Estimation of Coronavirus Disease 2019 (COVID-19) Burden and Potential for International Dissemination of Infection From Iran

Letters16 March 2020Estimation of Coronavirus Disease 2019 (COVID-19) Burden and Potential for International Dissemination of Infection From IranFREEAshleigh R. Tuite, PhD, MPH, Isaac I. Bogoch, MD, Ryan Sherbo, MSc, Alexander Watts, PhD, David Fisman, MD, MPH, and Kamran Khan, MD, MPHAshleigh R. Tuite, PhD, MPHUniversity of Toronto, Toronto, Ontario, Canada (A.R.T., D.F.), Isaac I. Bogoch, MDUniversity of Toronto and University Health Network, Toronto, Ontario, Canada (I.I.B.), Ryan Sherbo, MScSt. Michael's Hospital and BlueDot, Toronto, Ontario, Canada (R.S., A.W.), Alexander Watts, PhDSt. Michael's Hospital and BlueDot, Toronto, Ontario, Canada (R.S., A.W.), David Fisman, MD, MPHUniversity of Toronto, Toronto, Ontario, Canada (A.R.T., D.F.), and Kamran Khan, MD, MPHUniversity of Toronto, St. Michael's Hospital, and BlueDot, Toronto, Ontario, Canada (K.K.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-0696 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: The coronavirus disease 2019 (COVID-19) epidemic began in Wuhan, China, in late 2019 and continues to spread globally (1), with exported cases confirmed in 109 countries at the time of writing (2). During the interval between 19 February and 23 February 2020, Iran reported its first 43 cases, with 8 deaths. Three exported cases originating in Iran were identified, suggesting an underlying burden of disease in that country greater than that indicated by reported cases. A large epidemic in Iran could further fuel global dissemination of COVID-19.Objective: To quantify the COVID-19 outbreak size in Iran on the basis of known exported case counts and air travel links between Iran and other countries, and to anticipate where infections originating in Iran may spread next.Methods: We assessed interconnectivity between Iran and other countries by using direct and total traveler volumes and final destination cities of travelers originating in Iran in February 2019, according to data from the International Air Transport Association (accounting for 90% of global air travel, with the other 10% modeled by using market intelligence). Because exported cases were identified in United Arab Emirates (UAE), Lebanon, and Canada, we used the methods of Fraser and colleagues (3) to estimate the size of the underlying epidemic in Iran that would be needed for these cases to be observed with a reasonable probability. To estimate the time at risk for COVID-19 exposure among travelers departing Iran, we obtained data from the United Nations World Tourism Organization for the proportion of international travelers who are residents of Iran (4) and the average length of stay of tourists to Iran (5), and assumed that the Iranian outbreak began in early January 2020. We evaluated the relationship between the strength of travel links with Iran and the ranking of destination countries on the Infectious Disease Vulnerability Index (IDVI), a validated metric that estimates the capacity of a country to respond to an infectious disease outbreak. Scores range from 0 to 1, with higher scores reflecting greater capacity to manage infectious outbreaks.Findings: A total of 212 000 persons traveled from Iranian airports (Tehran, Rasht, and Arak) to international destinations in February 2019. Although Qom has reported COVID-19 cases, its international airport is still under construction. Global cities receiving the greatest number of total travelers from Iran during this period include Istanbul, Turkey (n = 46 550); Najaf, Iraq (n = 24 659); and Dubai, UAE (n = 16 340). Among the top 10 traveler-receiving cities, 4 (Najaf, Baghdad, Damascus, and Baku) are in countries with an IDVI score lower than 0.6, suggesting elevated vulnerability to infectious disease outbreaks as well as limited ability to detect cases (Figure 1).Figure 1. Top 20 international cities connected to Iran by commercial air travel and associated vulnerability to infectious disease outbreaks.Vulnerability is measured at the country level by using the IDVI score, with a lower value indicating reduced capacity to respond to outbreaks. Countries with the lowest IDVI scores are indicated in green. The top 20 cities accounted for 70% of international outbound traveler volumes from Iran in February 2019. The first and 20th ranked cities, Istanbul and Milan, had 46 550 and 2500 outbound passengers, respectively, during this period. IDVI = Infectious Disease Vulnerability Index. Download figure Download PowerPoint United Arab Emirates, Lebanon, and Canada ranked third, 21st, and 31st, respectively, in outbound air travel volume from Iran in February 2019. We estimated that 18 300 COVID-19 cases (95% CI, 3770 to 53 470 cases) would have had to occur in Iran, assuming an outbreak duration of 1.5 months in the country, in order to observe these 3 internationally exported cases reported at the time of writing.Given the low rankings for Lebanon and Canada for outbound air travel, it is unlikely that cases would be identified in these countries and not in Iraq, Syria, or Azerbaijan (countries with higher travel volumes but low IDVI scores). Considering traveler volume alone, the odds of a single case being imported into Iraq rather than Canada or Lebanon would be 33.6 to 1 and 15.4 to 1, respectively; for Azerbaijan, the odds would be 3.8 to 1 and 1.7 to 1, respectively; and for Syria, the odds would be 3.7 to 1 and 1.7 to 1, respectively. As such, we performed exploratory analyses in which we assumed that an unidentified exported case of COVID-19 was present in Iraq, Syria, Azerbaijan, or all 3 countries, in addition to Lebanon, Canada, and UAE, and estimated the outbreak size in Iran that would produce these results (Figure 2). We also evaluated a scenario in which we assumed perfect case detection in travelers from Iran, such that disease is truly absent in countries not reporting cases. Under this “best-case” scenario, the estimated outbreak size in Iran was smaller but still substantial (1820 cases [CI, 380 to 5320 cases]).Figure 2. Estimated outbreak size in Iran required to observe exported cases internationally.The estimated cumulative number of COVID-19 cases in Iran required to observe 3 cases exported to UAE, LBN, and CAN is shown in green. We also estimated the outbreak size required under alternate scenarios, including no additional exported cases to any other international destinations despite perfect case detection and 1 additional exported case to IRQ, AZE, or SYR (independently or to all 3 countries). Means and 95% CIs are presented. The rate at which persons become infected while in Iran was assumed to be the same for residents and visitors. The rate of infection among air passengers (λ) was estimated as number of exported cases ÷ person-time at risk while in Iran. Person-time at risk was calculated as number of outbound air passengers × (average length of stay for visitors × proportion of air passengers who are visitors + outbreak duration × proportion of air passengers who are residents of Iran). Outbreak size in Iran was then estimated as λ × population size of Iran × outbreak duration. AZE = Azerbaijan; CAN = Canada; COVID-19 = coronavirus disease 2019; IRQ = Iraq; LBN = Lebanon; SYR = Syria; UAE = United Arab Emirates. Download figure Download PowerPoint Discussion: Given the low volumes of air travel to countries with identified cases of COVID-19 originating in Iran (such as Canada), Iran probably is currently experiencing a COVID-19 epidemic of substantial size for such exportations to be occurring. Our analysis would be modified by travel restrictions from Iran due to the recent political situation and by variations in the R0 value. Further, the lack of identified COVID-19 cases in countries with far closer travel ties to Iran suggests that cases in these countries are probably being missed rather than being truly absent. This is concerning, both for public health in Iran itself and because of the high likelihood for outward dissemination of the disease to neighboring countries with lower capacity to respond to infectious disease epidemics. Supporting capacity for public health initiatives in the region is urgently needed.References1. Bogoch II, Watts A, Thomas-Bachli A, et al. Potential for global spread of a novel coronavirus from China. J Travel Med. 2020. [PMID: 31985790] doi:10.1093/jtm/taaa011 CrossrefMedlineGoogle Scholar2. World Health Organization. Coronavirus disease 2019 (COVID-19) situation report – 33. Accessed at www.who.int/docs/default-source/coronaviruse/situation-reports/20200222-sitrep-33-covid-19.pdf?sfvrsn=c9585c8f_2 on 22 February 2020. Google Scholar3. Fraser C, Donnelly CA, Cauchemez S, et al; WHO Rapid Pandemic Assessment Collaboration. Pandemic potential of a strain of influenza A (H1N1): early findings. Science. 