. Hokkaido Prefecture, Japan, on 14 February 2020, a surge of cases was observed in Hokkaido during Estimation of the Actual Incidence of February and March. As of 6 March, 90 cases were diagnosed in Hokkaido. Unfortunately, many Coronavirus Disease (COVID-19) in infected persons may not have been recognized due to having mild or no symptoms during the Emergent Hotspots: The Example of initial months of the outbreak. We therefore aimed to predict the actual number of COVID-19 cases Hokkaido, Japan during February– in (i) Hokkaido Prefecture and (ii) Sapporo city using data on cases diagnosed outside these areas. March 2020. J. Clin. Med. 2021, 10, Two statistical frameworks involving a balance equation and an extrapolated linear regression model 2392. https://doi.org/10.3390/ with a negative binomial link were used for deriving both estimates, respectively. The estimated jcm10112392 cumulative incidence in Hokkaido as of 27 February was 2,297 cases (95% confidence interval (CI): 382–7091) based on data on travelers outbound from Hokkaido. The cumulative incidence in Sapporo Academic Editor: Emmanuel Andrès city as of 28 February was estimated at 2233 cases (95% CI: 0–4893) based on the count of confirmed cases within Hokkaido. Both approaches resulted in similar estimates, indicating a higher incidence Received: 16 March 2021 Accepted: 24 May 2021 of infections in Hokkaido than were detected by the surveillance system. This quantification of Published: 28 May 2021 the gap between detected and estimated cases helped to inform the public health response at the beginning of the pandemic and provided insight into the possible scope of undetected transmission Publisher’s Note: MDPI stays neutral for future assessments. with regard to jurisdictional claims in published maps and institutional affil- Keywords: epidemiology; travel medicine; COVID-19; emerging infectious diseases iations. 1. Introduction Copyright: © 2021 by the authors. In December 2019, a cluster of 41 patients with atypical pneumonia of unknown Licensee MDPI, Basel, Switzerland. etiology was reported in the city of Wuhan, China [1,2]. The number of atypical pneumonia This article is an open access article cases in Wuhan rapidly increased in early January and cases began appearing across China distributed under the terms and and in other countries [3,4]. The cause of the pneumonia was recognized as a newly conditions of the Creative Commons emerged coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV- Attribution (CC BY) license (https:// 2), and the disease it causes was given the name coronavirus disease 2019 (COVID-19). creativecommons.org/licenses/by/ Cases of COVID-19 have now been reported in more than 120 countries worldwide [5], 4.0/). J. Clin. Med. 2021, 10, 2392. https://doi.org/10.3390/jcm10112392 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 2392 2 of 11 and the WHO declared it a pandemic on 11 March 2020. By the end of 2020, the disease had spread to nearly every country in the world. In the present paper, we examine the emergence of a COVID-19 hotspot in Hokkaido Prefecture, Japan, during the first wave of the pandemic. Because of the limited testing capacity in the first months of the outbreak [6] and the specific contact-based, centered surveillance of SARS-CoV-2 infections in Japan [7], a substantial fraction of infected individuals may have remained undetected during the first months of the pandemic. Control of COVID-19 spread is complicated by various factors, including nonspe- cific clinical symptoms, especially during the early phase of infection [8–10]; a relatively high proportion of pre-symptomatic and asymptomatic infections [11–15]; multiple pos- sible routes of transmission—including aerosol, direct contact, and fecal–oral transmis- sion [10,16,17]—as well as the moderate to high potential of superspreading events gener- ated by a small proportion of cases [18,19]. Additionally, the incubation period can vary widely [20,21], and re-occurrence of the disease after primary infection is possible [22]. Nonetheless, the transmission dynamics of COVID-19 in the community can be roughly grasped by exploring epidemiological indicators such as the number of confirmed infec- tions in a given location, or the number of exported cases. Clinical manifestation of COVID-19 begins with nonspecific symptoms (similar to seasonal influenza), which remain mild for most persons. Some infections may remain entirely asymptomatic. For a small fraction of symptomatic cases, the disease may resolve into a life-threatening onset of acute respiratory distress [19,23]. Despite efforts towards mitigation, the number of confirmed cases worldwide represents only a fraction of all infections, and the actual number of cases including mild and asymptomatic infections may be as large as four- or ten-fold [15,24,25]. Hence, the derivation of reliable estimates of the actual number of cases is needed to conduct risk assessments of the spread of COVID- 19 and inform policies related to containment and mitigation [26]. This was especially important for newly emerging hotspots in Japan and some other countries at the beginning of 2020 [4,27]. The increased number of cases in and exportation of cases from Hokkaido in February– March 2020 signaled an urgent need to increase containment efforts within the prefecture. To help guide the policymaking process and better understand the risk of further spread within and exportation from Hokkaido, we derived real-time estimates of the actual incidence by accounting for under-ascertained cases. The methods can be further expended to other areas or countries experiencing a surge of new cases of COVID-19, any other emergent disease, or their new variants. 2. Methods 2.1. Epidemiological Data Three sources of data were leveraged to estimate the actual incidence of COVID-19 in Hokkaido. Firstly, cases exported domestically and internationally from Hokkaido were identified based on government reports. The domestically exported cases were Kumamoto (1 case), Nagano (1 case), and Chiba (1 case) prefecture residents [28–30]. The internationally exported cases were reported from Malaysia (1 case) and Thailand (2 cases) [31,32]. Considering that the two Thailand cases were husband and wife and one case was asymptomatic, one infection may have been the result of household transmission, as similarly described in [33], rather than exported from Japan. Secondly, the total volume of air passengers from all airports in Hokkaido to Thailand and Malaysia over the two- month period of January and February 2019 was retrieved from the International Air Transport Association (IATA) and included 9349 passengers flown directly to Malaysia and 45,137 to Thailand. Lastly, the population size of Hokkaido was obtained from the Hokkaido Prefectural Government website [34]. The calculation of COVID-19 incidence in Sapporo was based on cases of non-Sapporo residents who (i) became infected in Sapporo and were diagnosed outside of Sapporo or (ii) cases diagnosed outside of Sapporo who had no information on their source of infection J. Clin. Med. 2021, 10, 2392 3 of 11 (i.e., unknown link). Cases who were infected outside of Sapporo by Sapporo residents were excluded from the analysis, as they did not represent true exportation of infection from Sapporo by a local case. For example, in one instance, a Sapporo resident travelled to Kitami city in Okhotsk subprefecture and caused secondary infections among Kitami residents. These Kitami residents were excluded from our analysis, as they were infected outside of Sapporo. However, if a case from Kitami were to travel to Sapporo, have likely been infected there, and then be subsequently diagnosed in Kitami, they would be eligible for our analysis. Data on cases reported through the end of February 2020, including dates of illness onset, subprefecture of diagnosis, history of travel to Sapporo, and epidemiologic linkage to other confirmed cases, were retrieved from the websites of government entities in Hokkaido. The estimate of the fraction of commuters between subprefectures was obtained with reference to a survey of the daytime and nighttime population sizes in Sapporo [35]. By subtracting the daytime population size from the nighttime population size and dividing the difference by the nighttime population, we obtained a value of 3.7% [35], reflecting the change in the population size of Sapporo due to commuting.

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