2009;324:1557-61. [PMID: 19433588] doi:10.1126/science.1176062 CrossrefMedlineGoogle Scholar4. United Nations World Tourism Organization. Tourism Statistics: Iran, Islamic Republic Of: Country-specific: Basic indicators (Compendium) 2014–2018. Accessed at www.e-unwto.org/doi/abs/10.5555/unwtotfb0364010020142018201912 on 22 February 2020. Google Scholar5. United Nations. Encyclopedia of the Nations: Average length of stay of visitors - Tourism indicators - UNCTAD Handbook of Statistics - Country Comparison. Accessed at www.nationsencyclopedia.com/WorldStats/UNCTAD-average-length-stay-visitors.html on 22 February 2020. Google Scholar Comments 0 Comments Sign In to Submit A Comment Ashleigh R Tuite, PhD, MPH, Isaac Bogoch, MD. David Fisman, MD, MPHToronto General Hospital4 May 2020 Authors' Response We appreciate the thoughtful comments and concerns raised by the authors of the letter. We agree that models are simplified representations of reality and are limited by the data used to parameterize them. In our analysis, we assumed that COVID-19 had been circulating in Iran for 1.5 months at the time of the analysis in late February, which would be consistent with an early- to mid-January initial case introduction. In support of this assumption, we now have data suggesting there was rapid global dissemination of COVID-19 cases in January (prior to implementation of travel restrictions on 23 January 2020) that was undetected due to the high prevalence of mildly symptomatic or asymptomatic infections (1). The use of data on average tourist behaviors was a required simplification and represented the best available data. We note that we conducted multiple sensitivity analyses and even our highly conservative estimate of the epidemic size in Iran, which assumed no undetected exported COVID-19 cases among all outbound air passengers, was more than 40-times the officially reported numbers at that time. The authors mistakenly assert that we used the Infectious Disease Vulnerability Index (IDVI) to estimate Iran’s outbreak response capacity. We actually used the IDVI to highlight other countries with high connectivity to Iran via air travel that would benefit from heighted surveillance. We concur that such a metric may not fully capture a country’s capacity to respond to public health threats, especially in the midst of a public health emergency, but would argue it has utility for stratifying risk and identifying particularly vulnerable countries, when used in conjunction with other data, as in our analysis. In conclusion, we recognize the limitations associated with our analysis, which mainly relate to simplifying assumptions. Despite these limitations, the key finding of our study has been validated by abundant observations consistent with a large COVID-19 epidemic in Iran (2, 3), including the appearance of new large burial sites in the country that become visible on satellite imagery after the epidemic began in the country (4). Our model results are one further piece of evidence lending support to this conclusion. References 1. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020. 2. Wood G. Iran has far more coronavirus cases than it is letting on. Accessed 1 May 2020: https://www.theatlantic.com/ideas/archive/2020/03/irans-coronavirus-problem-lot-worse-it-seems/607663/. 2020. 3. Zhuang Z, Zhao S, Lin Q, Cao P, Lou Y, Yang L, et al. Preliminary estimation of the novel coronavirus disease (COVID-19) cases in Iran: A modelling analysis based on overseas cases and air travel data. Int J Infect Dis. 2020;94:29-31. 4. J B. Satellite images show Iran has built mass graves amid coronavirus outbreak. Accessed 1 May 2020: https://www.theguardian.com/world/2020/mar/12/coronavirus-iran-mass-graves-qom. 2020. Hamid Sharifi,1 Mohammad Karamouzian,1 Zahra Khorrami,1 Malahat Khalili, Ehsan Mostafavi, 2 Sana Eybpoosh, Ali Mirzazadeh,3,1 Ali Akbar Haghdoost,41,Kerman University of Medical Sciences, 2,University of British Columbia,3, Pasteur Institute of Iran, 4,University of California San Francisco,4 May 2020 The accuracy of modeling the burden of COVID-19 in Iran using international airline travelers’ data We read a recent mathematical modeling study by Tuite et al. (1) with interest but are concerned about the accuracy of the reported estimates and their underlying assumptions. First, the authors assumed the onset date of the epidemic to be early January 2020 without providing any evidence. In the last week of February, when the study was done, Iran was not even among the top 50 international destinations from different cities in China, and therefore, it is unlikely that the epidemic in Iran started in early January (2). Moreover, relying on data from United Nations World Tourism Organization to estimate the proportion of international travelers that are residents of Iran as well as the average length of tourists’ stay in Iran is problematic because these data do not provide the number of days that people infected with COVID-19 were actually inside Iran. As the incubation period of COVID-19 ranges from 2-14 days, with possible outliers of up to 27 days (5), it is unclear whether the travelers identified in other countries got the infection in Iran or were already infected before their last stay in the country. Second, the Infectious Disease Vulnerability Index (IDVI) used to estimate Iran’s outbreak response capacity, is a tool to provide international agencies with a better understanding of countries’ vulnerability to infectious disease outbreaks in ‘normal’ situations and therefore, underestimates their capacities during outbreaks where surveillance systems are much more sensitive, and case detection is enhanced. Lastly, the authors assumed a similar prevalence of COVID-19 in cities with and without international airports while the chance of exposure to COVID-19 through national or international travels is uneven across these cities (3). Around 30% of Iran’s population lives in rural areas, and out of 54 airports in Iran, only 13 are international airports which are located in 12 cities (out of 434) (4). Overall, the above-mentioned assumptions would have overestimated the overall number of COVID-19 patients in Iran in this study. In brief, there are significant uncertainties about the magnitude of the COVID-19 epidemic in Iran, and several surveillance studies and epidemiologic field investigations are ongoing to help provide more reliable estimates. While mathematical models of COVID-19 might provide some insight for the COVID-19 response planning and decision-making in Iran, they may be misleading if not viewed with a critical eye for their limitations and subjective assumptions. References: 1. Tuite AR, Bogoch II, Sherbo R, et al. Estimation of Coronavirus Disease 2019 (COVID-19) Burden and Potential for International Dissemination of Infection From Iran. Ann Intern Med. 2020; [Epub ahead of print 16 March 2020]. doi: https://doi.org/10.7326/M20-0696 2. International Air Transport Association. Annual Review 2019. Accessed at https://www.iata.org/contentassets/c81222d96c9a4e0bb4ff6ced0126f0bb/iata-annual-review-2019.pdf on 13 March 2020. 3. Fraser C, Donnelly CA, Cauchemez S, et al. WHO Rapid Pandemic Assessment Collaboration. Pandemic potential of a strain of influenzaA (H1N1): early findings. Science. 2009; 324:1557-61. [PMID: 19433588] doi:10.1126/science .1176062 4. Ministry of Roads and Urban Development, Iran Airports and Air Navigation Company. Accessed at https://statistics.airport.ir/.17 march 2020. 5. Guan, Wei-jie, et al. "Clinical characteristics of coronavirus disease 2019 in China." N Engl J Med (2020). doi: 10.1056/NEJMoa2002032 Disclosures: Conflict of Interest: Ali Akbar Haghdoost is the Deputy Minister in Education of Ministry of Health. The rest of the authors have no conflict of interest to disclose Author, Article, and Disclosure InformationAuthors: Ashleigh R. Tuite, PhD, MPH; Isaac I. Bogoch, MD; Ryan Sherbo, MSc; Alexander Watts, PhD; David Fisman, MD, MPH; Kamran Khan, MD, MPHAffiliations: University of Toronto, Toronto, Ontario, Canada (A.R.T., D.F.)University of Toronto and University Health Network, Toronto, Ontario, Canada (I.I.B.)St. Michael's Hospital and BlueDot, Toronto, Ontario, Canada (R.S., A.W.)University of Toronto, St. Michael's Hospital, and BlueDot, Toronto, Ontario, Canada (K.K.)Note: Drs. Tuite and Bogoch contributed equally to this work.Grant Support: By grant 02179-000 from the Canadian Institutes of Health Research.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-0696.Reproducible Research Statement: Study protocol: Not applicable. Statistical code: Available from Dr. Tuite (ashleigh.tuite@utoronto.ca). Data set: Available from Dr. Khan (kamran.khan@unityhealth.to).Previous Posting: This manuscript was posted as a preprint on medRxiv on 25 February 2020. doi:10.1101/2020.02.24.20027375This article was published at Annals.org on 16 March 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEstimation of Coronavirus Disease 2019 Burden and Potential for International Dissemination of Infection From Iran Ashleigh R. Tuite , Isaac I. 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